Sample records for e26 transforming-specific leukaemia

  1. Low-expression of E-cadherin in leukaemia cells causes loss of homophilic adhesion and promotes cell growth.

    PubMed

    Rao, Qing; Wang, Ji-Ying; Meng, Jihong; Tang, Kejing; Wang, Yanzhong; Wang, Min; Xing, Haiyan; Tian, Zheng; Wang, Jianxiang

    2011-09-01

    E-cadherin (epithelial cadherin) belongs to the calcium-dependent adhesion molecule superfamily and is implicated in the interactions of haematopoietic progenitors and bone marrow stromal cells. Adhesion capacity to bone marrow stroma was impaired for leukaemia cells, suggesting that a breakdown of adhesive mechanisms governed by an adhesion molecule may exist in leukaemic microenvironment. We previously found that E-cadherin was low expressed in primary acute leukaemia cells compared with normal bone marrow mononuclear cells. In this study, we investigate the functional importance of low E-cadherin expression in leukaemia cell behaviours and investigate its effects in the abnormal interaction of leukaemic cells with stromal cells. After expression of E-cadherin was restored by a demethylating agent in leukaemia cells, E-cadherin-specific adhesion was enhanced. Additionally, siRNA (small interfering RNA)-mediated silencing of E-cadherin in Raji cells resulted in a reduction of cell homophilic adhesion and enhancement of cell proliferation and colony formation. These results suggest that low expression of E-cadherin contributes to the vigorous growth and transforming ability of leukaemic cells.

  2. Co-occurrence of biphenotypic acute leukaemia, glucose 6-phosphate dehydrogenase deficiency and haemoglobin E trait in a single child.

    PubMed

    Mallick, Debkrishna; Thapa, Rajoo; Biswas, Biswajit

    2016-02-01

    Acute leukaemias occur as the result of clonal expansion subsequent to transformation and arrest at a normal differentiation stage of haematopoietic precursors, which commit to a single lineage, such as myeloid or B-lymphoid or T-lymphoid cells. Biphenotypic acute leukaemia (BAL) constitutes a biologically different group of leukaemia arising from a precursor stem cell and co-expressing more than one lineage specific marker. The present report describes a child with unusual co-occurrence of biphenotypic (B-precursor cell and Myeloid) acute leukaemia, haemoglobin E trait and glucose 6-phosphate dehydrogenase (G6-PD) deficiency. To the best of our knowledge, this constellation of haematological conditions in a single child has never been described before. 2016 BMJ Publishing Group Ltd.

  3. Spontaneous tumour lysis syndrome secondary to the transformation of chronic myelomonocytic leukaemia into acute myeloid leukaemia.

    PubMed

    Langridge, Alexander; Musgrave, Kathryn; Upadhye, Yogesh

    2016-03-09

    A 78-year-old man, with a 6-year history of stable chronic myelomonocytic leukaemia (CMML), presented with general deterioration and worsening pancytopenia. Bone marrow biopsy showed that his disease had transformed into acute myeloid leukaemia (AML). He was started on a supportive transfusion regimen and did not receive any chemotherapy or corticosteroids. Several weeks later, he developed acute renal failure and was admitted to a medical admissions ward. Spontaneous tumour lysis syndrome (sTLS, grade 1) was diagnosed, as per the Cairo and Bishop criteria. He was treated with intravenous fluids, rasburicase and allopurinol. His renal function improved and he recovered from the sTLS. The authors believe that this is the first published case of sTLS occurring as a result of CMML transforming into AML; it highlights the importance of recognising sTLS as a cause of renal failure and electrolyte disturbance before cancer treatment begins. 2016 BMJ Publishing Group Ltd.

  4. Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia.

    PubMed

    Patel, Soonie R; Bate, Jessica; Borrow, Ray; Heath, Paul T

    2012-01-01

    Children treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been well studied. The authors measured serotype-specific pneumococcal IgG antibody concentrations in children treated for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) ≥6 months after completion of standard-dose chemotherapy. Pneumococcal serotype-specific IgG antibody concentrations were low. None of the subjects had protective concentrations against all the heptavalent-pneumococcal conjugate vaccine serotypes. There was no significant difference in antibody concentrations between subjects with ALL and AML (p≥0.05). Children treated for ALL and AML generally have non-protective antibody concentrations against S pneumoniae. There is significant morbidity associated with pneumococcal disease in this patient group and strategies for vaccination are required.

  5. Impact on learning of an e-learning module on leukaemia: a randomised controlled trial.

    PubMed

    Morgulis, Yuri; Kumar, Rakesh K; Lindeman, Robert; Velan, Gary M

    2012-05-28

    e-learning resources may be beneficial for complex or conceptually difficult topics. Leukaemia is one such topic, yet there are no reports on the efficacy of e-learning for leukaemia. This study compared the learning impact on senior medical students of a purpose-built e-learning module on leukaemia, compared with existing online resources. A randomised controlled trial was performed utilising volunteer senior medical students. Participants were randomly allocated to Study and Control groups. Following a pre-test on leukaemia administered to both groups, the Study group was provided with access to the new e-learning module, while the Control group was directed to existing online resources. A post-test and an evaluation questionnaire were administered to both groups at the end of the trial period. Study and Control groups were equivalent in gender distribution, mean academic ability, pre-test performance and time studying leukaemia during the trial. The Study group performed significantly better than the Control group in the post-test, in which the group to which the students had been allocated was the only significant predictor of performance. The Study group's evaluation of the module was overwhelmingly positive. A targeted e-learning module on leukaemia had a significant effect on learning in this cohort, compared with existing online resources. We believe that the interactivity, dialogic feedback and integration with the curriculum offered by the e-learning module contributed to its impact. This has implications for e-learning design in medicine and other disciplines.

  6. Impact on learning of an e-learning module on leukaemia: a randomised controlled trial

    PubMed Central

    2012-01-01

    Background e-learning resources may be beneficial for complex or conceptually difficult topics. Leukaemia is one such topic, yet there are no reports on the efficacy of e-learning for leukaemia. This study compared the learning impact on senior medical students of a purpose-built e-learning module on leukaemia, compared with existing online resources. Methods A randomised controlled trial was performed utilising volunteer senior medical students. Participants were randomly allocated to Study and Control groups. Following a pre-test on leukaemia administered to both groups, the Study group was provided with access to the new e-learning module, while the Control group was directed to existing online resources. A post-test and an evaluation questionnaire were administered to both groups at the end of the trial period. Results Study and Control groups were equivalent in gender distribution, mean academic ability, pre-test performance and time studying leukaemia during the trial. The Study group performed significantly better than the Control group in the post-test, in which the group to which the students had been allocated was the only significant predictor of performance. The Study group’s evaluation of the module was overwhelmingly positive. Conclusions A targeted e-learning module on leukaemia had a significant effect on learning in this cohort, compared with existing online resources. We believe that the interactivity, dialogic feedback and integration with the curriculum offered by the e-learning module contributed to its impact. This has implications for e-learning design in medicine and other disciplines. PMID:22640463

  7. Specific and Non-specific Clinical Presentations in the Year Before the Diagnosis of Childhood Leukaemia.

    PubMed

    Yang, TienYu Owen; Liu, Yen-Lin; Huang, Wan-Ting; Chen, Mei-Huei; Chen, Pau-Chung

    2016-08-01

    Clinical presentations of childhood leukaemia have been reported in case-only studies. The timing when these presentations start to occur prior to diagnosis is less clear. In this nested case-control study, 1,025 and 334 children with lymphoid and myeloid leukaemia, respectively, were matched (1:30) to population-based controls by sex, region and year of birth. An index date was assigned for each control when the matched case was diagnosed. Healthcare access records of cases and controls in the year before the index date were extracted. Children with lymphoid leukaemia started to visit doctors more often at least 2 months before leukaemia diagnosis (P < 0.05). Various presentations were recorded in these visits: rates of haematological presentations, musculoskeletal presentations, and injuries started to increase significantly at least 3 months before diagnosis; rates of respiratory, gastrointestinal and urinary tract presentations did not increase significantly until the last month. The findings for myeloid lymphoma were less clear, but children appeared to visit doctors more often at least 4 months before diagnosis, and the rate of haematological presentations also started to increase at least 4 months before leukaemia diagnosis. Although haematological presentations were most strongly associated with undiagnosed leukaemia (odds ratio > 290 in the last month), the majority (>96%) of children with haematological presentations did not have leukaemia if they had not been diagnosed in their first visit. We described a clinical picture in the year before leukaemia diagnosis. These findings revealed ongoing difficulties in early diagnosis of childhood leukaemia in healthcare settings. © 2016 Wiley Periodicals, Inc.

  8. Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity?

    PubMed

    Garnache-Ottou, Francine; Feuillard, Jean; Saas, Philippe

    2007-02-01

    CD4(+)/CD56(+) haematodermic neoplasm or 'early' plasmacytoid dendritic cell leukaemia/lymphoma (pDCL) was described as a disease entity in the last World Health Organisation/European Organisation for Research and Treatment of Cancer classification for cutaneous lymphomas. These leukaemia/lymphomas co-express CD4 and CD56 without any other lineage-specific markers and have been identified as arising from plasmacytoid dendritic cells. Despite a fairly homogeneous pattern of markers expressed by most pDCL, numerous distinctive features (e.g. cytological aspects and aberrant marker expression) have been reported. This may be related to the 'lineage-independent developmental' programme of dendritic cells, which may be able to develop from either immature or already committed haematopoietic progenitors. This highlights the need for specific validated markers to diagnose such aggressive leukaemia. Here, we propose--among others (e.g. T-cell leukaemia 1)--blood dendritic cell antigen-2 and high levels of CD123 expression as potential markers. In addition, we propose a multidisciplinary approach including several fields of haematology to improve pDCL diagnosis.

  9. Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

    PubMed

    Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

    2017-10-20

    Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

  10. Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy

    PubMed Central

    Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T.; Nishimura, Michael I.; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

    2017-01-01

    Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment. PMID:29152058

  11. Current status of gene expression profiling in the diagnosis and management of acute leukaemia.

    PubMed

    Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

    2009-06-01

    Gene expression profiling (GEP) enables the simultaneous investigation of the expression of tens of thousands of genes and was successfully introduced in leukaemia research a decade ago. Aiming to better understand the diversity of genetic aberrations in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), pioneer studies investigated and confirmed the predictability of many cytogenetic and molecular subclasses in AML and ALL. In addition, GEP can define new prognostic subclasses within distinct leukaemia subgroups, as illustrated in AML with normal karyotype. Another approach is the development of treatment-specific sensitivity assays, which might contribute to targeted therapy studies. Finally, GEP might enable the detection of new molecular targets for therapy in patients with acute leukaemia. Meanwhile, large multicentre studies, e.g. the Microarray Innovations in LEukaemia (MILE) study, prepare for a standardised introduction of GEP in leukaemia diagnostic algorithms, aiming to translate this novel methodology into clinical routine for the benefit of patients with the complex disorders of AML and ALL.

  12. Leukaemia at Queen Elizabeth Central Hospital in Blantyre, Malawi.

    PubMed

    Mukiibi, J M; Nyirenda, C M; Adewuyi, J O; Mzula, E L; Magombo, E D; Mbvundula, E M

    2001-07-01

    To determine the patterns of leukaemias seen in Malawians at Queen Elizabeth Central Hospital (QECH) and to compare the findings with those from elsewhere. An overview of the problems encountered in the management of leukaemia in developing countries especially those in sub-Saharan Africa are highlighted. Retrospective descriptive analysis of consecutive leukaemia cases seen from January 1994 through December 1998. Of the 95 leukaemia patients diagnosed during the study period, childhood (0-15 years) leukaemia occurred in 27 (28.4%) patients while adulthood (above 15 years) leukaemia accounted for 68 (71.6%) patients. The main leukaemia types were: acute lymphoblastic leukaemia (ALL) 14 (14.7%), acute myeloblastic leukaemia (AML) 25 (26.3%), chronic myeloid (granulocytic) leukaemia (CML) 32 (33.7%), chronic lymphocytic (lymphatic) leukaemia (CLL) 22 (23.2%) and hairy cell leukaemia (HCL) two (2.1%) patients. Most of the acute leukaemia (AL) cases occurred in the six to 15 year age bracket with a male preponderance. In ALL, lymphadenopathy was the commonest presenting feature followed by pallor (92.9%) while in the AML group, pallor occurred in 80% of cases. Abdominal swelling (87.5%) due to splenomegaly (81.3%) were the main clinical features in the CML group whereas lymphadenopathy (63.6%) followed by splenomegaly (59.1%) were the dominant presenting features in CLL. Haematologically, although leucocytosis characterised both acute and chronic leukaemias, most cases of acute leukaemia presented with more severe anaemia (Hb < 7 g/dl) and marked thrombocytopenia (Platelet count < 50 x 10(9)/l) than the chronic leukaemias. The study shows that leukaemias are not rare in Malawi and cases which were diagnosed in this series probably only represent the tip of the iceberg. While there is need to increase diagnostic awareness among clinicians and laboratory staff, the severe chronic shortage of cytotoxic drugs and lack of supportive care facilities commonly encountered in

  13. Immunocytochemical markers in acute leukaemias diagnosis.

    PubMed

    Gluzman, D F; Nadgornaya, V A; Sklyarenko, L M; Ivanovskaya, T S; Poludnenko, L Yu; Ukrainskaya, N I

    2010-09-01

    The study included 1742 patients with acute myeloblastic leukaemias (AML) and acute lymphoblastic leukaemias (ALL), Kyiv city residents and patients from 20 regions of Ukraine. Bone marrow and blood smears were sent at diagnosis to Reference Center. The analysis was based on May-Grünvald-Giemza (MGG) stain and cytochemical reactions (MPO, acNSE, CAE, AP, PAS). Immunocytochemical techniques (APAAP, LSAB) and broad panel of monoclonal antibodies (MoAbs) against lineage specific and differentiation antigens of leukocytes were employed for immunophenotyping of leukemic blast cells directly in blood and bone marrow smears. Different types of AML were defined by the expression of the cell surface and cytoplasmic antigens. Immunocytochemical study was required especially in diagnosing of AML with minimal differentiation, acute megakaryoblastic leukaemia, acute erythroid leukaemia and acute leukaemias of ambiguous lineage. Acute lymphoblastic leukaemias was broadly classified into B-lineage and T-lineage ALL. According to the degree of B-lymphoid differentiation of the blast cells four subtypes of B-lineage ALL were established. T-lineage ALL observed in patients were also divided into four subtypes. Immunocytochemical examination was required to diagnose AL of ambiguous lineage with no clear evidence of lineage differentiation (acute undifferentiated leukaemia) or those with blasts that express markers of more than one lineage (mixed phenotype acute leukaemias).

  14. Genital ulcers as diagnostic clue for acute myeloid leukaemia.

    PubMed

    Schröder, Sina D; Krause, Stefan W; Erfurt-Berge, Cornelia

    2018-04-23

    Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions. © 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  15. Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia.

    PubMed

    Edelmann, Michelle N; Krull, Kevin R; Liu, Wei; Glass, John O; Ji, Qing; Ogg, Robert J; Sabin, Noah D; Srivastava, Deo Kumar; Robison, Leslie L; Hudson, Melissa M; Reddick, Wilburn E

    2014-11-01

    Survivors of childhood acute lymphoblastic leukaemia are at risk for neurocognitive impairment, though little information is available on its association with brain integrity, particularly for survivors treated without cranial radiation therapy. This study compares neurocognitive function and brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone (n = 36) to those treated with cranial radiation therapy (n = 39) and to healthy control subjects (n = 23). Mean (standard deviation) age at evaluation was 24.9 (3.6) years for the chemotherapy group and 26.7 (3.4) years for the cranial radiation therapy group, while time since diagnosis was 15.0 (1.7) and 23.9 (3.1) years, respectively. Brain grey and white matter volume and diffusion tensor imaging was compared between survivor groups and to 23 healthy controls with a mean (standard deviation) age of 23.1 (2.6) years. Survivors treated with chemotherapy alone had higher fractional anisotropy in fibre tracts within the left (P < 0.05), but not in the right, hemisphere when compared to controls. Survivors of acute lymphoblastic leukaemia, regardless of treatment, had a lower ratio of white matter to intracranial volume in frontal and temporal lobes (P < 0.05) compared with control subjects. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone performed worse in processing speed (P < 0.001), verbal selective reminding (P = 0.01), and academics (P < 0.05) compared to population norms and performed better than survivors treated with cranial radiation therapy on verbal selective reminding (P = 0.02), processing speed (P = 0.05) and memory span (P = 0.009). There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal white and grey matter volume. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone demonstrated significant long-term differences in

  16. Application of the pMHC Array to Characterise Tumour Antigen Specific T Cell Populations in Leukaemia Patients at Disease Diagnosis.

    PubMed

    Brooks, Suzanne E; Bonney, Stephanie A; Lee, Cindy; Publicover, Amy; Khan, Ghazala; Smits, Evelien L; Sigurdardottir, Dagmar; Arno, Matthew; Li, Demin; Mills, Ken I; Pulford, Karen; Banham, Alison H; van Tendeloo, Viggo; Mufti, Ghulam J; Rammensee, Hans-Georg; Elliott, Tim J; Orchard, Kim H; Guinn, Barbara-ann

    2015-01-01

    Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T-cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms' Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8-1.4 x 10(6)). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1(126-134) (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1(950-958) epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients.

  17. Attentional ability among survivors of leukaemia.

    PubMed

    Rodgers, J; Horrocks, J; Britton, P G; Kernahan, J

    1999-04-01

    Attentional ability in 19 survivors of acute lymphoblastic leukaemia and 19 sibling controls was assessed using a neuropsychological model of attention. Analysis revealed that children who had received treatment for leukaemia exhibited significantly poorer performance on measures of the "focus encode" and "focus execute" elements of attention and on measures of the ability to respond to external cues and feedback. No significant differences in performance were found for measures of sustained attention and the ability to shift attention. These results indicate that children who have received treatment for leukaemia may experience highly specific attentional deficits that could have an impact on academic performance, particularly mathematical and reading skills. It is suggested that this underlying attentional deficit might be the source of the neuropsychological sequelae associated with the disease. Future attempts at remediation should incorporate activities specifically designed to ameliorate focusing difficulties.

  18. E6D25E, HPV16 Asian variant shows specific proteomic pattern correlating in cells transformation and suppressive innate immune response

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chopjitt, Peechanika; Pientong, Chamsai; Sunthamala, Nuchsupha

    HPV16 Asian variant (HPV16As) containing E6D25E oncogene, is commonly associated with cervical cancers of Asian populations. To explore a mechanism of E6D25E oncoprotein in carcinogenesis, we compared protein profiles in human keratinocytes expressing E6D25E with E6 of HPV16 prototype (E6Pro). A human cervical keratinocyte cell line, HCK1T, was transduced with retroviruses containing E6D25E or E6Pro genes. Biological properties of E6D25E or E6Pro transduced HCK1T cells were characterized. Protein profiles of the transduced HCK1T cells were analyzed using 2D-PAGE and characterized by mass spectrometry and western blotting. Reactomes of modulated proteins were analyzed by using the Reactome Knowledgebase. The E6D25E andmore » E6Pro oncoproteins were comparable for their abilities to degrade p53 and suppress the induction of p21, and induce cell proliferation. Interestingly, the protein profiles of the HCK1T cells transduced with E6D25E showed specific proteomic patterns different from those with E6Pro. Among altered proteins, more than 1.5-fold up- or down- regulation was observed in E6D25E-expressing cells for gp96 and keratin7 which involved in activation of TLR signaling and transformation of squamocolumnar junction cells, respectively. This report describes new cellular proteins specifically targeted by E6D25E oncoprotein that may contribute to impair immune response against viral infection and cell transformation associated with oncogenic property of HPV16As variant. - Highlights: • E6D25E HPV16 specifically modulates protein profile of human keratinocytes. • E6D25E HPV16 modulates protein profile which involves in TLR signalling and transformation of squamocolumnar junction cells. • E6D25E oncoprotein may correlate to impair of immune response against viral infection and cells transformation.« less

  19. Acute myeloid/T-lymphoblastic leukaemia (AMTL): a distinct category of acute leukaemias with common pathogenesis in need of improved therapy.

    PubMed

    Gutierrez, Alejandro; Kentsis, Alex

    2018-03-01

    Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches. © 2018 John Wiley & Sons Ltd.

  20. Between remission and cure: patients, practitioners and the transformation of leukaemia in the late twentieth century.

    PubMed

    Barnes, Emm

    2007-12-01

    During the course of the 1960s and 1970s, acute leukaemia in childhood ceased to be invariably fatal and was recategorized as curable. The meaning of cure in this case, however, was problematic, as it was impossible for physicians to be certain that cancer would not return. This paper uses historical methods to explore how remission was understood by families with children with acute leukaemia during the period in which the first cures were announced, roughly 1972-77. These comprised documentary analysis of records of the Medical Research Council's leukaemia working parties, published papers and letters on treatments for childhood leukaemia, and interviews with eight UK paediatric oncologists practising in UK hospitals in the 1960s and 1970s. Two approaches to defining 'cure' in leukaemia can be identified. The first relied on statistical assessment of survival rates. I argue that the concept of 'indefinite remission' came to serve for researchers and clinicians as a proxy measure of cure. However, the concept of 'indefinite remission' left many patients and their families quite uncertain as to whether a cure had really happened. A second approach to defining cure therefore developed. Faced with uncertainty, patients, parents and psychologists sought to develop alternative measures of success--including the notion of 'psychological cure'--that brought forward the moment of cure and its relief. Changing conceptualizations of leukaemia shaped and were shaped by negotiations over the meaning of 'remission' and 'cure'. On the one hand, the statistical definition of cure was not available for years. On the other hand, psychological cure could begin from the time of first remission, even if medical absolution was not available for years.

  1. An immunophenotypic and molecular diagnosis of composite hairy cell leukaemia and chronic lymphocytic leukaemia.

    PubMed

    Liptrot, Stuart; O' Brien, David; Langabeer, Stephen E; Quinn, Fiona; Mackarel, A Jill; Elder, Patrick; Vandenberghe, Elisabeth; Hayden, Patrick J

    2013-12-01

    Hairy cell leukaemia (HCL) and chronic lymphocytic leukaemia (CLL) are distinct clinicopathological B cell chronic lymphoproliferative disorders (B-CLPD). Both diseases have characteristic immunophenotypic and molecular features. The co-existence of two B-CLPD is perhaps more common than previously thought but a composite HCL and CLL has been rarely documented. A case is reported in which the morphology, integrated with an extensive immunophenotyping panel, and incorporation of the recently described HCL-associated BRAF V600E mutation, enabled the prompt diagnosis of composite HCL and CLL thus allowing appropriate treatment selection. This case serves to highlight the benefit of a multidisciplinary approach to the diagnosis of bi-clonal B-CLPD.

  2. Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study.

    PubMed

    Villumsen, Marie; Sørup, Signe; Jess, Tine; Ravn, Henrik; Relander, Thomas; Baker, Jennifer L; Benn, Christine Stabell; Sørensen, Thorkild I A; Aaby, Peter; Roth, Adam

    2009-11-16

    Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N=47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N=20) and lymphoma (N=51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N=2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR=0.49 (95% CI: 0.26-0.93)), whereas smallpox vaccination did not (HR=1.32 (0.56-3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR=0.81 (0.31-2.16); smallpox vaccination HR=1.32 (0.49-3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.

  3. Prolymphocytic leukaemia: surface morphology in 21 cases as seen by scanning electron microscopy and comparison with B-type CLL and CLL in 'prolymphocytoid' transformation.

    PubMed

    Polliack, A; Leizerowitz, R; Berrebi, A; Gamliel, H; Galili, N; Gurfel, D; Catovsky, D

    1984-08-01

    The surface architecture of leukaemic cells obtained from 21 cases of proven prolymphocytic leukaemia (PLL) and eight cases of chronic lymphocytic leukaemia (CLL) with 'prolymphocytoid' transformation (PL-CLL) was compared with the cell surface morphology of leukaemic cells obtained from 46 cases of B-type CLL, using the scanning electron microscope (SEM). All cases were defined by cytochemistry, immunological markers and transmission electron microscopy prior to SEM examination. B-CLL cells showed the well-recognized spectrum of surface architecture described in earlier studies. The majority of cells had moderate numbers of short microvilli, although in a minority, cells with relatively smooth surfaces predominated. In seven of the eight cases of PL-CLL, cells were villous in nature and in this respect similar to CLL cells; however, more cells with dense microvilli were seen. The prolymphocytic cells were recognized by their larger size and in 18 of the 19 cases of B-derived PLL, villous cells predominated. Two cases of T-derived PLL showed variable cell surface morphology ranging from smooth to moderately villous. It appears that B-PLL cells are most frequently villous and display more surface microvilli than B-CLL cells. B-prolymphocytes display the surface features regarded as characteristic for neoplastic B-cells as seen in patients with B-type lymphoma and leukaemia.

  4. Pattern Of Leukaemia Patients Admitted In Ayub Teaching Hospital Abbottabad.

    PubMed

    Khan, Tariq Mehmood

    2016-01-01

    Any tissue of the body can give rise to cancer. However, those tissues which multiply rapidly are at high risk of developing cancer and haematopoietic system is one of them. Neoplasms of this system are known as leukaemia and lymphoma, according to the types of white cells involved. Study of cancer patterns in different societies, however can contribute a substantial knowledge about the aetiology of cancer. The present Study was designed and aimed to estimate the frequency of different types of leukaemia in patients admitted in Ayub Teaching hospital Abbottabad. Data from the patients admitted at oncology Department of Ayub Teaching Hospital Abbottabad from 2010 to 2015 was collected and analysed to calculate cumulative and year-wise frequency of leukaemia and its major types. Frequency distribution with reference to gender and age was also calculated. In our analysis about 16% patients had acute myelocytic leukaemia and 32% patients had acute lymphocytic leukaemia; while chronic myeloid leukaemia outnumbered chronic lymphocytic leukaemia (11% and 3%); Hodgkin lymphoma was seen in 18% cases while Non Hodgkin lymphoma (NHL) was present in 20% cases. Out of the total, 150 cases (75%) belonged to mountainous areas of Hazara, i.e., 40 cases belonged to Kohistan, another 40 cases were residents of Battagram, 45 cases belonged to hilly areas of Mansehra and 25 cases to Kaghan valley, while only 50 (25%) cases were from the plain areas of Abbottabad and Haripur districts, i.e., 20 and 30 cases respectively. Leukaemia is more common in hilly areas of Hazara, since majority of the cases belonged to well-known mountainous regions of Kohistan, Battagram, Kaghan or Mansehra and only few cases belonged to the plain areas of Abbottabad and Haripur districts.

  5. Measurable residual disease testing in acute myeloid leukaemia.

    PubMed

    Hourigan, C S; Gale, R P; Gormley, N J; Ossenkoppele, G J; Walter, R B

    2017-07-01

    There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.

  6. Subsequent leukaemia in autoimmune disease patients.

    PubMed

    Hemminki, Kari; Liu, Xiangdong; Försti, Asta; Ji, Jianguang; Sundquist, Jan; Sundquist, Kristina

    2013-06-01

    Previous studies have shown that patients diagnosed with some autoimmune (AI) diseases are at an increased risk of leukaemia but limited data are available on survival. We systematically analysed the risks (standardized incidence ratio, SIR) and survival (hazard ratio, HR) in nine types of leukaemia among 402 462 patients hospitalized for any of 33 AI diseases and compared to persons not hospitalized for AI diseases. Risk for all leukaemia was increased after 13 AI diseases and survival was decreased after six AI diseases. SIRs were increased after all AI diseases for seven types of leukaemia, including SIR 1·69 (95% confidence interval (CI): 1·29-2·19) for acute lymphoblastic leukaemia (ALL), 1·85 (95% CI: 1·65-2·07) for acute myeloid leukaemia, 1·68 (95% CI: 1·37-2·04) for chronic myeloid leukaemia, 2·20 (95% CI: 1·69-2·81) for 'other myeloid leukaemia', 2·45 (95% 1·99-2·98) for 'other and unspecified leukaemia', 1·81 (95% CI: 1·11-2·81) for monocytic leukaemia, and 1·36 (95% CI: 1·08-1·69) for myelofibrosis. The HRs were increased for four types of leukaemia, most for myelofibrosis (1·74, 95% CI: 1·33-2·29) and ALL (1·42, 95% CI: 1·03-1·95). Some AI diseases, including rheumatoid arthritis, were associated with increased SIRs and HRs in many types of leukaemia. The present data showed increases in risk and decreases in survival for many types of leukaemia after various AI diseases. Leukaemia is a rare complication in AI disease but findings about this comorbidity at the time of leukaemia diagnosis may help to optimize the treatment and improve survival. © 2013 John Wiley & Sons Ltd.

  7. IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

    PubMed

    Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

    2015-12-17

    The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

  8. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

    PubMed

    Guo, Jianfeng; Cahill, Mary R; McKenna, Sharon L; O'Driscoll, Caitriona M

    2014-12-01

    Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated. Copyright © 2014

  9. Blastic natural killer cell leukaemia in a dog--a case report.

    PubMed

    Bonkobara, Makoto; Saito, Taro; Yamashita, Masahiro; Tamura, Kyoichi; Yagihara, Hiroko; Isotani, Mayu; Sato, Takashi; Washizu, Tsukimi

    2007-11-01

    A case of canine non-T, non-B lymphoid leukaemia was determined to be of natural killer (NK) cell lineage by detecting specific expression of canine CD56 mRNA by reverse transcriptase polymerase chain reaction analysis. Although NK cells are usually considered to be morphologically large granular lymphocytes, the malignant NK cells in this case were agranular and blast-like, resembling human blastic NK cell leukaemia. The prognosis of human NK cell leukaemia is usually poor. In this case, the dog died 10 days after initial presentation, despite chemotherapy.

  10. Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia.

    PubMed

    Garnache-Ottou, Francine; Feuillard, Jean; Ferrand, Christophe; Biichle, Sabeha; Trimoreau, Franck; Seilles, Estelle; Salaun, Véronique; Garand, Richard; Lepelley, Pascale; Maynadié, Marc; Kuhlein, Emilienne; Deconinck, Eric; Daliphard, Sylvie; Chaperot, Laurence; Beseggio, Lucille; Foisseaud, Vincent; Macintyre, Elizabeth; Bene, Marie-Christine; Saas, Philippe; Jacob, Marie-Christine

    2009-06-01

    The diagnosis of plasmacytoid dendritic cell leukaemia (pDCL) is based on the immunophenotypic profile: CD4(+) CD56(+) lineage(neg) CD45RA(+)/RO(neg) CD11c(neg) CD116(low) CD123(+) CD34(neg) CD36(+) HLA-DR(+). Several studies have reported pDCL cases that do not express this exact profile or expressing some lineage antigens that could thus be misdiagnosed. This study aimed to validate pDCL-specific markers for diagnosis by flow-cytometry or quantitative reverse transcription polymerase chain reaction on bone marrow samples. Expression of markers previously found in normal pDC was analysed in 16 pDCL, four pDCL presenting an atypical phenotype (apDCL) and 113 non-pDC - lymphoid or myeloid - acute leukaemia. CD123 was expressed at significantly higher levels in pDCL and apDCL. BDCA-2 was expressed on 12/16 pDCL and on 2/4 apDCL, but was never detected in the 113 non-pDC acute leukaemia cases. BDCA-4 expression was found on 13/16 pDCL, but also in 12% of non-pDC acute leukaemia. High levels of LILRA4 and TCL1A transcripts distinguished pDCL and apDCL from all other acute leukaemia (except B-cell acute lymphoblastic leukaemia for TCL1A). We thus propose a diagnosis strategy, scoring first the CD4(+) CD56(+/-) MPO(neg) cCD3(neg) cCD79a(neg) CD11c(neg) profile and then the CD123(high), BDCA-2 and BDCA-4 expression. Atypical pDCL can be also identified this way and non-pDC acute leukaemia excluded: this scoring strategy is useful for diagnosing pDCL and apDCL.

  11. SERUM metabolomics of acute lymphoblastic leukaemia and acute myeloid leukaemia for probing biomarker molecules.

    PubMed

    Musharraf, Syed Ghulam; Siddiqui, Amna Jabbar; Shamsi, Tahir; Naz, Arshi

    2017-12-01

    Acute leukaemia (AL) is a critical neoplasm of white blood cells. Diagnosing AL requires bone marrow puncture procedure, which many patients do not consent to for it is invasive. Hence sensitive and specific early diagnostic biomarkers are essential for non-invasive diagnosis, new therapeutics and improving the disease prognosis. To differentiate the metabolic alterations associated with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), we investigated serum of ALL and AML patients in comparison with two controls using gas chromatography coupled with triple quadrupole tandem mass spectrometry and multivariate statistical analysis. Twenty seven out of 1425 metabolites were found differentiative among ALL, AML, aplastic anaemia (APA) patients and healthy control using p-value ≤ 0.001. ALL is the most dissimilar group from other three groups as in hierarchical clustering showed 72.1% dissimilarity. Model generation using PLSDA gave an overall accuracy of 91.9%. This study helps in metabolic fingerprinting of control and disease serum at high significance levels and could be used for early diagnosing of AL. Based on pathways analysis, fatty acid metabolism is deregulated in patients with AL and may represent an underlying metabolic pathway associated with disease progression. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial.

    PubMed

    Jones, Jeffrey A; Mato, Anthony R; Wierda, William G; Davids, Matthew S; Choi, Michael; Cheson, Bruce D; Furman, Richard R; Lamanna, Nicole; Barr, Paul M; Zhou, Lang; Chyla, Brenda; Salem, Ahmed Hamed; Verdugo, Maria; Humerickhouse, Rod A; Potluri, Jalaja; Coutre, Steven; Woyach, Jennifer; Byrd, John C

    2018-01-01

    Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled

  13. Myeloid leukaemia in systemic lupus erythematosus--a nested case-control study based on Swedish registers.

    PubMed

    Löfström, Björn; Backlin, Carin; Sundström, Christer; Hellström-Lindberg, Eva; Ekbom, Anders; Lundberg, Ingrid E

    2009-10-01

    To assess the risk factors for leukaemic transformation and myeloid leukaemia in patients with SLE. A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case-control study in SLE patients who developed acute or chronic myeloid leukaemia was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed and bone marrow specimens were re-evaluated. A Medline search of previously published cases of SLE and myeloid leukaemia was performed. After confirmation of SLE diagnosis according to the ACR criteria, eight patients with SLE and myeloid leukaemia and 18 SLE controls were included in the study. Preceding leucopenia was significantly associated with leukaemia development, whereas other SLE manifestations were not. Two cases had a preceding bone marrow confirming myelodysplastic syndrome (MDS). Only two cases were significantly treated with cyclophosphamide or AZA. A Medline search resulted in only 15 previously published cases of coincident SLE and myeloid leukaemia. Preceding MDS was reported in five of these, whereas only eight had been treated with cytotoxic drugs. Low-dose chemotherapy was not a major cause of myeloid malignancy in our population-based cohort of SLE patients nor in the reported cases from literature. Leucopenia was a risk factor for myeloid leukaemia development and an MDS was frequently seen. Therefore bone marrow investigation should be considered in SLE patients with long-standing leucopenia and anaemia.

  14. Diagnosis and management of neonatal leukaemia.

    PubMed

    van der Linden, Marieke H; Creemers, Sara; Pieters, Rob

    2012-08-01

    Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL. Copyright © 2012. Published by Elsevier Ltd.

  15. Association between leukaemia and X-ray in children: a nationwide study.

    PubMed

    Shih, Tian-Yu; Wu, Jay; Muo, Chin-Shin; Kao, Chia-Hung

    2014-08-01

    The frequency of employing radiography is increasing. Long-term risks of performing X-ray procedures on children and adolescents for medical diagnosis have raised significant concerns. In this study, we adopt the case-control methodology to evaluate the relationship between the incidence rate of acute leukaemia and exposure to radiation during diagnostic X-ray examinations for children. Based on 1998-2010 data obtained from the Taiwan Bureau of National Health Insurance database, we selected 58 children with leukaemia and randomly selected an additional 232 children as the control group. The mean age of children with leukaemia is 8.92 ± 5.24 years. The risk of leukaemia in children who underwent X-ray examinations increased 2.14-fold (95% CI, 1.18-3.87). In this study, we identified that, when undergoing X-ray examinations, the risk of leukaemia in children increased for both sex and age groups. Specifically, the relationship between leukaemia and X-ray in boys (OR = 3.28, 95%CI, 1.33-8.07) and in ages of 6 to 11 years (OR = 2.58, 95%CI, 1.09-6.10) was significant. Overall, the risk of leukaemia in children who underwent X-ray examinations progressively increased from a ratio of 1.65 to 3.14. Moreover, an identical trend was observed for boys (1.85 to 6.42). Exposure to X-ray increased the risk of leukaemia in children. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  16. Leukaemia and residence near electricity transmission equipment: a case-control study.

    PubMed Central

    Coleman, M. P.; Bell, C. M.; Taylor, H. L.; Primic-Zakelj, M.

    1989-01-01

    A population-based case-control study of leukaemia and residential proximity to electricity supply equipment has been carried out in south-east England. A total of 771 leukaemias was studied, matched for age, sex, year of diagnosis and district of residence to 1,432 controls registered with a solid tumour excluding lymphoma; 231 general population controls aged 18 and over from one part of the study area were also used. The potential for residential exposure to power frequency magnetic fields from power-lines and transformer substations was assessed indirectly from the distance, type and loading of the equipment near each subject's residence. Only 0.6% of subjects lived within 100 m of an overhead power-line, and the risk of leukaemia relative to cancer controls for residence within 100 m was 1.45 (95% confidence interval (CI) 0.54-3.88); within 50 m the relative risk was 2.0 but with a wider confidence interval (95% CI 0.4-9.0). Over 40% of subjects lived within 100 m of a substation, for which the relative risk of leukaemia was 0.99. Residence within 25 m carried a risk of 1.3 (95% CI 0.8-2.0). Weighted exposure indices incorporating measures of the current load carried by the substations did not materially alter these risks estimates. For persons aged less than 18 the relative risk of leukaemia from residence within 50 m of a substation was higher than in adults (PR = 1.5, 95% CI 0.7-3.4). PMID:2486298

  17. Time Trends and Geographical Distribution of Childhood Leukaemia in Basrah, Iraq, from 2004 to 2009

    PubMed Central

    Alrudainy, Laith A; Hassan, Jenan G; Salih, Hussam M; Abbas, Mohammed K; Majeed, Athar AS

    2011-01-01

    Objectives: This study aimed to assess the incidence and trend of childhood leukaemia in Basrah. Methods: This was a hospital-based cancer registry study carried out at the Pediatric Oncology Ward, Maternity & Children’s Hospital and other institutes in Basrah, Iraq. All children with leukaemia, aged 0 to 14 years diagnosed and registered in Basrah from January 2004 to December 2009 were included in the study. Their records were retrieved and studied. The pattern of childhood leukaemia by year of diagnosis, age at diagnosis, morphological subtypes, and geographical distribution was analysed. Rates of childhood leukaemia over time were calculated for six years using standard linear regression. Results: The total number of cases of childhood leukaemia was 181. The number of cases ranged from 21 in year 1, to 31 in the final year reaching a peak of 39 in 2006. Leukaemia rates did not change over the study period (test for trend was not significant, P = 0.81). The trend line shows a shift towards younger children (less than 5 years). The commonest types of leukaemia were acute lymphoblastic leukaemia (ALL), then acute myeloid leukaemia (AML) and finally chronic myeloid leukaemia (CML). Conclusion: Annual rates of childhood leukaemia in Basrah were similar to those in other countries with a trend towards younger children. This raises the question about the effect of environmental catastrophes in the alteration of some specific rates of childhood leukaemia, rather than the overall incidence rate. There is a need for further epidemiological studies to understand the aetiology of childhood leukaemia in Basrah. PMID:21969893

  18. CD45RA, a specific marker for leukaemia stem cell sub-populations in acute myeloid leukaemia.

    PubMed

    Kersten, Bas; Valkering, Matthijs; Wouters, Rolf; van Amerongen, Rosa; Hanekamp, Diana; Kwidama, Zinia; Valk, Peter; Ossenkoppele, Gert; Zeijlemaker, Wendelien; Kaspers, Gertjan; Cloos, Jacqueline; Schuurhuis, Gerrit J

    2016-04-01

    Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34(+) CD38(-) LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification. Compared to our best other markers (CLL-1, also termed CLEC12A, CD33 and CD123), CD45RA was the most reliable marker. Patients with high percentages (>90%) of CD45RA on CD34(+) CD38(-) LSC have 1·69-fold higher scatter values compared to HSC (P < 0·001), indicating a more mature CD34(+) CD38(-) phenotype. Patients with low (<10%) or intermediate (10-90%) CD45RA expression on LSC showed no significant differences to HSC (1·12- and 1·15-fold higher, P = 0·31 and P = 0·44, respectively). CD45RA-positive LSC tended to represent more favourable cytogenetic/molecular markers. In conclusion, CD45RA contributes to more accurate LSC detection and is recommended for inclusion in stem cell tracking panels. CD45RA may contribute to define new LSC-specific therapies and to monitor effects of anti-LSC treatment. © 2016 John Wiley & Sons Ltd.

  19. Indoor radon and childhood leukaemia.

    PubMed

    Raaschou-Nielsen, Ole

    2008-01-01

    This paper summarises the epidemiological literature on domestic exposure to radon and risk for childhood leukaemia. The results of 12 ecological studies show a consistent pattern of higher incidence and mortality rates for childhood leukaemia in areas with higher average indoor radon concentrations. Although the results of such studies are useful to generate hypotheses, they must be interpreted with caution, as the data were aggregated and analysed for geographical areas and not for individuals. The seven available case-control studies of childhood leukaemia with measurement of radon concentrations in the residences of cases and controls gave mixed results, however, with some indication of a weak (relative risk < 2) association with acute lymphoblastic leukaemia. The epidemiological evidence to date suggests that an association between indoor exposure to radon and childhood leukaemia might exist, but is weak. More case-control studies are needed, with sufficient statistical power to detect weak associations and based on designs and methods that minimise misclassification of exposure and provide a high participation rate and low potential selection bias.

  20. Intelligent Techniques Using Molecular Data Analysis in Leukaemia: An Opportunity for Personalized Medicine Support System

    PubMed Central

    Adelson, David; Brown, Fred; Chaudhri, Naeem

    2017-01-01

    The use of intelligent techniques in medicine has brought a ray of hope in terms of treating leukaemia patients. Personalized treatment uses patient's genetic profile to select a mode of treatment. This process makes use of molecular technology and machine learning, to determine the most suitable approach to treating a leukaemia patient. Until now, no reviews have been published from a computational perspective concerning the development of personalized medicine intelligent techniques for leukaemia patients using molecular data analysis. This review studies the published empirical research on personalized medicine in leukaemia and synthesizes findings across studies related to intelligence techniques in leukaemia, with specific attention to particular categories of these studies to help identify opportunities for further research into personalized medicine support systems in chronic myeloid leukaemia. A systematic search was carried out to identify studies using intelligence techniques in leukaemia and to categorize these studies based on leukaemia type and also the task, data source, and purpose of the studies. Most studies used molecular data analysis for personalized medicine, but future advancement for leukaemia patients requires molecular models that use advanced machine-learning methods to automate decision-making in treatment management to deliver supportive medical information to the patient in clinical practice. PMID:28812013

  1. Intelligent Techniques Using Molecular Data Analysis in Leukaemia: An Opportunity for Personalized Medicine Support System.

    PubMed

    Banjar, Haneen; Adelson, David; Brown, Fred; Chaudhri, Naeem

    2017-01-01

    The use of intelligent techniques in medicine has brought a ray of hope in terms of treating leukaemia patients. Personalized treatment uses patient's genetic profile to select a mode of treatment. This process makes use of molecular technology and machine learning, to determine the most suitable approach to treating a leukaemia patient. Until now, no reviews have been published from a computational perspective concerning the development of personalized medicine intelligent techniques for leukaemia patients using molecular data analysis. This review studies the published empirical research on personalized medicine in leukaemia and synthesizes findings across studies related to intelligence techniques in leukaemia, with specific attention to particular categories of these studies to help identify opportunities for further research into personalized medicine support systems in chronic myeloid leukaemia. A systematic search was carried out to identify studies using intelligence techniques in leukaemia and to categorize these studies based on leukaemia type and also the task, data source, and purpose of the studies. Most studies used molecular data analysis for personalized medicine, but future advancement for leukaemia patients requires molecular models that use advanced machine-learning methods to automate decision-making in treatment management to deliver supportive medical information to the patient in clinical practice.

  2. Surgery in Management of Patients with Leukaemia

    PubMed Central

    Spiers, A. S. D.

    1973-01-01

    Though leukaemia is not a “surgical” disease, the need for surgery in patients with leukaemia is increasing. Acute surgical problems in such patients present diagnostic difficulties, and accepted surgical principles do not necessarily apply in patients with very abnormal haematological and immunological features. The improved prognosis in some types of leukaemia means that elective surgical procedures, which formerly would not have been considered, may now be applicable just as they would be in patients with non-malignant conditions. Recent advances in the management of the leukaemias include several surgical procedures—for example, to facilitate intravenous or intrathecal therapy. Splenectomy is of value in chronic lymphocytic leukaemia when the correct indications are present, while early elective splenectomy, when no classical indications are present, may have a useful role in the management of patients with chronic granulocytic leukaemia. PMID:4517729

  3. Pattern of childhood leukaemia in University College Hospital, Ibadan.

    PubMed

    Babatunde, T O; Ogun, G O; Brown, B J; Akang, E E; Aken'Ova, Y A

    2014-06-01

    Leukaemias are haematological malignancies characterized by unregulated clonal proliferation of haematopoietic cells. To determine the pattern of childhood leukaemia in Ibadan. This was a retrospective study of leukaemia cases diagnosed at the University College Hospital (UCH), Ibadan between January 1991 and December 2010 in children less than 15 years of age. Data obtained was subjected to statistical analysis using the Statistical Package for Social Sciences version 20. There were 64 cases of childhood leukaemia, accounting for 10.2% of childhood cancers seen during this study period. The male to female ratio was 2:1 and modal age group was between 10 and 14 years. Thirty (46.9%) cases were acute lymphoblastic leukaemia (ALL), 22 (34.4%) were acute myelogenous leukaemia (AML) and 12 (18.8%) were unspecified acute leukaemias. There was no case of chronic myeloid or lymphocytic leukaemia. There has been a relative increase in the frequency of leukaemia cases at UCH, Ibadan, which may be largely explained by increased awareness and referrals. There is a need for further collaborative multicentre studies of childhood leukaemias in Nigeria and other developing countries and focused research on childhood leukaemias in order to unravel the aetiology.

  4. Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia.

    PubMed

    Alvarez-Larrán, Alberto; Senín, Alicia; Fernández-Rodríguez, Concepción; Pereira, Arturo; Arellano-Rodrigo, Eduardo; Gómez, Montse; Ferrer-Marin, Francisca; Martínez-López, Joaquín; Camacho, Laura; Colomer, Dolors; Angona, Anna; Navarro, Blanca; Cervantes, Francisco; Besses, Carlos; Bellosillo, Beatriz; Hernández-Boluda, Juan Carlos

    2017-09-01

    The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2-0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9-4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1-5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1-3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival. © 2017 John Wiley & Sons Ltd.

  5. 26. VIEW, LOOKING NORTHWEST INSIDE TRANSFORMER ROOM, SHOWING OIL FILLED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    26. VIEW, LOOKING NORTHWEST INSIDE TRANSFORMER ROOM, SHOWING OIL- FILLED TRANSFORMER POTS - Sacramento River Bridge, Spanning Sacramento River at California State Highway 275, Sacramento, Sacramento County, CA

  6. Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

    PubMed

    Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

    2014-05-19

    Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells. 2014 BMJ Publishing Group Ltd.

  7. Mortality from leukaemia and cancer in shipyard nuclear workers.

    PubMed

    Najarian, T; Colton, T

    1978-05-13

    A review of death certificates in New Hampshire, Maine, and Massachusetts for 1959-77 yielded a total of 1722 deaths among former workers at the Portsmouth Naval Shipyard where nuclear submarines are repaired and refuelled. Next of kin were contacted for 592. All deaths under age 80 were classified as being in former nuclear or non-nuclear workers depending on information supplied by next of kin. With U.S. age-specific proportional cancer mortality for White males as a standard, the observed/expected ratio of leukaemia deaths was 5.62 (6 observed, 1.1 expected) among the 146 former nuclear workers. For all cancer deaths, this ratio was 1.78. Among non-nuclear workers there was no statistically significant increase in proportional mortality from either leukaemia or from all cancers. The excess proportional leukaemia and cancer mortality among nuclear workers exceeds predictions based on previous data of radiation effects in man.

  8. Antibody therapy for acute myeloid leukaemia.

    PubMed

    Gasiorowski, Robin E; Clark, Georgina J; Bradstock, Kenneth; Hart, Derek N J

    2014-02-01

    Novel therapies with increased efficacy and decreased toxicity are desperately needed for the treatment of acute myeloid leukaemia (AML). The anti CD33 immunoconjugate, gemtuzumab ozogamicin (GO), was withdrawn with concerns over induction mortality and lack of efficacy. However a number of recent trials suggest that, particularly in AML with favourable cytogenetics, GO may improve overall survival. This data and the development of alternative novel monoclonal antibodies (mAb) have renewed interest in the area. Leukaemic stem cells (LSC) are identified as the subset of AML blasts that reproduces the leukaemic phenotype upon transplantation into immunosuppressed mice. AML relapse may be caused by chemoresistant LSC and this has refocused interest on identifying and targeting antigens specific for LSC. Several mAb have been developed that target LSC effectively in xenogeneic models but only a few have begun clinical evaluation. Antibody engineering may improve the activity of potential new therapeutics for AML. The encouraging results seen with bispecific T cell-engaging mAb-based molecules against CD19 in the treatment of B-cell acute lymphobalstic leukaemia, highlight the potential efficacy of engineered antibodies in the treatment of acute leukaemia. Potent engineered mAb, possibly targeting novel LSC antigens, offer hope for improving the current poor prognosis for AML. © 2013 John Wiley & Sons Ltd.

  9. Radon and monocytic leukaemia in England.

    PubMed

    Eatough, J P; Henshaw, D L

    1993-12-01

    The relationship between the standardised registration ratio (SRR) for monocytic leukaemia and the radon concentration by county in England was investigated. Leukaemia data were obtained from the OPCS and cover the age range 0-74 years and the period 1975-86. Radon concentrations were obtained from a recent National Radiological Protection Board report. A significant correlation was observed between the SRR for monocytic leukaemia and the radon concentration by county.

  10. Klinefelter syndrome and acute basophilic leukaemia--case report.

    PubMed

    Ljubić, Nives; Lang, Nada; Skelin, Ika Kardum; Lasan, Ruzica; Dominis, Mara; Perković, Leila; Zupanić-Krmek, Dubraka; Grgurević-Batinica, Anita

    2010-06-01

    Patients with 47, XXY karyotype (Klinefelter syndrome) appear to have increased risk of developing cancer, especially male breast cancer, germ cell tumours and non Hodgkin lymphomas, but rarely acute myeloid leukaemia. We report a patient with acute basophilic leukaemia with 47, XXY karyotype in both the tumour and constitutional cells. Acute basophilic leukaemia is very rare disease comprising less than 1% of all acute myeloid leukaemias. Morphological characteristic of leukaemic blast cells is moderately basophilic cytoplasm containing a variable number of coarse basophilic granules. The most characteristic cytochemical reaction is metachromatic positivity with toluidine blue. Blast are myeloperoxidase negative. Also leukemic blasts express myeloid and monocyte markers. There is no consistent chromosomal abnormality identified in this leukaemia. This is the first reported case of acute basophilic leukaemia in patient with Klinefelter syndrome. In this article the medical history of the patient is given and the possible connection between Klinefelter syndrome and acute myeloid leukaemia is discussed.

  11. Perceptually specific and perceptually non-specific influences on rereading benefits for spatially transformed text: evidence from eye movements.

    PubMed

    Sheridan, Heather; Reingold, Eyal M

    2012-12-01

    The present study used eye tracking methodology to examine rereading benefits for spatially transformed text. Eye movements were monitored while participants read the same target word twice, in two different low-constraint sentence frames. The congruency of perceptual processing was manipulated by either applying the same type of transformation to the word during the first and second presentations (i.e., the congruent condition), or employing two different types of transformations across the two presentations of the word (i.e., the incongruent condition). Perceptual specificity effects were demonstrated such that fixation times for the second presentation of the target word were shorter for the congruent condition compared to the incongruent condition. Moreover, we demonstrated an additional perceptually non-specific effect such that second reading fixation times were shorter for the incongruent condition relative to a baseline condition that employed a normal typography (i.e., non-transformed) during the first presentation and a transformation during the second presentation. Both of these effects (i.e., perceptually specific and perceptually non-specific) were similar in magnitude for high and low frequency words, and both effects persisted across a 1 week lag between the first and second readings. We discuss the present findings in the context of the distinction between conscious and unconscious memory, and the distinction between perceptually versus conceptually driven processing. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Promyelocytic blast crisis of chronic myelogenous leukaemia with translocations (9;22) and (15;17).

    PubMed

    Scolnik, M P; Palacios, M F; Acevedo, S H; Castuma, M V; Larripa, I B; Palumbo, A; Moiraghi, E B; Sasot, A M; Huberman, A B

    1998-09-01

    The promyelocytic blast crisis is a rare form of transformation during the evolution of chronic myeloid leukaemia (CML). We report a case of promyelocytic blast crisis with t(15;17) in addition to t(9;22). The morphology and immunophenotype of the blasts were similar to those seen in acute promyelocytic leukaemia (APL). The t(15;17) was confirmed by FISH. The patient had evidence of coagulopathy with clinical and laboratory findings of disseminated intravascular coagulation (DIC). This report highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis of the promyelocytic blast crisis of CML.

  13. Radon and monocytic leukaemia in England.

    PubMed Central

    Eatough, J P; Henshaw, D L

    1993-01-01

    The relationship between the standardised registration ratio (SRR) for monocytic leukaemia and the radon concentration by county in England was investigated. Leukaemia data were obtained from the OPCS and cover the age range 0-74 years and the period 1975-86. Radon concentrations were obtained from a recent National Radiological Protection Board report. A significant correlation was observed between the SRR for monocytic leukaemia and the radon concentration by county. PMID:8120509

  14. Residential exposure to pesticides and childhood leukaemia: a systematic review and meta-analysis.

    PubMed

    Van Maele-Fabry, Geneviève; Lantin, Anne-Catherine; Hoet, Perrine; Lison, Dominique

    2011-01-01

    To conduct a systematic review of published studies on the association between residential/household/domestic exposure to pesticides and childhood leukaemia, and to provide a quantitative estimate of the risk. Publications in English were searched in MEDLINE (1966-31 December 2009) and from the reference list of identified publications. Extraction of relative risk (RR) estimates was performed independently by 2 authors using predefined inclusion criteria. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Separate analyses were conducted after stratification for exposure time windows, residential exposure location, biocide category and type of leukaemia. RR estimates were extracted from 13 case-control studies published between 1987 and 2009. Statistically significant associations with childhood leukaemia were observed when combining all studies (mRR: 1.74, 95% CI: 1.37-2.21). Exposure during and after pregnancy was positively associated with childhood leukaemia, with the strongest risk for exposure during pregnancy (mRR: 2.19, 95% CI: 1.92-2.50). Other stratifications showed the greatest risk estimates for indoor exposure (mRR: 1.74, 95% CI: 1.45-2.09), for exposure to insecticides (mRR: 1.73, 95% CI: 1.33-2.26) as well as for acute non-lymphocytic leukaemia (ANLL) (mRR: 2.30, 95% CI: 1.53-3.45). Outdoor exposure and exposure of children to herbicides (after pregnancy) were not significantly associated with childhood leukaemia (mRR: 1.21, 95% CI: 0.97-1.52; mRR: 1.16, 95% CI: 0.76-1.76, respectively). Our findings support the assumption that residential pesticide exposure may be a contributing risk factor for childhood leukaemia but available data were too scarce for causality ascertainment. It may be opportune to consider preventive actions, including educational measures, to decrease the use of pesticides for residential purposes and particularly the use of indoor insecticides during pregnancy. Copyright © 2010 Elsevier

  15. Vaccination history and risk of childhood leukaemia.

    PubMed

    Ma, Xiaomei; Does, Monique B; Metayer, Catherine; Russo, Carolyn; Wong, Alan; Buffler, Patricia A

    2005-10-01

    Previous studies on vaccination and childhood leukaemia generated inconsistent results. In the Northern California Childhood Leukaemia Study, a case-control study with incident cases and matched birth certificate controls, detailed written vaccination records were collected. A total of 323 cases aged 0-14 years at diagnosis and 409 controls were included in this analysis. All vaccinations were censored on the reference date (date of diagnosis for cases and the corresponding date for matched controls). Conditional logistic regression analysis was conducted, adjusting for potential confounding factors. A primary variable of interest is the number of administrations (doses) of various types of vaccines. Vaccinations against diphtheria, pertussis, tetanus, poliomyelitis, measles, mumps, and rubella were not associated with the risk of leukaemia. The odds ratio for each dose of Haemophilus influenzae type b (Hib) vaccine was 0.81 (95% CI 0.68-0.96). Compared with children who received two or fewer doses of Hib vaccine, those who received three or more doses had a significantly reduced risk of childhood leukaemia (odds ratio = 0.55, 95% confidence interval 0.32-0.94). The number of doses of hepatitis B vaccine received was not associated with leukaemia risk. Hib vaccination is associated with a reduced risk of childhood leukaemia. Future studies with detailed exposure assessment and large sample sizes are needed to further address the role of vaccinations in the etiology of childhood leukaemia.

  16. Bombyx mori E26 transformation-specific 2 (BmEts2), an Ets family protein, represses Bombyx mori Rels (BmRels)-mediated promoter activation of antimicrobial peptide genes in the silkworm Bombyx mori.

    PubMed

    Tanaka, H; Sagisaka, A; Suzuki, N; Yamakawa, M

    2016-10-01

    E26 transformation-specific (Ets) family transcription factors are known to play roles in various biological phenomena, including immunity, in vertebrates. However, the mechanisms by which Ets proteins contribute to immunity in invertebrates remain poorly understood. In this study, we identified a cDNA encoding BmEts2, which is a putative orthologue of Drosophila Yan and human translocation-ets-leukemia/Ets-variant gene 6, from the silkworm Bombyx mori. Expression of the BmEts2 gene was significantly increased in the fat bodies of silkworm larvae in response to injection with Escherichia coli and Staphylococcus aureus. BmEts2 overexpression dramatically repressed B. mori Rels (BmRels)-mediated promoter activation of antimicrobial peptide genes in silkworm cells. Conversely, gene knockdown of BmEts2 significantly enhanced BmRels activity. In addition, two κB sites located on the 5' upstream region of cecropin B1 were found to be involved in the repression of BmRels-mediated promoter activation. Protein-competition analysis further demonstrated that BmEts2 competitively inhibited binding of BmRels to κB sites. Overall, BmEts2 acts as a repressor of BmRels-mediated transactivation of antimicrobial protein genes by inhibiting the binding of BmRels to κB sites. © 2016 The Royal Entomological Society.

  17. Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.

    PubMed

    Ali, Mohamed A E; Naka, Kazuhito; Yoshida, Akiyo; Fuse, Kyoko; Kasada, Atsuo; Hoshii, Takayuki; Tadokoro, Yuko; Ueno, Masaya; Ohta, Kumiko; Kobayashi, Masahiko; Takahashi, Chiaki; Hirao, Atsushi

    2014-07-18

    Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. 10 CFR 26.9 - Specific exemptions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Specific exemptions. 26.9 Section 26.9 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Administrative Provisions § 26.9 Specific exemptions. Upon application of any interested person or on its own initiative, the Commission may grant such exemptions from...

  19. 10 CFR 26.9 - Specific exemptions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Specific exemptions. 26.9 Section 26.9 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Administrative Provisions § 26.9 Specific exemptions. Upon application of any interested person or on its own initiative, the Commission may grant such exemptions from...

  20. 10 CFR 26.9 - Specific exemptions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Specific exemptions. 26.9 Section 26.9 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Administrative Provisions § 26.9 Specific exemptions. Upon application of any interested person or on its own initiative, the Commission may grant such exemptions from...

  1. 10 CFR 26.9 - Specific exemptions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Specific exemptions. 26.9 Section 26.9 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Administrative Provisions § 26.9 Specific exemptions. Upon application of any interested person or on its own initiative, the Commission may grant such exemptions from...

  2. 10 CFR 26.9 - Specific exemptions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Specific exemptions. 26.9 Section 26.9 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Administrative Provisions § 26.9 Specific exemptions. Upon application of any interested person or on its own initiative, the Commission may grant such exemptions from...

  3. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

    PubMed

    Cruickshank, V Adam; Sroczynska, Patrycja; Sankar, Aditya; Miyagi, Satoru; Rundsten, Carsten Friis; Johansen, Jens Vilstrup; Helin, Kristian

    2015-01-01

    Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes.

  4. Magnetic fields and leukaemia risks in UK electricity supply workers.

    PubMed

    Sorahan, T

    2014-04-01

    To investigate whether leukaemia risks are related to occupational exposure to low-frequency magnetic fields. Leukaemia risks experienced by 73 051 employees of the former Central Electricity Generating Board of England and Wales were investigated for the period 1973-2010. All employees were hired in the period 1952-82 and were employed for at least 6 months with some employment in the period 1973-82. Detailed calculations had been performed by others to enable an assessment to be made of exposures to magnetic fields. Poisson regression was used to calculate relative risks (rate ratios) of developing leukaemia or leukaemia subtypes for categories of lifetime, distant (lagged) and recent (lugged) exposure. Findings for all leukaemias combined were unexceptional; risks were close to unity for all exposure categories and there was no suggestion of risks increasing with cumulative (or recent or distant) magnetic field exposures. There were no statistically significant dose-response effects shown for acute myeloid leukaemia, chronic myeloid leukaemia or chronic lymphocytic leukaemia. There was a significant positive trend for acute lymphocytic leukaemia (ALL), but this was based, in the main, on unusually low risks in the lowest exposure category. This study found no convincing evidence to support the hypothesis that exposure to magnetic fields is a risk factor for leukaemia, and the findings are consistent with the hypotheses that both distant and recent magnetic field exposures are not causally related to the generality of leukaemia. The limited positive findings for ALL may well be chance findings.

  5. Transcription control by the ENL YEATS domain in acute leukaemia.

    PubMed

    Erb, Michael A; Scott, Thomas G; Li, Bin E; Xie, Huafeng; Paulk, Joshiawa; Seo, Hyuk-Soo; Souza, Amanda; Roberts, Justin M; Dastjerdi, Shiva; Buckley, Dennis L; Sanjana, Neville E; Shalem, Ophir; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K; Dhe-Paganon, Sirano; Zhang, Feng; Orkin, Stuart H; Winter, Georg E; Bradner, James E

    2017-03-09

    Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

  6. Radon exposure and leukaemia in adulthood.

    PubMed

    Viel, J F

    1993-08-01

    Positive associations between leukaemia and radon concentrations have been observed in England, Scotland and Wales, and Canada. Results of a similar study for the populations of 41 French administrative areas ('départements') are reported for 1984-1986. The average indoor radon and gamma ray concentrations per 'département' range from 12 to 147 Bq.m-3 and from 28 to 142 nG.h-1, respectively. Acute lymphoid leukaemia mortality rate is similar to the national level, whereas an excess of acute myeloid leukaemia deaths is observed. According to Poisson regression models and modified tests for partial correlation, acute myeloid leukaemia mortality is significantly and positively related to indoor radon concentration whether or not adjustment is made for indoor gamma ray dose, socioeconomic status and linear gradient. This result reinforces the evidence that indoor exposure to high levels of radon is a leukaemic environmental hazard.

  7. The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy.

    PubMed

    Trendowski, Matthew

    2015-05-01

    Nearly all cancers are linked by the inexorable phenotype of metastasis as malignant growths have the capability to spread from their place of origin to distant sites throughout the body. While different cancers may have various propensities to migrate towards specific locations, they are all linked by this unifying principal. Unlike most neoplasms, leukaemia has inherent cell motility as leukocytes are required to move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. As such, it seems likely that leukaemias are inherently metastatic, endowed with the deadliest phenotype of cancer simply due to cell of origin. This article presents the biology of metastasis development and how leukaemia cells are inherently provided these phenotypic characteristics. It is then proposed how clinicians may be able to exploit the motility of leukaemia and metastatic emboli of other cancer types through an approach known as sonodynamic therapy (SDT), a treatment modality that combines chemotherapeutic agents with ultrasound to preferentially damage malignant cells. As experimental evidence has indicated, SDT is a promising therapeutic approach in need of clinical testing for further validation. Copyright © 2014 The Author. Published by Elsevier Ireland Ltd.. All rights reserved.

  8. Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia.

    PubMed

    Sekiya, Yuko; Xu, Yinyan; Muramatsu, Hideki; Okuno, Yusuke; Narita, Atsushi; Suzuki, Kyogo; Wang, Xinan; Kawashima, Nozomu; Sakaguchi, Hirotoshi; Yoshida, Nao; Hama, Asahito; Takahashi, Yoshiyuki; Kato, Koji; Kojima, Seiji

    2017-01-01

    We assessed the clinical utility of next-generation sequencing (NGS)-based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B-cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre- (4-5 months) and post- (24 months) maintenance therapy time points, and at relapse. We identified leukaemia-specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4-5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561-21·6), P < 0·001], at 4-5 months [RR (95% CI) = 10·24 (3·374-31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974-74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia-free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS-MRD for patients with B-cell ALL. © 2016 John Wiley & Sons Ltd.

  9. Geographical variation in the incidence of childhood leukaemia in Manitoba.

    PubMed

    Torabi, Mahmoud; Singh, Harminder; Galloway, Katie; Israels, Sara J

    2015-11-01

    Identification of geographical areas and ecological factors associated with higher incidence of childhood leukaemias can direct further study for preventable factors and location of health services to manage such individuals. The aim of this study was to describe the geographical variation and the socio-demographic factors associated with childhood leukaemia in Manitoba. Information on childhood leukaemia incidence between 1992 and 2008 was obtained from the Canadian Cancer Registry and the socio-demographic characteristics for the area of residence from the 2006 Canadian Census. Bayesian spatial Poisson mixed models were used to describe the geographical variation of childhood leukaemia and to determine the association between childhood leukaemia and socio-demographic factors. The south-eastern part of the province had a higher incidence of childhood leukaemia than other parts of the province. In the age and sex-adjusted Poisson regression models, areas with higher proportions of visible minorities and immigrant residents had higher childhood leukaemia incidence rate ratios. In the saturated Poisson regression model, the childhood leukaemia rates were higher in areas with higher proportions of immigrant residents. Unemployment rates were not a significant factor in leukaemia incidence. In Manitoba, areas with higher proportions of immigrants experience higher incidence rates of childhood leukaemia. We have identified geographical areas with higher incidence, which require further study and attention. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  10. Risk factors and time to symptomatic presentation in leukaemia, lymphoma and myeloma.

    PubMed

    Howell, Debra A; Warburton, Fiona; Ramirez, Amanda-Jane; Roman, Eve; Smith, Alexandra G; Forbes, Lindsay J L

    2015-09-29

    UK policy aims to improve cancer outcomes by promoting early diagnosis, which for many haematological malignancies is particularly challenging as the pathways leading to diagnosis can be difficult and prolonged. A survey about symptoms was sent to patients in England with acute leukaemia, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), myeloma and non-Hodgkin lymphoma (NHL). Symptoms and barriers to first help seeking were examined for each subtype, along with the relative risk of waiting >3 months' time from symptom onset to first presentation to a doctor, controlling for age, sex and deprivation. Of the 785 respondents, 654 (83.3%) reported symptoms; most commonly for NHL (95%) and least commonly for CLL (67.9%). Some symptoms were frequent across diseases while others were more disease-specific. Overall, 16% of patients (n=114) waited >3 months before presentation; most often in CML (24%) and least in acute leukaemia (9%). Significant risk factors for >3 months to presentation were: night sweats (particularly CLL and NHL), thirst, abdominal pain/discomfort, looking pale (particularly acute leukaemias), and extreme fatigue/tiredness (particularly CML and NHL); and not realising symptom(s) were serious. These findings demonstrate important differences by subtype, which should be considered in strategies promoting early presentation. Not realising the seriousness of some symptoms indicates a worrying lack of public awareness.

  11. Risk factors and time to symptomatic presentation in leukaemia, lymphoma and myeloma

    PubMed Central

    Howell, Debra A; Warburton, Fiona; Ramirez, Amanda-Jane; Roman, Eve; Smith, Alexandra G; Forbes, Lindsay J L

    2015-01-01

    Background: UK policy aims to improve cancer outcomes by promoting early diagnosis, which for many haematological malignancies is particularly challenging as the pathways leading to diagnosis can be difficult and prolonged. Methods: A survey about symptoms was sent to patients in England with acute leukaemia, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), myeloma and non-Hodgkin lymphoma (NHL). Symptoms and barriers to first help seeking were examined for each subtype, along with the relative risk of waiting >3 months' time from symptom onset to first presentation to a doctor, controlling for age, sex and deprivation. Results: Of the 785 respondents, 654 (83.3%) reported symptoms; most commonly for NHL (95%) and least commonly for CLL (67.9%). Some symptoms were frequent across diseases while others were more disease-specific. Overall, 16% of patients (n=114) waited >3 months before presentation; most often in CML (24%) and least in acute leukaemia (9%). Significant risk factors for >3 months to presentation were: night sweats (particularly CLL and NHL), thirst, abdominal pain/discomfort, looking pale (particularly acute leukaemias), and extreme fatigue/tiredness (particularly CML and NHL); and not realising symptom(s) were serious. Conclusions: These findings demonstrate important differences by subtype, which should be considered in strategies promoting early presentation. Not realising the seriousness of some symptoms indicates a worrying lack of public awareness. PMID:26325101

  12. Risk of leukaemia in children infected with enterovirus: a nationwide, retrospective, population-based, Taiwanese-registry, cohort study.

    PubMed

    Lin, Jiun-Nong; Lin, Cheng-Li; Lin, Ming-Chia; Lai, Chung-Hsu; Lin, Hsi-Hsun; Yang, Chih-Hui; Sung, Fung-Chang; Kao, Chia-Hung

    2015-10-01

    The association between enterovirus infections in children and risk of leukaemia is unclear. We aimed to assess the risk of leukaemia after enterovirus infection in children. We did a nationwide retrospective cohort study by analysing data from the National Health Insurance Research Database (NHIRD) in Taiwan. Children with enterovirus infections aged younger than 18 years were identified. With use of computer-generated random numbers, children not infected with enterovirus were randomly selected and frequency matched (1:1) with children infected with enterovirus by sex, age, urbanisation level, parental occupation, and index year of enterovirus infection. We only included children with complete baseline data for age and sex and who had at least three clinic visits with the diagnosis of enterovirus infection. The diagnosis date of the first clinic visit for the enterovirus infection was defined as the index date for initiation of follow-up person-year measurement and participants. All study patients were followed up until they developed leukaemia, were lost to follow-up, withdrew from the NHI programme, or until the end of the study without leukaemia (censored). Our primary endpoint was a diagnosis of leukaemia during follow-up. Insurance claims data for 3 054 336 children younger than 18 years were randomly selected from all insured children in the NHIRD. We identified 282 360 children infected with enterovirus and 282 355 children not infected with enterovirus between Jan 1, 2000, and Dec 31, 2007. The incidence density rates of leukaemia were 3·26 per 100 000 person-years for the enterovirus-infected and 5·84 per 100 000 person-years for the non-enterovirus-infected cohorts. The risk of leukaemia was significantly lower in the enterovirus-infected cohort than in the non-enterovirus-infected cohort (adjusted subhazard ratio [SHR] 0·44, 95% CI 0·31-0·60; p<0·0001). Children infected with enterovirus have a reduced risk of both lymphocytic

  13. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study.

    PubMed

    Leuraud, Klervi; Richardson, David B; Cardis, Elisabeth; Daniels, Robert D; Gillies, Michael; O'Hagan, Jacqueline A; Hamra, Ghassan B; Haylock, Richard; Laurier, Dominique; Moissonnier, Monika; Schubauer-Berigan, Mary K; Thierry-Chef, Isabelle; Kesminiene, Ausrele

    2015-07-01

    There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. We assembled a cohort of 308,297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8.22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Doses were accrued at very low rates (mean 1.1 mGy per year, SD 2.6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2.96 per Gy (90% CI 1.17-5.21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10.45, 90% CI 4.48-19.65). This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Leukaemia mortality and low-dose ionising radiation in the WISMUT uranium miner cohort (1946-2013).

    PubMed

    Kreuzer, Michaela; Sobotzki, Christina; Fenske, Nora; Marsh, James W; Schnelzer, Maria

    2017-03-01

    To examine the risk of death from leukaemia in relation to occupational chronic low-level external and internal radiation exposure in a cohort of 58 972 former German uranium miners with mortality follow-up from 1946 to 2013. The red bone marrow (RBM) dose from low-linear energy transfer (LET) (mainly external γ-radiation) and high-LET (mainly radon gas) radiation was estimated based on a job-exposure matrix and biokinetic/dosimetric models. Linear excess relative risks (ERR) and 95% CIs were estimated via Poisson regression for chronic lymphatic leukaemia (CLL) and non-CLL. The mean cumulative low-LET and high-LET RBM doses among the 86% radiation-exposed workers were 48 and 9 mGy, respectively. There was a positive non-significant dose-response for mortality from non-CLL (n=120) in relation to low-LET (ERR/Gy=2.18; 95% CI -0.41 to 6.37) and high-LET radiation (ERR/Gy=16.65; 95% -1.13 to 46.75). A statistically significant excess was found for the subgroup chronic myeloid leukaemia (n=31) in relation to low-LET radiation (ERR/Gy=7.20; 95% CI 0.48 to 24.54) and the subgroup myeloid leukaemia (n=99) (ERR/Gy=26.02; 95% CI 2.55 to 68.99) for high-LET radiation. The ERR/Gy tended to be about five to ten times higher for high-LET versus low-LET radiation; however, the CIs largely overlapped. Results indicate no association of death from CLL (n=70) with either type of radiation. Our findings indicate an increased risk of death for specific subtypes from non-CLL in relation to chronic low-LET and high-LET radiation, but no such relation for CLL. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Supplementary oxygen and risk of childhood lymphatic leukaemia.

    PubMed

    Naumburg, E; Bellocco, R; Cnattingius, S; Jonzon, A; Ekbom, A

    2002-01-01

    Childhood leukaemia has been linked to several factors, such as asphyxia and birthweight, which in turn are related to newborn resuscitation. Based on the findings from a previous study a population-based case-control study was performed to investigate the association between childhood leukaemia and exposure to supplementary oxygen and other birth-related factors. Children born in Sweden and diagnosed with lymphatic leukaemia between 1973 and 1989 (578 cases) were individually matched by gender and date of birth to a randomly selected control. Children with Down's syndrome were excluded. Exposure data were blindly gathered from antenatal, obstetric and other standardized medical records. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by conditional logistic regression. Resuscitation with 100% oxygen with a facemask and bag immediately postpartum was significantly associated with an increased risk of childhood lymphatic leukaemia (OR = 2.57, 95% Cl 1.21-6.82). The oxygen-related risk further increased if the manual ventilation lasted for 3 min or more (OR = 3.54, 95% CI 1.16-10.80). Low Apgar scores at 1 and 5 min were associated with a non-significantly increased risk of lymphatic leukaemia. There were no associations between lymphatic leukaemia and supplementary oxygen later in the neonatal period or other birth-related factors. Resuscitation with 100% oxygen immediately postpartum is associated with childhood lymphatic leukaemia, but further studies are warranted to confirm the findings.

  16. CD26: A Prognostic Marker of Acute Lymphoblastic Leukemia in Children in the Post Remission Induction Phase.

    PubMed

    Mehde, Atheer Awad; Yusof, Faridah; Adel Mehdi, Wesen; Zainulabdeen, Jwan Abdulmohsin

    2015-01-01

    ALL is an irredeemable disease due to the resistance to treatment. There are several influences which are involved in such resistance to chemotherapy, including oxidative stress as a result of the generation of reactive oxygen species (ROS) and presence of hypodiploid cells. Cluster of differentiation 26 (CD26), also known as dipeptidyl peptidase-4, is a 110 kDa, multifunctional, membrane-bound glycoprotein. The aim of this study was to evaluate the clinical significance of serum CD26 in patients with acute lymphoblastic leukaemia patients in the post remission induction phase, as well as the relationship between CD26 activity and the oxidative stress status. CD26, total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), in addition to activity of related enzymes myeloperoxidase, glutathione- s-transferase and xanthine oxidase, were analysed in sixty children with acute lymphoblastic leukaemia in the post remission induction phase. The study showed significant elevation in CD26, TOS and OSI levels in patients with acute lymphoblastic leukaemia in the post remission induction phase in comparison to healthy control samples. In contrast, myeloperoxidase, glutathione-s-transferase and xanthine oxidase activities were decreased significantly. A significant correlation between CD26 concentration and some oxidative stress parameters was evident in ALL patients. Serum levels of CD26 appear to be useful as a new biomarker of oxidative stress in children with acute lymphoblastic leukaemia in the post remission induction phase, and levels of antioxidants must be regularly estimated during the treatment of children with ALL.

  17. Host, family and community proxies for infections potentially associated with leukaemia.

    PubMed

    Law, Graham Richard

    2008-01-01

    Three hypotheses have proposed the involvement of infections in the aetiology of childhood leukaemia, suggesting either a specific leukaemogenic infection or a series of common infections that lead to a dysregulation of the immune system. Much of the evidence for the link with infections has been based on epidemiological observations, often using proxy measures of infection. Proxy measures include population mixing, parental occupation, age distribution of incidence, spatial and space-time clustering of cases, birth order and day care during infancy. This paper discusses the proxies used and examines to what extent a commonly used proxy measure, birth order, is a fair representation of either specific infections or general infectious load. It is clear that although leukaemia, and other diseases, may be linked with infections, one needs to (1) measure specific and general infections with more accuracy and (2) understand how proxy measures relate to real infections in the population.

  18. Fallout, radiation doses near Dounreay, and childhood leukaemia.

    PubMed Central

    Darby, S C; Doll, R

    1987-01-01

    Possible explanations for the recently reported increased incidence of childhood leukaemia around Dounreay were examined in the light of changes in the national incidence of leukaemia that occurred during the period of exposure to fallout from international testing of nuclear weapons in the atmosphere. It was concluded that the increase could not be accounted for by an underestimate of the risk of leukaemia per unit dose of radiation at low doses and low dose rates, nor by an underestimate of the relative biological efficiency of high as compared with low linear energy transfer radiation. One possible explanation was underestimation of doses to the red bone marrow due to the discharges at Dounreay relative to the dose from fallout, though investigation of ways in which this might have occurred did not suggest anything definite. Other possible explanations included a misconception of the site of origin of childhood leukaemia, outbreaks of an infectious disease, and exposure to some other, unidentified environmental agent. These findings weigh heavily against the hypothesis that the recent increase in childhood leukaemia near Dounreay might be accounted for by radioactive discharges from nuclear plants, unless the doses to the stem cells from which childhood leukaemia originates have been grossly underestimated. PMID:3103820

  19. Computer-Aided Diagnosis of Acute Lymphoblastic Leukaemia

    PubMed Central

    2018-01-01

    Leukaemia is a form of blood cancer which affects the white blood cells and damages the bone marrow. Usually complete blood count (CBC) and bone marrow aspiration are used to diagnose the acute lymphoblastic leukaemia. It can be a fatal disease if not diagnosed at the earlier stage. In practice, manual microscopic evaluation of stained sample slide is used for diagnosis of leukaemia. But manual diagnostic methods are time-consuming, less accurate, and prone to errors due to various human factors like stress, fatigue, and so forth. Therefore, different automated systems have been proposed to wrestle the glitches in the manual diagnostic methods. In recent past, some computer-aided leukaemia diagnosis methods are presented. These automated systems are fast, reliable, and accurate as compared to manual diagnosis methods. This paper presents review of computer-aided diagnosis systems regarding their methodologies that include enhancement, segmentation, feature extraction, classification, and accuracy. PMID:29681996

  20. Occupation and risk of lymphoid and myeloid leukaemia in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    PubMed

    Saberi Hosnijeh, Fatemeh; Christopher, Yvette; Peeters, Petra; Romieu, Isabelle; Xun, Wei; Riboli, Elio; Raaschou-Nielsen, Ole; Tjønneland, Anne; Becker, Nikolaus; Nieters, Alexandra; Trichopoulou, Antonia; Bamia, Christina; Orfanos, Philip; Oddone, Enrico; Luján-Barroso, Leila; Dorronsoro, Miren; Navarro, Carmen; Barricarte, Aurelio; Molina-Montes, Esther; Wareham, Nick; Vineis, Paolo; Vermeulen, Roel

    2013-07-01

    Established risk factors for leukaemia do not explain the majority of leukaemia cases. Previous studies have suggested the importance of occupation and related exposures in leukaemogenesis. We evaluated possible associations between job title and selected hazardous agents and leukaemia in the European Prospective Investigation into Cancer and Nutrition. The mean follow-up time for 241 465 subjects was 11.20 years (SD 2.42 years). During the follow-up period, 477 incident cases of myeloid and lymphoid leukaemia occurred. Data on 52 occupations considered a priori to be at high risk of developing cancer were collected through standardised questionnaires. Occupational exposures were estimated by linking the reported occupations to a job exposure matrix. Cox proportional hazard models were used to explore the association between occupation and related exposures and risk of leukaemia. The risk of lymphoid leukaemia significantly increased for working in chemical laboratories (HR 8.35, 95% CI 1.58 to 44.24), while the risk of myeloid leukaemia increased for working in the shoe or other leather goods industry (HR 2.54, 95% CI 1.28 to 5.06). Exposure-specific analyses showed a non-significant increased risk of myeloid leukaemias for exposure to benzene (HR 1.15, 95% CI 0.75 to 1.40; HR=1.60, 95% CI 0.95 to 2.69 for the low and high exposure categories, respectively). This association was present both for acute and chronic myeloid leukaemia at high exposure levels. However, numbers were too small to reach statistical significance. Our findings suggest a possible role of occupational exposures in the development of both lymphoid and myeloid leukaemia. Exposure to benzene seemed to be associated with both acute and chronic myeloid leukaemia.

  1. Circulating tight junction proteins mirror blood-brain barrier integrity in leukaemia central nervous system metastasis.

    PubMed

    Zhu, Jing-Cheng; Si, Meng-Ya; Li, Ya-Zhen; Chen, Huan-Zhu; Fan, Zhi-Cheng; Xie, Qing-Dong; Jiao, Xiao-Yang

    2017-09-01

    The aim of this study was to evaluate the clinical significance of circulating tight junction (TJ) proteins as biomarkers reflecting of leukaemia central nervous system (CNS) metastasis. TJs [claudin5 (CLDN5), occludin (OCLN) and ZO-1] concentrations were measured in serum and cerebrospinal fluid (CSF) samples obtained from 45 leukaemia patients. Serum ZO-1 was significantly higher (p < 0.05), but CSF ZO-1 levels were not significantly higher in the CNS leukaemia (CNSL) compared to the non-CNSL. The CNSL patients also had a lower CLDN5/ZO1 ratio in both serum and CSF than in non-CNSL patients (p < 0.05). The TJ index was negatively associated with WBC CSF , ALB CSF and BBB values in leukaemia patients. Among all of the parameters studied, CLDN5 CSF had the highest specificity in discriminating between CNSL and non-CNSL patients. Therefore, analysing serum and CSF levels of CLDN5, OCLN and the CLDN5/ZO1 ratio is valuable in evaluating the potential of leukaemia CNS metastasis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  2. [Historical epidemiology of leukaemia mortality in Salento (Italy) from 1902 to 2002].

    PubMed

    Montinari, Maria Rosa

    2009-01-01

    The aim of this study is to investigate leukaemia mortality in Salento. Leukaemia mortality in Salento's population is compared to data for Apulia and Italy, for 1902 to 2002. With particular reference to the period from 1969 to 2002, the paper looks at leukaemia mortality in male and female populations. Data on all eligible leukaemia deaths was obtained from the National Institute of Statistics (ISTAT). An increase of leukaemia mortality was observed both in male and female populations. Leukaemia mortality in Salento's female population was greater than amongst males.

  3. Birth weight, maternal weight and childhood leukaemia

    PubMed Central

    McLaughlin, C C; Baptiste, M S; Schymura, M J; Nasca, P C; Zdeb, M S

    2006-01-01

    There is mounting evidence that childhood leukaemia is associated with high birth weight, but few studies have examined the relationship between leukaemia and other perinatal factors that influence birth weight, such as maternal weight or gestational weight gain. This case-cohort study included 916 acute lymphocytic leukaemia (ALL) and 154 acute myeloid leukaemia (AML) cases diagnosed prior to age 10 years between 1985 and 2001 and born in New York State excluding New York City between 1978 and 2001. Controls (n=9686) were selected from the birth cohorts for the same years. Moderate increased risk of both ALL and AML was associated with birth weight 3500 g or more. For ALL, however, there was evidence of effect modification with birth weight and maternal prepregnancy weight. High birth weight was associated with ALL only when the mother was not overweight while heavier maternal weight was associated with ALL only when the infant was not high birth weight. Increased pregnancy-related weight gain was associated with ALL. For AML, birth weight under 3000 g and higher prepregnancy weight were both associated with increased risk. These findings suggest childhood leukaemia may be related to factors influencing abnormal fetal growth patterns. PMID:16736025

  4. Maternal diet quality before pregnancy and risk of childhood leukaemia.

    PubMed

    Singer, Amanda W; Carmichael, Suzan L; Selvin, Steve; Fu, Cecilia; Block, Gladys; Metayer, Catherine

    2016-10-01

    Previous studies on maternal nutrition and childhood leukaemia risk have focused on the role of specific nutrients such as folate and have not considered broader measures of diet quality, which may better capture intake of diverse nutrients known to impact fetal development. We examined the relationship between maternal diet quality before pregnancy, as summarised by a diet quality index, and risk of childhood acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in a case-control study in California. Dietary intake in the year before pregnancy was assessed using FFQ in 681 ALL cases, 103 AML cases and 1076 matched controls. Conditional logistic regression was used to estimate OR and 95 % CI for diet quality continuous score and quartiles (Q1-Q4). Higher maternal diet quality score was associated with reduced risk of ALL (OR 0·66; 95 % CI 0·47, 0·93 for Q4 v. Q1) and possibly AML (OR 0·42; 95 % CI 0·15, 1·15 for Q4 v. Q1). No single index component appeared to account for the association. The association of maternal diet quality with risk of ALL was stronger in children diagnosed under the age of 5 years and in children of women who did not report using vitamin supplements before pregnancy. These findings suggest that the joint effects of many dietary components may be important in influencing childhood leukaemia risk.

  5. Lorenz system in the thermodynamic modelling of leukaemia malignancy.

    PubMed

    Alexeev, Igor

    2017-05-01

    The core idea of the proposed thermodynamic modelling of malignancy in leukaemia is entropy arising within normal haematopoiesis. Mathematically its description is supposed to be similar to the Lorenz system of ordinary differential equations for simplified processes of heat flow in fluids. The hypothetical model provides a description of remission and relapse in leukaemia as two hierarchical and qualitatively different states of normal haematopoiesis with their own phase spaces. Phase space transition is possible through pitchfork bifurcation, which is considered the common symmetrical scenario for relapse, induced remission and the spontaneous remission of leukaemia. Cytopenia is regarded as an adaptive reaction of haematopoiesis to an increase in entropy caused by leukaemia clones. The following predictions are formulated: a) the percentage of leukaemia cells in marrow as a criterion of remission or relapse is not necessarily constant but is a variable value; b) the probability of remission depends upon normal haematopoiesis reaching bifurcation; c) the duration of remission depends upon the eradication of leukaemia cells through induction or consolidation therapies; d) excessively high doses of chemotherapy in consolidation may induce relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Monoclonal antibody anti-MPO is useful in recognizing minimally differentiated acute myeloid leukaemia.

    PubMed

    Praxedes, M K; De Oliveira, L Z; Pereira, W da V; Quintana, I Z; Tabak, D G; De Oliveira, M S

    1994-01-01

    The enzyme myeloperoxidase (MPO) is the most specific marker of myeloid lineage. The recognition of acute myeloid leukaemia (AML) with minimally differentiation (AML-M0) is established with methods that include myeloid markers CD13/CD33 and detection of MPO in blast cells by immunological techniques or electron microscopy cytochemistry (EM). We have analysed the presence of MPO in leukaemic blast cells by conventional cytochemistry and immunological methods using a monoclonal antibody anti-MPO (CLB-MPO1) in 121 cases of acute leukaemia. The aim of the study was to investigate the sensitivity of this McAb to identify AML-M0, as CD13/CD33 can be expressed in some cases of acute lymphoblastic leukaemia (ALL) and EM cytochemistry is not always available in many laboratories. Anti-MPO was positive in all cases of AML (M1-M5) which were positive by Sudan Black B reaction in similar or higher percentage ratio for each case, although in some of them did not label with CD13/CD33 tested by IF and IPc techniques. Based on the anti-MPO positivity, 5 out of 10 cases called undifferentiated leukaemia (AUL) were reclassified as AML-M0, though 4 cases were CD13/CD33 negative. Furthermore, after analysing the anti-MPO expression among 32 cases of ALL, we had to reclassify four of them as acute biphenotypic leukaemia. We conclude that anti-MPO is a very sensitive and reliable tool in AML diagnosis and has an important role in distinguishing minimally differentiated AML and biphenotypic acute leukaemia from AUL and ALL.

  7. Clinical presentation of acute myeloid leukaemia - A decade-long institutional follow-up.

    PubMed

    Kulsoom, Bibi; Shamsi, Tahir Sultan; Ahmed, Nikhat; Hasnain, Syed Nazrul

    2017-12-01

    To analyse a decade-long pattern of clinical presentation of acute myeloid leukaemia patients and compare it with contemporary data. The retrospective cohort study was conducted at the National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, and comprised of medical record of acute myeloid leukaemia patients from March 2006 to October 2016. Data noted age at presentation, gender, medical history, physical examination, blood and bone marrow investigations such as, haemoglobin levels, blood cell count myeloperoxidase activity, periodic acid-Schiff and reticulin staining as well as final diagnosis. Comparison, where possible, was done with contemporary literature. SPSS 19 was used for data analysis. Of the 626 subjects, 248(39.6%) were females and 378(60.4%) males. The overall mean age was 35.3±17.1 years. The most common age group was 15-40 years with 354(56.5%) patients. The most common subtype was acute myeloid leukaemia with maturation 183(33.6%). Myeloperoxidase activity was positive for the majority of the acute myeloid leukaemia patients. Periodic acid-Schiff test, done on only selected patients, was mostly negative. Reticulin staining was positive for 113(65.3%) patients. The most common presenting complaints were fever 266(71.9%) and weakness 168(45.4%). Mean haemoglobin and red blood cell count were 8.3 ± 2.4 g/dL and 2.9 ± 1.2 1012/L, respectively. Acute myeloid leukaemia was found to be a highly variable disease that presented with non-specific signs and symptoms.

  8. Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children's Oncology Group.

    PubMed

    Slater, Megan E; Linabery, Amy M; Blair, Cindy K; Spector, Logan G; Heerema, Nyla A; Robison, Leslie L; Ross, Julie A

    2011-11-01

    Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible. © 2011 Blackwell Publishing Ltd.

  9. Richter transformation driven by Epstein-Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia.

    PubMed

    García-Barchino, Maria J; Sarasquete, Maria E; Panizo, Carlos; Morscio, Julie; Martinez, Antonio; Alcoceba, Miguel; Fresquet, Vicente; Gonzalez-Farre, Blanca; Paiva, Bruno; Young, Ken H; Robles, Eloy F; Roa, Sergio; Celay, Jon; Larrayoz, Marta; Rossi, Davide; Gaidano, Gianluca; Montes-Moreno, Santiago; Piris, Miguel A; Balanzategui, Ana; Jimenez, Cristina; Rodriguez, Idoia; Calasanz, Maria J; Larrayoz, Maria J; Segura, Victor; Garcia-Muñoz, Ricardo; Rabasa, Maria P; Yi, Shuhua; Li, Jianyong; Zhang, Mingzhi; Xu-Monette, Zijun Y; Puig-Moron, Noemi; Orfao, Alberto; Böttcher, Sebastian; Hernandez-Rivas, Jesus M; Miguel, Jesus San; Prosper, Felipe; Tousseyn, Thomas; Sagaert, Xavier; Gonzalez, Marcos; Martinez-Climent, Jose A

    2018-05-01

    The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV - tumours, EBV + DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV + DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV + DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2 -/- IL2γc -/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV + B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV + DLBCL in patients. Accordingly, clonally related and unrelated EBV + DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV + DLBCL. Copyright © 2018 Pathological

  10. Hypereosinophilia in childhood acute lymphoblastic leukaemia at diagnosis: report of 2 cases and review of the literature.

    PubMed

    Parasole, Rosanna; Petruzziello, Fara; De Matteo, Antonia; Maisto, Giovanna; Castelli, Luisa; Errico, Maria Elena; Menna, Giuseppe; Poggi, Vincenzo

    2014-04-10

    Hypereosinophilia as first clinical presentation has rarely been reported in paediatric acute lymphoblastic leukaemia. It is commonly associated with specific cytogenetic abnormalities. Although eosinophilia is considered a reactive, non-neoplastic epiphenomenon, it adversely affects patient outcomes, both in children and adults. We describe herewith two paediatric patients who had marked eosinophilia at onset of acute lymphoblastic leukaemia. We point out the importance of a correct differential diagnosis in persistent, unexplained peripheral hypereosinophilia. Clinicians should keep in mind that eosinophilia can be part of the overall pattern of acute leukaemia and therefore needs to be properly investigated. We also provide some recommendations for an appropriate approach to hypereosinophilia - related morbidities.

  11. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome

    PubMed Central

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2014-01-01

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress. PMID:24932421

  12. Childhood leukaemia in areas with different radon levels: a spatial and temporal analysis using GIS

    PubMed Central

    Kohli, S; Noorlind, B; Lofman, O

    2000-01-01

    OBJECTIVES—To evaluate the relation between exposure to ground radon levels and leukaemia among children using existing population and disease registers.
DESIGN—Ecological correlation study.
SETTING—The county of Östergötland in Sweden.
METHODS—Every child born in the county between 1979 and 1992 was mapped to the property centroid coordinates by linking addresses in the population and property registers. Population maps were overlaid with radon maps and exposure at birth and each subsequent year was quantified as high, normal, low or unknown. This was analysed with data from the tumour registry. Standardised mortality ratios (SMRs) were calculated using the age and sex specific rates for Sweden for the year 1995.
RESULTS—90 malignancies occurred among 53 146 children (498 887 person years) who formed the study population. SMRs for acute lymphatic leukaemia (ALL) among children born in high, normal and low risk areas were 1.43, 1.17 and 0.25 respectively. The relative risk for the normal risk group and high risk group as compared with the low risk group was 4.64 (95% CI 1.29, 28.26) and 5.67 (95% CI 1.06, 42.27). The association between ALL and continued residence at normal or high risk areas showed a similar trend. No association between radon risk levels and any other malignancy was seen.
CONCLUSION—Children born in and staying at areas where the risk from ground radon has been classified as low are less likely to develop ALL than those born in areas classified as normal and high risk.


Keywords: leukaemia; cancer; radon; ionising radiation; Geographic Information Systems PMID:11027195

  13. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.

    PubMed

    Koehler, Philipp; Hamprecht, Axel; Bader, Oliver; Bekeredjian-Ding, Isabelle; Buchheidt, Dieter; Doelken, Gottfried; Elias, Johannes; Haase, Gerhard; Hahn-Ast, Corinna; Karthaus, Meinolf; Kekulé, Alexander; Keller, Peter; Kiehl, Michael; Krause, Stefan W; Krämer, Carolin; Neumann, Silke; Rohde, Holger; La Rosée, Paul; Ruhnke, Markus; Schafhausen, Philippe; Schalk, Enrico; Schulz, Katrin; Schwartz, Stefan; Silling, Gerda; Staib, Peter; Ullmann, Andrew; Vergoulidou, Maria; Weber, Thomas; Cornely, Oliver A; Vehreschild, Maria J G T

    2017-02-01

    Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  14. Birth weight and risk of childhood acute leukaemia.

    PubMed

    Gholami, A; Salarilak, S; Hejazi, S; Khalkhali, H R

    2013-02-01

    Studies of risk factors for acute leukaemia are inconclusive. This case-control study was done in West Azerbaijan province, Islamic Republic of Iran, to determine the relationship between birth weight and acute leukaemia in children aged under 15 years. For every patient 2 age- and sex-matched controls were selected from hospital and community populations. Of 130 cases diagnosed over the period 2003-2009,108 (83.1%) had lymphoblastic and 22 (16.9%) myloblastic type. Significantly more of them were male than female (55.4% versus 44.6%). In a multivariate logistic regression model variables significantly associated with acute leukaemia were: birth weight (OR = 2.25), birth order (OR = 2.25), birth place (OR = 7.93), history of chickenpox (OR = 0.46) and mothers' education (OR = 3.23). The risk of acute leukaemia increased significantly with increasing birth weight in the total group and among girls, but not among boys.

  15. Leukaemia cutis after starting bendamustine: cause or coincidence?

    PubMed

    Mawri, Sagger; Nabi, Shahzaib; Jallad, Bassel; Won, Joseph

    2015-09-21

    A 55-year-old man with a history of chronic lymphocytic leukaemia presented with diffuse skin lesions that began 1 week after starting a new chemotherapy regimen with bendamustine and rituximab. The lesions appeared as erythematous papules that were neither itchy nor tender, and did not blanch with pressure. Initially, they began on his scalp and flanks and, over the next few days, spread diffusely throughout his body, becoming darker in colour. Skin biopsy showed atypical clonal B-cell proliferation in a perivascular, periadnexal and dermal band-like distribution, which was further characterised by immunohistochemical evaluation. These findings were suggestive of leukaemia cutis and consistent with the patient's chronic lymphocytic leukaemia, which was previously confirmed by bone marrow biopsy. The bendamustine was stopped and the patient's chemotherapy regimen was switched to fludarabine, cyclophosphamide and rituximab. Shortly thereafter, the leukaemia cutis regressed significantly. 2015 BMJ Publishing Group Ltd.

  16. Prognostic factors for acute myeloid leukaemia in adults--biological significance and clinical use.

    PubMed

    Liersch, Ruediger; Müller-Tidow, Carsten; Berdel, Wolfgang E; Krug, Utz

    2014-04-01

    Acute myeloid leukaemia (AML) is a heterogeneous disease. Prognosis of AML is influenced both by patient-specific as well as disease-specific factors. Age is the most prominent patient-specific risk factor, while chromosomal aberrations are the strongest disease-specific risk factors. For patients with cytogenetically normal AML, prognosis can be specified by mutational status of the genes NPM1, FLT3 and CEBPA. A growing number of recurrent mutations in additional genes have recently been identified, for which the prognostic effect yet has to be determined. Performance status, geriatric assessment, secondary leukaemia following myelodysplastic syndrome or cytotoxic treatment, common laboratory parameters, leukaemic stem cell frequency, bone marrow microenvironment, gene expression levels, epigenetic changes, micro-RNA's as well as kinetics and depth of response to treatment influence prognosis of AML patients. Despite the high number of established risk factors, only few predictive markers exist which can truly aid therapy decisions in patients with AML. © 2014 John Wiley & Sons Ltd.

  17. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

    PubMed Central

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  18. Isolated extraocular muscle involvement as the ophthalmic manifestation of leukaemia.

    PubMed

    Kiratli, Hayyam; Balci, Kadriye E; Himmetoğlu, Ciğdem; Uner, Ayşegül

    2009-08-01

    Clinical and imaging features of patients with orbital leukaemia primarily involving extraocular muscles were evaluated. This retrospective case series includes patients with leukaemia whose only ophthalmic manifestation was extraocular muscle enlargement. Demographic data, clinical information on the systemic disease, prominent ocular signs and symptoms, computed tomography and magnetic resonance imaging characteristics, treatments applied and the outcomes were collected. Five patients were diagnosed as leukaemic infiltration of extraocular muscle between 1995 and 2008. The age at presentation ranged between 3 and 61 years. Acute myeloid leukaemia was the diagnosis in two patients, and chronic lymphocytic leukaemia, chronic myeloid leukaemia and biphenotypic acute leukaemia were found in one patient each, respectively. One patient had bilateral involvement. The lateral rectus muscle was affected in four patients and the superior rectus muscle in one case. Restricted ocular motility was the most common finding. In one patient who had no prior history of leukaemia, an incisional biopsy established the diagnosis. All patients received multi-agent chemotherapy. Four patients expired after a rapid decline of the systemic status within a mean period of 7 months. Leukaemic infiltration of extraocular muscles is a rare and late manifestation of the advanced disease associated with relapse and there seems to be a predilection for the lateral rectus muscle. Systemic prognosis remains dismal despite intensive chemotherapy.

  19. Spatial clustering of childhood leukaemia in Switzerland: A nationwide study.

    PubMed

    Konstantinoudis, Garyfallos; Kreis, Christian; Ammann, Roland A; Niggli, Felix; Kuehni, Claudia E; Spycher, Ben D

    2017-10-01

    The aetiology of childhood leukaemia remains largely unknown. Several hypotheses involve environmental exposures that could implicate spatial clustering of cases. The evidence from previous clustering studies is inconclusive. Most of them used areal data and thus had limited spatial resolution. We investigated whether childhood leukaemia tends to cluster in space using exact geocodes of place of residence both at the time of birth or diagnosis. We included 1,871 leukaemia cases diagnosed between 1985 and 2015 at age 0-15 years from the Swiss Childhood Cancer Registry. For each case, we randomly sampled 10 age and sex matched controls from national censuses closest in time. We used the difference of k-functions, Cuzick-Edwards' test and Tango's index for point data to assess spatial clustering and Kulldorff's circular scan to detect clusters. We separately investigated acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), different age groups at diagnosis (0-4, 5-15 years) and adjusted for multiple testing. After adjusting for multiple testing, we found no evidence of spatial clustering of childhood leukaemia neither around time of birth (p = 0.52) nor diagnosis (p = 0.51). Individual tests indicated spatial clustering for leukaemia diagnosed at age 5-15 years, p k-functions = 0.05 and p Cuzick-Edwards' = 0.04 and a cluster of ALL cases diagnosed at age 0-4 years in a small rural area (p = 0.05). This study provides little evidence of spatial clustering of childhood leukaemia in Switzerland and highlights the importance of accounting for multiple testing in clustering studies. © 2017 UICC.

  20. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study

    PubMed Central

    McKinney, P A; Juszczak, E; Findlay, E; Smith, K; Thomson, C S

    1999-01-01

    A case control study of Scottish children aimed to identify risk factors for leukaemia and other cancers operating in the prenatal environment, during delivery and neonatally. Cases (0–14 years) were age-and sex- matched to two population-based controls and details abstracted from the mother's hospital obstetric notes. Analyses of 144 leukaemias (124 acute lymphoblastic leukaemias (ALL)), 45 lymphomas, 75 central nervous system (CNS) tumours and 126 ‘other solid tumours’ were conducted using conditional logistic regression. The presence of a neonatal infection significantly reduced the risk of ALL (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26–0.95), particularly in 0- to 4-year-olds. Positive swab tests confirmed 47% of ALL cases with any infection and 46% of controls. This is consistent with the hypothesis that early exposure to infections may reduce the risk of childhood ALL. Asphyxia at birth significantly increased the risk of leukaemia, which was accounted for by ALL. For the ‘other solid tumours’ higher levels of maternal education were inversely associated with risk (OR 0.59, 95% CI 0.37–0.94) but positively associated with antibiotics (OR 2.16 95% CI 1.10–4.25) and respiratory tract infections (OR 14.1, 95% CI 1.76–113.7) in pregnancy. No obvious plausible patterns of risk were detected either within or across disease subgroups. © 1999 Cancer Research Campaign PMID:10468308

  1. Transforming Aggregate Object-Oriented Formal Specifications to Code

    DTIC Science & Technology

    1999-03-01

    integration issues associated with a formal-based software transformation system, such as the source specification, the problem space architecture , design architecture ... design transforms, and target software transforms. Software is critical in today’s Air Force, yet its specification, design, and development

  2. Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

    PubMed Central

    Röösli, Martin; Lörtscher, Manfred; Egger, Matthias; Pfluger, Dominik; Schreier, Nadja; Lörtscher, Emanuel; Locher, Peter; Spoerri, Adrian; Minder, Christoph

    2007-01-01

    Aims To investigate the relationship between extremely low frequency magnetic field (ELF‐MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. Methods 20 141 Swiss railway employees with 464 129 person‐years of follow‐up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 μT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 μT). In addition, individual cumulative exposure was calculated from on‐site measurements and modelling of past exposures. Results The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non‐Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. Conclusions Some evidence of an exposure–response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours. PMID:17525094

  3. Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy.

    PubMed

    Frishman-Levy, Liron; Izraeli, Shai

    2017-01-01

    Central nervous system acute lymphoblastic leukaemia (CNS-ALL) is a major clinical problem. CNS-directed 'prophylactic' chemo- or radio - therapy is associated with significant early and long-term toxicity. Moreover, greater than a third of the relapses occur in the CNS. To design specific, more effective and less toxic therapy and for personalized precise adjustment of prophylactic therapy there is a need for better understanding of the biology of this disease. Specifically, the precise neurotropic mechanisms of ALL are currently unclear, as is the pathogenesis of CNS relapse. Here we review and contrast the recent findings with earlier studies of pathogenesis of CNS leukaemia. We also describe the challenges in research of this devastating complication of ALL. © 2016 John Wiley & Sons Ltd.

  4. Bone marrow and splenic histology in hairy cell leukaemia.

    PubMed

    Wotherspoon, Andrew; Attygalle, Ayoma; Mendes, Larissa Sena Teixeira

    2015-12-01

    Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic

  5. Dermatoglyphics in Children with Acute Leukaemia

    PubMed Central

    Purvis-Smith, S. G.; Menser, Margaret A.

    1973-01-01

    The dermatoglyphics of 135 children with acute leukaemia differed significantly from those of normal controls, and examination of 174 of the patients' first degree relatives indicated that familial factors were involved. The findings suggested that within the racial group studied dermatoglyphics may partly identify a population subgroup which is at increased risk of leukaemogenesis. While these observations may not have immediate clinical application, they are likely to contribute to a greater understanding of individuals who have increased constitutional susceptibility to leukaemia. PMID:4519014

  6. Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children’s Oncology Group

    PubMed Central

    Slater, Megan E.; Linabery, Amy M.; Blair, Cindy K.; Spector, Logan G.; Heerema, Nyla A.; Robison, Leslie L.; Ross, Julie A.

    2012-01-01

    Summary Several case–control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children’s Oncology Group case–control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements (‘MLL+’) [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case–control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible. PMID:21980945

  7. Segmentation and Accretionary Processes Near the Andrew Bain Mega-Transform Fault: The Southwest Indian Ridge 25°-35°E

    NASA Astrophysics Data System (ADS)

    Takeuchi, C. S.; Sclater, J. G.; Grindlay, N. R.; Madsen, J. A.; Rommevaux-Jestin, C.

    2008-12-01

    The ultra-slow spreading Southwest Indian Ridge (SWIR) separates the Antarctic and African plates. We present results from two surveys covering the SWIR between 26° and 27°30'E and between 32° and 35°E, lying on either side of the long-offset Andrew Bain transform fault. The objectives of the surveys were to characterize the segmentation of an ultra-slow spreading ridge on either side of a long-offset transform fault and to examine the structure of the individual segments. Four transform faults, the Du Toit, Andrew Bain, Marion, and Prince Edward, and one non-transform discontinuity bound four accretionary segments in the survey areas. Two segments lie northeast of the Andrew Bain (32°-35°E). Large central axial volcanoes, deep, broad mantle Bouguer anomaly (MBA) lows, and high magnetization intensities centered on the spreading axis result from high magmatic activity. Increased magmatism on the ridge axis is likely caused by high mantle temperatures produced by the close proximity of the Marion Plume, which abuts the northern end of the Andrew Bain. Two segments lie southwest of the Andrew Bain (26°-27°30'E). Discrepancies in the locations of the axial rift valley, central magnetization high, and an irregularly-shaped MBA low suggest complex accretionary processes at the western segment (~26°-27° E). The eastern segment (~27°-27°30'E), which abuts the southwest end of the Andrew Bain, shows a deep axial valley, MBA values which increase to the east, and nearly nonexistent magnetization intensity. These features are probably the result of amagmatic accretion caused by the transform edge effect of the Andrew Bain. A transition in the character of topography at 26°45'E suggests that the current segment configuration may not be temporally stable. High-relief (~1 km) ridge-trough structures south of the spreading axis may be the result of an episodic interplay between accretion, both magmatic and amagmatic, and tectonic extension.

  8. Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia.

    PubMed

    Basilico, Silvia; Göttgens, Berthold

    2017-07-01

    Haematopoietic stem cells (HSC) are situated at the apex of the haematopoietic differentiation hierarchy, ensuring the life-long supply of mature haematopoietic cells and forming a reservoir to replenish the haematopoietic system in case of emergency such as acute blood loss. To maintain a balanced production of all mature lineages and at the same time secure a stem cell reservoir, intricate regulatory programs have evolved to control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells (HSPCs). Leukaemogenic mutations commonly disrupt these regulatory programs causing a block in differentiation with simultaneous enhancement of proliferation. Here, we briefly summarize key aspects of HSPC regulatory programs, and then focus on their disruption by leukaemogenic fusion genes containing the mixed lineage leukaemia (MLL) gene. Using MLL as an example, we explore important questions of wider significance that are still under debate, including the importance of cell of origin, to what extent leukaemia oncogenes impose specific regulatory programs and the relevance of leukaemia stem cells for disease development and prognosis. Finally, we suggest that disruption of stem cell regulatory programs is likely to play an important role in many other pathologies including ageing-associated regenerative failure.

  9. Active acute leukaemia: should transplant be offered to all patients?

    PubMed

    Avni, Batia; Shapira, Michael Y; Resnick, Igor B; Stepensky, Polina; Or, Reuven; Grisariu, Sigal

    2017-12-01

    The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. We retrospectively analyzed 361 acute leukaemia patients, who underwent allogeneic SCT in the Hadassah's bone marrow transplantation department between the years 2005 and 2012 and identified 84 patients with active leukaemia at transplantation. Median age was 34 years. Sixty four patients were diagnosed with acute myeloid leukaemia (AML), 18 patients with acute lymphoblastic leukaemia and two with biphenotypic leukaemia. The majority of patients were diagnosed with de-novo AML and transplanted at relapse. In the surviving patients, median follow up was 15 months. One year OS was 20%. At time of last follow up, 13 patients were alive (15.5%): ten patients with AML and two patients with acute lymphoblastic leukaemia. In the univariate analysis, factors associated with significantly better overall survival were as follows: matched unrelated donor (p = 0.006), matched donor (p = 0.014) and occurrence of acute graft-versus-host disease (aGVHD) (p = 0.019). Karnofsky performance score at SCT and occurrence of cGVHD were found to be borderline significant. Only matched unrelated donor and aGVHD were found to affect overall survival significantly in the multivariate analysis. Other than performance score at SCT, none of the pretransplant patients' characteristics were found to influence survival. In conclusion, as none of the pretransplant characteristics were found to influence the ability to select the patients that will benefit from HSC transplantation, this work supports offering HSCT to all active leukaemia eligible patients with reasonable performance status. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Leukaemic infiltration and cytomegalovirus retinitis in a patient with acute T-cell lymphoblastic leukaemia in complete remission.

    PubMed

    Saldaña Garrido, J D; Martínez Rubio, M; Carrión Campo, R; Moya Moya, M A; Rico Sergado, L

    2017-03-01

    A 43-year-old woman in remission from T- cell acute lymphoblastic leukaemia was referred to our hospital with suspected leukaemic retinitis. The funduscopic examination of her left eye revealed multifocal yellow-white peripheral retinitis and retinal haemorrhage. The patient was treated for cytomegalovirus retinitis after an extended haematological investigation showed no abnormalities. Initial improvement was followed by papillitis in the left eye and motility restriction in the right eye. Magnetic resonance and lumbar puncture confirmed leukaemia relapse. Specific treatment was initiated with complete resolution. Ocular involvement may precede haematological leukaemia relapse. Physicians should be alerted when ocular symptoms appear in these cases. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Symptoms of adult chronic and acute leukaemia before diagnosis: large primary care case-control studies using electronic records.

    PubMed

    Shephard, Elizabeth A; Neal, Richard D; Rose, Peter W; Walter, Fiona M; Hamilton, Willie

    2016-03-01

    Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types. To identify the symptom profiles of chronic and acute leukaemia in adults in primary care. Matched case-control studies using Clinical Practice Research Datalink records. Putative symptoms of leukaemia were identified in the year before diagnosis. Conditional logistic regression was used for analysis, and positive predictive values (PPVs) were calculated to estimate risk. Of cases diagnosed between 2000 and 2009, 4655 were aged ≥40 years (2877 chronic leukaemia (CL), 937 acute leukaemia (AL), 841 unreported subtype). Ten symptoms were independently associated with CL, the three strongest being: lymphadenopathy (odds ratio [OR] 22, 95% confidence interval [CI] = 13 to 36), weight loss (OR 3.0, 95% CI = 2.1 to 4.2), and bruising (OR 2.3, 95% CI = 1.6 to 3.2). Thirteen symptoms were independently associated with AL, the three strongest being: nosebleeds and/or bleeding gums (OR 5.7, 95% CI = 3.1 to 10), fever (OR 5.3, 95% CI = 2.7 to 10), and fatigue (OR 4.4, 95% CI = 3.3 to 6.0). No individual symptom or combination of symptoms had a PPV >1%. The symptom profiles of CL and AL have both overlapping and distinct features. This presents a dichotomy for GPs: diagnosis, by performing a full blood count, is easy; however, the symptoms of leukaemia are non-specific and of relatively low risk. This explains why many leukaemia diagnoses are unexpected findings. © British Journal of General Practice 2016.

  12. Symptoms of adult chronic and acute leukaemia before diagnosis: large primary care case-control studies using electronic records

    PubMed Central

    Shephard, Elizabeth A; Neal, Richard D; Rose, Peter W; Walter, Fiona M; Hamilton, Willie

    2016-01-01

    Background Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types. Aim To identify the symptom profiles of chronic and acute leukaemia in adults in primary care. Design and setting Matched case-control studies using Clinical Practice Research Datalink records. Method Putative symptoms of leukaemia were identified in the year before diagnosis. Conditional logistic regression was used for analysis, and positive predictive values (PPVs) were calculated to estimate risk. Results Of cases diagnosed between 2000 and 2009, 4655 were aged ≥40 years (2877 chronic leukaemia (CL), 937 acute leukaemia (AL), 841 unreported subtype). Ten symptoms were independently associated with CL, the three strongest being: lymphadenopathy (odds ratio [OR] 22, 95% confidence interval [CI] = 13 to 36), weight loss (OR 3.0, 95% CI = 2.1 to 4.2), and bruising (OR 2.3, 95% CI = 1.6 to 3.2). Thirteen symptoms were independently associated with AL, the three strongest being: nosebleeds and/or bleeding gums (OR 5.7, 95% CI = 3.1 to 10), fever (OR 5.3, 95% CI = 2.7 to 10), and fatigue (OR 4.4, 95% CI = 3.3 to 6.0). No individual symptom or combination of symptoms had a PPV >1%. Conclusion The symptom profiles of CL and AL have both overlapping and distinct features. This presents a dichotomy for GPs: diagnosis, by performing a full blood count, is easy; however, the symptoms of leukaemia are non-specific and of relatively low risk. This explains why many leukaemia diagnoses are unexpected findings. PMID:26917658

  13. Pneumonia diagnosis in childhood and incidence of leukaemia, lymphoma and brain cancer: a Danish nationwide cohort study.

    PubMed

    Søgaard, Kirstine Kobberøe; Farkas, Dóra Körmendiné; Sørensen, Henrik Toft

    2017-12-29

    There is an ongoing debate on the possible association between infections in early childhood and subsequent cancer risk, but it remains unclear if a hospital admission for infection is associated with risk of childhood cancer diagnosis. We examined if a hospital-based diagnosis of pneumonia was a clinical marker of the three most common childhood cancers. Population-based cohort study. Denmark, hospital diagnoses, 1994-2013. Using national health registries, we compared the observed incidence of leukaemia, lymphoma and brain cancer among 83 935 children with a hospital-based pneumonia diagnosis with that expected among children in the general population. We calculated absolute cancer risks and standardised incidence ratios (SIRs) as a measure of relative risk. The cancer SIRs were substantially increased during the first 6 months of follow-up; lymphoid leukaemia: 6.2 (95% CI 3.5 to 10.3); myeloid leukaemia: 14.8 (95% CI 6.0 to 30.6); Hodgkin's lymphoma: 60.8 (95% CI 26.2 to 120), non-Hodgkin's lymphoma: 15.9 (95% CI 5.2 to 37.2) and brain cancer: 4.4 (95% CI 1.9 to 8.7). The 6-month absolute risks of leukaemia, lymphoma and brain cancer were all low, reaching 0.05% when combined. An increased risk persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the 5-year absolute cancer risk was 0.14%. The short-term incidence of leukaemia, lymphoma and brain cancer was higher than expected and persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the absolute cancer risk was low. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukaemia and chronic myelogenous leukaemia in the Korean population.

    PubMed

    Hur, M; Park, J Y; Cho, H C; Lee, K M; Shin, H Y; Cho, H I

    2006-06-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism, DNA methylation and synthesis. We investigated the association between MTHFR polymorphisms and the risks of acute and chronic leukaemias. MTHFR C677T and A1298C were genotyped in 396 Korean individuals using multiplex polymerase chain reaction/restriction fragment-length polymorphism. They were acute lymphoblastic leukaemia (ALL, n = 89), acute myeloid leukaemia (AML, n = 55), biphenotypic acute leukaemia (n = 12), chronic myelogenous leukaemia (CML, n = 40), and normal controls (n = 200). C677T genotypes were not associated with the risk of each disease. A1298C variants, however, significantly decreased the risks of ALL and CML compared with 1298AA. Odds ratios and 95% confidence intervals of 1298AC and 1298AC + CC were 0.53 (0.31-0.93) and 0.54 (0.31-0.93) in ALL, and 0.34 (0.14-0.80) and 0.40 (0.18-0.89) in CML, respectively, compared with 1298AA. These findings demonstrate that the development of ALL and CML is more dependent on folate status, and more susceptible to DNA instability than that of AML. In addition, A1298C rather than C677T may be a more important genetic risk modifier in leukaemogenesis at least in the Korean population.

  15. Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia.

    PubMed

    Barker, Juliet N; Fei, Mingwei; Karanes, Chatchada; Horwitz, Mitchell; Devine, Steven; Kindwall-Keller, Tamila L; Holter, Jennifer; Adams, Alexia; Logan, Brent; Navarro, Willis H; Riches, Marcie

    2015-02-01

    Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 10(7) /kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51-76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed. © 2014 John Wiley & Sons Ltd.

  16. XMI2USE: A Tool for Transforming XMI to USE Specifications

    NASA Astrophysics Data System (ADS)

    Sun, Wuliang; Song, Eunjee; Grabow, Paul C.; Simmonds, Devon M.

    The UML-based Specification Environment (USE) tool supports syntactic analysis, type checking, consistency checking, and dynamic validation of invariants and pre-/post conditions specified in the Object Constraint Language (OCL). Due to its animation and analysis power, it is useful when checking critical non-functional properties such as security policies. However, the USE tool requires one to specify (i.e., "write") a model using its own textual language and does not allow one to import any model specification files created by other UML modeling tools. Hence, to make the best use of existing UML tools, we often create a model with OCL constraints using a modeling tool such as the IBM Rational Software Architect (RSA) and then use the USE tool for model validation. This approach, however, requires a manual transformation between the specifications of two different tool formats, which is error-prone and diminishes the benefit of automated model-level validations. In this paper, we describe our own implementation of a specification transformation engine that is based on the Model Driven Architecture (MDA) framework and currently supports automatic tool-level transformations from RSA to USE.

  17. Breaking bad news--parents' experience of learning that their child has leukaemia.

    PubMed

    Oshea, J; Smith, O; O'Marcaigh, A; McMahon, C; Geoghegan, R; Cotter, M

    2007-10-01

    This study aimed to seek parents' experiences of how they learned their child had leukaemia and therefore identify ways of improving this process. To achieve this task a questionnaire was designed to ask parents about specific elements of the initial interview and give them opportunity to add their thoughts and feelings on the subject. All children with a diagnosis of leukaemia over an eighteen-year period were identified and parents of those children still alive were invited to partake in the study. 49 out of 50 families agreed to participate of which 35 (72%) returned completed questionnaires. The majority 29 (83%) expressed overall satisfaction. Their replies confirmed some findings of previous studies, and also offered some new insights. Examples of new findings or expansion on previous findings include observations on the presence of young children at the initial interview; the importance of the language used in conveying the diagnosis and prognostic information, and a preference for actuarial terms when discussing prognosis. Telling parents their child has leukaemia is a challenging and important task. The experience of parents gives us valuable insights into our own communication skills and highlights areas of possible improvement in this difficult area.

  18. Case-control study of paternal occupation and childhood leukaemia in Great Britain, 1962-2006.

    PubMed

    Keegan, T J; Bunch, K J; Vincent, T J; King, J C; O'Neill, K A; Kendall, G M; MacCarthy, A; Fear, N T; Murphy, M F G

    2012-10-23

    Paternal occupational exposures have been proposed as a risk factor for childhood leukaemia. This study investigates possible associations between paternal occupational exposure and childhood leukaemia in Great Britain. The National Registry of Childhood Tumours provided all cases of childhood leukaemia born and diagnosed in Great Britain between 1962 and 2006. Controls were matched on sex, period of birth and birth registration subdistrict. Fathers' occupations were assigned to 1 or more of 33 exposure groups. Social class was derived from father's occupation at the time of the child's birth. A total of 16 764 cases of childhood leukaemia were ascertained. One exposure group, paternal social contact, was associated with total childhood leukaemia (odds ratio 1.14, 1.05-1.23); this association remained significant when adjusted for social class. The subtypes lymphoid leukaemia (LL) and acute myeloid leukaemia showed increased risk with paternal exposure to social contact before adjustment for social class. Risk of other leukaemias was significantly increased by exposure to electromagnetic fields, persisting after adjustment for social class. For total leukaemia, the risks for exposure to lead and exhaust fumes were significantly <1. Occupationally derived social class was associated with risk of LL, with the risk being increased in the higher social classes. Our results showed some support for a positive association between childhood leukaemia risk and paternal occupation involving social contact. Additionally, LL risk increased with higher paternal occupational social class.

  19. Childhood infectious diseases and risk of leukaemia in an adult population.

    PubMed

    Parodi, Stefano; Crosignani, Paolo; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Stagnaro, Emanuele

    2013-10-15

    Our study is aimed at investigating the association between common childhood infectious diseases (measles, chickenpox, rubella, mumps and pertussis) and the risk of developing leukaemia in an adult population. A reanalysis of a large population-based case-control study was carried out. Original data included 1,771 controls and 649 leukaemia cases from 11 Italian areas. To contain recall bias, the analysis was restricted to subjects directly interviewed and with a good quality interview (1,165 controls and 312 cases). Odds ratios (ORs) and their related 95% confidence intervals (95% CIs) were estimated by unconditional polychotomous logistic regression model adjusting for age, gender and occupational and lifestyle exposures. A protective effect of at least one infection (OR = 0.66, 95% CI: 0.45-0.97), measles (OR = 0.57, 95% CI: 0.39-0.82) and pertussis (OR = 0.66, 95% CI: 0.45-0.98) was observed for chronic lymphoid leukaemia (CLL). The number of infections was strongly inversely associated with the risk of CLL (p = 0.002, test for trend). With regard to the other types of leukaemia, only a protective effect of pertussis was observed for AML (OR = 0.52, 95% CI: 0.32-0.87). Our results pointed out a protective role of childhood infectious diseases on the risk of CLL in adults. Although a specific antioncogenic effect of some infectious disease, especially measles, cannot be ruled out, the observed decrease of risk with increasing number of infections suggests that a more general "hygiene hypothesis" could be the most likely explanation of the detected association. The protective role of pertussis remains to be elucidated. Copyright © 2013 UICC.

  20. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells

    PubMed Central

    George, Joshy; Uyar, Asli; Young, Kira; Kuffler, Lauren; Waldron-Francis, Kaiden; Marquez, Eladio; Ucar, Duygu; Trowbridge, Jennifer J.

    2016-01-01

    The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML. PMID:27397025

  1. Spatial clustering of childhood leukaemia with the integration of the Paediatric Environmental History.

    PubMed

    Cárceles-Álvarez, Alberto; Ortega-García, Juan A; López-Hernández, Fernando A; Orozco-Llamas, Mayra; Espinosa-López, Blanca; Tobarra-Sánchez, Esther; Alvarez, Lizbeth

    2017-07-01

    Leukaemia remains the most common type of paediatric cancer and its aetiology remains unknown, but considered to be multifactorial. It is suggested that the initiation in utero by relevant exposures and/or inherited genetic variants and, other promotional postnatal exposures are probably required to develop leukaemia. This study aimed to map the incidence and analyse possible clusters in the geographical distribution of childhood acute leukaemia during the critical periods and to evaluate the factors that may be involved in the aetiology by conducting community and individual risk assessments. We analysed all incident cases of acute childhood leukaemia (<15 years) diagnosed in a Spanish region during the period 1998-2013. At diagnosis, the addresses during pregnancy, early childhood and diagnosis were collected and codified to analyse the spatial distribution of acute leukaemia. Scan statistical test methodology was used for the identification of high-incidence spatial clusters. Once identified, individual and community risk assessments were conducted using the Paediatric Environmental History. A total of 158 cases of acute leukaemia were analysed. The crude rate for the period was 42.7 cases per million children. Among subtypes, acute lymphoblastic leukaemia had the highest incidence (31.9 per million children). A spatial cluster of acute lymphoblastic leukaemia was detected using the pregnancy address (p<0.05). The most common environmental risk factors related with the aetiology of acute lymphoblastic leukaemia, identified by the Paediatric Environmental History were: prenatal exposure to tobacco (75%) and alcohol (50%); residential and community exposure to pesticides (62.5%); prenatal or neonatal ionizing radiation (42.8%); and parental workplace exposure (37.5%) CONCLUSIONS: Our study suggests that environmental exposures in utero may be important in the development of childhood leukaemia. Due to the presence of high-incidence clusters using pregnancy address

  2. Urinary level of nickel and acute leukaemia in Chinese children.

    PubMed

    Yang, Y; Jin, X M; Yan, C H; Tian, Y; Tang, J Y; Shen, X M

    2008-10-01

    The 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidized nucleoside of DNA, not only is a widely used biomarker for the measurement of endogenous oxidative DNA damage but might also be a risk factor for many diseases including cancer. Metal exposure may play an important role in oxidative DNA damage among children. However, few studies on urinary 8-OHdG and metals have been conducted in children with acute leukemia. In the present study, urinary Ni and 8-OHdG were examined in 116 children with acute leukaemia (94 acute lymphoid leukaemia [ALL] and 22 acute myeloid leukaemia [AML]) and 51 healthy child controls. Our result showed that urinary Ni in acute leukaemia patients (ALL: 68.40 +/- 133.98, AML: 41.48 +/- 76.31 ng/mg creatinine) was significantly higher than that in controls (62.47 +/- 124.90 vs 17.63 +/- 46.17 ng/mg creatinine, P < 0.05). Similarly, the pretherapy level of urinary 8-OHdG in patients (ALL: 11.83 +/- 16.23, AML: 12.36 +/- 11.36 ng/mg creatinine) was significantly elevated compared with controls (11.92 +/- 15.42 vs 4.03 +/- 4.70 ng/mg creatinine, P < 0.05). Moreover, urinary 8-OHdG and urinary Ni showed a weak but significant association with increased risk of childhood leukaemia. The present study suggests that Ni may be an etiologic factor for childhood acute leukaemia by oxidative DNA damage.

  3. Diagnosis of invasive fungal infections using real-time PCR assay in paediatric acute leukaemia induction.

    PubMed

    Mandhaniya, Sushil; Iqbal, Sobuhi; Sharawat, Surender Kumar; Xess, Immaculata; Bakhshi, Sameer

    2012-07-01

    Invasive fungal infections (IFI) lead to morbidity and mortality in neutropenic patients and in allogenic stem cell transplantation. Serum-based fungal detection assays have limitation of specificity or sensitivity. Studies on fungal DNA detection using real-time PCR in childhood leukaemia are lacking. The aim of this study was to develop sensitive and specific diagnostic tools for IFI in paediatric acute leukaemia patients using real-time PCR. Of 100 randomised paediatric acute leukaemia patients receiving antifungal prophylaxis with voriconazole/amphotericin B, single peripheral whole blood sample in EDTA was used for Pan-AC real-time PCR assay (detects nine Candida and six Aspergillus species) in patients who failed prophylaxis due to proven, probable, possible or suspected fungal infections. PCR results were retrospectively correlated with clinical profile. Real-time PCR test was positive in 18/29 (62%) patients who failed prophylaxis. The only patient with proven IFI (mucormycosis), real-time PCR assay was negative. Real-time PCR was positive in 2/4 (50%) patients with possible and 16/24 (66.6%) suspected IFI and 5/10 (50%) patients with pneumonia. By applying method A/B, sensitivity and positive predictive value could not be commented due to unproven Aspergillus or Candida infections; specificity and negative predictive values (NPV) were 41% and 100% respectively; by method C (included episodes of possible IFI as true positive), sensitivity, specificity, PPV and NPV were 50%, 36%, 11% and 81% respectively. In those with suspected IFI, 8/24 (33.3%) were PCR negative and unnecessarily received empirical antifungal therapy (EAFT). Real-time PCR is a practical, rapid, non-invasive screening test for excluding IFI in paediatric leukaemia. The high NPV makes real-time PCR a promising tool to use this prior to initiating EAFT in antibiotic-resistant febrile neutropenic patients; this would avoid toxicity, cost and hospitalisation for EAFT (Clinical

  4. 21 CFR 660.26 - Specificity tests and avidity tests.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Specificity tests and avidity tests. 660.26 Section 660.26 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.26 Specificity tests and avidity...

  5. 21 CFR 660.26 - Specificity tests and avidity tests.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Specificity tests and avidity tests. 660.26 Section 660.26 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.26 Specificity tests and avidity...

  6. Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

    PubMed Central

    Hardisty, R. M.; McElwain, T. J.; Darby, Caryl W.

    1969-01-01

    A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity. PMID:5254045

  7. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

    PubMed Central

    Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn; Li, Yongjin; Liu, Yu; Harvey, Richard C.; McCastlain, Kelly; Reshmi, Shalini C.; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, I-Ming; Valentine, Marcus; Pei, Deqing; Mungall, Karen L.; Mungall, Andrew J.; Ma, Yussanne; Moore, Richard; Marra, Marco; Stonerock, Eileen; Gastier-Foster, Julie M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent; Borowitz, Michael; Larsen, Eric E.; Maloney, Kelly; Mattano Jr, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony V.; Patel, Bella; Fielding, Adele K.; Rowe, Jacob M.; Luger, Selina M.; Bhatia, Ravi; Aldoss, Ibrahim; Forman, Stephen J.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; L. Loh, Mignon; P. Hunger, Stephen; Mullighan, Charles G.

    2016-01-01

    Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. PMID:27824051

  8. Traffic-related air pollution and risk for leukaemia of an adult population.

    PubMed

    Raaschou-Nielsen, Ole; Ketzel, Matthias; Harbo Poulsen, Aslak; Sørensen, Mette

    2016-03-01

    Air pollution causes lung cancer, but associations with other cancers have not been established. We investigated whether long-term exposure to traffic-related air pollution is associated with the risk of the general population for leukaemia. We identified 1,967 people in whom leukaemia was diagnosed in 1992-2010 from a nation-wide cancer registry and selected 3,381 control people at random, matched on sex and year of birth, from the entire Danish population. Residential addresses since 1971 were traced in a population registry, and outdoor concentrations of NOx and NO2 , as indicators of traffic-related air pollution, were calculated at each address in a dispersion model. We used conditional logistic regression to estimate the risk for leukaemia after adjustment for income, educational level, cohabitation status and co-morbidity. In linear analyses, we found odds ratios for acute myeloid leukaemia of 1.20 (95% confidence interval: 1.04-1.38) per 20 µg/m(3) increase in NOx and 1.31 (1.02-1.68) per 10 µg/m(3) increase in NO2 , calculated as time-weighted average exposure at all addresses since 1971. We found no association with chronic myeloid or lymphocytic leukaemia. This study indicates an association between long-term exposure to traffic-related air pollution and acute myeloid leukaemia in the general population, but not for other subtypes of leukaemia. © 2015 UICC.

  9. Hyperleukocytosis and leukocytapheresis in acute leukaemias: experience from a single centre and review of the literature of leukocytapheresis in acute myeloid leukaemia.

    PubMed

    Bruserud, Ø; Liseth, K; Stamnesfet, S; Cacic, D L; Melve, G; Kristoffersen, E; Hervig, T; Reikvam, H

    2013-12-01

    Hyperleukocytosis is usually defined as leukocyte count >100 × 10(9)  L(-1) and can be seen in newly diagnosed leukaemias. Hyperleukocytic leukaemia is associated with a risk of organ failure and early death secondary to leukostasis. Mechanical removal of leukocytes by the apheresis technique, leukocytapheresis, is a therapeutic option in these patients. During a 16-year period, 16 patients were treated with leukocytapheresis (35 apheresis procedures) for hyperleukocytosis/leukostasis. We present our experience, and in addition we review previous studies of hyperleukocytosis/leukocytapheresis in patients with acute myeloid leukaemia (AML). We used a highly standardised approach for leukocytapheresis in leukaemia patients with hyperleukocytosis. The average leukocytapheresis number for each patient was 2·2 (range 1-6). Median leukocyte count before apheresis was 309 × 10(9)  L(-1) (range 104-935); the mean leukocyte count reduction was 71%, corresponding to a mean absolute reduction of 219 × 10(9)  L(-1). No serious side effects were seen during or immediately after apheresis. The data suggest that our standardised technique for leukocytapheresis effectively reduced the peripheral blood leukaemia cell counts. Previous studies in AML also support the conclusion that this is a safe and effective procedure for the treatment of a potentially life-threatening complication, but apheresis should always be combined with early chemotherapy. © 2013 The Authors. Transfusion Medicine © 2013 British Blood Transfusion Society.

  10. 21 CFR 660.26 - Specificity tests and avidity tests.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Specificity tests and avidity tests. 660.26 Section 660.26 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.26 Specificity tests and avidity test...

  11. 21 CFR 660.26 - Specificity tests and avidity tests.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Specificity tests and avidity tests. 660.26... (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Blood Grouping Reagent § 660.26 Specificity tests and avidity tests. Specificity and avidity tests shall be performed...

  12. Two rare diagnoses during chronic lymphocytic leukaemia follow-up: Kaposi's sarcoma and Merkel cell carcinoma.

    PubMed

    Dogu, Mehmet H; Sari, Ismail; Hacioglu, Sibel; Degirmencioglu, Serkan; Şen, Nilay; Keskin, Ali

    2016-02-01

    Chronic lymphocytic leukaemia often has a clinical presentation characterised by increased neoplastic lymphocytes which are mostly mature looking due to B lymphocytes. Increased secondary cancer prevalence has been detected among patients with chronic lymphocytic leukaemia diagnosis. In this report, we present three chronic lymphocytic leukaemia patients who developed secondary rare cancers during their follow-up at our clinic. Case 1: A 54-year-old female patient was diagnosed with stage I chronic lymphocytic leukaemia in 2003 and was diagnosed with Merkel cell carcinoma in February 2013. Case 2: A 66-year-old male patient was diagnosed with stage II chronic lymphocytic leukaemia in 2009 and was diagnosed with Kaposi's sarcoma in March 2013. Case 3: A 77-year-old male patient was diagnosed with stage I chronic lymphocytic leukaemia in 2006 and was diagnosed with Kaposi's sarcoma in 2011. In conclusion, secondary cancers are observed in patients diagnosed with chronic lymphocytic leukaemia. Therefore, follow-up of chronic lymphocytic leukaemia requires additional attention in this context. © The Author(s) 2016.

  13. Childhood leukaemia near nuclear sites in Belgium, 2002–2008

    PubMed Central

    Bollaerts, Kaatje; Simons, Koen; Van Bladel, Lodewijk; De Smedt, Tom; Sonck, Michel; Fierens, Sébastien; Poffijn, André; Geraets, David; Gosselin, Pol; Van Oyen, Herman; Francart, Julie

    2018-01-01

    This paper describes an ecological study investigating whether there is an excess incidence of acute leukaemia among children aged 0–14 years living in the vicinity of the nuclear sites in Belgium. Poisson regression modelling was carried out for proximity areas of varying sizes. In addition, the hypothesis of a gradient in leukaemia incidence with increasing levels of surrogate exposures was explored by means of focused hypothesis tests and generalized additive models. For the surrogate exposures, three proxies were used, that is, residential proximity to the nuclear site, prevailing winds and simulated radioactive discharges, on the basis of mathematical dispersion modelling. No excess incidence of acute leukaemia was observed around the nuclear power plants of Doel or Tihange nor around the nuclear site of Fleurus, which is a major manufacturer of radioactive isotopes in Europe. Around the site of Mol-Dessel, however, two- to three-fold increased leukaemia incidence rates were found in children aged 0–14 years living in the 0–5, 0–10 and the 0–15 km proximity areas. For this site, there was evidence for a gradient in leukaemia incidence with increased proximity, prevailing winds and simulated radioactive discharges, suggesting a potential link with the site that needs further investigation. An increased incidence of acute leukaemia in children aged 0–14 years was observed around one nuclear site that hosted reprocessing activities in the past and where nuclear research activities and radioactive waste treatment are ongoing. PMID:27380513

  14. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia.

    PubMed

    Pasmant, E; Gilbert-Dussardier, B; Petit, A; de Laval, B; Luscan, A; Gruber, A; Lapillonne, H; Deswarte, C; Goussard, P; Laurendeau, I; Uzan, B; Pflumio, F; Brizard, F; Vabres, P; Naguibvena, I; Fasola, S; Millot, F; Porteu, F; Vidaud, D; Landman-Parker, J; Ballerini, P

    2015-01-29

    Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.

  15. Tracing the origins of relapse in acute myeloid leukaemia to stem cells.

    PubMed

    Shlush, Liran I; Mitchell, Amanda; Heisler, Lawrence; Abelson, Sagi; Ng, Stanley W K; Trotman-Grant, Aaron; Medeiros, Jessie J F; Rao-Bhatia, Abilasha; Jaciw-Zurakowsky, Ivana; Marke, Rene; McLeod, Jessica L; Doedens, Monica; Bader, Gary; Voisin, Veronique; Xu, ChangJiang; McPherson, John D; Hudson, Thomas J; Wang, Jean C Y; Minden, Mark D; Dick, John E

    2017-07-06

    In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia

  16. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure.

    PubMed

    de Thé, Hugues; Chen, Zhu

    2010-11-01

    The fusion oncogene, promyelocytic leukaemia (PML)-retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML-RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

  17. Child and adolescent Down syndrome-associated leukaemia: the Irish experience.

    PubMed

    O'Rafferty, C; Kelly, J; Storey, L; Ryan, C; O'Marcaigh, A; Smith, O

    2015-12-01

    Down syndrome (DS), the most common syndromic chromosomal abnormality is associated with a unique susceptibility to develop both acute myeloid (ML) and lymphoblastic leukaemia (ALL). These leukaemias differ from the non-DS-related types of leukaemia and are thought to be distinct biological entities. To perform a retrospective review of our experience of treating DS-related leukaemia at Our Lady's Children's Hospital. Data were extracted from a database established in 2000 to prospectively gather data on DS-associated leukaemias and their outcomes following polychemotherapy. Kaplan-Meier survival curves were constructed. Nineteen patients with DS-ML were treated and 19 with DS-ALL. Sixteen (84%) patients with DS-ML are alive and in complete remission with a median follow-up of 7 years. All deaths in this cohort were due to treatment-related mortality (TRM). Of the DS-ALL patients, 12 (63%) remain alive with a median follow-up of 3.6 years. TRM accounted for five of the six deaths. One death was due to leukaemic relapse. High cure rates are seen in DS-ML using contemporary polychemotherapy protocols, however, there is significant TRM in this cohort. DS-ALL does not have the same high cure rate as non-DS-ALL (>90%) and again this is mainly due to an excess of TRM.

  18. Case–control study of paternal occupation and childhood leukaemia in Great Britain, 1962–2006

    PubMed Central

    Keegan, T J; Bunch, K J; Vincent, T J; King, J C; O'Neill, K A; Kendall, G M; MacCarthy, A; Fear, N T; MFG, Murphy

    2012-01-01

    Background: Paternal occupational exposures have been proposed as a risk factor for childhood leukaemia. This study investigates possible associations between paternal occupational exposure and childhood leukaemia in Great Britain. Methods: The National Registry of Childhood Tumours provided all cases of childhood leukaemia born and diagnosed in Great Britain between 1962 and 2006. Controls were matched on sex, period of birth and birth registration subdistrict. Fathers' occupations were assigned to 1 or more of 33 exposure groups. Social class was derived from father's occupation at the time of the child's birth. Results: A total of 16 764 cases of childhood leukaemia were ascertained. One exposure group, paternal social contact, was associated with total childhood leukaemia (odds ratio 1.14, 1.05–1.23); this association remained significant when adjusted for social class. The subtypes lymphoid leukaemia (LL) and acute myeloid leukaemia showed increased risk with paternal exposure to social contact before adjustment for social class. Risk of other leukaemias was significantly increased by exposure to electromagnetic fields, persisting after adjustment for social class. For total leukaemia, the risks for exposure to lead and exhaust fumes were significantly <1. Occupationally derived social class was associated with risk of LL, with the risk being increased in the higher social classes. Conclusion: Our results showed some support for a positive association between childhood leukaemia risk and paternal occupation involving social contact. Additionally, LL risk increased with higher paternal occupational social class. PMID:22968649

  19. The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability.

    PubMed

    Grey, William; Ivey, Adam; Milne, Thomas A; Haferlach, Torsten; Grimwade, David; Uhlmann, Frank; Voisset, Edwige; Yu, Veronica

    2018-01-01

    The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCF Skp2 and APC Cdc20 . Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the Mll N and Mll C subunits of Mll1 (Mixed-lineage leukaemia 1), and together, the Cks proteins define Mll1 levels throughout the cell cycle. Overexpression of CKS1B and CKS2 is observed in multiple human cancers, including various MLL-rearranged (MLLr) AML subtypes. To explore the importance of MLL-Fusion Protein regulation by CKS1/2, we used small molecule inhibitors (MLN4924 and C1) to modulate their protein degradation functions. These inhibitors specifically reduced the proliferation of MLLr cell lines compared to primary controls. Altogether, this study uncovers a novel regulatory pathway for MLL1, which may open a new therapeutic approach to MLLr leukaemia. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

    PubMed

    Hattori, Ayuna; Tsunoda, Makoto; Konuma, Takaaki; Kobayashi, Masayuki; Nagy, Tamas; Glushka, John; Tayyari, Fariba; McSkimming, Daniel; Kannan, Natarajan; Tojo, Arinobu; Edison, Arthur S; Ito, Takahiro

    2017-05-25

    Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.

  1. Oral complications and dental care in children with acute lymphoblastic leukaemia.

    PubMed

    Valéra, Marie-Cécile; Noirrit-Esclassan, Emmanuelle; Pasquet, Marléne; Vaysse, Fréderic

    2015-08-01

    Acute leukaemia is the most common type of childhood cancer, the acute lymphoblastic type accounting for the majority of cases. Children affected by leukaemia receive various forms of treatments including chemotherapeutic agents and stem cell transplants. Leukaemia and its treatment can directly or indirectly affect oral health and further dental treatments. The oral complications include mucositis, opportunistic infections, gingival inflammation and bleeding, xerostomia and carious lesions. An additional consideration in children is the impact of the treatments on the developing dentition and on orofacial growth. The aim of this review is to describe the oral complications in children with acute lymphoblastic leukaemia and the methods of prevention and management before, during and after the cancer treatment. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.

    PubMed

    Place, Andrew E; Stevenson, Kristen E; Vrooman, Lynda M; Harris, Marian H; Hunt, Sarah K; O'Brien, Jane E; Supko, Jeffrey G; Asselin, Barbara L; Athale, Uma H; Clavell, Luis A; Cole, Peter D; Kelly, Kara M; Laverdiere, Caroline; Leclerc, Jean-Marie; Michon, Bruno; Schorin, Marshall A; Welch, Jennifer J G; Lipshultz, Steven E; Kutok, Jeffery L; Blonquist, Traci M; Neuberg, Donna S; Sallan, Stephen E; Silverman, Lewis B

    2015-12-01

    , 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. National Cancer Institute and Enzon Pharmaceuticals. Copyright © 2015 Elsevier Ltd. All rights

  3. RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.

    PubMed

    Estécio, Marcos R H; Maddipoti, Sirisha; Bueso-Ramos, Carlos; DiNardo, Courtney D; Yang, Hui; Wei, Yue; Kondo, Kimie; Fang, Zhihong; Stevenson, William; Chang, Kun-Sang; Pierce, Sherry A; Bohannan, Zachary; Borthakur, Gautam; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2015-05-01

    Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias. © 2015 John Wiley & Sons Ltd.

  4. Alginate foam-based three-dimensional culture to investigate drug sensitivity in primary leukaemia cells.

    PubMed

    Karimpoor, Mahroo; Yebra-Fernandez, Eva; Parhizkar, Maryam; Orlu, Mine; Craig, Duncan; Khorashad, Jamshid S; Edirisinghe, Mohan

    2018-04-01

    The development of assays for evaluating the sensitivity of leukaemia cells to anti-cancer agents is becoming an important aspect of personalized medicine. Conventional cell cultures lack the three-dimensional (3D) structure of the bone marrow (BM), the extracellular matrix and stromal components which are crucial for the growth and survival of leukaemia stem cells. To accurately predict the sensitivity of the leukaemia cells in an in vitro assay a culturing system containing the essential components of BM is required. In this study, we developed a porous calcium alginate foam-based scaffold to be used for 3D culture. The new 3D culture was shown to be cell compatible as it supported the proliferation of both normal haematopoietic and leukaemia cells. Our cell differential assay for myeloid markers showed that the porous foam-based 3D culture enhanced myeloid differentiation in both leukaemia and normal haematopoietic cells compared to two-dimensional culture. The foam-based scaffold reduced the sensitivity of the leukaemia cells to the tested antileukaemia agents in K562 and HL60 leukaemia cell line model and also primary myeloid leukaemia cells. This observation supports the application of calcium alginate foams as scaffold components of the 3D cultures for investigation of sensitivity to antileukaemia agents in primary myeloid cells. © 2018 The Author(s).

  5. Enzyme and membrane markers in leukaemia: recent developments.

    PubMed Central

    Hoffbrand, A V; Janossy, G

    1981-01-01

    Terminal deoxynucleotidyl transferase (TdT) assay has proved a valuable test for distinguishing lymphoblastic from myeloblastic leukaemias, particularly in adults whose blast cells are often negative for the c-ALL antigen. The immunofluorescence assay, particularly when used in combination with antisera to surface membrane antigens, has proved a sensitive technique for detecting small numbers of lymphoblasts in extramedullary sites, for example, testis or cerebrospinal fluid, or of residual Thy-ALL blasts in the marrow, which might otherwise be difficult to recognise. Differences in concentration of several enzymes concerned in purine metabolism have been detected between the blast cells in the various acute leukaemias. Adenosine deaminase (ADA) concentrations tend to be higher in Thy-ALL than in other forms of leukaemia, but the wide overlap reduces the diagnostic value of this assay. Thy-ALL blasts, however, appear to be selectively and exquisitely susceptible to inhibition of ADA by the drug deoxycoformycin, which has now been used sucessfully in a number of other wise resistant patients with Thy-ALL to obtain a complete remission. The recently introduced technique for the production of monoclonal antibodies has substantially widened the reagents available for analysing the membrane characteristics of bone marrow stem cells and of cell lineages derived from them. These have revealed previously unsuspected heterogeneity among different cases of acute lymphoblastic leukaemia, for example, among Thy-ALL blasts from different patients, and they have also delineated minor populations of immature thymocytes from which these leukaemic cells are derived. The potential use of these antibodies to prevent graft-versus-host disease by selective removal of T-lymphocytes from donor bone marrow before allogeneic bone marrow transplantation, or to prevent recurrence of Thy-ALL and other lymphoblastic leukaemias or lymphomas by selective removal of leukaemic or lymphoma

  6. Childhood leukaemia in areas with different radon levels: a spatial and temporal analysis using GIS.

    PubMed

    Kohli, S; Noorlind Brage, H; Löfman, O

    2000-11-01

    To evaluate the relation between exposure to ground radon levels and leukaemia among children using existing population and disease registers. Ecological correlation study. The county of Ostergötland in Sweden. Every child born in the county between 1979 and 1992 was mapped to the property centroid coordinates by linking addresses in the population and property registers. Population maps were overlaid with radon maps and exposure at birth and each subsequent year was quantified as high, normal, low or unknown. This was analysed with data from the tumour registry. Standardised mortality ratios (SMRs) were calculated using the age and sex specific rates for Sweden for the year 1995. 90 malignancies occurred among 53 146 children (498 887 person years) who formed the study population. SMRs for acute lymphatic leukaemia (ALL) among children born in high, normal and low risk areas were 1.43, 1.17 and 0.25 respectively. The relative risk for the normal risk group and high risk group as compared with the low risk group was 4.64 (95% CI 1.29, 28.26) and 5. 67 (95% CI 1.06, 42.27). The association between ALL and continued residence at normal or high risk areas showed a similar trend. No association between radon risk levels and any other malignancy was seen. Children born in and staying at areas where the risk from ground radon has been classified as low are less likely to develop ALL than those born in areas classified as normal and high risk.

  7. Oral manifestations as an early clinical sign of acute myeloid leukaemia: a case report.

    PubMed

    Guan, G; Firth, N

    2015-03-01

    Leukaemia is the most common malignancy in children and one of the most common malignancies in young adults. Acute myeloid leukaemia is often associated with early oral manifestations. The purpose of this study is to report the case of a 49-year-old male with spontaneous gingival bleeding for over two years with undiagnosed leukaemia. Haematological investigation was instigated and on referral to the Haematology Department at Dunedin Public Hospital, the diagnosis of an acute myeloid leukaemia was confirmed. Since oral lesions can be one of the early events of acute myeloid leukaemia, they may be considered as an important diagnostic indicator for oral health practitioners, and their roles in diagnosing and treating such patients. © 2015 Australian Dental Association.

  8. Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research.

    PubMed

    Pelkonen, Olavi; Terron, Andrea; Hernandez, Antonio F; Menendez, Pablo; Bennekou, Susanne Hougaard

    2017-08-01

    Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.

  9. E-health: transforming the physician/patient relationship.

    PubMed

    Ball, M J; Lillis, J

    2001-04-01

    Healthcare delivery is being transformed by advances in e-health and by the empowered, computer-literate public. Ready to become partners in their own health and to take advantage of online processes, health portals, and physician web pages and e-mail, this new breed of consumer is slowly redefining the physician/patient relationship. Such changes can effect positive results like improved clinical decision-making, increased efficiency, and strengthened communication between physicians and patients. First, however, physicians and the organizations that support them must fully understand their role in the e-health revolution. Both must advance their awareness of the new consumers and their needs and define specific action items that will help them realize the benefits of e-health. Through a combination of timely research and advice, this article will aid them in fulfilling both tasks.

  10. How have advances in our understanding of the molecular genetics of paediatric leukaemia led to improved targeted therapies for these diseases?

    PubMed

    Szychot, Elwira; Brodkiewicz, Andrzej; Peregud-Pogorzelski, Jarosław

    2014-01-01

    The term "leukaemia" refers to a large and heterogenous group of diseases, with treatment response and outcome dependent on the specific type of malignancy. New molecular methods allow us to specifically evaluate the type of disorder, and provide treatment of necessary intensity. The aim of this review is to provide insight into the progress in leukaemia treatment that had been possible due to advances in molecular genetics over the last few decades. Those new sophisticated diagnostic methods have allowed us not only to predict patients' prognosis but also to provide a specific therapy depending on the molecular and genetic characteristics of patients. Our review is based on 25 articles regarding novel diagnostic and therapeutic methods as well as prognostic factors, released between 1992 and 2011. Those articles focus mostly on molecular and cytogenetic testing allowing revolutionary methods of patient classification and individual therapy for this highly heterogeneous group of disorders. Implementation of molecular genetic testing to evaluate the type of leukaemia allowed paediatric oncologists and haematologists to adjust the intensity of treatment, improve outcome, minimize toxicity of therapies and considerably lower the risk of side effects. In the last few decades there has been a great improvement in survival among children suffering from haematopoietic malignancies. Progress made in molecular genetics allowed the creation of new treatment protocols that are designed to maintain a high cure rate for children with leukaemia while reducing toxicity.

  11. 7 CFR 1753.26 - Plans and specifications (P&S).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 11 2011-01-01 2011-01-01 false Plans and specifications (P&S). 1753.26 Section 1753... Buildings § 1753.26 Plans and specifications (P&S). (a) For headquarters and commercial office buildings only, the borrower shall prepare preliminary P&S showing the floor plan and general architectural...

  12. 7 CFR 1753.26 - Plans and specifications (P&S).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 11 2014-01-01 2014-01-01 false Plans and specifications (P&S). 1753.26 Section 1753... Buildings § 1753.26 Plans and specifications (P&S). (a) For headquarters and commercial office buildings only, the borrower shall prepare preliminary P&S showing the floor plan and general architectural...

  13. 7 CFR 1753.26 - Plans and specifications (P&S).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 11 2013-01-01 2013-01-01 false Plans and specifications (P&S). 1753.26 Section 1753... Buildings § 1753.26 Plans and specifications (P&S). (a) For headquarters and commercial office buildings only, the borrower shall prepare preliminary P&S showing the floor plan and general architectural...

  14. 7 CFR 1753.26 - Plans and specifications (P&S).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 11 2012-01-01 2012-01-01 false Plans and specifications (P&S). 1753.26 Section 1753... Buildings § 1753.26 Plans and specifications (P&S). (a) For headquarters and commercial office buildings only, the borrower shall prepare preliminary P&S showing the floor plan and general architectural...

  15. Long term survival in children with acute leukaemia and complications requiring mechanical ventilation.

    PubMed

    Steinbach, Daniel; Wilhelm, Bernhard; Kiermaier, Hans-Rudolf; Creutzig, Ursula; Schrappe, Martin; Zimmermann, Martin; Debatin, Klaus-Michael; Gruhn, Bernd; von Stackelberg, Arend; Jürgens, Heribert; Strahm, Brigitte; Reinhardt, Dirk; Möricke, Anja

    2011-11-01

    Previous reports have indicated that the short term prognosis for patients with malignant diseases and serious adverse events requiring mechanical ventilation (SAEV) is improving. The purpose of this study was to determine whether these patients can be cured of malignant disease or whether they survive SAEV only to subsequently relapse. The authors report the outcome of children with SAEV treated in the multicentre studies ALL-BFM 95 and AML-BFM 98. Data from 1182 patients with acute lymphoblastic leukaemia (ALL) and 334 patients with acute myeloid leukaemia (AML) were analysed. 88 patients (51 ALL and 37 AML) developed SAEV. The prognosis was almost identical in ALL and AML patients (survival of SAEV patients: 48%, 95% CI 38% to 58%; overall survival after 5 years: 31%, 95% CI 21% to 41%). Prognosis was independent of the time between leukaemia diagnosis and SAEV. Approximately 20% of children who required haemodialysis (n=14) or cardiac resuscitation (n=16) achieved long term survival, but no patient who fulfilled more than three of six identified risk factors (age ≥10 years, high risk leukaemia, C reactive protein ≥150 mg/l, administration of inotropic infusion, cardiac resuscitation and haemodialysis) survived (n=16; 0%, 95% CI 0% to 20%). Intensive care improves the short and long term survival of children with leukaemia. 64% (95% CI 50% to 78%) of children with acute leukaemia who survived SAEV achieved long term survival. Prognosis mainly depends on age and leukaemia risk group.

  16. Molecular and Phenotypic Characterization of Escherichia coli O26:H8 among Diarrheagenic E. coli O26 Strains Isolated in Brazil

    PubMed Central

    Piazza, Roxane M. F.; Delannoy, Sabine; Fach, Patrick; Saridakis, Halha O.; Pedroso, Margareth Z.; Rocha, Letícia B.; Gomes, Tânia A. T.; Vieira, Mônica A. M.; Beutin, Lothar

    2013-01-01

    Escherichia coli strains of serogroup O26 comprise two distinct groups of pathogens, characterized as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC). Among the several genes related to type III secretion system-secreted effector proteins, espK was found to be highly specific for EHEC O26:H11 and its stx-negative derivative strains isolated in European countries. E. coli O26 strains isolated in Brazil from infant diarrhea, foods, and the environment have consistently been shown to lack stx genes and are thus considered atypical EPEC. However, no further information related to their genetic background is known. Therefore, in this study, we aimed to discriminate and characterize these Brazilian O26 stx-negative strains by phenotypic, genetic, and biochemical approaches. Among 44 isolates confirmed to be O26 isolates, most displayed flagellar antigen H11 or H32. Out of the 13 nonmotile isolates, 2 tested positive for fliCH11, and 11 were fliCH8 positive. The identification of genetic markers showed that several O26:H11 and all O26:H8 strains tested positive for espK and could therefore be discriminated as EHEC derivatives. The presence of H8 among EHEC O26 and its stx-negative derivative isolates is described for the first time. The interaction of three isolates with polarized Caco-2 cells and with intestinal biopsy specimen fragments ex vivo confirmed the ability of the O26 strains analyzed to cause attaching-and-effacing (A/E) lesions. The O26:H32 strains, isolated mostly from meat, were considered nonvirulent. Knowledge of the virulence content of stx-negative O26 isolates within the same serotype helped to avoid misclassification of isolates, which certainly has important implications for public health surveillance. PMID:23974139

  17. MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells.

    PubMed

    Shiratori, Erika; Itoh, Mai; Tohda, Shuji

    2017-11-01

    Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth. Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules. ST2825 suppressed the growth of all cell lines by inducing apoptosis and down-regulating phosphorylation of NF-κB pathway components inhibitor of nuclear factor kappa B kinase (IκB) and reticuloendotheliosis oncogene A (RelA), as well as of MYD88 activator Bruton tyrosine kinase (BTK), suggesting that MYD88 may affect BTK activity. ST2825 effects were specific as MYD88-targeting siRNA also suppressed phosphorylation of NF-κB signalling proteins and BTK in TMD8 cells. ST2825 may be a novel drug targeting not only B-lymphoid malignancies with MYD88 mutations, but also lymphoma and leukaemia with wild-type MYD88. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. ETV6-RUNX1 + Acute Lymphoblastic Leukaemia in Identical Twins.

    PubMed

    Ford, Anthony M; Greaves, Mel

    2017-01-01

    Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.

  19. Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations

    PubMed Central

    Rehe, Klaus; Wilson, Kerrie; Bomken, Simon; Williamson, Daniel; Irving, Julie; den Boer, Monique L; Stanulla, Martin; Schrappe, Martin; Hall, Andrew G; Heidenreich, Olaf; Vormoor, Josef

    2013-01-01

    Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-‘high-risk’ sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34high and CD34low blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia. PMID:23229821

  20. Infection during remission induction in childhood leukaemia

    PubMed Central

    Chessells, Judith M; Leiper, Alison D

    1980-01-01

    We have analysed our experience in the management of suspected infection in a group of 221 children with acute leukaemia undergoing induction of first remission. Patients with suspected infection received early empirical antibiotic therapy with cephalothin and gentamicin pending results of bacteriological investigations. Infection occurred in 17% of children with acute lymphoblastic leukaemia (ALL) whose initial treatment comprised prednisolone and vincristine, and was serious in 6·5%. 27% of children with ALL treated with intensive induction had infections which were serious in 20%; the figures for children with acute myeloblastic leukaemia (AML) were 49% and 22% respectively. The organisms responsible for most infections were Pseudomonas aeruginosa and Staphylococcus aureus; the former being most often associated with bacteraemia. One child (0·5%) died from infection. We conclude that with the use of early empirical antibiotic therapy, and granulocytes when appropriate, infection is no longer a major cause of death during remission induction. No special precautions are necessary to prevent its acquisition in most cases of ALL. In patients receiving early intensive treatment, including those with AML, measures designed to prevent acquisition of infection may reduce morbidity and enable the use of more effective chemotherapy. PMID:6929664

  1. The therapeutic power of play: examining the play of young children with leukaemia.

    PubMed

    Gariépy, N; Howe, N

    2003-11-01

    The therapeutic function of play has been investigated in relation to recognized stressors such as hospitalization, illness and medical treatments for ill children. While medical treatments in the past 30 years have improved survival rates, children's psychological experiences and quality of life during and after their illness have received limited attention. The present study investigated the therapeutic effects of play on 3- to 5-year-old children with leukaemia compared with a control group of healthy children. The participants with leukaemia (n = 11) were from the external oncology clinic of an urban children's hospital; control children (n = 11) attended a day care centre. Measures included children's experience of stress, social and cognitive play behaviours, and daily mood. A series of manova revealed that the children with leukaemia, compared with the control children, engaged in (a) significantly fewer total play behaviours, and in particular less (b) parallel, (c) group and (d) dramatic play. Pearson correlations revealed significant relationships between reports of 'being happy' and play only for children with leukaemia. Quantitative and qualitative analyses revealed a pattern of repetitive play activities week after week for children with leukaemia, but not controls. Findings are discussed in light of the theoretical and practical implications for children undergoing treatment for leukaemia.

  2. History of Maternal Fetal Loss and Childhood Leukaemia Risk in Subsequent Offspring: Differentials by Miscarriage or Stillbirth History and Disease Subtype.

    PubMed

    Karalexi, M A; Skalkidou, A; Thomopoulos, T P; Belechri, M; Biniaris-Georgallis, S-I; Bouka, E; Baka, M; Hatzipantelis, E; Kourti, M; Polychronopoulou, S; Sidi, V; Stiakaki, E; Moschovi, M; Dessypris, N; Petridou, E Th

    2015-09-01

    Despite the putative intrauterine origins of childhood (0-14 years) leukaemia, it is complex to assess the impact of perinatal factors on disease onset. Results on the association of maternal history of fetal loss (miscarriage/stillbirth) with specific disease subtypes in the subsequent offspring are in conflict. We sought to investigate whether miscarriage and stillbirth may have different impacts on the risk of acute lymphoblastic leukaemia (ALL) and of its main immunophenotypes (B-cell and T-cell ALL), as contrasted to acute myeloid leukaemia (AML). One thousand ninety-nine ALL incidents (957 B-ALL) and 131 AML cases along with 1:1 age and gender-matched controls derived from the Nationwide Registry for Childhood Hematological Malignancies and Brain Tumors (1996-2013) were studied. Multivariable regression models were used to assess the roles of previous miscarriage(s) and stillbirth(s) on ALL (overall, B-, T-ALL) and AML, controlling for potential confounders. Statistically significant exposure and disease subtype-specific associations of previous miscarriage(s) exclusively with AML [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.00, 2.81] and stillbirth(s) with ALL [OR 4.82, 95% CI 1.63, 14.24] and B-ALL particularly, emerged. Differential pathophysiological pathways pertaining to genetic polymorphisms or cytogenetic aberrations are likely to create hostile environments leading either to fetal loss or the development of specific leukaemia subtypes in subsequent offspring, notably distinct associations of maternal miscarriage history confined to AML and stillbirth history confined to ALL (specifically B-ALL). If confirmed and further supported by studies revealing underlying mechanisms, these results may shed light on the divergent leukemogenesis processes. © 2015 John Wiley & Sons Ltd.

  3. The Krümmel (Germany) Childhood Leukaemia Cluster: a review and update.

    PubMed

    Grosche, B; Kaatsch, P; Heinzow, B; Wichmann, H-E

    2017-12-01

    The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krümmel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig-Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krümmel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krümmel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krümmel site shows that the incidence rates are now comparable to the average rate in Germany.

  4. Ecological association between indoor radon concentration and childhood leukaemia incidence in France, 1990-1998.

    PubMed

    Evrard, A S; Hémon, D; Billon, S; Laurier, D; Jougla, E; Tirmarche, M; Clavel, J

    2005-04-01

    The objective of this study was to evaluate the ecological association between indoor radon concentration and acute leukaemia incidence among children under 15 years of age in the 348 geographical units (zones d'emploi, ZE) of France between 1990 and 1998. During that period, 4015 cases were registered by the French National Registry of Childhood Leukaemia and Lymphoma. Exposure assessment was based on a campaign of 13 240 measurements covering the whole country. The arithmetic mean radon concentration was 85 Bq/m (range, 15-387 Bq/m) and the geometric mean, 59 Bq/m (range: 13-228 Bq/m). A positive ecological association, on the borderline of statistical significance (P=0.053), was observed between indoor radon concentration and childhood leukaemia incidence. The association was highly significant for acute myeloid leukaemia (AML) (P=0.004) but not for acute lymphocytic leukaemia (ALL) (P=0.49). The standardized incidence ratio (SIR) increased by 7, 3 and 24% for all acute leukaemia, ALL and AML, respectively, when radon concentration increased by 100 Bq/m. In conclusion, the present ecological study supports the hypothesis of a moderate association between indoor radon concentration and childhood acute myeloid leukaemia. It is consistent with most previous ecological studies. Since the association is moderate, this result does not appear inconsistent with the five published case-control studies, most of which found no significant association.

  5. The experience of acute leukaemia in adult patients: a qualitative thematic synthesis.

    PubMed

    Papadopoulou, Constantina; Johnston, Bridget; Themessl-Huber, Markus

    2013-10-01

    The aim of this review was to systematically identify and synthesise all qualitative evidence on how adult patients diagnosed with acute leukaemia experience living with their illness. A systematic search strategy was developed comprising of two search strings: i) acute leukaemia and ii) qualitative methodology. The search strategy was run in seven electronic databases (Medline, CINAHL, PsychINFO, EMBASE, BNI & Archive, SSCI and ASSIA). Nine qualitative studies in adult patients with acute leukaemia, published in peer reviewed journals between 01/1990 and 01/2013 were included in the final sample. The qualitative thematic synthesis resulted in the development of a conceptual model describing a person's path to build a renewed self. Following the initial blow of diagnosis with the range of initial reactions, patients with acute leukaemia are living in a contracting world; they have to deal with the life in hospital, the several losses and the impact of their illness on their emotions and interpersonal relationships. Several factors take up a buffering role at that stage: coping, support, information and hope. Finally, patients accommodate acute leukaemia in their lives through re-evaluating personal values and assigning new meaning to their experience. Results from this thematic synthesis are indicative of the impact of acute leukaemia on patients' lives and the processes they use to make sense and accommodate the illness in their life. Increasing our understanding of these processes is warranted to improve patient care. Copyright © 2013. Published by Elsevier Ltd.

  6. Exogenous hormone use, reproductive history and risk of adult myeloid leukaemia.

    PubMed

    Poynter, J N; Fonstad, R; Blair, C K; Roesler, M; Cerhan, J R; Hirsch, B; Nguyen, P; Ross, J A

    2013-10-01

    A hormonal aetiology is one explanation for the lower incidence of myeloid leukaemia in women compared with men. In this population-based case-control study, we evaluated associations between exogenous hormone use and reproductive history and myeloid leukaemia, overall and by disease subtype. We observed a suggestive association between oral contraceptive use and acute myeloid leukaemia (odds ratio=0.55, 95% confidence interval=0.32-0.96). Hormone replacement therapy and reproductive factors were not associated with risk. Despite the biological plausibility for a role of oestrogen in leukaemogenesis, other aetiologic factors are likely to explain the differing incidence rates in males and females.

  7. Visual acuity loss and OCT changes as initial signs of leukaemia

    PubMed Central

    Ortiz, Jose M; Ruiz-Moreno, Jose M; Pozo-Martos, Paola; Montero, Javier A

    2010-01-01

    AIM To report two cases where decreased visual acuity was the first symptom of leukaemia and optical coherence tomography (OCT) allowed identification and localization of the retinal lesions. METHODS Retrospective, interventional, case reports. RESULTS One case of lymphoblastic acute leukaemia and chronic lymphoid leukaemia were diagnosed following decreased visual acuity. OCT showed macular serous detachment in the first case. The second case presented hypo fluorescent retinal infiltrates which appeared as hyper reflective lesions by OCT. Retinal changes disappeared and visual acuity was recovered following complete remission of the neoplasm. CONCLUSION OCT is a valuable, non invasive diagnostic tool permitting detection, localization and follow-up of ocular dissemination of neoplasms. PMID:22553573

  8. The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia.

    PubMed

    Blanco, Teresa Mortera; Mantalaris, Athanasios; Bismarck, Alexander; Panoskaltsis, Nicki

    2010-03-01

    Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  9. Increased regulatory T cells in acute lymphoblastic leukaemia patients.

    PubMed

    Idris, Siti-Zuleha; Hassan, Norfarazieda; Lee, Le-Jie; Md Noor, Sabariah; Osman, Raudhawati; Abdul-Jalil, Marsitah; Nordin, Abdul-Jalil; Abdullah, Maha

    2016-05-01

    Regulation in adaptive immune response balances a fine line that prevents instigation of self-damage or fall into unresponsiveness permitting abnormal cell growth. Mechanisms that keep this balance in check include regulatory T cells (Tregs). Tregs consist of a small but heterogeneous population, which may be identified by the phenotype, CD3+CD4+CD25+CD127-. The role of Tregs in pathogenesis of cancers is thus far supported by evidence of increased Tregs in various cancers and may contribute to poorer prognosis. Tregs may also be important in acute leukaemias. A review of the literature on Tregs in acute leukaemias was conducted and Tregs were determined in B-cell acute lymphoblastic leukaemias (ALLs). Studies on Tregs in B-cell ALL are few and controversial. We observed a significantly increased percentage of Tregs (mean±SD, 9.72 ± 3.79% vs. 7.05 ± 1.74%; P = 0.047) in the bone marrow/peripheral blood of ALL (n = 17) compared to peripheral blood of normal controls (n = 35). A positive trend between Tregs and age (R = 0.474, P = 0.055, n = 17) implicates this factor of poor prognosis in B-cell ALL. Tregs in cancer are particularly significant in immunotherapy. The manipulation of the immune system to treat cancer has for a long time ignored regulatory mechanisms inducible or in place. In lymphoma studies, tumour-specific mechanisms that are unlike conventional methods in the induction of Tregs have been hypothesized. In addition, tumour-infiltrating Tregs may present different profiles from peripheral blood pictures. Tregs will continue to be dissected to reveal its mysteries and their impact on clinical significance.

  10. Carcinocythaemia (carcinoma cell leukaemia) in a dog: an acute leukaemia-like picture due to metastatic carcinoma.

    PubMed

    Amati, M; Miele, F; Avallone, G; Banco, B; Bertazzolo, W

    2012-08-01

    An eight-year-old entire female boxer was presented with a two-week history of anorexia and lethargy and two-day history of unilateral left epistaxis. Clinical findings and laboratory test results suggested disseminated intravascular coagulation. On blood smear evaluation, occasional large epithelioid-like unclassified cells were detected. Occasionally these cells were organised in small clusters. Bone marrow examination revealed a marked infiltration by a malignant population of the same epithelioid-like cells. The dog was euthanased because of the guarded prognosis. Following histology and immunohistochemistry, a widespread undifferentiated carcinoma of unknown primary origin was diagnosed. To the authors' knowledge, this is the first case of carcinoma cell leukaemia reported in a dog. Carcinoma cell leukaemia is a rare oncological condition previously described in humans, characterised by non-haematopoietic neoplastic cells in peripheral blood. © 2012 British Small Animal Veterinary Association.

  11. Radon as a causative factor in induction of myeloid leukaemia and other cancers.

    PubMed

    Henshaw, D L; Eatough, J P; Richardson, R B

    1990-04-28

    The international incidence of myeloid leukaemia, cancer of the kidney, melanoma, and certain childhood cancers all show significant correlation with radon exposure in the home. For myeloid leukaemia, analysis suggests that in the UK 6-12% of incidence may be attributed to radon. In Cornwall, where radon levels are higher, the range is 23-43%. For the world average radon exposure of 50 Bq.m-3, 13-25% of myeloid leukaemia at all ages may be caused by radon.

  12. Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group.

    PubMed

    Drozd-Sokołowska, Joanna; Mądry, Krzysztof; Waszczuk-Gajda, Anna; Biecek, Przemysław; Szwedyk, Paweł; Budziszewska, Katarzyna; Raźny, Magdalena; Dutka, Magdalena; Obara, Agata; Wasilewska, Ewa; Lewandowski, Krzysztof; Piekarska, Agnieszka; Bober, Grażyna; Krzemień, Helena; Stella-Hołowiecka, Beata; Kapelko-Słowik, Katarzyna; Sawicki, Waldemar; Paszkowska-Kowalewska, Małgorzata; Machowicz, Rafał; Dwilewicz-Trojaczek, Jadwiga

    2018-03-07

    Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 10 9 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 10 9 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses. Copyright © 2018 John Wiley & Sons, Ltd.

  13. Evidence for under-diagnosis of childhood acute lymphoblastic leukaemia in poorer communities within Great Britain.

    PubMed

    Kroll, M E; Stiller, C A; Richards, S; Mitchell, C; Carpenter, L M

    2012-04-24

    Recorded incidence of childhood acute lymphoblastic leukaemia tends to be lower in poorer communities. A 'preemptive infection hypothesis' proposes that some children with leukaemia die from infection without diagnosis of leukaemia. Various different blood abnormalities can occur in untreated leukaemia. Logistic regression was used to compare pre-treatment blood counts among children aged 1-13 years at recruitment to national clinical trials for acute lymphoblastic leukaemia during 1980-2002 (N=5601), grouped by address at diagnosis within Great Britain into quintiles of the 1991 Carstairs deprivation index. Children combining severe neutropenia (risk of serious infection) with relatively normal haemoglobin and platelet counts (lack of pallor and bleeding) were postulated to be at risk of dying from infection without leukaemia being suspected. A deficit of these children among diagnosed patients from poorer communities was predicted. As predicted, there was a deficit of children at risk of non-diagnosis (two-sided P(trend)=0.004; N=2009), and an excess of children with pallor (P(trend)=0.045; N=5535) and bleeding (P(trend)=0.036; N=5541), among cases from poorer communities. Under-diagnosis in poorer communities may have contributed to socioeconomic variation in recorded childhood acute lymphoblastic leukaemia incidence within Great Britain, and elsewhere. Implications for clinical practice and epidemiological studies should be considered.

  14. Gynecomastia in a case of hairy cell leukaemia--cladribine induced?

    PubMed

    Abhyankar, D; Saikia, T; Advani, S

    2001-06-01

    Gynecomastia is benign enlargement of the male breast and is commonly drug induced. Various drugs are responsible and chemotherapeutic drugs can also cause gynecomastia. Cladribine is now widely used for the treatment of hairy cell leukaemia. We present a case report of development of unilateral gynecomastia in a case of hairy cell leukaemia treated with cladribine and question whether this was induced by the chemotherapy.

  15. HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo.

    PubMed

    Chen, Shibing; Yu, Juan; Lv, Xin; Zhang, Lijuan

    2017-10-01

    Progress in the understanding of the molecular mechanism for acute myeloid leukaemia is of great significance to generate new potential targets for treatment. Recent studies showed that HOXA9, a homeodomain-containing transcription factor, is commonly deregulated in acute leukaemia. In this study, we elucidated the direct correlation between HoxA9 expression and progression of leukaemia using 2 different types of leukaemia cells HL-60 and MOLT-3. The HoxA9 expression level was decreased in leukaemia cells with the treatment of all-trans retinoic acid or arsenic trioxide (As 2 O 3 ). Downregulation of HoxA9 could impair the proliferation and promote the leukaemia cell death. HoxA9 silencing also potentiated the differentiation of leukaemia cells, and in vivo studies demonstrated that HoxA9 downregulation could interfere the tumour growth. Interestingly, HoxA9 silencing also led to the alteration in miRNA expression, mediating the promoting effect on the leukaemia cell differentiation. Therefore, this work provided a promising and potentially efficient target to leukaemia treatment, indicating that HoxA9 is likely to be an ideal candidate in the gene therapy against acute myeloid leukaemia. In this study, we elucidated the critical role of HoxA9 in the proliferation and differentiation of leukaemia cells both in vitro and in vivo. The effect of HoxA9 modulation was correlated with the clinical effect of all-trans retinoic acid and As 2 O 3 . Furthermore, HoxA9 also regulated the miRNA expression, controlling the leukaemia cell differentiation. Therefore, this work provided new insights into molecular mechanism underlying the leukaemia treatment, potentially putting forward a brand new target to the gene therapy against leukaemia. Copyright © 2017 John Wiley & Sons, Ltd.

  16. Presence of functional, autoreactive human milk-specific IgE in infants with cow's milk allergy.

    PubMed

    Järvinen, K M; Geller, L; Bencharitiwong, R; Sampson, H A

    2012-02-01

    Occasionally, exclusively breastfed infants with cow's milk allergy (CMA) remain symptomatic despite strict maternal milk avoidance. To determine whether or not persistence of symptoms could be due to sensitization against endogenous human milk proteins with a high degree of similarity to bovine allergens. Ten peptides representing known bovine milk IgE-binding epitopes [α-lactalbumin (ALA), β- and κ-casein] and the corresponding, highly homologous human milk peptides were labelled with sera from 15 breastfed infants with CMA, aged 3 weeks to 12 months, and peptide (epitope)-specific IgE antibodies were assessed. Nine of the 15 breastfed infants became asymptomatic during strict maternal avoidance of milk and other major food allergens; six infants remained symptomatic until weaned. Ten older children, aged 5-15 years, with CMA were also assessed. The functional capacity of specific IgE antibodies was assessed by measuring β-hexosaminidase release from rat basophilic leukaemia cells passively sensitized and stimulated with human and bovine ALA. A minimum of one human milk peptide was recognized by IgE antibodies from 9 of 15 (60%) milk-allergic infants, and the majority of older children with CMA. Genuine sensitization to human milk peptides in the absence of IgE to bovine milk was occasionally seen. There was a trend towards specific IgE being detected to more human milk peptides in those infants who did not respond to the maternal milk elimination diet than in those who did (P = 0.099). Functional IgE antibody to human ALA was only detected in infants not responding to the maternal diet. Endogenous human milk epitopes are recognized by specific IgE from the majority of infants and children with CMA. Such autoreactive, human milk-specific IgE antibodies appear to have functional properties in vitro. Their role in provoking allergic symptoms in infants exclusively breastfed by mothers strictly avoiding dietary milk remains unclear. © 2011 Blackwell

  17. Acute myeloid leukaemia genomics.

    PubMed

    Medinger, Michael; Passweg, Jakob R

    2017-11-01

    Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies. © 2017 John Wiley & Sons Ltd.

  18. FLT3 mutation and expression did not adversely affect clinical outcome of childhood acute leukaemia: a study of 531 Southeast Asian children by the Ma-Spore study group.

    PubMed

    Leow, Shuangjie; Kham, Shirley Kow-Yin; Ariffin, Hany; Quah, Thuan Chong; Yeoh, Allen Eng-Juh

    2011-12-01

    FMS-like tyrosine kinase 3 (FLT3) is critical for normal haematopoiesis and have been reported to be expressed in the majority of acute myeloid and lymphoid malignancies. We correlated the impact of FLT3 mutations and its expression with age, WHO 2008 classification and treatment outcome in 531 childhood acute leukaemias. Of 150 acute myeloid leukaemia (AMLs), 18 (12%) harboured FLT3-ITD while nine (6%) had FLT3-TKD. FLT3-ITD and -TKD were rare in acute megakaryoblastic leukaemia (AMKL; FLT3-ITD 0/26, FLT3-TKD 1/26) and children below 3 years (n = 2/48). Acute promyelocytic leukaemia (APL) with t(15;17);PML-RARα (n = 7/18; 39%) harboured the highest frequency of FLT3 mutations, followed by myelomonocytic (n = 4/18; 22%) and AML with t(8;21);RUNX1-RUNX1T1 (n = 2/21; 9%). FLT3 expression levels were also lowest in AMKL, both in Down's and non-Down's (p = 0.002) followed by patients <3 years (p = 0.001). The rarity of FLT3 mutations and expression levels in AMKL were independent of age. Conversely, only 2% of childhood acute lymphoblastic leukaemia (ALL) harboured FLT3 mutations (ITD = 1/381; TKD = 6/381). FLT3 was highly expressed in hyperdiploid ALL (p < 0.001). Of the 121 AMLs with clinical history, there were no significant differences in 4-year event-free survival (EFS) (46% vs. 38%; p = 0.46) and overall-survival (OS) (55% vs. 43%; p = 0.30) between FLT3-wildtype and ITD+ patients. Similarly, FLT3 expression levels did not influence survival in AML in both the good risk and non-good risk subgroups. FLT3 does not appear to be involved in the pathogenesis of AMKL, both in Down's and non-Down's. Therapeutic targets using FLT3 inhibitors may not be useful in AMKL and in young children with AML. Copyright © 2011 John Wiley & Sons, Ltd.

  19. Avascular necrosis of the femoral head in patients treated for leukaemia. Assessment of the need for a diagnostic protocol.

    PubMed

    Alguacil Pinel, J; Vila Vives, P; Salom Taverner, M

    To evaluate the incidence of avascular necrosis of the hip in leukaemia patients treated in our hospital with high doses of corticosteroids in order to evaluate the necessity for an early detection protocol. Observational-descriptive and retrospective study from 2005 to 2016 of 253 patients diagnosed with paediatric leukaemia. Patients with musculoskeletal pathology were identified and patients with avascular necrosis were analysed. A total of 26 patients (10%) had musculoskeletal symptoms. Three patients with avascular necrosis (1.2%) were analysed. One girl, 7 years old, was treated conservatively with traction - suspension and discharge. Two boys, an 11 and a 15.4 year-old,who developed graft-versus-host disease secondary to bone marrow transplantation, and whose treatment included high doses of corticosteroids, developed avascular necrosis of the hip. One was treated with bisphosphonates and forage and the other ended up with a total hip arthroplasty. The occurrence of musculoskeletal symptoms during the treatment of leukaemia is different according to the bibliographic series (0.43 -12.6%). Some authors observe an increased risk in female patients between the ages of 10 and 17. A retrospective study reveals that there is a delay of 3.9 months in the diagnosis of CAP since the onset of pain. Other authors relate NAV to loading joints, age and high doses of corticosteroids. Based on the low incidence of avascular necrosis of the hip in our 14-year-old population treated for leukaemia, the creation of diagnostic protocols seems not to be necessary. However, close monitoring of patients with potential risk factors recognized in the literature, is advisable. Copyright © 2017 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

    PubMed

    Wan, Liling; Wen, Hong; Li, Yuanyuan; Lyu, Jie; Xi, Yuanxin; Hoshii, Takayuki; Joseph, Julia K; Wang, Xiaolu; Loh, Yong-Hwee E; Erb, Michael A; Souza, Amanda L; Bradner, James E; Shen, Li; Li, Wei; Li, Haitao; Allis, C David; Armstrong, Scott A; Shi, Xiaobing

    2017-03-09

    Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.

  1. Community lifestyle characteristics and risk of acute lymphoblastic leukaemia in children.

    PubMed

    Alexander, F E; Ricketts, T J; McKinney, P A; Cartwright, R A

    1990-12-15

    High rates of leukaemia in children and young people have been associated with features of community isolation and population growth. Incidence data collected by two specialist registries were used to compare incidence rates at ward level with relevant ward characteristics derived from routine census and Ordnance Survey data for England and Wales. An excess risk of childhood acute lymphoblastic leukaemia (ALL) was found for wards which are farthest from large urban centres. The excess was greatest for wards of higher socioeconomic status and for children aged 1-7 years (the childhood peak), for which a two-fold excess was seen. These findings in general support the hypothesis that childhood leukaemia has an infectious aetiology.

  2. Acute B cell lymphoblastic leukaemia in a 12-week-old greyhound.

    PubMed

    Adams, J; Mellanby, R J; Villiers, E; Baines, S; Woodger, N

    2004-11-01

    A 12-week-old greyhound had a two-day history of lethargy, inappetence and shifting lameness. Clinical examination revealed pyrexia and hepatosplenomegaly. Haematological examination showed anaemia, thrombocytopenla, neutropenla and large numbers of atypical mononuclear leucocytes. A diagnosis of acute B cell lymphoblastic leukaemia was made following flow cytometric immunophenotyping of the leucocytes. The owner declined further evaluation and the dog was treated symptomatically with antibiotics. After a brief improvement, the dog's condition deteriorated and it was euthanased four days after initial presentation. The case was unusual because acute lymphoid leukaemia in the dog is most frequently reported in mature animals. This is in contrast to humans, where acute leukaemia is one of the most common childhood cancers.

  3. Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia.

    PubMed

    Popat, Uday; Carrum, George; Heslop, Helen E

    2003-02-01

    The majority of children and some adults with acute lymphocytic leukaemia (ALL) can be cured with current intensive chemotherapy regimens. For those patients who relapse or who do not achieve remission, allogeneic haemopoietic stem cell transplantation (HSCT) offers the best chance for long-term disease control. Different sources of haemopoietic stem cells including marrow, peripheral blood, and cord blood are now available and the introduction of subablative regimens has increased the number of patients who are transplant candidates. Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored.

  4. Frequency-dependent ultrasound-induced transformation in E. coli.

    PubMed

    Deeks, Jeremy; Windmill, James; Agbeze-Onuma, Maduka; Kalin, Robert M; Argondizza, Peter; Knapp, Charles W

    2014-12-01

    Ultrasound-enhanced gene transfer (UEGT) is continuing to gain interest across many disciplines; however, very few studies investigate UEGT efficiency across a range of frequencies. Using a variable frequency generator, UEGT was tested in E. coli at six ultrasonic frequencies. Results indicate frequency can significantly influence UEGT efficiency positively and negatively. A frequency of 61 kHz improved UEGT efficiency by ~70 % higher, but 99 kHz impeded UEGT to an extent worse than no ultrasound exposure. The other four frequencies (26, 133, 174, and 190 kHz) enhanced transformation compared to no ultrasound, but efficiencies did not vary. The influence of frequency on UEGT efficiency was observed across a range of operating frequencies. It is plausible that frequency-dependent dynamics of mechanical and chemical energies released during cavitational-bubble collapse (CBC) are responsible for observed UEGT efficiencies.

  5. Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis.

    PubMed

    Versluis, Jurjen; Hazenberg, Carin L E; Passweg, Jakob R; van Putten, Wim L J; Maertens, Johan; Biemond, Bart J; Theobald, Matthias; Graux, Carlos; Kuball, Jurgen; Schouten, Harry C; Pabst, Thomas; Löwenberg, Bob; Ossenkoppele, Gert; Vellenga, Edo; Cornelissen, Jan J

    2015-10-01

    Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50-60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older. For this time-dependent analysis, we used the results from four successive prospective HOVON-SAKK acute myeloid leukaemia trials. Between May 3, 2001, and Feb 5, 2010, a total of 1155 patients aged 60 years and older were entered into these trials, of whom 640 obtained a first complete remission after induction chemotherapy and were included in the analysis. Post-remission therapy consisted of allogeneic HSCT following reduced-intensity conditioning (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=44), autologous HSCT (n=23), or no further treatment (n=366). Reduced-intensity conditioning regimens consisted of fludarabine combined with 2 Gy of total body irradiation (n=71), fludarabine with busulfan (n=10), or other regimens (n=16). A time-dependent analysis was done, in which allogeneic HSCT was compared with other types of post-remission therapy. The primary endpoint of the study was 5-year overall survival for all treatment groups, analysed by a time-dependent analysis. 5-year overall survival was 35% (95% CI 25-44) for patients who received an allogeneic HSCT, 21% (17-26) for those who received no additional post-remission therapy, and 26% (19-33) for patients who received either additional chemotherapy or autologous HSCT. Overall survival at 5

  6. Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions.

    PubMed

    Bain, Barbara J; Ahmad, Shahzaib

    2015-11-01

    Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction. © 2015 John Wiley & Sons Ltd.

  7. The relation of illness perceptions to stress, depression, and fatigue in patients with chronic lymphocytic leukaemia.

    PubMed

    Westbrook, Travis D; Maddocks, Kami; Andersen, Barbara L

    2016-07-01

    Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia and is incurable. The course and treatment of CLL is unique and characterised by repeated cycles of treatment, stable disease and relapse. Utilising a Self-Regulatory Model framework, we examined the relationship between patients' illness perceptions and cancer-specific stress, depressive symptoms and fatigue. Our aim was to test illness perceptions as predictors of these outcomes when variance due to disease and treatment variables was controlled. Data were collected on 147 patients with relapsed/refractory CLL as they entered a phase II clinical trial of an investigational medication at a university affiliated, National Cancer Institute designated comprehensive cancer center. Cancer-specific stress, depressive symptoms and fatigue interference. . Hierarchical multiple regression was used. Consequences and emotional representation were related to all outcomes (ps < .01). Illness concern was related to cancer-specific stress (p < .01), and identity was related to fatigue interference (p < .01). All relationships were observed while controlling for number of previous CLL therapies received. Illness perceptions are related to cancer-specific stress, depressive symptoms and fatigue interference in relapsed/refractory CLL. Interventions targeted at restructuring maladaptive illness perceptions may have clinical benefit in this population.

  8. Air pollution and childhood leukaemia: a nationwide case-control study in Italy.

    PubMed

    Badaloni, C; Ranucci, A; Cesaroni, G; Zanini, G; Vienneau, D; Al-Aidrous, F; De Hoogh, K; Magnani, C; Forastiere, F

    2013-12-01

    Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged ≤10 years from these regions (period 1998-2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM2.5 and PM10- and gases -NO2 and O3-) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM10 levels were 33.3 (SD=6.3) and 33.4 µg/m(3) (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia.

  9. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort.

    PubMed

    Essig, Stefan; Li, Qiaozhi; Chen, Yan; Hitzler, Johann; Leisenring, Wendy; Greenberg, Mark; Sklar, Charles; Hudson, Melissa M; Armstrong, Gregory T; Krull, Kevin R; Neglia, Joseph P; Oeffinger, Kevin C; Robison, Leslie L; Kuehni, Claudia E; Yasui, Yutaka; Nathan, Paul C

    2014-07-01

    Treatment of patients with paediatric acute lymphoblastic leukaemia has evolved such that the risk of late effects in survivors treated in accordance with contemporary protocols could be different from that noted in those treated decades ago. We aimed to estimate the risk of late effects in children with standard-risk acute lymphoblastic leukaemia treated with contemporary protocols. We used data from similarly treated members of the Childhood Cancer Survivor Study cohort. The Childhood Cancer Survivor Study is a multicentre, North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. We included cohort members if they were aged 1·0-9·9 years at the time of diagnosis of acute lymphoblastic leukaemia and had received treatment consistent with contemporary standard-risk protocols for acute lymphoblastic leukaemia. We calculated mortality rates and standardised mortality ratios, stratified by sex and survival time, after diagnosis of acute lymphoblastic leukaemia. We calculated standardised incidence ratios and absolute excess risk for subsequent neoplasms with age-specific, sex-specific, and calendar-year-specific rates from the Surveillance, Epidemiology and End Results Program. Outcomes were compared with a sibling cohort and the general US population. We included 556 (13%) of 4329 cohort members treated for acute lymphoblastic leukaemia. Median follow-up of the survivors from 5 years after diagnosis was 18·4 years (range 0·0-33·0). 28 (5%) of 556 participants had died (standardised mortality ratio 3·5, 95% CI 2·3-5·0). 16 (57%) deaths were due to causes other than recurrence of acute lymphoblastic leukaemia. Six (1%) survivors developed a subsequent malignant neoplasm (standardised incidence ratio 2·6, 95% CI 1·0-5·7). 107 participants (95% CI 81-193) in each group would need to be followed-up for 1 year to observe one extra chronic health disorder in the survivor group compared with the sibling group. 415 participants

  10. Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells.

    PubMed

    Rushworth, Stuart A; Pillinger, Genevra; Abdul-Aziz, Amina; Piddock, Rachel; Shafat, Manar S; Murray, Megan Y; Zaitseva, Lyubov; Lawes, Matthew J; MacEwan, David J; Bowles, Kristian M

    2015-05-01

    Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib

  11. Lysosomal isoenzyme profiles used to classify a case of acute undifferentiated leukaemia.

    PubMed

    Eden, O B; Darbyshire, P; Simpson, R M; Besley, G T; Moss, S; Gentle, T

    1985-01-01

    Lysosomal enzyme activities and isoenzyme profiles were measured in lymphoid and non-lymphoid leukaemic cells from childhood patients. High activities, especially of beta-hexosaminidase and alpha-mannosidase, were associated with leukaemic cells of myeloid or monocytic origin. Leukaemic cells from two children with acute myeloid leukaemia had a relative reduction in the B isoenzyme of beta-hexosaminidase activity, whereas in patients with non T, non B cell acute lymphoblastic leukaemia, intermediate beta-hexosaminidase isoenzymes were expressed. A patient is described on whom conventional marker studies were either negative or equivocal, but lysosomal enzyme markers were consistent with a myeloid leukaemia. This observation was supported by the clinical course of this patient.

  12. Eliminating malignant cells from cryopreserved ovarian tissue is possible in leukaemia patients.

    PubMed

    Soares, Michelle; Saussoy, Pascale; Maskens, Mathilde; Reul, Hélène; Amorim, Christiani A; Donnez, Jacques; Dolmans, Marie-Madeleine

    2017-07-01

    Reimplantation of cryopreserved ovarian tissue (OT) can successfully restore ovarian function in young cancer patients after gonadotoxic treatment. However, for patients with leukaemia, there is a risk of malignant cell transmission. Our objective was to evaluate minimal disseminated disease in OT from leukaemia patients and test a follicle isolation technique to obtain disease-free follicle suspensions. Cryopreserved OT from 12 leukaemia patients was thawed and analysed by histology and long-term xenografting in immunosuppressed mice. In 10 patients, follicles were isolated from OT, and polymerase chain reaction (PCR) was performed on tissue, digested ovarian suspensions and isolated follicle suspensions to investigate leukaemic cell presence. Mean patient age was 17·1 years. An average of 3·2 follicles were isolated per mm² of cortex. Xenografting of OT induced leukaemic masses in 2/12 mice. PCR identified leukaemic cell presence in 66% of OT. Malignant cells were also detected in digested ovarian suspensions. However, none of the follicle samples (>2300 follicles tested) showed any malignant cell presence after washing. This study demonstrates that it is possible to recover large numbers of viable follicles from cryopreserved OT of leukaemia patients. All isolated and washed follicle suspensions tested negative for leukaemic cells, giving leukaemia patients genuine hope of fertility restoration. © 2017 John Wiley & Sons Ltd.

  13. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia.

    PubMed

    Emerenciano, Mariana; Meyer, Claus; Mansur, Marcela B; Marschalek, Rolf; Pombo-de-Oliveira, Maria S

    2013-04-01

    Acute leukaemia in early childhood - and mainly infant leukaemia (IL) - is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia (≤24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60·5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis ≤6 months (P < 0·001), high white blood cell count (P = 0·001), and MLL-r (P = 0·002) in ALL, while children with AML displayed a poorer outcome (P = 0·009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients. © 2013 Blackwell Publishing Ltd.

  14. Presence of functional, autoreactive human milk-specific IgE in infants with cow’s milk allergy

    PubMed Central

    Järvinen, K. M.; Geller, L.; Bencharitiwong, R.; Sampson, H. A.

    2013-01-01

    Summary Background Occasionally, exclusively breastfed infants with cow’s milk allergy (CMA) remain symptomatic despite strict maternal milk avoidance. Objective To determine whether or not persistence of symptoms could be due to sensitization against endogenous human milk proteins with a high degree of similarity to bovine allergens. Methods Ten peptides representing known bovine milk IgE-binding epitopes [α-lactalbumin (ALA), β- and κ-casein] and the corresponding, highly homologous human milk peptides were labelled with sera from 15 breastfed infants with CMA, aged 3 weeks to 12 months, and peptide (epitope)-specific IgE antibodies were assessed. Nine of the 15 breastfed infants became asymptomatic during strict maternal avoidance of milk and other major food allergens; six infants remained symptomatic until weaned. Ten older children, aged 5–15 years, with CMA were also assessed. The functional capacity of specific IgE antibodies was assessed by measuring β-hexosaminidase release from rat basophilic leukaemia cells passively sensitized and stimulated with human and bovine ALA. Results A minimum of one human milk peptide was recognized by IgE antibodies from 9 of 15 (60%) milk-allergic infants, and the majority of older children with CMA. Genuine sensitization to human milk peptides in the absence of IgE to bovine milk was occasionally seen. There was a trend towards specific IgE being detected to more human milk peptides in those infants who did not respond to the maternal milk elimination diet than in those who did (P = 0.099). Functional IgE antibody to human ALA was only detected in infants not responding to the maternal diet. Conclusions and Clinical Relevance Endogenous human milk epitopes are recognized by specific IgE from the majority of infants and children with CMA. Such autoreactive, human milk-specific IgE antibodies appear to have functional properties in vitro. Their role in provoking allergic symptoms in infants exclusively breastfed by

  15. Association between childhood leukaemia and exposure to power-frequency magnetic fields in Middle Europe.

    PubMed

    Jirik, Vitezslav; Pekarek, Ludek; Janout, Vladimir; Tomaskova, Hana

    2012-10-01

    Higher levels of exposure to extremely low-frequency magnetic fields (ELF-MF) are associated with a slightly increased risk of childhood leukaemia. Compared with more-developed Western countries, higher exposure levels are evident in the Czech Republic, probably because of the different types of housing. In light of this, we aimed to examine the association between ELF-MF exposure and childhood leukaemia in the Czech Republic. We conducted a paired case-control study. The cases (children with leukaemia) were age- sex- and permanent residence-matched to controls (children without leukaemia). Although this limited potential bias and confounding, it also limited our number of participants. The matched analyses included 79 case-control pairs. No significant association between ELF-MF exposure and childhood leukaemia was observed for exposures over 0.2 μT (odds ratio [OR]=0.93, confidence interval [CI]=0.45-1.93), 0.3 μT (OR=0.77, CI=0.34-1.75), or 0.4 μT (OR=0.9, CI=0.37-2.22). Despite higher levels of exposure in Middle and Eastern Europe, no indication of an association between ELF-MF exposure and childhood leukaemia was determined. This in contrast to the findings of previous studies conducted in different countries. Copyright © 2012 The Editorial Board of Biomedical and Environmental Sciences. Published by Elsevier B.V. All rights reserved.

  16. Residential exposures to pesticides and childhood leukaemia

    PubMed Central

    Metayer, Catherine; Buffler, Patricia A.

    2008-01-01

    Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case–control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of ∼600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene–environment interaction studies. PMID:18940823

  17. Acute undifferentiated leukaemia in a dog.

    PubMed

    Miglio, A; Antognoni, M T; Miniscalco, B; Caivano, D; Lepri, E; Birettoni, F; Mangili, V

    2014-12-01

    Acute undifferentiated leukaemia (AUL) is considered a separate entity in the context of acute leukaemias. AUL is extremely rare in both humans and dogs, has a rapid clinical course and does not respond to treatment. It is characterised by the presence of blast cells within the bone marrow and/or peripheral blood at levels ≥ 20% and even up to 100% of all nucleated cells. Blast cells are unable to be differentiated on morphological, cytochemical and phenotypic criteria into myeloid or lymphoid lineages because of their immaturity and/or atypia. An 8-year-old German Shepherd dog was referred for depression, asthenia, mild anaemia, thrombocytopenia and marked leucocytosis. Abdominal ultrasound showed hepatomegaly, splenomegaly, bilateral nephromegaly and enlargement of mesenteric lymph nodes. Echocardiography revealed biventricular hypertrophy with abnormal tissue density of the myocardium. Blood and bone marrow smears were composed of 95% unclassifiable and/or atypical blast cells and signs of dysplasia of the erythroid and thrombocytic/megakaryocytic lineages were present. Blast cells were negative for all cytochemical stains used and flow cytometry of peripheral blood revealed 85% of total leucocytes consisting of small-to-medium-sized cells, negative for all lymphoid and myeloid markers except CD45 and CD34. After necropsy, cytology and histology revealed that blast cells had diffusely infiltrated all tissues examined. Both erythroid and megakaryocytic extramedullary haemopoiesis was also detected in the spleen, lymph nodes and liver. All immunohistochemical stains used were negative. On the basis of all the results, a diagnosis of acute leukaemia involving a very primitive haematopoietic precursor was made. © 2014 Australian Veterinary Association.

  18. 7 CFR 1753.26 - Plans and specifications (P&S).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....26 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE... Buildings § 1753.26 Plans and specifications (P&S). (a) For headquarters and commercial office buildings... details of the building to be constructed using loan funds. In particular, the preliminary P&S shall...

  19. Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia.

    PubMed

    Morley, N J; Marks, D I

    2016-01-01

    Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC-544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice 'standard of care' chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant.

  20. Immunophenotyping of acute leukaemias by flow cytometry: a review.

    PubMed

    Pamnani, R

    2009-12-01

    To provide an overview of the utility of flow cytometry for phenotyping of acute leukaemias and selection-of monoclonal antibodies. The literature review was obtained through internet, journals and chapters in the relevant books. Relevant articles and chapters on immunophenotyping of acute leukaemias were selected from respected international journals and books in the field of haematology and were reviewed. Complete articles relevant to the topic were selected and reviewed and the necessary information extracted for this review. Flow cytometry has been used extensively in recent years to characterise haemopoeitic malignancies and done routinely in the developed world. This technique has greatly improved the diagnosis and classification of haemopoeitic malignancies and has been recommended by World Health Organisation classification (WHO) of tumours of haemopoeitic and lymphoid tissue. Application of flow cytometry for the diagnosis of leukaemias has been recently introduced in Kenya and is currently being undertaken in research using limited but appropriate panels of monoclonal antibodies. It is hoped that findings of this research will inform the use of flow cytometry as an ancillary diagnostic technique in our resource-constrained set up.

  1. 10 CFR 72.26 - Contents of application: Technical specifications.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false Contents of application: Technical specifications. 72.26 Section 72.26 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR THE INDEPENDENT STORAGE OF SPENT NUCLEAR FUEL, HIGH-LEVEL RADIOACTIVE WASTE, AND REACTOR-RELATED GREATER THAN CLASS C...

  2. 10 CFR 72.26 - Contents of application: Technical specifications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Contents of application: Technical specifications. 72.26 Section 72.26 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) LICENSING REQUIREMENTS FOR THE INDEPENDENT STORAGE OF SPENT NUCLEAR FUEL, HIGH-LEVEL RADIOACTIVE WASTE, AND REACTOR-RELATED GREATER THAN CLASS C...

  3. Residential radon exposure and adult acute leukaemia.

    PubMed

    Law, G R; Kane, E V; Roman, E; Smith, A; Cartwright, R

    2000-05-27

    Exposure to radioactive radon gas in homes, from natural sources, is an important public-health issue for many countries. We found no association between household exposure to radon and leukaemia in adults in the UK.

  4. Ibrutinib: A Review in Chronic Lymphocytic Leukaemia.

    PubMed

    Deeks, Emma D

    2017-02-01

    Ibrutinib (Imbruvica ® ) is an oral irreversible inhibitor of Bruton's tyrosine kinase, a B-cell receptor (BCR) signalling kinase expressed by various haematopoietic cells, B-cell lymphomas and leukaemias. The drug is indicated for the treatment of certain haematological malignancies, including chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), which are the focus of this review. In phase III CLL/SLL trials, ibrutinib monotherapy was more effective than chlorambucil in the first-line treatment of elderly patients (RESONATE-2) and more effective than ofatumumab in previously-treated adults (RESONATE). Likewise, a combination of ibrutinib, bendamustine and rituximab was more effective in previously-treated adults than bendamustine plus rituximab in a phase III placebo-controlled study (HELIOS). These ibrutinib regimens were associated with significantly better progression-free survival, overall response rates, and overall survival than the comparators (in protocol-specified or planned analyses), with ibrutinib therapy providing benefit regardless of adverse prognostic factors, such as del(17p)/TP53 mutation and del(11q). Ibrutinib has an acceptable tolerability profile, although certain adverse events (e.g. bleeding and atrial fibrillation) require consideration. Redistribution lymphocytosis can occur, but is not indicative of disease progression. Although longer-term data would be beneficial, ibrutinib is a welcome treatment option for patients with CLL, including those who have higher-risk disease or are less physically fit. Indeed, current EU and US guidelines recommend/prefer the drug for the first- and/or subsequent-line treatment of certain patients, including those with del(17p)/TP53 mutation.

  5. 'Shouting from the roof tops': a qualitative study of how children with leukaemia are diagnosed in primary care.

    PubMed

    Clarke, Rachel T; Jones, Caroline Hd; Mitchell, Christopher D; Thompson, Matthew J

    2014-02-18

    To investigate the prehospital presentation of paediatric leukaemia and identify the disease and non-disease related factors which facilitate or impede diagnosis. Thematic analysis of qualitative semistructured interviews. One tertiary referral centre in Southern England. 21 parents and 9 general practitioners (GPs) of 18 children (<18-year-old) with a new diagnosis of acute leukaemia. The majority of children were first seen by GPs before the characteristic signs and symptoms of leukaemia had developed. In their absence, behavioural cues such as the child becoming apathetic or 'not themselves' often triggered parents to seek medical help. Most GPs were unclear about the nature and severity of the child's presentation: then, safety netting, thorough history-taking and examination, and reliance on contextual information about the parents or from prior hospital paediatrics experience were used to manage diagnostic uncertainty. The nature of the doctor-parent relationship helped and hindered the diagnostic pathway. GPs' prior perceptions of parents as being 'sensible' or 'worriers' influenced how gravely they treated parental concerns, with 'worriers' being taken less seriously. Some parents believed GPs failed to listen to their anxieties and discounted their expert knowledge of their child. Specific delay factors included lack of continuity of GP; some GPs' reluctance to take blood from children; and some parents feeling unable to voice effectively their concerns. The presentation of paediatric leukaemia in primary care differs from that described in many hospital studies, with greater diversity and intermittency of symptoms, and the frequent absence of 'red flags' of serious illness. A wide range of non-disease related factors potentially delay the diagnosis of paediatric leukaemia, including tensions in the doctor-patient relationship and the doctors' cognitive biases. The identification and attempted modification of these factors may minimise diagnostic delay

  6. [Immunophenotype of lymphoblastic leukaemia in children in relation to clinical symptoms and laboratory tests, preceding its diagnosis].

    PubMed

    Zapolska, Beata; Krawczuk-Rybak, Maryna; Łuczyński, Włodzimierz; Zak, Janusz; Leszczyńska, Elzbieta

    2004-01-01

    The aim of study was to compare the clinical picture and results of laboratory tests according to the acute lymphoblastic leukaemia (ALL) immunophenotype. The observation was carried out on a group of 67 patients treated in the IIIrd Department of Paediatrics and Department of Children Oncology in the Medical Academy of Białystok from January 1994 to April 2001. This group consists of 4 children with pro-B acute lymphoblastic leukaemia, 52 children with pre-B cell ALL, 1 child with B-cell acute lymphoblastic leukaemia and 9 children with T-cell acute lymphoblastic leukaemia. Haemorrhagic diathesis. splenomegaly, enlargement of peripheral lymph nodes as well as higher values of white blood cells count, blasts count, haemoglobin concentration, haematocrit and LDH activity were observed more frequently in patients with T-cell leukaemia than in others.

  7. 21 CFR 660.26 - Specificity tests and avidity tests.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Specificity tests and avidity tests. 660.26 Section 660.26 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... using test procedures approved by the Director, Center for Biologics Evaluation and Research. [53 FR...

  8. Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1.

    PubMed

    Petrella, Antonello; D'Acunto, Cosimo Walter; Rodriquez, Manuela; Festa, Michela; Tosco, Alessandra; Bruno, Ines; Terracciano, Stefania; Taddei, Maurizio; Paloma, Luigi Gomez; Parente, Luca

    2008-03-01

    FR235222, a novel histone deacetylase inhibitor (HDACi), at 50nM caused accumulation of acetylated histone H4, inhibition of cell proliferation and G1 cycle arrest accompanied by increase of p21 and down-regulation of cyclin E in human promyelocytic leukaemia U937 cells. The compound was also able to increase the protein and mRNA levels of annexin A1 (ANXA1) without effects on apoptosis. Similar effects were observed in human chronic myelogenous leukaemia K562 cells and human T cell leukaemia Jurkat cells. Cycle arrest and ANXA1 expression, without significant effects on apoptosis, were also induced by different HDACi like suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). FR235222 at 0.5 microM stimulated apoptosis of all leukaemia cell lines associated to an increased expression of the full-length (37kDa) protein and the appearance of a 33kDa N-terminal cleavage product in both cytosol and membrane. These results suggest that ANXA1 expression may mediate cycle arrest induced by low doses FR235222, whereas apoptosis induced by high doses FR235222 is associated to ANXA1 processing.

  9. Wt-p53 action in human leukaemia cell lines corresponding to different stages of differentiation.

    PubMed

    Rizzo, M G; Zepparoni, A; Cristofanelli, B; Scardigli, R; Crescenzi, M; Blandino, G; Giuliacci, S; Ferrari, S; Soddu, S; Sacchi, A

    1998-05-01

    Recent studies support the potential application of the wt-p53 gene in cancer therapy. Expression of exogenous wt-p53 suppresses a variety of leukaemia phenotypes by acting on cell survival, proliferation and/or differentiation. As for tumour gene therapy, the final fate of the neoplastic cells is one of the most relevant points. We examined the effects of exogenous wt-p53 gene expression in several leukaemia cell lines to identify p53-responsive leukaemia. The temperature-sensitive p53Val135 mutant or the human wt-p53 cDNA was transduced in leukaemia cell lines representative of different acute leukaemia FAB subtypes, including M1 (KG1), M2 (HL-60), M3 (NB4), M5 (U937) and M6 (HEL 92.1.7), as well as blast crisis of chronic myelogenous leukaemia (BC-CML: K562, BV173) showing diverse differentiation features. By morphological, molecular and biochemical analyses, we have shown that exogenous wt-p53 gene expression induces apoptosis only in cells corresponding to M1, M2 and M3 of the FAB classification and in BC-CML showing morphological and cytochemical features of undifferentiated blast cells. In contrast, it promotes differentiation in the others. Interestingly, cell responsiveness was independent of the vector used and the status of the endogenous p53 gene.

  10. Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission.

    PubMed

    Kittai, Adam; Yu, Eun-Mi; Tabbara, Imad

    2014-12-23

    Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia. 2014 BMJ Publishing Group Ltd.

  11. Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population.

    PubMed

    Hussain, Syed Rizwan; Naqvi, Hena; Raza, Syed Tasleem; Ahmed, Faisal; Babu, Sunil G; Kumar, Ashutosh; Zaidi, Zeashan Haider; Mahdi, Farzana

    2012-08-01

    Leukaemia is a heterogeneous disease in which haematopoietic progenitor cells acquire genetic lesions that lead to a block in differentiation, increased self-renewal, and unregulated proliferation. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), involved in folate metabolism, plays a crucial role in cells because folate availability is important for DNA integrity. The aim of this case-control study was to evaluate the association of the C677T MTHFR gene polymorphism with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL). A total of 275 leukaemia cases - including AML (n = 112), ALL (n = 81), CML (n = 43), CLL (n = 39) - and 251 age/sex-matched healthy control individuals participated in this study. MTHFR C677T polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total leukaemia cases were 68.73%, 19.64%, and 11.64% in cases, and 71.71%, 24.30%, and 3.98% in healthy controls, respectively. The average frequency of the MTHFR 677T allele was 21.45% among the cases compared to 16.13% among the controls. In the present case-control study we have observed a higher frequency of the MTHFR 677TT genotype in cases of leukaemia (AML, ALL, CML and CLL) as compared with controls; this might be due to ethnic and geographic variation. As per our findings, although the frequency of the MTHFR 677T allele is moderately high in AML, ALL and CLL, no statistically significant association was found; on the other hand statistically significant association was found in the context of CML cases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. [Neurological complications in the population of children with leukaemia].

    PubMed

    Martínez-Cayuelas, Elena; Domingo-Jiménez, Rosario; Pascual-Gázquez, Juan F; Martínez-Salcedo, Eduardo; Alarcón-Martínez, Helena; Bermúdez-Cortés, Mar; Fuster-Soler, José L; Pérez-Fernández, Virginia

    2015-02-01

    Leukaemia is the most frequent type of cancer at the paediatric age. The cure rate is 80% with intensive chemotherapy, which improves survival but also often increases the frequency of adverse side effects, including those of a neurological nature. To describe the frequency and characteristics of the neurological complications (NC) in patients with acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML), as well as to identify factors associated to their presence, neurological morbidity and survival rate. A retrospective study was conducted of the NC present in patients with ALL and AML between 1997 and 2012 treated and followed up by the child onco-haematology unit. The following variables were analysed: demographic data, oncological diagnosis, treatment and NC. Altogether 157 patients were included, 145 without infiltration of the central nervous system at diagnosis and eight with infiltration (rate of NC of 14% and 12%, respectively). The most frequent NC were: neuropathies (31%), altered levels of consciousness (27%), convulsions (22%) and headache (12%). Forty per cent of the patients with NC presented sequelae but none of them died as a consequence of the NC. More NC were detected in the age group of children aged under 6 years with high-degree ALL, at higher levels of severity and in patients who had received a haematopoietic stem-cell transplant, all of them with statistically significant differences. Neurological complications are common in patients with acute leukaemia, especially in those at a high-risk stage (above all if they are under the age of 6 years) and with haematopoietic stem-cell transplant. The associated mortality rate is low.

  13. Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis.

    PubMed

    Nagler, Arnon; Savani, Bipin N; Labopin, Myriam; Polge, Emmanuelle; Passweg, Jakob; Finke, Jürgen; Kyrcz-Krzemien, Slawomira; Volin, Liisa; Anagnostopoulos, Achilles; Aljurf, Mahmoud; Beelen, Dietrich W; Vigouroux, Stephane; Milpied, Noel; Suarez, Felipe; Mohty, Mohamad

    2015-09-01

    Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen. In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival. We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99

  14. Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

    PubMed

    Yap, B S; McCredie, K B; Benjamin, R S; Bodey, G P; Freireich, E J

    1978-09-16

    Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

  15. BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside.

    PubMed

    Boer, Judith M; den Boer, Monique L

    2017-09-01

    Acute lymphoblastic leukaemia (ALL) occurs in approximately 1:1500 children and is less frequently found in adults. The most common immunophenotype of ALL is the B cell lineage and within B cell precursor ALL, specific genetic aberrations define subtypes with distinct biological and clinical characteristics. With more advanced genetic analysis methods such as whole genome and transcriptome sequencing, novel genetic subtypes have recently been discovered. One novel class of genetic aberrations comprises tyrosine kinase-activating lesions, including translocations and rearrangements of tyrosine kinase and cytokine receptor genes. These newly discovered genetic aberrations are harder to detect by standard diagnostic methods such as karyotyping, fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR) because they are diverse and often cryptic. These lesions involve one of several tyrosine kinase genes (among others, v-abl Abelson murine leukaemia viral oncogene homologue 1 (ABL1), v-abl Abelson murine leukaemia viral oncogene homologue 2 (ABL2), platelet-derived growth factor receptor beta polypeptide (PDGFRB)), each of which can be fused to up to 15 partner genes. Together, they compose 2-3% of B cell precursor ALL (BCP-ALL), which is similar in size to the well-known fusion gene BCR-ABL1 subtype. These so-called BCR-ABL1-like fusions are mutually exclusive with the sentinel translocations in BCP-ALL (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and KMT2A (MLL) rearrangements) and have the promising prospect to be sensitive to tyrosine kinase inhibitors similar to BCR-ABL1. In this review, we discuss the types of tyrosine kinase-activating lesions discovered, and the preclinical and clinical evidence for the use of tyrosine kinase inhibitors in the treatment of this novel subtype of ALL. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Incidence and survival time trends for Spanish children and adolescents with leukaemia from 1983 to 2007.

    PubMed

    Marcos-Gragera, R; Galceran, J; Martos, C; de Munain, A L; Vicente-Raneda, M; Navarro, C; Quirós-Garcia, J R; Sánchez, M-J; Ardanaz, E; Ramos, M; Mateos, A; Salmerón, D; Felipe, S; Peris-Bonet, R

    2017-03-01

    We have analysed incidence and survival trends of children and adolescents with leukaemia registered in Spanish population-based cancer registries during the period 1983-2007. Childhood and adolescent leukaemia cases were drawn from the 11 Spanish population-based cancer registries. For survival, registries with data for the period 1991-2005 and follow-up until 31-12-2010 were included. Overall incidence trends were evaluated using joinpoint analysis. Observed survival rates were estimated using Kaplan-Meier, and trends were tested using the log-rank test. Based on 2606 cases (2274 children and 332 adolescents), the overall age-adjusted incidence rate (ASRw) of leukaemia was 47.9 cases per million child-years in children and 23.8 in adolescents. The ASRw of leukaemia increased with an annual percentage change of 9.6 % (95 % CI: 2.2-17.6) until 1990 followed by a stabilisation of rates. In adolescents, incidence did not increase. Five-year survival increased from 66 % in 1991-1995 to 76 % in 2001-2005. By age, survival was dramatically lower in infants (0) and adolescents (15-19) than in the other age groups and no improvement was observed. In both children and adolescents, differences in 5-year survival rates among major subgroups of leukaemias were significant. The increasing incidence trends observed in childhood leukaemias during the study period were confined to the beginning of the period. Remarkable improvements in survival have been observed in Spanish children with leukaemias. However, this improvement was not observed in infants and adolescents.

  17. Role of the histone deacetylase complex in acute promyelocytic leukaemia.

    PubMed

    Lin, R J; Nagy, L; Inoue, S; Shao, W; Miller, W H; Evans, R M

    1998-02-19

    Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

  18. Effects of the HIF1 inhibitor, echinomycin, on growth and NOTCH signalling in leukaemia cells.

    PubMed

    Yonekura, Satoru; Itoh, Mai; Okuhashi, Yuki; Takahashi, Yusuke; Ono, Aya; Nara, Nobuo; Tohda, Shuji

    2013-08-01

    To examine the effects of echinomycin, a compound that inhibits DNA-binding activity of hypoxia-inducible factor-1 (HIF1), on leukaemia cell growth. Three acute myeloid leukaemia cell lines and three T-lymphoblastic leukaemia cell lines were cultured with echinomycin. Cell growth, mRNA and protein expression levels were examined by WST-1 assay, reverse-transcription polymerase chain reaction and immunoblotting, respectively. HIF1α protein was expressed in all cell lines under normoxia. Treatment with echinomycin suppressed cell growth and induced apoptosis in association with decreased mRNA expression of HIF1 targets, glucose transporter-1 (GLUT1) and B-cell CLL/lymphoma-2 (BCL2). Echinomycin also suppressed the protein expression of NOTCH1, cleaved NOTCH1, v-myc myelocytomatosis viral oncogene homolog (MYC), v-akt murine thymoma viral oncogene homolog-1 (AKT), phosphorylated AKT, mechanistic target of rapamycin (mTOR), and phosphorylated mTOR and increased that of cleaved caspase-3 in some cell lines. Echinomycin suppresses leukaemia cell growth in association with reduced NOTCH1 expression. This is the first report to show that HIF inhibitor treatment suppresses NOTCH1 signalling. HIF inhibitors could be novel candidates for a molecular-targeted therapy against leukaemia.

  19. Living with cancer: a qualitative report of the experiences of leukaemia patients in Lagos, Nigeria.

    PubMed

    Adejoh, Samuel Ojima; Temilola, Olusegun Moses; Olayiwola, Bolutife

    2013-12-01

    The study examined the qualitative, cognitive and psychosocial experiences of those living with leukaemia undergoing treatment at a teaching hospital. Twenty respondents who consented to participate were purposively selected from the cancer patients with leukaemia receiving treatment in the said teaching hospital. The in-depth interview method was used to collect data. The data was analysed using manual content analysis. Data showed that patients lack basic knowledge about leukaemia and had no beliefs regarding leukaemia. Some patients believed in God and a medical breakthrough for a cure, while for some, the hope of living was not certain. The ill-health condition had brought about financial predicament to both patients and family members and has limited their productivity in terms of income-generating activities. Good interpersonal relationships and support from their care providers aided their compliance to treatment regime and provided hope for living positively with their condition. The study concludes that there is a need to educate the patients on the causes of their condition. Financial supports should be rendered to those living with leukaemia, while health care providers should be encouraged to continue to maintain good interpersonal relationships with their patients.

  20. Ovarian minimal residual disease in chronic myeloid leukaemia.

    PubMed

    Abir, Ronit; Aviram, Adina; Feinmesser, Meora; Stein, Jerry; Yaniv, Isaac; Parnes, Doris; Ben-Haroush, Avi; Meirow, Dror; Rabizadeh, Esther; Fisch, Benjamin

    2014-02-01

    The options for fertility preservation include cryopreservation of ovarian tissue. Although transplantation of cryopreserved-thawed ovarian tissue in cancer survivors has resulted in live births, there is evidence of malignancy involvement in ovarian tissue, especially in leukaemia. The objectives of this study were to investigate the involvement of chronic myeloid leukaemia (CML) in ovaries by both pathological/immunohistochemical methods and PCR for the identification of the Philadelphia chromosome (BCR-ABL transcripts). The patient was a survivor of paediatric CML whose ovaries were cryopreserved. The patient became infertile and requested ovarian reimplantation in adulthood. Pathological examinations of ovarian tissue with immunohistochemical stainings, quantitative PCR and two-step nested PCR were applied to identify BCR-ABL transcripts. Despite the lack of positive pathological/immunohistochemical evidence, PCR and two-step nested PCR revealed that the ovary was contaminated by malignant minimal residual CML. Survivors of childhood CML may harbour minimal residual disease in the ovaries. This finding stresses the danger of reseeding cancer by ovarian grafting, especially in patients with leukaemia. If ovarian grafting is considered, reimplantation should be preceded by examination of ovarian samples both pathologically and by molecular techniques. On the basis of molecular findings, ovarian autografting was not recommended in this case report. Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  1. Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes.

    PubMed

    Vrhovac, R; Labopin, M; Ciceri, F; Finke, J; Holler, E; Tischer, J; Lioure, B; Gribben, J; Kanz, L; Blaise, D; Dreger, P; Held, G; Arnold, R; Nagler, A; Mohty, M

    2016-02-01

    Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.

  2. CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

    NASA Astrophysics Data System (ADS)

    Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

    2011-07-01

    Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33low. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

  3. SOX12: a novel potential target for acute myeloid leukaemia.

    PubMed

    Wan, Haixia; Cai, Jiayi; Chen, Fangyuan; Zhu, Jianyi; Zhong, Jihua; Zhong, Hua

    2017-02-01

    The role of SRY-related high-mobility-group box (SOX) 12 in leukaemia progression and haematopoiesis remains elusive. This study aimed to examine the expression and function of SOX12 in acute myeloid leukaemia (AML) using human myeloid leukaemia samples and the acute myeloid cell line THP1. Mononuclear cells were isolated from the bone marrow of AML patients and healthy donors. SOX12 expression in haematopoietic cells was evaluated by reverse transcription polymerase chain reaction (RT-PCR). SOX12 short hairpin RNAs (shRNAs) were transduced into THP1 cells, and gene knockdown was confirmed by quantitative RT-PCR and Western blot analysis. SOX12 was preferentially expressed in CD34 + cells in AML patients. The THP1 cells transduced with SOX12 shRNAs exhibited significantly reduced SOX12 expression and cell proliferation. SOX12 knockdown had no effect on apoptosis, but it induced cell cycle arrest at G1 phase and reduced the number of colonies. The transduced THP1 and primary AML cells were reconstituted in non-obese diabetic-severe combined immunodeficient (NOD/SCID) mice, and their numbers were significantly reduced 6-12 weeks after transplantation. The mRNA and protein levels of β-catenin were significantly diminished following SOX12 knockdown, accompanied by a decrease in TCF/Wnt activity. SOX12 may be involved in leukaemia progression by regulating the expression of β-catenin and then interfering with TCF/Wnt pathway, which may be a target for AML. © 2016 John Wiley & Sons Ltd.

  4. Antibiotic use from conception to diagnosis of child leukaemia as compared to the background population: A nested case-control study.

    PubMed

    Gradel, Kim Oren; Kaerlev, Linda

    2015-07-01

    The role of infection in the aetiology of childhood leukaemia is unknown. We used prescriptions of antibiotics from Danish pharmacies as a proxy measure for the occurrence of infections. We investigated the association between exposure to antibiotics, from conception to leukaemia diagnosis, and the risk of leukaemia. Incident cases of leukaemia among children in Denmark, 1995-2008, with mothers having their earliest conception date in 1995, were individually matched to population controls by age, sex and municipality. Conditional logistic regression analyses assessed antibiotic redemptions in different time periods from conception up to 6 months before the diagnoses of all leukaemia types, acute lymphoblastic leukaemia [ALL] and ALL in 2- to 5-year-old children, adjusting for several potential confounders. A total of 120/360 (33.3%) leukaemia mothers and 1,081/3,509 (30.8%) control mothers redeemed antibiotics during pregnancy (P = 0.32). For children, the equivalent numbers were 276 (76.7%) and 2,665 (75.9%) (P = 0.76). Histograms of antibiotic redemptions showed no temporal differences between leukaemia mothers/children and controls, which was confirmed in adjusted regression analyses (OR [95% CI]: 1.02 [0.75-1.38]). Only antibiotics redeemed during the first year after birth differed from this (OR [95% CI] for ALL diagnosed in 2- to 5-year-old children: 0.46 [0.31-0.66]). In this hypothesis generating study, the similar amount and pattern of antibiotic redemptions in children with and without leukaemia indicate that infections play a minor role in the aetiology of childhood leukaemia. However, less antibiotic redemptions during the first year of life conform to Greaves' 'delayed infection hypothesis'. © 2015 Wiley Periodicals, Inc.

  5. 26 CFR 1.503(e)-2 - Requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Requirements. 1.503(e)-2 Section 1.503(e)-2...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(e)-2 Requirements. (a) In general. The requirements... price may not be a valid price for 1,000 bonds and the purchase may therefore not meet the requirements...

  6. 26 CFR 1.503(e)-2 - Requirements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Requirements. 1.503(e)-2 Section 1.503(e)-2...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(e)-2 Requirements. (a) In general. The requirements... price may not be a valid price for 1,000 bonds and the purchase may therefore not meet the requirements...

  7. 26 CFR 1.503(e)-2 - Requirements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Requirements. 1.503(e)-2 Section 1.503(e)-2...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(e)-2 Requirements. (a) In general. The requirements... price may not be a valid price for 1,000 bonds and the purchase may therefore not meet the requirements...

  8. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan.

    PubMed

    Chen, Teng-Chou; Chen, Li-Chia; Huang, Yaw-Bin; Chang, Chao-Sung

    2014-02-01

    Since the launch of imatinib, chronic myeloid leukaemia has become a chronic condition requiring costly long-term treatment. Emerging evidence from several short-term studies has raised concerns on the detrimental clinical outcomes and waste of resources associated with poor adherence to imatinib. This study aims to evaluate the effects of long-term imatinib adherence on clinical treatment responses and mortality. This retrospective cohort study was conducted in a medical centre in southern Taiwan. Chronic myeloid leukaemia patients who were prescribed for more than 1 month of imatinib were identified and their medical charts were reviewed from the first date of imatinib prescription to the last date of medical record or upon patients' death. Patients' basic characteristics, imatinib prescriptions, results of laboratory tests, episodes of imatinib-related side effects and mortality rate were recorded. Participants' basic characteristics, medication possession ratio and their mortality rate; the association between the medication possession ratio and treatment responses. Of the 119 included patients, the mean follow-up time was 3.9 ± 2.9 patient-years and the mean medication possession ratio was 89.7 %. At the 18th month of imatinib treatment, 67.2, 54.3 and 34.5 % patients achieved complete cytogenetic, major molecular and complete molecular responses, respectively. There was a significant difference in the 4-year survival rate between the adherence (n = 87) and non-adherence (n = 32) groups (91 vs. 72 %; p = 0.0076). Logistic regression analysis revealed that imatinib adherence was the only factor that significantly influenced the 18th month complete cytogenetic response [odds ratio (OR) 11.6; 95 % confidence interval (CI) 1.7, 114.7; p = 0.0131] and major molecular response (OR 5.1; 95 % CI 1.1, 26.8; p = 0.0351). Cox regression analysis demonstrated that a medication possession ratio greater than 90 % significantly reduced the mortality risk (hazard ratio 0

  9. Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies.

    PubMed

    Teh, Benjamin W; Tam, Constantine S; Handunnetti, Sasanka; Worth, Leon J; Slavin, Monica A

    2018-04-23

    Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia.

    PubMed

    Barber, Lisa M; McGrath, Helen E N; Meyer, Stefan; Will, Andrew M; Birch, Jillian M; Eden, Osborn B; Taylor, G Malcolm

    2003-04-01

    The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

  11. Pooled analysis of recent studies on magnetic fields and childhood leukaemia

    PubMed Central

    Kheifets, L; Ahlbom, A; Crespi, C M; Draper, G; Hagihara, J; Lowenthal, R M; Mezei, G; Oksuzyan, S; Schüz, J; Swanson, J; Tittarelli, A; Vinceti, M; Wunsch Filho, V

    2010-01-01

    Background: Previous pooled analyses have reported an association between magnetic fields and childhood leukaemia. We present a pooled analysis based on primary data from studies on residential magnetic fields and childhood leukaemia published after 2000. Methods: Seven studies with a total of 10 865 cases and 12 853 controls were included. The main analysis focused on 24-h magnetic field measurements or calculated fields in residences. Results: In the combined results, risk increased with increase in exposure, but the estimates were imprecise. The odds ratios for exposure categories of 0.1–0.2 μT, 0.2–0.3 μT and ⩾0.3 μT, compared with <0.1 μT, were 1.07 (95% CI 0.81–1.41), 1.16 (0.69–1.93) and 1.44 (0.88–2.36), respectively. Without the most influential study from Brazil, the odds ratios increased somewhat. An increasing trend was also suggested by a nonparametric analysis conducted using a generalised additive model. Conclusions: Our results are in line with previous pooled analyses showing an association between magnetic fields and childhood leukaemia. Overall, the association is weaker in the most recently conducted studies, but these studies are small and lack methodological improvements needed to resolve the apparent association. We conclude that recent studies on magnetic fields and childhood leukaemia do not alter the previous assessment that magnetic fields are possibly carcinogenic. PMID:20877339

  12. Childhood leukaemia and distance from power lines in California: a population-based case-control study.

    PubMed

    Crespi, Catherine M; Vergara, Ximena P; Hooper, Chris; Oksuzyan, Sona; Wu, Sheng; Cockburn, Myles; Kheifets, Leeka

    2016-06-28

    Studies have reported an increased risk of childhood leukaemia associated with living near high-voltage electric power transmission lines that extend to distances at which magnetic fields from lines are negligible. We conducted a large records-based case-control study of childhood leukaemia risk in the population living near power lines in California. The study included 5788 childhood leukaemia and 3308 central nervous system (CNS) cancer cases (for comparison) born in and diagnosed in California (1986-2008), and matched to population-based controls by age and sex. We geocoded birth address and estimated the distance from residence to transmission lines using geographic information systems, aerial imagery, and, for some residences, site visits. For leukaemia, there was a slight excess of cases within 50 m of a transmission line over 200 kV (odds ratio 1.4, 95% confidence interval 0.7-2.7). There was no evidence of increased risk for distances beyond 50 m, for lower-voltage lines, or for CNS cancers. Our findings did not clearly support an increased childhood leukaemia risk associated with close proximity (<50 m) to higher voltage lines, but could be consistent with a small increased risk. Reports of increased risk for distances beyond 50 m were not replicated.

  13. Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)

    PubMed Central

    Marcotte, Erin L; Thomopoulos, Thomas P; Infante-Rivard, Claire; Clavel, Jacqueline; Petridou, Eleni Th; Schüz, Joachim; Ezzat, Sameera; Dockerty, John D; Metayer, Catherine; Magnani, Corrado; Scheurer, Michael E; Mueller, Beth A; Mora, Ana M; Wesseling, Catharina; Skalkidou, Alkistis; Rashed, Wafaa M; Francis, Stephen S; Ajrouche, Roula; Erdmann, Friederike; Orsi, Laurent; Spector, Logan G

    2017-01-01

    Summary Background Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. Methods We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. Findings The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1.06 (95% CI 0.99–1.13), and was significant for prelabour caesarean delivery and ALL (1.23 [1.04-1.47]; p=0.018). Emergency caesarean delivery was not associated with ALL (OR 1.02 [95% CI 0.81-1.30]). AML was not associated with caesarean delivery (all indications OR 0.99 [95% CI 0.84-1.17]; prelabour caesarean delivery 0.83 [0.54-1.26]; and emergency caesarean delivery 1.05 [0.63-1.77]). Interpretation Our

  14. Life-threatening complications associated with acute monocytic leukaemia after dental treatment.

    PubMed

    Koulocheris, P; Metzger, M C; Kesting, M R; Hohlweg-Majert, B

    2009-03-01

    It is highly recommended to conduct a prophylactic check for any dental problems on patients who suffer from leukaemia before chemotherapy begins. Bacteraemia caused by oral microflora may be very dangerous for patients with haematological malignancies. However, it should be noted that the prophylactic process itself might bring about life-threatening complications if there is only a short interval between dental treatment and the beginning of chemotherapy, or if the dental treatment is too aggressive. We present a case where this prophylactic procedure produced life-threatening complications for a patient with acute myeloid leukaemia.

  15. The role of multiparametric flow cytometry in the detection of minimal residual disease in acute leukaemia.

    PubMed

    Lee, Denise; Grigoriadis, George; Westerman, David

    2015-12-01

    Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations.

  16. MPLW515L mutation in acute megakaryoblastic leukaemia.

    PubMed

    Hussein, K; Bock, O; Theophile, K; Schulz-Bischof, K; Porwit, A; Schlue, J; Jonigk, D; Kreipe, H

    2009-05-01

    The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPL(W515K/L) mutation by pyrosequencing. In three cases (25%), MPL(W515L) was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPL(W515K/L) (n=4). We conclude that MPL(W515L) occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.

  17. Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

    PubMed Central

    Kutszegi, Nóra; Semsei, Ágnes F.; Gézsi, András; Sági, Judit C.; Nagy, Viktória; Csordás, Katalin; Jakab, Zsuzsanna; Lautner-Csorba, Orsolya; Gábor, Krisztina Míta; Kovács, Gábor T.; Erdélyi, Dániel J.; Szalai, Csaba

    2015-01-01

    L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. PMID:26457809

  18. Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children.

    PubMed

    Jeljeli, Mohamed; Guérin-El Khourouj, Valérie; Porcher, Raphael; Fahd, Mony; Leveillé, Sandrine; Yakouben, Karima; Ouachée-Chardin, Marie; LeGoff, Jerome; Cordeiro, Debora Jorge; Pédron, Beatrice; Baruchel, Andre; Dalle, Jean-Hugues; Sterkers, Ghislaine

    2014-07-01

    The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naïve CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR. © 2014 John Wiley & Sons Ltd.

  19. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.

    PubMed

    Hawkins, Edwin D; Duarte, Delfim; Akinduro, Olufolake; Khorshed, Reema A; Passaro, Diana; Nowicka, Malgorzata; Straszkowski, Lenny; Scott, Mark K; Rothery, Steve; Ruivo, Nicola; Foster, Katie; Waibel, Michaela; Johnstone, Ricky W; Harrison, Simon J; Westerman, David A; Quach, Hang; Gribben, John; Robinson, Mark D; Purton, Louise E; Bonnet, Dominique; Lo Celso, Cristina

    2016-10-27

    It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment

  20. Case of relentless chronic phase of chronic myeloid leukaemia.

    PubMed

    Chan, Onyee; Chen, Hao; Krishnadasan, Ravitharan; Anwer, Faiz

    2016-06-22

    Initial treatment of chronic phase chronic myeloid leukaemia is straightforward in today's era of tyrosine kinase inhibitors. However, managing refractory cases remain a major challenge due to the multiple factors that can influence decision-making, including medication tolerance, disease burden, mutation status, comorbidities, availability of donor, and fitness for an ablative conditioning. We report a male patient presenting with chronic phase chronic myeloid leukaemia who was treated with 5 different tyrosine kinase inhibitors either due to intolerance and/or failed response. He subsequently received 2 haploidentical haematopoietic stem cells transplants before achieving complete remission. This case highlights various treatment options, need for vigilant disease monitoring, and the possibility of complete positive response even after many lines of therapy failure. 2016 BMJ Publishing Group Ltd.

  1. DNA methylation and targeted sequencing of methyltransferases family genes in canine acute myeloid leukaemia, modelling human myeloid leukaemia.

    PubMed

    Bronzini, I; Aresu, L; Paganin, M; Marchioretto, L; Comazzi, S; Cian, F; Riondato, F; Marconato, L; Martini, V; Te Kronnie, G

    2017-09-01

    Tumours shows aberrant DNA methylation patterns, being hypermethylated or hypomethylated compared with normal tissues. In human acute myeloid leukaemia (hAML) mutations in DNA methyltransferase (DNMT3A) are associated to a more aggressive tumour behaviour. As AML is lethal in dogs, we defined global DNA methylation content, and screened the C-terminal domain of DNMT3 family of genes for sequence variants in 39 canine acute myeloid leukaemia (cAML) cases. A heterogeneous pattern of DNA methylation was found among cAML samples, with subsets of cases being hypermethylated or hypomethylated compared with healthy controls; four recurrent single nucleotide variations (SNVs) were found in DNMT3L gene. Although SNVs were not directly correlated to whole genome DNA methylation levels, all hypomethylated cAML cases were homozygous for the deleterious mutation at p.Arg222Trp. This study contributes to understand genetic modifications of cAML, leading up to studies that will elucidate the role of methylome alterations in the pathogenesis of AML in dogs. © 2016 John Wiley & Sons Ltd.

  2. The occurrence of antibodies against single-stranded DNA in the sera of patients with acute and chronic leukaemia.

    PubMed Central

    Izui, S; Lambert, P H; Carpentier, N; Miescher, P A

    1976-01-01

    One hundred and seventy-five sera from thirty-three patients with acute myeloid leukaemia, forty-two patients with chronic myeloid leukaemia and twelve patients with acute lymphatic leukaemia were examined by a radioimmunological technique for the presence of antibodies against single-stranded and double-stranded DNA. The levels of single-stranded DNA binding activity was significantly higher in all three types of leukaemia compared to those of healthy controls. In contrast, none of these sera exhibited a positive reaction with double-stranded DNA. In some cases the level of serum anti-DNA antibodies increased after the decrease of the leucocyte count. The presence of anti-DNA antibodies in leukaemic patients may have some biological significance. PMID:780020

  3. Coffee and tea consumption and risk of leukaemia in an adult population: A reanalysis of the Italian multicentre case-control study.

    PubMed

    Parodi, Stefano; Merlo, Domenico Franco; Stagnaro, Emanuele

    2017-04-01

    Coffee and tea are the most frequently consumed beverages in the world. Their potential effect on the risk of developing different types of malignancies has been largely investigated, but studies on leukaemia in adults are scarce. The present investigation is aimed at evaluating the potential role of regular coffee and tea intake on the risk of adult leukaemia by reanalysing a large population based case-control study carried out in Italy, a country with a high coffee consumption and a low use of green tea. Interviewed subjects, recruited between 1990 and 1993 in 11 Italian areas, included 1771 controls and 651 leukaemia cases. Association between Acute Myeloid Leukaemia (AML), Acute Lymphoid Leukaemia, Chronic Myeloid Leukaemia, Chronic Lymphoid Leukaemia, and use of coffee and tea was evaluated by standard logistic regression. Odds Ratios (OR) were estimated adjusting for the following potential confounders: gender, age, residence area, smoking habit, educational level, previous chemotherapy treatment, alcohol consumption and exposure to electromagnetic fields, radiation, pesticides and aromatic hydrocarbons. No association was observed between regular use of coffee and any type of leukaemia. A small protective effect of tea intake was found among myeloid malignancies, which was more evident among AML (OR=0.68, 95%CI: 0.49-0.94). However, no clear dose-response relation was found. The lower risk of leukaemia among regular coffee consumers, reported by a few of previous small studies, was not confirmed. The protective effect of tea on the AML risk is only partly consistent with results from other investigations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Childhood leukaemia and distance from power lines in California: a population-based case-control study

    PubMed Central

    Crespi, Catherine M; Vergara, Ximena P; Hooper, Chris; Oksuzyan, Sona; Wu, Sheng; Cockburn, Myles; Kheifets, Leeka

    2016-01-01

    Background: Studies have reported an increased risk of childhood leukaemia associated with living near high-voltage electric power transmission lines that extend to distances at which magnetic fields from lines are negligible. We conducted a large records-based case-control study of childhood leukaemia risk in the population living near power lines in California. Methods: The study included 5788 childhood leukaemia and 3308 central nervous system (CNS) cancer cases (for comparison) born in and diagnosed in California (1986–2008), and matched to population-based controls by age and sex. We geocoded birth address and estimated the distance from residence to transmission lines using geographic information systems, aerial imagery, and, for some residences, site visits. Results: For leukaemia, there was a slight excess of cases within 50 m of a transmission line over 200 kV (odds ratio 1.4, 95% confidence interval 0.7–2.7). There was no evidence of increased risk for distances beyond 50 m, for lower-voltage lines, or for CNS cancers. Conclusions: Our findings did not clearly support an increased childhood leukaemia risk associated with close proximity (<50 m) to higher voltage lines, but could be consistent with a small increased risk. Reports of increased risk for distances beyond 50 m were not replicated. PMID:27219016

  5. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis.

    PubMed

    Conter, Valentino; Valsecchi, Maria Grazia; Buldini, Barbara; Parasole, Rosanna; Locatelli, Franco; Colombini, Antonella; Rizzari, Carmelo; Putti, Maria Caterina; Barisone, Elena; Lo Nigro, Luca; Santoro, Nicola; Ziino, Ottavio; Pession, Andrea; Testi, Anna Maria; Micalizzi, Concetta; Casale, Fiorina; Pierani, Paolo; Cesaro, Simone; Cellini, Monica; Silvestri, Daniela; Cazzaniga, Giovanni; Biondi, Andrea; Basso, Giuseppe

    2016-02-01

    Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols. In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival. Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow

  6. T-cell acute lymphoblastic leukaemia after liver transplantation: post-transplant lymphoproliferative disorder or coincidental de novo leukaemia?

    PubMed

    Fang, Yanan; Pinkney, Kerice A; Lee, John C; Gindin, Tatyana; Weiner, Michael A; Alobeid, Bachir; Bhagat, Govind

    2013-03-01

    Post-transplant lymphoproliferative disorders of T-cell origin are quite uncommon, and the vast majority represent neoplasms of mature, post-thymic T- or natural killer cells. Here, we report a rare case of T-cell acute lymphoblastic leukaemia (T-ALL), which occurred in an 18-year-old man who had undergone three liver transplants, initially for biliary atresia and subsequently for graft failure due to chronic rejection. He had received immunosuppression with cyclosporine and tacrolimus, as well as short-term treatment with OKT3. The T-ALL occurred 16 years after the first liver transplant. This case highlights the challenge for classifying rare neoplasms occurring in recipients of solid organ transplants that are currently not recognized to lie within the spectrum of post-transplant lymphoproliferative disorders. Given the long interval between the liver transplants and the development of T-ALL, a coincidental occurrence of the leukaemia cannot be ruled out. However, the potential roles of immunosuppressive therapy and other co-morbid conditions of the individual as possible risk factors for the pathogenesis of T-ALL are discussed. Copyright © 2012 John Wiley & Sons, Ltd.

  7. A Geometric Comparison of the Transformation Loci with Specific and Mobile Capital

    ERIC Educational Resources Information Center

    Colander, David; Gilbert, John; Oladi, Reza

    2008-01-01

    The authors show how the transformation loci in the specific factors model (capital specificity) and the Heckscher-Ohlin-Samuelson model (capital mobility) can be rigorously derived and easily compared by using geometric techniques on the basis of Savosnick geometry. The approach shows directly that the transformation locus with capital…

  8. Electron Resonance Decay into a Biological Function: Decrease in Viability of E. coli Transformed by Plasmid DNA Irradiated with 0.5-18 eV Electrons.

    PubMed

    Kouass Sahbani, S; Cloutier, P; Bass, A D; Hunting, D J; Sanche, L

    2015-10-01

    Transient negative ions (TNIs) are ubiquitous in electron-molecule scattering at low electron impact energies (0-20 eV) and are particularly effective in damaging large biomolecules. Because ionizing radiation generates mostly 0-20 eV electrons, TNIs are expected to play important roles in cell mutagenesis and death during radiotherapeutic cancer treatment, although this hypothesis has never been directly verified. Here, we measure the efficiency of transforming E. coli bacteria by inserting into the cells, pGEM-3ZfL(-) plasmid DNA that confers resistance to the antibiotic ampicillin. Before transformation, plasmids are irradiated with electrons of specific energies between 0.5 and 18 eV. The loss of transformation efficiency plotted as a function of irradiation energy reveals TNIs at 5.5 and 9.5 eV, corresponding to similar states observed in the yields of DNA double strand breaks. We show that TNIs are detectable in the electron-energy dependence of a biological process and can decrease cell viability.

  9. Childhood leukaemia risks: from unexplained findings near nuclear installations to recommendations for future research.

    PubMed

    Laurier, D; Grosche, B; Auvinen, A; Clavel, J; Cobaleda, C; Dehos, A; Hornhardt, S; Jacob, S; Kaatsch, P; Kosti, O; Kuehni, C; Lightfoot, T; Spycher, B; Van Nieuwenhuyse, A; Wakeford, R; Ziegelberger, G

    2014-09-01

    Recent findings related to childhood leukaemia incidence near nuclear installations have raised questions which can be answered neither by current knowledge on radiation risk nor by other established risk factors. In 2012, a workshop was organised on this topic with two objectives: (a) review of results and discussion of methodological limitations of studies near nuclear installations; (b) identification of directions for future research into the causes and pathogenesis of childhood leukaemia. The workshop gathered 42 participants from different disciplines, extending widely outside of the radiation protection field. Regarding the proximity of nuclear installations, the need for continuous surveillance of childhood leukaemia incidence was highlighted, including a better characterisation of the local population. The creation of collaborative working groups was recommended for consistency in methodologies and the possibility of combining data for future analyses. Regarding the causes of childhood leukaemia, major fields of research were discussed (environmental risk factors, genetics, infections, immunity, stem cells, experimental research). The need for multidisciplinary collaboration in developing research activities was underlined, including the prevalence of potential predisposition markers and investigating further the infectious aetiology hypothesis. Animal studies and genetic/epigenetic approaches appear of great interest. Routes for future research were pointed out.

  10. 26 CFR 1.514(e)-1 - Allocation rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Allocation rules. 1.514(e)-1 Section 1.514(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.514(e)-1...

  11. 26 CFR 1.514(e)-1 - Allocation rules.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Allocation rules. 1.514(e)-1 Section 1.514(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.514(e)-1...

  12. CREBBP mutations in relapsed acute lymphoblastic leukaemia

    PubMed Central

    Mullighan, Charles G.; Zhang, Jinghui; Kasper, Lawryn H.; Lerach, Stephanie; Payne-Turner, Debbie; Phillips, Letha A.; Heatley, Sue L.; Holmfeldt, Linda; Collins-Underwood, J. Racquel; Ma, Jing; Buetow, Kenneth H.; Pui, Ching-Hon; Baker, Sharyn D.; Brindle, Paul K.; Downing, James R.

    2010-01-01

    Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways1,2, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse3. However, detailed analysis of sequence mutations in ALL has not been performed. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP)4. The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the HAT domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism

  13. [An immunological approach to acute myeloid leukaemia].

    PubMed

    González, B; Bueno, D; Rubio, P M; San Román, S; Plaza, D; Sastre, A; García-Miguel, P; Fernández, L; Valentín, J; Martínez, I; Pérez-Martínez, A

    2016-04-01

    Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  14. Time series models on analysing mortality rates and acute childhood lymphoid leukaemia.

    PubMed

    Kis, Maria

    2005-01-01

    In this paper we demonstrate applying time series models on medical research. The Hungarian mortality rates were analysed by autoregressive integrated moving average models and seasonal time series models examined the data of acute childhood lymphoid leukaemia.The mortality data may be analysed by time series methods such as autoregressive integrated moving average (ARIMA) modelling. This method is demonstrated by two examples: analysis of the mortality rates of ischemic heart diseases and analysis of the mortality rates of cancer of digestive system. Mathematical expressions are given for the results of analysis. The relationships between time series of mortality rates were studied with ARIMA models. Calculations of confidence intervals for autoregressive parameters by tree methods: standard normal distribution as estimation and estimation of the White's theory and the continuous time case estimation. Analysing the confidence intervals of the first order autoregressive parameters we may conclude that the confidence intervals were much smaller than other estimations by applying the continuous time estimation model.We present a new approach to analysing the occurrence of acute childhood lymphoid leukaemia. We decompose time series into components. The periodicity of acute childhood lymphoid leukaemia in Hungary was examined using seasonal decomposition time series method. The cyclic trend of the dates of diagnosis revealed that a higher percent of the peaks fell within the winter months than in the other seasons. This proves the seasonal occurrence of the childhood leukaemia in Hungary.

  15. 26 CFR 1.72(e)-1T - Treatment of distributions where substantially all contributions are employee contributions...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Treatment of distributions where substantially all contributions are employee contributions (temporary). 1.72(e)-1T Section 1.72(e)-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Items Specifically Included in...

  16. Intussusception: a rare complication in a patient with acute leukaemia after consolidation chemotherapy.

    PubMed

    Qasrawi, Ayman; Abu Ghanimeh, Mouhanna; Abughanimeh, Omar; Qasem, Abdulraheem

    2017-02-28

    Intussusception is telescoping of one segment of the gastrointestinal tract into an adjacent one. It is more common in children than adults. When it occurs in adults, it is usually associated with a lead point. Intussusception is very rare in acute leukaemia and has only been reported in few cases. We present a case of an adult woman who presented with intussusception after a cycle of consolidation chemotherapy with high-dose cytarabine for acute myeloid leukaemia. Other causes of acute abdominal pain were excluded, and the diagnosis was established by CT scan of the abdomen and barium enema. No pathological lead points were found intraoperatively. She underwent a right-sided hemicolectomy with complete recovery. To the best of our knowledge, this is only the fourth case of intussusception that has been reported in an adult patient with acute myeloid leukaemia. 2017 BMJ Publishing Group Ltd.

  17. Side scatter versus CD45 flow cytometric plot can distinguish acute leukaemia subtypes.

    PubMed

    Saksena, Annapurna; Gautam, Parul; Desai, Parth; Gupta, Naresh; Dubey, A P; Singh, Tejinder

    2016-05-01

    Flow cytometry is an important tool to diagnose acute leukaemia. Attempts are being made to find the minimal number of antibodies for correctly diagnosing acute leukaemia subtypes. The present study was designed to evaluate the analysis of side scatter (SSC) versus CD45 flow dot plot to distinguish acute myeloid leukaemia (AML) from acute lymphoblastic leukaemia (ALL), with minimal immunological markers. One hundred consecutive cases of acute leukaemia were evaluated for blast cluster on SSC versus CD45 plots. The parameters studied included visual shape, CD45 and side scatter expression, continuity with residual granulocytes/lymphocytes/monocytes and ratio of maximum width to maximum height (w/h). The final diagnosis of ALL and AML and their subtypes was made by morphology, cytochemistry and immunophenotyping. Two sample Wilcoxon rank-sum (Mann Whitney) test and Kruskal-Wallis equality-of-populations rank tests were applied to elucidate the significance of the above ratios of blast cluster for diagnosis of ALL, AML and their subtypes. Receiver operating characteristic (ROC) curves were generated and the optimal cut-offs of the w/h ratio to distinguish between ALL and AML determined. Of the 100 cases, 57 of ALL and 43 cases of AML were diagnosed. The median w/h ratio of blast population was 3.8 for ALL and 1 for AML (P<0.001). ROC had area under curve of 0.9772.The optimal cut-off of the w/h ratio for distinction of ALL from AML was found to be 1.6. Our findings suggest that if w/h ratio on SSC versus CD45 plot is less than 1.6, AML may be considered, and if it is more than 1.6, ALL may be diagnosed. Using morphometric analysis of the blast cluster on SSC versus CD45, it was possible to distinguish between ALL and AML, and their subtypes.

  18. Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years.

    PubMed

    de la Fuente, Josu; Baruchel, André; Biondi, Andrea; de Bont, Eveline; Dresse, Marie-Françoise; Suttorp, Meinolf; Millot, Frédéric

    2014-10-01

    Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand. © 2014 John Wiley & Sons Ltd.

  19. Diagnosis of haematological disease using anti-i. II. Distinction between acute myeloblastic and acute lymphoblastic leukaemia.

    PubMed

    Shumak, K H; Rachkewich, R A; Beldotti, L E

    1979-03-01

    Leukaemic blast cells were obtained from the blood of six patients with acute lymphoblastic leukaemia (ALL) and 15 patients with acute myeloblastic leukaemia (AML). The blasts were compared with lymphocytes from normal subjects in cytotoxicity and 125I-labelled antibody binding tests using several examples of anti-i. As much i antigen was detected on ALL blasts as on normal lymphocytes; much less i antigen was detected on AML blasts. Studies of three patients with morphologically undifferentiated acute leukaemia suggest that, in tests with anti-i, blasts from such patients react either like lymphoblasts or myeloblasts despite the absence of the corresponding morphological features.

  20. 26 CFR 49.4264(e)-1 - Round trips.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Round trips. 49.4264(e)-1 Section 49.4264(e)-1... TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4264(e)-1 Round trips. (a) In general. For purposes of the regulations in this subpart, a round trip shall be considered to consist of...

  1. 26 CFR 49.4264(e)-1 - Round trips.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Round trips. 49.4264(e)-1 Section 49.4264(e)-1... TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4264(e)-1 Round trips. (a) In general. For purposes of the regulations in this subpart, a round trip shall be considered to consist of...

  2. 26 CFR 49.4264(e)-1 - Round trips.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Round trips. 49.4264(e)-1 Section 49.4264(e)-1... TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4264(e)-1 Round trips. (a) In general. For purposes of the regulations in this subpart, a round trip shall be considered to consist of...

  3. Comprehensive Analysis of MILE Gene Expression Data Set Advances Discovery of Leukaemia Type and Subtype Biomarkers.

    PubMed

    Labaj, Wojciech; Papiez, Anna; Polanski, Andrzej; Polanska, Joanna

    2017-03-01

    Large collections of data in studies on cancer such as leukaemia provoke the necessity of applying tailored analysis algorithms to ensure supreme information extraction. In this work, a custom-fit pipeline is demonstrated for thorough investigation of the voluminous MILE gene expression data set. Three analyses are accomplished, each for gaining a deeper understanding of the processes underlying leukaemia types and subtypes. First, the main disease groups are tested for differential expression against the healthy control as in a standard case-control study. Here, the basic knowledge on molecular mechanisms is confirmed quantitatively and by literature references. Second, pairwise comparison testing is performed for juxtaposing the main leukaemia types among each other. In this case by means of the Dice coefficient similarity measure the general relations are pointed out. Moreover, lists of candidate main leukaemia group biomarkers are proposed. Finally, with this approach being successful, the third analysis provides insight into all of the studied subtypes, followed by the emergence of four leukaemia subtype biomarkers. In addition, the class enhanced DEG signature obtained on the basis of novel pipeline processing leads to significantly better classification power of multi-class data classifiers. The developed methodology consisting of batch effect adjustment, adaptive noise and feature filtration coupled with adequate statistical testing and biomarker definition proves to be an effective approach towards knowledge discovery in high-throughput molecular biology experiments.

  4. How animal models of leukaemias have already benefited patients.

    PubMed

    Ablain, Julien; Nasr, Rihab; Zhu, Jun; Bazarbachi, Ali; Lallemand-Breittenbach, Valérie; de Thé, Hugues

    2013-04-01

    The relative genetic simplicity of leukaemias, the development of which likely relies on a limited number of initiating events has made them ideal for disease modelling, particularly in the mouse. Animal models provide incomparable insights into the mechanisms of leukaemia development and allow exploration of the molecular pillars of disease maintenance, an aspect often biased in cell lines or ex vivo systems. Several of these models, which faithfully recapitulate the characteristics of the human disease, have been used for pre-clinical purposes and have been instrumental in predicting therapy response in patients. We plea for a wider use of genetically defined animal models in the design of clinical trials, with a particular focus on reassessment of existing cancer or non-cancer drugs, alone or in combination. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  5. Methylation-specific digital karyotyping of HPV16E6E7-expressing human keratinocytes identifies novel methylation events in cervical carcinogenesis.

    PubMed

    Steenbergen, Renske D M; Ongenaert, Maté; Snellenberg, Suzanne; Trooskens, Geert; van der Meide, Wendy F; Pandey, Deeksha; Bloushtain-Qimron, Noga; Polyak, Kornelia; Meijer, Chris J L M; Snijders, Peter J F; Van Criekinge, Wim

    2013-09-01

    Transformation of epithelial cells by high-risk human papillomavirus (hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations, often affecting tumour suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping (MSDK) to screen for genome-wide DNA-methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes (CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX-1, PHACTR3, PRDM14, SOST and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation-specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3 and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed significantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16-transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3 and PRDM14 genes in cervical carcinogenesis. These genes may

  6. Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC).

    PubMed

    Marcotte, Erin L; Thomopoulos, Thomas P; Infante-Rivard, Claire; Clavel, Jacqueline; Petridou, Eleni Th; Schüz, Joachim; Ezzat, Sameera; Dockerty, John D; Metayer, Catherine; Magnani, Corrado; Scheurer, Michael E; Mueller, Beth A; Mora, Ana M; Wesseling, Catharina; Skalkidou, Alkistis; Rashed, Wafaa M; Francis, Stephen S; Ajrouche, Roula; Erdmann, Friederike; Orsi, Laurent; Spector, Logan G

    2016-04-01

    Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]). Our results suggest an increased risk of

  7. First-line treatment of chronic myeloid leukaemia.

    PubMed

    O'Dwyer, Michael

    2010-02-01

    Since the introduction of imatinib just over a decade ago, there has been a dramatic change in the treatment and prognosis of early chronic phase chronic myeloid Leukaemia (CML). This review article focuses on recent advances, culminating in the approval of nilotinib by the US Food and Drug Administration for the treatment of adult patients with newly diagnosed CML in the chronic phase.

  8. Are the children of fathers whose jobs involve contact with many people at an increased risk of leukaemia?

    PubMed Central

    Fear, N. T.; Roman, E.; Reeves, G.; Pannett, B.

    1999-01-01

    OBJECTIVES: To investigate the hypothesis that children of men whose jobs involve contact with many people (particularly children) are at an increased risk of leukaemia. METHODS: A population based dataset obtained from routinely collected death certificates involving 14,168 cancer deaths occurring before the age of 15 years registered in England and Wales between 1959-63 and 1970-90. Associations were assessed with the proportional cancer mortality ratio (PCMR), with all childhood cancer deaths forming the standard for comparison. The PCMRs were adjusted, by stratification, for age and year of death (in 1-year bands) and paternal social class (nine categories). Analyses were performed by estimated level of paternal occupational social contact (high, medium, and low) for all leukaemias, leukaemia subtype, age at death, year of death, and individual occupation. RESULTS: Out of 223 occupations, 36 (16%) were identified as having potentially high levels of social contact, and 27 (12%) as having potentially medium levels of social contact. No associations were found between paternal occupational social contact and death during childhood from leukaemia (high social contact: PCMR 94, 95% confidence interval (95% CI) 87 to 102; medium social contact: 101, 95 to 106). No associations were found when the data were analysed by leukaemia subtype, age at death, year of death, or individual occupation. CONCLUSION: The findings presented here do not support the suggestion that childhood leukaemia is related to the amount of social contact that fathers experience at work.   PMID:10472313

  9. The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study.

    PubMed

    Iqbal, Javaid; Nussenzweig, Andre; Lubinski, Jan; Byrski, Tomasz; Eisen, Andrea; Bordeleau, Louise; Tung, Nadine M; Manoukian, Siranoush; Phelan, Catherine M; Sun, Ping; Narod, Steven A

    2016-05-10

    Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers. We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer. We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3-18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11-2.19, P=0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61-6.58, P=0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR=4.76, 95% CI:1.21-12.96, P=0.03), in particular for women who received chemotherapy (SIR=8.11, 2.06-22.07, P=0.007). We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer.

  10. Detection of different Ikaros isoforms in human leukaemias using real-time quantitative polymerase chain reaction.

    PubMed

    Olivero, S; Maroc, C; Beillard, E; Gabert, J; Nietfeld, W; Chabannon, C; Tonnelle, C

    2000-09-01

    The Ikaros gene is an essential regulator in development and haematopoiesis. Dysregulated Ikaros gene expression participates in leukaemic processes, as evidenced in animal models, and by analyses of blast-cell populations from leukaemic patients. We used real-time quantitative polymerase chain reaction (PCR) to evaluate the relative abundance of several Ikaros transcript isoforms in a variety of leukaemic-cell samples. Total RNA was isolated from bone-marrow or blood-cell samples collected at diagnosis in children or adult patients, 18 of whom had acute myeloblastic leukaemia (AML), 61 of whom had acute lymphoblastic leukaemia (ALL) and 11 of whom had chronic myeloid leukaemia (CML). The ratio (Ik1 + Ik2)/(Ik1 + Ik2 + Ik4 + Ik7 + Ik8) ranged from 13.5% to 85% and was lower (P < 0. 05) in samples from patients with m-bcr-abl ALL. An alternative splicing resulting in the deletion of 30 nucleotides at the end of exon 6 was observed in leukaemic samples, and in normal thymus and bone marrow. Our results are consistent with previous reports and suggest that the pattern of expression of the different human Ikaros isoforms are not homogeneous among different subsets of leukaemias.

  11. Glucocorticoid sensitisation in Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia by the pan-BCL-2 family inhibitors gossypol and AT-101.

    PubMed

    Spijkers-Hagelstein, Jill A P; Schneider, Pauline; Pinhanços, Sandra Mimoso; Garrido Castro, Patricia; Pieters, Rob; Stam, Ronald W

    2014-06-01

    Resistance to glucocorticoids (GCs) remains a major problem in the treatment of infants with acute lymphoblastic leukaemia (ALL) carrying Mixed Lineage Leukaemia (MLL) translocations. Despite intensive research, the mechanism(s) underlying GC resistance remain poorly understood. Recent studies suggested an important role for the pro-survival BCL-2 family member MCL1 in GC resistance in MLL-rearranged ALL. We exposed GC-resistant MLL-rearranged SEMK2 cells to potent MCL1-inhibiting agents, including gossypol, AT-101, rapamycin, SU9516 and obatoclax (GX15-070) and determined GC sensitisation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays. Using Western blotting we analysed the protein expression of most BCL-2 family members in MLL-rearranged SEMK2 cells after treatment with potent MCL-1 inhibiting agents. Only gossypol and its synthetic analogue AT-101 induced GC sensitivity in MLL-rearranged ALL cells. Remarkably, the GC-sensitising effects of gossypol and AT-101 appeared not to be mediated by down-regulation MCL1 or other anti-apoptotic BCL-2 family members, but rather involved up-regulation of multiple pro-apoptotic BCL-2 family members, in particular that of BIM and BID. In conclusion, gossypol and AT-101 induce GC sensitivity in MLL-rearranged ALL cells, most likely mediated by the activation of BID and BIM without the necessity to down-regulate anti-apoptotic BCL-2 family members like MCL1. Hence, co-administration of either gossypol or AT-101 during GC treatment of GC-resistant MLL-rearranged ALL patients may overcome GC resistance and improve prognosis in this high-risk childhood leukaemia. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12).

    PubMed

    Panagopoulos, Ioannis; Kerndrup, Gitte; Carlsen, Niels; Strömbeck, Bodil; Isaksson, Margareth; Johansson, Bertil

    2007-01-01

    Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1(SETBP1) fusion signals; other analyses showed that exon 12 of NUP98 was fused in-frame with exon 5 of SETBP1. Nested polymerase chain reaction did not amplify the reciprocal SETBP1/NUP98, suggesting that NUP98/SETBP1 transcript is pathogenetically important. SETBP1 has previously not been implicated in leukaemias; however, it encodes a protein that specifically interacts with SET, fused to NUP214 in a case of acute undifferentiated leukaemia.

  13. Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission.

    PubMed

    Lee, Joyce S-S; Frederiksen, Peter; Kossard, Steven

    2008-02-01

    A 70-year old Caucasian man with chronic lymphocytic leukaemia developed trichodysplasia spinulosa 2 months after ceasing chemotherapy. Histological features characteristic to this condition include dilated and enlarged hair follicles, hyperplastic hair bulbs, hyperplasia of inner root sheath cells with numerous large, eosinophilic, trichohyaline granules, and hypercornification. Although he was in remission for chronic lymphocytic leukaemia, lesions were slowly progressive 15 months after cessation of chemotherapy. We also describe a painless pull-test where spicules can be easily plucked and assessed microscopically for inner root sheath keratinization, or observed with surface microscopy in a clinic setting.

  14. Acute leukaemia and myelodysplastic syndromes with chromosomal rearrangement involving 11q23 locus, but not MLL gene.

    PubMed

    Zuo, Wenli; Wang, Sa A; DiNardo, Courtney; Yabe, Mariko; Li, Shaoying; Medeiros, L Jeffrey; Tang, Guilin

    2017-03-01

    Chromosome 11q23 translocations, resulting in MLL (KMT2A ) rearrangement, have been well characterised in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). However, little is known of haematopoietic neoplasms associated with 11q23 translocation but without MLL rearrangement (11q23+/ MLL -). The aim of this study is to characterise such cases with 11q23+/ MLL -. We retrospectively searched our database for cases with haematopoietic malignancies with 11q23+/ MLL -. We identified nine patients, two with AML, two with B-lymphoblastic leukaemia (B-ALL); two with T-lymphoblastic leukaemia (T-ALL), two with myelodysplastic syndrome (MDS) and one with chronic myelomonocytic leukaemia (CMML). The translocations included t(X;11)(p11.2;q23), t(2;11)(p21;q23), t(6;11)(q27;q23), t(8;9;11)(q13;q13;q23), t(11;11)(p15;q23), t(11;14)(q23;q24) and t(11;15)(q23;q14). Five of six patients with acute leukaemia had received chemotherapy and detection of 11q23 translocation occurred at time of disease relapse. Both patients with MDS and the patient with CMML had 11q23 translocation detected at time of initial diagnosis, all three patients progressed to AML after >1 year on hypomethylating agent therapy. All patients received risk-adapted therapies, including stem cell transplant in five patients. At the last follow-up, eight patients died with a median overall survival of 14 months. 11q23+/ MLL - occurs rarely, involving different partner chromosomes and showing clinical and pathological features and disease subtypes different from those cases with MLL rearrangement. 11q23+/ MLL - appears to be associated with clonal evolution/disease progression in acute leukaemia, a high risk for AML progression in MDS/CMML and a high incidence of disease relapse. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Feedback regulation in a stem cell model with acute myeloid leukaemia.

    PubMed

    Jiao, Jianfeng; Luo, Min; Wang, Ruiqi

    2018-04-24

    The haematopoietic lineages with leukaemia lineages are considered in this paper. In particular, we mainly consider that haematopoietic lineages are tightly controlled by negative feedback inhibition of end-product. Actually, leukemia has been found 100 years ago. Up to now, the exact mechanism is still unknown, and many factors are thought to be associated with the pathogenesis of leukemia. Nevertheless, it is very necessary to continue the profound study of the pathogenesis of leukemia. Here, we propose a new mathematical model which include some negative feedback inhibition from the terminally differentiated cells of haematopoietic lineages to the haematopoietic stem cells and haematopoietic progenitor cells in order to describe the regulatory mechanisms mentioned above by a set of ordinary differential equations. Afterwards, we carried out detailed dynamical bifurcation analysis of the model, and obtained some meaningful results. In this work, we mainly perform the analysis of the mathematic model by bifurcation theory and numerical simulations. We have not only incorporated some new negative feedback mechanisms to the existing model, but also constructed our own model by using the modeling method of stem cell theory with probability method. Through a series of qualitative analysis and numerical simulations, we obtain that the weak negative feedback for differentiation probability is conducive to the cure of leukemia. However, with the strengthening of negative feedback, leukemia will be more difficult to be cured, and even induce death. In contrast, strong negative feedback for differentiation rate of progenitor cells can promote healthy haematopoiesis and suppress leukaemia. These results demonstrate that healthy progenitor cells are bestowed a competitive advantage over leukaemia stem cells. Weak g 1 , g 2 , and h 1 enable the system stays in the healthy state. However, strong h 2 can promote healthy haematopoiesis and suppress leukaemia.

  16. Severe asymptomatic hypophosphataemia in a child with T-acute lymphoblastic leukaemia.

    PubMed

    Zakaria, N H; Sthaneshwar, P; Shanmugam, H

    2017-12-01

    Hypophosphataemia is a metabolic disorder that is commonly encountered in critically ill patients. Phosphate has many roles in physiological functions, thus the depletion of serum phosphate could lead to impairment in multiple organ systems, which include the respiratory, cardiovascular, neurological and muscular systems and haematological and metabolic functions. Hypophosphataemia is defined as plasma phosphate level below 0.80 mmol per litre (mmol/L) and can be further divided into subgroups of mild (plasma phosphate of 0.66 to 0.79 mmol/L), moderate (plasma phosphate of 0.32 to 0.65 mmol/L) and severe (plasma phosphate of less than 0.32 mmol/L). The causes of hypophosphataemia include inadequate phosphate intake, decreased intestinal absorption, gastrointestinal or renal phosphate loss, and redistribution of phosphate into cells. Symptomatic hypophosphataemia associated with haematological malignancies has been reported infrequently. We report here a case of asymptomatic severe hypophosphataemia in a child with acute T-cell lymphoblastic leukaemia. A 14-year-old Chinese boy was diagnosed to have acute T cell lymphoblastic leukaemia (ALL). His serum biochemistry results were normal except inorganic phosphate and lactate dehydrogenase levels. The serum inorganic phosphate level was 0.1mmol/L and the level was low on repeated analysis. The child had no symptoms related to low phosphate levels. The possible causes of low phosphate were ruled out and urine Tmp/GFR was normal. Chemotherapy regime was started and the serum phosphate levels started to increase. Hypophosphataemia in leukaemia was attributed to shift of phosphorus into leukemic cells and excessive cellular phosphate consumption by rapidly proliferating cells. Several reports of symptomatic hypophosphataemia in myelogenous and lymphoblastic leukaemia in adults have been reported. To our knowledge this is the first case of severe asymptomatic hypophosphataemia in a child with ALL.

  17. Clinical presentation of childhood leukaemia: a systematic review and meta-analysis.

    PubMed

    Clarke, Rachel T; Van den Bruel, Ann; Bankhead, Clare; Mitchell, Christopher D; Phillips, Bob; Thompson, Matthew J

    2016-10-01

    Leukaemia is the most common cancer of childhood, accounting for a third of cases. In order to assist clinicians in its early detection, we systematically reviewed all existing data on its clinical presentation and estimated the frequency of signs and symptoms presenting at or prior to diagnosis. We searched MEDLINE and EMBASE for all studies describing presenting features of leukaemia in children (0-18 years) without date or language restriction, and, when appropriate, meta-analysed data from the included studies. We screened 12 303 abstracts for eligibility and included 33 studies (n=3084) in the analysis. All were cohort studies without control groups. 95 presenting signs and symptoms were identified and ranked according to frequency. Five features were present in >50% of children: hepatomegaly (64%), splenomegaly (61%), pallor (54%), fever (53%) and bruising (52%). An additional eight features were present in a third to a half of children: recurrent infections (49%), fatigue (46%), limb pain (43%), hepatosplenomegaly (42%), bruising/petechiae (42%), lymphadenopathy (41%), bleeding tendency (38%) and rash (35%). 6% of children were asymptomatic on diagnosis. Over 50% of children with leukaemia have palpable livers, palpable spleens, pallor, fever or bruising on diagnosis. Abdominal symptoms such as anorexia, weight loss, abdominal pain and abdominal distension are common. Musculoskeletal symptoms such as limp and joint pain also feature prominently. Children with unexplained illness require a thorough history and focused clinical examination, which should include abdominal palpation, palpation for lymphadenopathy and careful scrutiny of the skin. Occurrence of multiple symptoms and signs should alert clinicians to possible leukaemia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Levels of house dust mite-specific serum immunoglobulin E (IgE) in different cat populations using a monoclonal based anti-IgE enzyme-linked immunosorbent assay.

    PubMed

    Bexley, Jennifer; Hogg, Janice E; Hammerberg, Bruce; Halliwell, Richard E W

    2009-10-01

    Levels of serum immunoglobulin E (IgE) specific for the house dust mites (HDMs) Dermatophagoides farinae (DF) and Dermatophagoides pteronyssinus (DP) in 58 cats with clinical signs suggestive of atopic dermatitis (allergic dermatitis cats), 52 cats with no history of allergic or immunological disease (nonallergic cats) and 26 specific pathogen-free (SPF) cats were measured using a monoclonal anti-IgE enzyme-linked immunosorbent assay. Reactivity to both native and reduced HDM allergens was compared. SPF cats had significantly lower levels of HDM-specific serum IgE than cats with allergic dermatitis and nonallergic cats. The difference in levels of HDM-specific IgE in the serum of cats with allergic dermatitis and nonallergic cats was significant for native DF allergen, but not for native DP allergen or reduced HDM allergens. The results suggest that DF in its native form may be a significant allergen in cats with allergic dermatitis. The clinical relevance of these reactions, however, remains to be proven.

  19. Influence of radiation quality on mouse chromosome 2 deletions in radiation-induced acute myeloid leukaemia.

    PubMed

    Brown, Natalie; Finnon, Rosemary; Manning, Grainne; Bouffler, Simon; Badie, Christophe

    2015-11-01

    Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15-25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality. Crown Copyright © 2015. Published by Elsevier B.V. All rights

  20. [Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia].

    PubMed

    Szerafin, László; Jakó, János; Riskó, Ferenc

    2015-04-01

    The low peripheral absolute lymphocyte and high monocyte count have been reported to correlate with poor clinical outcome in various lymphomas and other cancers. However, a few data known about the prognostic value of absolute monocyte count in chronic lymphocytic leukaemia. The aim of the authors was to investigate the impact of absolute monocyte count measured at the time of diagnosis in patients with chronic lymphocytic leukaemia on the time to treatment and overal survival. Between January 1, 2005 and December 31, 2012, 223 patients with newly-diagnosed chronic lymphocytic leukaemia were included. The rate of patients needing treatment, time to treatment, overal survival and causes of mortality based on Rai stages, CD38, ZAP-70 positivity and absolute monocyte count were analyzed. Therapy was necessary in 21.1%, 57.4%, 88.9%, 88.9% and 100% of patients in Rai stage 0, I, II, III an IV, respectively; in 61.9% and 60.8% of patients exhibiting CD38 and ZAP-70 positivity, respectively; and in 76.9%, 21.2% and 66.2% of patients if the absolute monocyte count was <0.25 G/l, between 0.25-0.75 G/l and >0.75 G/l, respectively. The median time to treatment and the median overal survival were 19.5, 65, and 35.5 months; and 41.5, 65, and 49.5 months according to the three groups of monocyte counts. The relative risk of beginning the therapy was 1.62 (p<0.01) in patients with absolute monocyte count <0.25 G/l or >0.75 G/l, as compared to those with 0.25-0.75 G/l, and the risk of overal survival was 2.41 (p<0.01) in patients with absolute monocyte count lower than 0.25 G/l as compared to those with higher than 0.25 G/l. The relative risks remained significant in Rai 0 patients, too. The leading causes of mortality were infections (41.7%) and the chronic lymphocytic leukaemia (58.3%) in patients with low monocyte count, while tumours (25.9-35.3%) and other events (48.1 and 11.8%) occurred in patients with medium or high monocyte counts. Patients with low and high monocyte

  1. Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

    PubMed

    Upadhyay, Vivek A; Fathi, Amir T

    2018-03-01

    This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

  2. [A brief history of treatments for childhood acute lymphoblastic leukaemia].

    PubMed

    Leverger, Guy; Baruchel, André; Schaison, Gérard

    2009-10-01

    Acute lymphoblastic leukaemia is the most frequent childhood malignancy. The first effective drugs, which provided only short-lived complete remission, started to be used in the 1950s. All the effective drugs currently in use were discovered in the 1960s, when the first multidrug chemotherapy regimens were shown to confer prolonged complete remission, raising the possibility of a cure. Simultaneously, progress in our knowledge of leukaemic cells, and the identification of prognostic factors such as leukocytosis, age, cytogenetic and molecular abnormalities, and the early therapeutic response of leukaemic cells, led to randomized multicenter national and international trials. As a result, the chance of cure increased gradually over the last three decades. In rich countries, the overall survival rate among children with acute lymphoblastic leukaemia now reaches 85 to 90%.

  3. First-line treatment of chronic myeloid leukaemia

    PubMed Central

    O'Dwyer, Michael

    2010-01-01

    Since the introduction of imatinib just over a decade ago, there has been a dramatic change in the treatment and prognosis of early chronic phase chronic myeloid Leukaemia (CML). This review article focuses on recent advances, culminating in the approval of nilotinib by the US Food and Drug Administration for the treatment of adult patients with newly diagnosed CML in the chronic phase. PMID:23556068

  4. Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.

    PubMed

    Usumoto, Yosuke; Sameshima, Naomi; Tsuji, Akiko; Kudo, Keiko; Nishida, Naoki; Ikeda, Noriaki

    2014-12-01

    We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives.

  5. ARPA-E: Innovating Today. Transforming Tomorrow.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rohlfing, Eric; Brown, Kristen; Gerbi, Jennifer

    Innovation and entrepreneurism are integral parts of America’s national fiber and driving forces behind many of the technologies that define our modern lives. It’s this entrepreneurial spirit – in conjunction with world-class institutions and talent – that enable the United States to develop advanced energy technologies that can solve the many challenges we face. Featuring remarks from multiple ARPA-E staff, this video explores how ARPA-E leverages our nation’s resources to help nurture and grow America’s energy innovation community. The video also incorporates footage shot onsite with several ARPA-E awardees who are innovating solutions to transform tomorrow’s energy future.

  6. Trends and territorial inequalities of incidence and survival of childhood leukaemia and their relations to socioeconomic status in Hungary, 1971-2015.

    PubMed

    Jakab, Zsuzsanna; Juhasz, Attila; Nagy, Csilla; Schuler, Dezso; Garami, Miklos

    2017-09-01

    The Hungarian Childhood Cancer Registry, a population-based national registry of the Hungarian Paediatric Haemato-Oncology Network founded in 1971, monitors the incidence and mortality of childhood cancer. Our aims were to carry out a longitudinal study to investigate the trends and spatial inequalities of incidence and survival of leukaemia, and the association between survival and deprivation in Hungary. All cases of childhood leukaemia and myelodysplasia were analysed (3157 cases, 1971-2015, age: 0-14 years). Time trends and the annual percentage change in direct standardized incidence and mortality were assessed. Survival and association with deprivation were assessed using the Kaplan-Meier method and Cox regression. Incidence rates of leukaemia (23.5-56.0/million) increased with an average annual percent change (AAPC) of 1%, determined by an increase in the incidence of acute lymphoblastic leukaemia (14.6-39.2/million, AAPC: 1.25%). Kaplan-Meier analysis showed a significant improvement in overall survival over the study period. Starting from 25% of cases surviving 5 years in the 70s; the overall 5-year survival reached 80% by 2010. Survival differences were observed with sex, leukaemia type and age at diagnosis. A reverse association was found in the survival probability of leukaemia by degree of deprivation. The Cox proportional hazards model verified a significant reverse association with deprivation [hazard ratio=1.08 (1.04-1.12)]. This is the first nationwide study to confirm the prognostic role of deprivation on the basis of a large cohort of patients with childhood leukaemia during a 45-year period. To maintain further improvement in treatment results, it is important to detect inequalities. Our results showed that deprivation may also be important in the survival of leukaemia.

  7. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial.

    PubMed

    Wermke, Martin; Eckoldt, Julia; Götze, Katharina S; Klein, Stefan A; Bug, Gesine; de Wreede, Liesbeth C; Kramer, Michael; Stölzel, Friedrich; von Bonin, Malte; Schetelig, Johannes; Laniado, Michael; Plodeck, Verena; Hofmann, Wolf-Karsten; Ehninger, Gerhard; Bornhäuser, Martin; Wolf, Dominik; Theurl, Igor; Platzbecker, Uwe

    2018-05-01

    The effect of systemic iron overload on outcomes after allogeneic haemopoietic cell transplantation (HCT) has been a matter of substantial debate. We aimed to investigate the predictive value of both stored (MRI-derived liver iron content) and biologically active iron (enhanced labile plasma iron; eLPI) on post-transplantation outcomes in patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogenic HCT. The prospective, multicentre, observational, ALLogeneic Iron inVEstigators (ALLIVE) trial recruited patients at five centres in Germany. We enrolled patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogeneic HCT. Patients underwent cytotoxic conditioning for a median of 6 days (IQR 6-7) before undergoing allogeneic HCT and were followed up for up to 1 year (±3 months) post-transplantation. eLPI was measured in serum samples with the FeROS eLPI kit (Aferrix, Tel-Aviv, Israel) and values greater than 0·4 μmol/L were considered to represent raised eLPI. Liver iron content was measured by MRI. The primary endpoints were the quantitative delineation of eLPI dynamics during allogeneic HCT and the correlation coefficient between liver iron content before HCT and dynamic eLPI (eLPI dyn ; maximum eLPI minus baseline eLPI). All patients with available data were included in all analyses. This is the final analysis of this completed trial, which is registered with ClinicalTrials.gov, number NCT01746147. Between Dec 13, 2012, and Dec 23, 2014, 112 patients underwent allogeneic HCT. Liver iron content before allogeneic HCT was not significantly correlated with eLPI dyn (ρ=0·116, p=0·22). Serum eLPI concentrations rapidly increased during conditioning, and most (79 [73%] of 108) patients had raised eLPI by the day of transplantation. Patients with a pretransplant liver iron content greater than or equal to 125 μmol/g had an increased incidence of non-relapse mortality (20%, 95% CI 14-26) compared with those with lower

  8. Leukaemia Evoked with 7,8,12-Trimethylbenz(a)Anthracene in Rat. III. Changes in Lymphoid Tissues

    PubMed Central

    Bird, C. C.; Mainzer, K.

    1972-01-01

    Profound changes in the level of certain dehydrogenase enzymes were observed in lymphoid tissues of rats involved by erythroblastic stem cell leukaemia. In lymphoid tissues free of leukaemic involvement, activity of malate dehydrogenase (MDH) always exceeded that of lactate dehydrogenase (LDH). In those which contained substantial infiltrates of leukaemic cells, activity of LDH was increased while MDH activity was reduced. In leukaemic spleen significant changes were observed in the molecular forms of LDH; the proportion of LDH-5 (muscle-type LDH) was greatly increased while the other molecular forms were reduced. The spleen of rats with leukaemia exhibited a marked increase in the normal level of aerobic and anaerobic glycolysis but the rate of respiration was unchanged. The terminal stages of stem cell leukaemia in the rat are characterized by wide-spread leukaemic infiltration of liver and other tissues. Lymph node involvement, however, was found to be selective. Coeliac lymph nodes greatly exceeded other lymph node groups in their incidence of leukaemic involvement. It is considered that the selective nature of lymph node involvement in stem cell leukaemia derives from topographical considerations. PMID:5085676

  9. Liquid chromatographic determination of urinary 5-methyl-2'-deoxycytidine and pseudouridine as potential biological markers for leukaemia.

    PubMed

    Zambonin, C G; Aresta, A; Palmisano, F; Specchia, G; Liso, V

    1999-12-01

    A simple reversed-phase liquid chromatographic (LC) method for the determination of urinary 5-methyl-2'-deoxycytidine (m5dCyd), recently claimed (on the basis of an imuno-technique) to be a potential marker for leukaemia, has been developed. Sample pre-treatment is based on a microcolumn clean-up step with an average recovery of 79% and a RSD of 3%. Detection limit was 0.2 microg/ml which is about tenfold lower than levels previously measured by an ELISA method in urine of healthy individuals. The creatinine (Cre) excretion, necessary for normalising the m5dCyd excretion, was evaluated by ion-pair liquid chromatography which permitted the simultaneous determination of pseudouridine (psi), a modified nucleoside also potentially useful as a marker for leukaemia. The described LC procedures were applied to the analysis of urine samples from healthy individuals and leukaemia patients. While the urinary psi/Cre ratio was found significantly increased for leukaemia patients, the urinary m5dCyd levels in healthy individuals were below the detection limits and did not increase in presence of the malignant disease.

  10. Remission death in acute lymphoblastic leukaemia: a changing pattern.

    PubMed Central

    Atra, A; Richards, S M; Chessells, J M

    1993-01-01

    The pattern of remission deaths was examined in 842 children with acute lymphoblastic leukaemia (ALL) treated at a single centre over 18 years. The mortality rate from leukaemia fell significantly during three consecutive time periods during which treatment became progressively more intensive and that during remission induction fell from 3.5% to under 1%, but the rate of death in remission stayed constant at 5-6%. The factors associated with an increased risk of remission death were: young age, a higher leucocyte count, bone marrow transplantation, and Down's syndrome. The pattern of remission deaths changed over the years; measles and herpes viruses decreased while deaths associated with periods of intensification and gut toxicity increased. Four children developed second neoplasms. Treatment of ALL is still associated with a significant risk of death in remission but the pattern of infective deaths has changed. Many should be avoidable by provision of adequate supportive care, close supervision after periods of intensive treatment, and appropriate antibiotic, antifungal, and cytokine therapy. PMID:8257173

  11. Feline leukaemia virus: half a century since its discovery.

    PubMed

    Willett, Brian J; Hosie, Margaret J

    2013-01-01

    In the early 1960s, Professor William (Bill) F.H. Jarrett was presented with a time-space cluster of cats with lymphoma identified by a local veterinary practitioner, Harry Pfaff, and carried out experiments to find if the condition might be caused by a virus, similar to lymphomas noted previously in poultry and mice. In 1964, the transmission of lymphoma in cats and the presence of virus-like particles that resembled 'the virus of murine leukaemias' in the induced tumours were reported in Nature. These seminal studies initiated research on feline leukaemia virus (FeLV) and launched the field of feline retrovirology. This review article considers the way in which some of the key early observations made by Bill Jarrett and his coworkers have developed in subsequent years and discusses progress that has been made in the field since FeLV was first discovered. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Transformation-specific interaction of the bovine papillomavirus E5 oncoprotein with the platelet-derived growth factor receptor transmembrane domain and the epidermal growth factor receptor cytoplasmic domain.

    PubMed Central

    Cohen, B D; Goldstein, D J; Rutledge, L; Vass, W C; Lowy, D R; Schlegel, R; Schiller, J T

    1993-01-01

    The bovine papillomavirus E5 transforming protein appears to activate both the epidermal growth factor receptor (EGF-R) and the platelet-derived growth factor receptor (PDGF-R) by a ligand-independent mechanism. To further investigate the ability of E5 to activate receptors of different classes and to determine whether this stimulation occurs through the extracellular domain required for ligand activation, we constructed chimeric genes encoding PDGF-R and EGF-R by interchanging the extracellular, membrane, and cytoplasmic coding domains. Chimeras were transfected into NIH 3T3 and CHO(LR73) cells. All chimeras expressed stable protein which, upon addition of the appropriate ligand, could be activated as assayed by tyrosine autophosphorylation and biological transformation. Cotransfection of E5 with the wild-type and chimeric receptors resulted in the ligand-independent activation of receptors, provided that a receptor contained either the transmembrane domain of the PDGF-R or the cytoplasmic domain of the EGF-R. Chimeric receptors that contained both of these domains exhibited the highest level of E5-induced biochemical and biological stimulation. These results imply that E5 activates the PDGF-R and EGR-R by two distinct mechanisms, neither of which specifically involves the extracellular domain of the receptor. Consistent with the biochemical and biological activation data, coimmunoprecipitation studies demonstrated that E5 formed a complex with any chimera that contained a PDGF-R transmembrane domain or an EGF-R cytoplasmic domain, with those chimeras containing both domains demonstrating the greatest efficiency of complex formation. These results suggest that although different domains of the PDGF-R and EGF-R are required for E5 activation, both receptors are activated directly by formation of an E5-containing complex. Images PMID:8394451

  13. Indoor transformer stations and ELF magnetic field exposure: use of transformer structural characteristics to improve exposure assessment.

    PubMed

    Okokon, Enembe Oku; Roivainen, Päivi; Kheifets, Leeka; Mezei, Gabor; Juutilainen, Jukka

    2014-01-01

    Previous studies have shown that populations of multiapartment buildings with indoor transformer stations may serve as a basis for improved epidemiological studies on the relationship between childhood leukaemia and extremely-low-frequency (ELF) magnetic fields (MFs). This study investigated whether classification based on structural characteristics of the transformer stations would improve ELF MF exposure assessment. The data included MF measurements in apartments directly above transformer stations ("exposed" apartments) in 30 buildings in Finland, and reference apartments in the same buildings. Transformer structural characteristics (type and location of low-voltage conductors) were used to classify exposed apartments into high-exposure (HE) and intermediate-exposure (IE) categories. An exposure gradient was observed: both the time-average MF and time above a threshold (0.4 μT) were highest in the HE apartments and lowest in the reference apartments, showing a statistically significant trend. The differences between HE and IE apartments, however, were not statistically significant. A simulation exercise showed that the three-category classification did not perform better than a two-category classification (exposed and reference apartments) in detecting the existence of an increased risk. However, data on the structural characteristics of transformers is potentially useful for evaluating exposure-response relationship.

  14. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

    PubMed

    Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

    2016-06-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Specificity of perceptual processing in rereading spatially transformed materials.

    PubMed

    Horton, K D; McKenzie, B D

    1995-05-01

    While most studies using the task of reading spatially transformed text do not reveal evidence of specific perceptual transfer, a study by Masson (1986, Experiment 3) provides clear evidence of such effects. Several experiments were designed to identify the basis for this empirical discrepancy. The only substantive evidence of specific perceptual transfer occurred when the words were presented in an unfamiliar typography, although each study suggested a trend toward perceptual specificity effects. The results are discussed in terms of Graf and Ryan's (1990) ideas about the role of distinctive memory representations.

  16. Incidence of childhood leukaemia and non-Hodgkin's lymphoma in the vicinity of nuclear sites in Scotland, 1968-93.

    PubMed Central

    Sharp, L; Black, R J; Harkness, E F; McKinney, P A

    1996-01-01

    OBJECTIVES: The primary aims were to investigate the incidence of leukaemia and non-Hodgkin's lymphoma in children resident near seven nuclear sites in Scotland and to determine whether there was any evidence of a gradient in risk with distance of residence from a nuclear site. A secondary aim was to assess the power of statistical tests for increased risk of disease near a point source when applied in the context of census data for Scotland. METHODS: The study data set comprised 1287 cases of leukaemia and non-Hodgkin's lymphoma diagnosed in children aged under 15 years in the period 1968-93, validated for accuracy and completeness. A study zone around each nuclear site was constructed from enumeration districts within 25 km. Expected numbers were calculated, adjusting for sex, age, and indices of deprivation and urban-rural residence. Six statistical tests were evaluated. Stone's maximum likelihood ratio (unconditional application) was applied as the main test for general increased incidence across a study zone. The linear risk score based on enumeration districts (conditional application) was used as a secondary test for declining risk with distance from each site. RESULTS: More cases were observed (O) than expected (E) in the study zones around Rosyth naval base (O/E 1.02), Chapelcross electricity generating station (O/E 1.08), and Dounreay reprocessing plant (O/E 1.99). The maximum likelihood ratio test reached significance only for Dounreay (P = 0.030). The linear risk score test did not indicate a trend in risk with distance from any of the seven sites, including Dounreay. CONCLUSIONS: There was no evidence of a generally increased risk of childhood leukaemia and non-Hodgkin's lymphoma around nuclear sites in Scotland, nor any evidence of a trend of decreasing risk with distance from any of the sites. There was a significant excess risk in the zone around Dounreay, which was only partially accounted for by the sociodemographic characteristics of the area

  17. Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey.

    PubMed

    Beguin, Y; Selleslag, D; Meers, S; Graux, C; Bries, G; Deeren, D; Vrelust, I; Ravoet, C; Theunissen, K; Voelter, V; Potier, H; Trullemans, F; Noens, L; Mineur, P

    2015-02-01

    We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. The median age of patients was 74·7 (range: 43·9-87·8) years; 69·4% had MDS, 26·5% had primary or secondary AML, and 4·1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67·3%, 28·6%, and 18·4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41·4% had CR, PR, or HI, 41·4% had SD, and 17·2% had TF. Among AML patients (n = 9), 44·4% had CR or PR, 33·3% had SD, and 22·2% had TF. TI was observed in 14/32 (43·8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0·571 (0·422-0·696). Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

  18. Infusion of a non-HLA-matched ex-vivo expanded cord blood progenitor cell product after intensive acute myeloid leukaemia chemotherapy: a phase 1 trial.

    PubMed

    Delaney, Colleen; Milano, Filippo; Cicconi, Laura; Othus, Megan; Becker, Pamela S; Sandhu, Vicky; Nicoud, Ian; Dahlberg, Ann; Bernstein, Irwin D; Appelbaum, Frederick R; Estey, Elihu H

    2016-07-01

    The intensive chemotherapy regimens used to treat acute myeloid leukaemia routinely result in serious infections, largely due to prolonged neutropenia. We investigated the use of non-HLA-matched ex-vivo expanded cord blood progenitor cells to accelerate haemopoietic recovery and reduce infections after chemotherapy. We enrolled patients with a diagnosis of acute myeloid leukaemia by WHO criteria and aged 18-70 years inclusive at our institution (Fred Hutchinson Cancer Research Center) into this phase 1 trial. The primary endpoint of the study was safety of infusion of non-HLA-matched expanded cord blood progenitor cells after administration of clofarabine, cytarabine, and granulocyte-colony stimulating factor priming. The protocol is closed to accrual and analysis was performed per protocol. The trial is registered with ClinicalTrials.gov, NCT01031368. Between June 29, 2010, and June 26, 2012, 29 patients with acute myeloid leukaemia (19 newly diagnosed, ten relapsed or refractory) were enrolled. The most common adverse events were fever (27 [93%] of 29 patients) and infections (25 [86%] of 29 patients). We observed one case of acute infusional toxicity (attributed to an allergic reaction to dimethyl sulfoxide) in the 29 patients enrolled, who received 42 infusions of expanded progenitor cells. The following additional serious but expected adverse events were observed (each in one patient): grade 4 atrial fibrillation, grade 4 febrile neutropenia, lung infection with grade 4 absolute neutrophil count, colon infection with grade 4 absolute neutrophil count, grade 4 changed mental status, and one death from liver failure. No unexpected toxicity or graft-versus-host disease was observed. There was no evidence of in-vivo persistence of the expanded progenitor cell product in any patient beyond 14 days or induced alloimmunisation. Infusion of the expanded progenitor cell product seemed safe and might provide a promising treatment method for patients with acute myeloid

  19. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

    PubMed

    Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

    2015-09-01

    -escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Leukaemia and occupation: a New Zealand Cancer Registry-based case-control Study.

    PubMed

    McLean, David; Mannetje, Andrea 't; Dryson, Evan; Walls, Chris; McKenzie, Fiona; Maule, Milena; Cheng, Soo; Cunningham, Chris; Kromhout, Hans; Boffetta, Paolo; Blair, Aaron; Pearce, Neil

    2009-04-01

    To examine the association between occupation and leukaemia. We interviewed 225 cases (aged 20-75 years) notified to the New Zealand Cancer Registry during 2003-04, and 471 controls randomly selected from the Electoral Roll collecting demographic details, information on potential confounders and a comprehensive employment history. Associations between occupation and leukaemia were analysed using logistic regression adjusted for gender, age, ethnicity and smoking. Elevated odds ratios (ORs) were observed in agricultural sectors including horticulture/fruit growing (OR: 2.62, 95% confidence interval (CI): 1.51, 4.55), plant nurseries (OR: 7.51, 95% CI: 1.85, 30.38) and vegetable growing (OR: 3.14, 95% CI: 1.18, 8.40); and appeared greater in women (ORs: 4.71, 7.75 and 7.98, respectively). Elevated ORs were also observed in market farmers/crop growers (OR: 1.84, 95% CI: 1.12, 3.02), field crop/vegetable growers (OR: 3.98, 95% CI: 1.46, 10.85), market gardeners (OR: 5.50, 95% CI: 1.59, 19.02), and nursery growers/workers (OR: 4.23, 95% CI: 1.34, 13.35); also greater in women (ORs: 3.48, 7.62, 15.74 and 11.70, respectively). These elevated ORs were predominantly for chronic lymphocytic leukaemia (CLL). Several associations persisted after semi-Bayes adjustment. Elevated ORs were observed in rubber/plastics products machine operators (OR: 3.76, 95% CI: 1.08, 13.08), predominantly in plastic product manufacturing. CLL was also elevated in tailors and dressmakers (OR: 7.01, 95% CI: 1.78, 27.68), cleaners (OR: 2.04, 95% CI: 1.00, 4.14) and builder's labourers (OR: 4.03, 95% CI: 1.30, 12.53). These findings suggest increased leukaemia risks associated with certain agricultural, manufacturing, construction and service occupations in New Zealand.

  1. Transforming Personnel Accessions: Recruiting in the E-Business World

    DTIC Science & Technology

    2002-04-09

    levels of PC-ownership and online access. Finally, the 1999 report found that poor rural households had replaced poor central city households as the...digital divide clearly impacts any transformation to an eBusiness, eEnterprise, and eCommerce etc. model for recruiting. This research will not assume the

  2. Living with the Diagnosis and Treatment of Leukaemia in a Child with Down's Syndrome: A Mother's Reflection

    ERIC Educational Resources Information Center

    Self, Donna

    2008-01-01

    In this article I will discuss the impact of my 2-year-old son's diagnosis and treatment of leukaemia. I will outline the background to being told he had leukaemia before describing the family dynamics that emerged during this time for me, my husband and our other child. My story will focus on managing the practicalities of a long stay in hospital…

  3. Acute myeloid leukaemia diagnosed by intra-oral myeloid sarcoma. A case report.

    PubMed

    Papamanthos, Mattheos K; Kolokotronis, Alexandros E; Skulakis, Haralampos E; Fericean, Angela-Monika A; Zorba, Matina T; Matiakis, Apostolos T

    2010-06-01

    Myeloid sarcoma (MS) is a rare extramedullary malignant tumor composed of immature myeloid cells. It is strongly associated with a well known or covert acute myeloid leukaemia, chronic myeloproliferative diseases or myelodysplastic syndromes. Intraoral MS scarcely occurs. An unusual case of acute myeloid leukaemia, which was diagnosed by mandibular MS that was developed in the alveolar socket after a dental extraction, is reported. The histological examination (including immunohistochemical analysis) of a subsequent biopsy showed infiltration of the oral mucosa by neoplastic cells. This lesion was therefore classified as acute myeloid leukaemia. The patient was referred to oncologists that confirmed the initial diagnosis. The patient underwent chemotherapy and the mandibular tumor disappeared. Forty days later, a relapse of the disease, which appeared as a great-ulcerated lesion, was developed in the hard palate. Thirty days after the second chemotherapy had finished, a new intraoral tumor was developed in the vestibular maxillary gingiva. Review of the literature shows no report of intraoral relapse and particularly multiple relapse of a MS that involves the oral cavity. Even though MS is encountered infrequently in the oral cavity, it should be considered in the differential diagnosis of conditions (especially tumors) with a similar clinical appearance.

  4. Acute Myeloid Leukaemia Diagnosed by Intra-Oral Myeloid Sarcoma. A Case Report

    PubMed Central

    Papamanthos, Mattheos K.; Skulakis, Haralampos E.; Fericean, Angela-Monika A.; Zorba, Matina T.; Matiakis, Apostolos T.

    2010-01-01

    Myeloid sarcoma (MS) is a rare extramedullary malignant tumor composed of immature myeloid cells. It is strongly associated with a well known or covert acute myeloid leukaemia, chronic myeloproliferative diseases or myelodysplastic syndromes. Intraoral MS scarcely occurs. An unusual case of acute myeloid leukaemia, which was diagnosed by mandibular MS that was developed in the alveolar socket after a dental extraction, is reported. The histological examination (including immunohistochemical analysis) of a subsequent biopsy showed infiltration of the oral mucosa by neoplastic cells. This lesion was therefore classified as acute myeloid leukaemia. The patient was referred to oncologists that confirmed the initial diagnosis. The patient underwent chemotherapy and the mandibular tumor disappeared. Forty days later, a relapse of the disease, which appeared as a great-ulcerated lesion, was developed in the hard palate. Thirty days after the second chemotherapy had finished, a new intraoral tumor was developed in the vestibular maxillary gingiva. Review of the literature shows no report of intraoral relapse and particularly multiple relapse of a MS that involves the oral cavity. Even though MS is encountered infrequently in the oral cavity, it should be considered in the differential diagnosis of conditions (especially tumors) with a similar clinical appearance. PMID:20512638

  5. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.

    PubMed

    Sperling, Adam S; Gibson, Christopher J; Ebert, Benjamin L

    2017-01-01

    Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

  6. Dermatoglyphics in childhood leukaemia: a guide to prognosis and aetiology?

    PubMed Central

    Till, M.; Larrauri, S.; Smith, P. G.

    1978-01-01

    The results of analysis of the dermatoglyphics of 152 children with acute lymphoblastic leukaemia (ALL) (and the first-degree relatives of 54 of them) contrast with those of 31 children with acute myeloblastic leukaemia (AML) (and the first-degree relatives of 25 of them). In ALL our findings suggest that neither genetic susceptibility nor an environmental factor, effective during the early antenatal period, is of aetiological importance; but the response to treatment, assessed as length of first remission, was found to be related to the amount of fingertip pattern. This may have clinical application. In AML there is evidence of a genetically determined factor carrying a high risk of the development of the disease, in that a member of each of 5 different families of the 25 studied bore a rare hypothenar pattern, compared with none in 75 control families. No dermatoglyphic features were of prognostic significance in AML. PMID:277206

  7. Human retroviruses in leukaemia and AIDS: reflections on their discovery, biology and epidemiology.

    PubMed

    Karpas, Abraham

    2004-11-01

    The study of retroviruses has had a profound impact by unveiling an unusual form of viral replication: the multiplication of RNA viruses via a proviral DNA, for which Jan Svoboda provided the experimental model over forty years ago. In 1970 Temin, Mizutani and Baltimore discovered that this group of viruses contains a unique enzyme catalysing the synthesis of a DNA copy of the viral RNA: reverse transcriptase (RT). The discovery of RT has itself had an enormous impact on molecular biology in general, but also stimulated many premature claims of its detection in human disease. Claims by Gallo's laboratory that the cytoplasm of human leukaemia cells contained RT proved to be unfounded, as did his report in collaboration with Weiss that myeloid leukaemia contained HL23 virus, this organism proving not to be human but a laboratory contaminant of three monkey viruses. Conclusive demonstration of a retroviral involvement in human leukaemia was first provided in 1981 by Hinuma and his associates, showing that adult T-cell leukaemia (ATL), a rare form of leukaemia endemic to south-west Japan, is caused by a new retrovirus (ATLV). Other publications in December 1980 and through 1981 claimed the discovery of a new human T-cell leukaemia virus involved in mycosis fungoides (MF) and Sézary's syndrome (SS). This virus was termed HTLV by Gallo. The nucleotide sequence of ATLV is strongly conserved, that of my 1983 isolate from a black British ATL patient being practically identical with the Japanese virus isolates. After AIDS was recognised in 1981 by Gottlieb and coworkers as a new human disease, several papers were published by Gallo and his associates during 1983-4, invoking the oncovirus responsible for adult T-cell leukaemia as the cause of AIDS. In 1983 the French scientist Barré-Sinoussi and her colleagues succeeded in isolating a new agent in the disease, a lentivirus, which they named LAV. The French immunologist Klatzmann and his colleagues discovered that LAV killed

  8. Diagnosis of feline leukaemia virus infection by semi-quantitative real-time polymerase chain reaction.

    PubMed

    Pinches, Mark D G; Helps, Christopher R; Gruffydd-Jones, Tim J; Egan, Kathy; Jarrett, Oswald; Tasker, Séverine

    2007-02-01

    In this paper the design and use of a semi-quantitative real-time polymerase chain reaction assay (RT-PCR) for feline leukaemia virus (FeLV) provirus is described. Its performance is evaluated against established methods of FeLV diagnosis, including virus isolation and enzyme-linked immunoassay (ELISA) in a population of naturally infected cats. The RT-PCR assay is found to have both a high sensitivity (0.92) and specificity (0.99) when examined by expectation maximisation methods and is also able to detect a large number of cats with low FeLV proviral loads that were negative by other conventional test methods.

  9. Herpesvirus in the oral cavity of children with leukaemia and its impact on the oral bacterial community profile.

    PubMed

    Bezerra, Tacíria M; Ferreira, Dennis C; Carmo, Flávia L; Pinheiro, Raquel; Leite, Deborah C A; Cavalcante, Fernanda S; Belinho, Raquel A; Peixoto, Raquel S; Rosado, Alexandre S; dos Santos, Kátia R N; Castro, Gloria F B A

    2015-03-01

    This cross-sectional study investigated the association between eight herpesviruses and the bacterial community profiles from the oral cavity of children with and without leukaemia. Sixty participants (aged 3-13), divided into the leukaemia group (LG) and healthy group (HG), were evaluated. Collection of medical data, intraoral examination and collection of clinical specimens were carried out. Single PCR and nested-PCR techniques were used to identify the viral types; denaturing gradient gel electrophoresis (DGGE) and real-time PCR techniques were used to evaluate the profile and abundance of bacterial communities. All the children with leukaemia were positive for at least one type of herpesvirus, compared with healthy participants (33.3%; p<0.000). Human cytomegalovirus (HCMV; 46.7%), human herpesvirus-7 (HHV-7; 20%) and HHV-8 (77.3%) were in higher prevalence in the LG (p ≤ 0.01). Children with leukaemia had positive associations with the presence of HCMV, HHV-7 and HHV-8 in the oral cavity when under chemotherapy (p<0.05). There was a qualitative (means of DGGE bands) and quantitative (means of 16S rRNA gene abundance) difference in relation to the bacterial community between the two groups (p<0.05). Based on the results, the prevalence of herpesviruses and the qualitative bacterial profiles was higher in children with leukaemia and HCMV, HHV-7 and HHV-8 were related to the use of chemotherapy. Moreover, HHV-6 was correlated with an increased bacterial community profile in patients with leukaemia (p<0.05). More attention should be paid to the oral health of these individuals, mainly those under chemotherapy, in order to prevent infections by opportunistic pathogens. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Out come of induction of remission in undernourished children with acute lymphoblastic leukaemia.

    PubMed

    Begum, M; Jahan, S; Tawfique, M; Mannan, M A

    2012-10-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood leukaemia. On the other hand under-nutrition is a common problem in our country. This prospective study was conducted to see the outcome of induction of remission in undernourished children with acute lymphoblastic leukaemia. This study was carried out in the department of Paediatric hematology and oncology of Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period from November 2002 to October 2004. A total of sixty (60) children who were diagnosed as acute lymphoblastic leukaemia in 1 to 15 years of age were included in this study. But the children with previous history of congenital disease and that of chemotherapy or steroid were excluded from this study. Patients were divided into two groups on the basis of Z score of weight for age. Thirty (30) children those with Z score- 2 or less were classified as undernourished and was labeled as Group A and another thirty (30) patient those Z score above-2 were classified as well nourished and was placed in Group B, After inclusion into the study, completion of induction of remission was monitored by physical examination and laboratory investigations. The result showed that mean age in Group A was 77.16 ± 7.07 months and that in Group B was 74.13 ± 5.09 months with male preponderance in both the groups. Mean body weight in Group A was 14.55 ± 0.76 Kg and that in Group B was 21.40 ± 1.05 kg (p<0.001). Children in Group A required 39.06 ± 0.72 days to complete induction but in Group B it required 31.63 ± 0.17 days (p<0.04). Hospital stay in Group A children was 52.10 ± 1.08 days and in Group B 42.37 ± 0.50 (p<0.002). The result suggested that under nutrition has an influence on the out come of induction of remission in undernourished children with acute lymphoblastic leukaemia. So appropriate measures are essential to improve nutritional status of children for successful management of ALL in children.

  11. Gingival enlargement in a pregnant woman with acute monocytic leukaemia: a case report.

    PubMed

    Fu, Y-W; Xu, H-Z

    2017-09-01

    The objective of the present study was to report the case of a pregnant woman with severe gingival enlargement for 3 months with undiagnosed acute leukaemia. The pregnant woman presented with anaemia and generalized gingival enlargement. A provisional diagnosis of gingival enlargement in pregnancy was made. Twelve days after the initial treatment, the patient was referred and admitted to the haematology department of a local hospital with clinical signs of anaemia and thrombocytopenia. Blood count showed a white blood cell count of 9.68 × 10 9 /L, with a haemoglobin count of 64.0 g/L and a platelet count of 17 × 10 9 /L. Bone marrow aspiration showed 94.5% monoblasts, and the morphological diagnosis was acute monocytic leukaemia. One day after admission, the patient delivered a male infant by Caesarean section. Ten days after the Caesarean section, the patient was started on a course of chemotherapy. Pulmonary infection, hypokalaemia, and respiratory failure developed, and the patient died 23 days after the Caesarean section. The present case shows the importance of awareness of severe gingival enlargement as an initial oral sign of acute leukaemia. © 2017 Australian Dental Association.

  12. EBP1 is a novel E2F target gene regulated by transforming growth factor-β.

    PubMed

    Judah, David; Chang, Wing Y; Dagnino, Lina

    2010-11-10

    Regulation of gene expression requires transcription factor binding to specific DNA elements, and a large body of work has focused on the identification of such sequences. However, it is becoming increasingly clear that eukaryotic transcription factors can exhibit widespread, nonfunctional binding to genomic DNA sites. Conversely, some of these proteins, such as E2F, can also modulate gene expression by binding to non-consensus elements. E2F comprises a family of transcription factors that play key roles in a wide variety of cellular functions, including survival, differentiation, activation during tissue regeneration, metabolism, and proliferation. E2F factors bind to the Erb3-binding protein 1 (EBP1) promoter in live cells. We now show that E2F binding to the EBP1 promoter occurs through two tandem DNA elements that do not conform to typical consensus E2F motifs. Exogenously expressed E2F1 activates EBP1 reporters lacking one, but not both sites, suggesting a degree of redundancy under certain conditions. E2F1 increases the levels of endogenous EBP1 mRNA in breast carcinoma and other transformed cell lines. In contrast, in non-transformed primary epidermal keratinocytes, E2F, together with the retinoblastoma family of proteins, appears to be involved in decreasing EBP1 mRNA abundance in response to growth inhibition by transforming growth factor-β1. Thus, E2F is likely a central coordinator of multiple responses that culminate in regulation of EBP1 gene expression, and which may vary depending on cell type and context.

  13. Incidence of persistent viraemia and latent feline leukaemia virus infection in cats with lymphoma.

    PubMed

    Stützer, Bianca; Simon, Karin; Lutz, Hans; Majzoub, Monir; Hermanns, Walter; Hirschberger, Johannes; Sauter-Louis, Carola; Hartmann, Katrin

    2011-02-01

    In the past, feline leukaemia virus (FeLV) infection, and also latent FeLV infection, were commonly associated with lymphoma and leukaemia. In this study, the prevalence of FeLV provirus in tumour tissue and bone marrow in FeLV antigen-negative cats with these tumours was assessed. Seventy-seven diseased cats were surveyed (61 antigen-negative, 16 antigen-positive). Blood, bone marrow, and tumour samples were investigated by two polymerase chain reaction (PCR) assays detecting deoxyribonucleic acid (DNA) sequences of the long terminal repeats (LTR) and the envelope (env) region of the FeLV genome. Immunohistochemistry (IHC) was performed in bone marrow and tumour tissue. None of the antigen-negative cats with lymphoma was detectably infected with latent FeLV. The prevalence of FeLV viraemia in cats with lymphoma was 20.8%. This suggests that causes other than FeLV play a role in tumorigenesis, and that latent FeLV infection is unlikely to be responsible for most feline lymphomas and leukaemias. Copyright © 2010. Published by Elsevier Ltd.

  14. A review of the automated detection and classification of acute leukaemia: Coherent taxonomy, datasets, validation and performance measurements, motivation, open challenges and recommendations.

    PubMed

    Alsalem, M A; Zaidan, A A; Zaidan, B B; Hashim, M; Madhloom, H T; Azeez, N D; Alsyisuf, S

    2018-05-01

    Acute leukaemia diagnosis is a field requiring automated solutions, tools and methods and the ability to facilitate early detection and even prediction. Many studies have focused on the automatic detection and classification of acute leukaemia and their subtypes to promote enable highly accurate diagnosis. This study aimed to review and analyse literature related to the detection and classification of acute leukaemia. The factors that were considered to improve understanding on the field's various contextual aspects in published studies and characteristics were motivation, open challenges that confronted researchers and recommendations presented to researchers to enhance this vital research area. We systematically searched all articles about the classification and detection of acute leukaemia, as well as their evaluation and benchmarking, in three main databases: ScienceDirect, Web of Science and IEEE Xplore from 2007 to 2017. These indices were considered to be sufficiently extensive to encompass our field of literature. Based on our inclusion and exclusion criteria, 89 articles were selected. Most studies (58/89) focused on the methods or algorithms of acute leukaemia classification, a number of papers (22/89) covered the developed systems for the detection or diagnosis of acute leukaemia and few papers (5/89) presented evaluation and comparative studies. The smallest portion (4/89) of articles comprised reviews and surveys. Acute leukaemia diagnosis, which is a field requiring automated solutions, tools and methods, entails the ability to facilitate early detection or even prediction. Many studies have been performed on the automatic detection and classification of acute leukaemia and their subtypes to promote accurate diagnosis. Research areas on medical-image classification vary, but they are all equally vital. We expect this systematic review to help emphasise current research opportunities and thus extend and create additional research fields. Copyright

  15. Tobacco and the risk of acute leukaemia in adults

    PubMed Central

    Kane, E V; Roman, E; Cartwright, R; Parker, J; Morgan, G

    1999-01-01

    Self-reported smoking histories were collected during face-to-face interviews with 807 patients with acute leukaemia and 1593 age- and sex-matched controls. Individuals who had smoked regularly at some time during their lives were more likely to develop acute leukaemia than those who had never smoked (odds ratio (OR) = 1.2, 95% confidence interval (CI) 1.0–1.4). The association was strongest for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4, 95% CI 1.1–1.7). With respect to the numbers of years smoked, risk estimates were raised in all groups except those who had smoked for fewer than 10 years. Similarly, the odds ratio decreased as the number of years ‘stopped smoking’ increased, falling to one amongst those who had given up smoking for more than 10 years. No significant linear trends were found, however, with either the numbers of years smoked or the numbers of years stopped smoking, and no significant differences were found between AML and ALL. © 1999 Cancer Research Campaign PMID:10584886

  16. 26 CFR 1.642(e)-1 - Depreciation and depletion.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Depreciation and depletion. 1.642(e)-1 Section 1... (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.642(e)-1 Depreciation and depletion. An estate or trust is allowed the deductions for depreciation and depletion, but only to the extent the...

  17. Residential exposure to extremely low-frequency magnetic fields and risk of childhood leukaemia, CNS tumour and lymphoma in Denmark.

    PubMed

    Pedersen, Camilla; Johansen, Christoffer; Schüz, Joachim; Olsen, Jørgen H; Raaschou-Nielsen, Ole

    2015-11-03

    We previously reported that children exposed to elevated extremely low-frequency magnetic fields (ELF-MF) had a five to six times higher risk of leukaemia, central nervous system (CNS) tumour and malignant lymphoma. Here we extend the study from 1968 to 1986 through 2003. We included 3277 children with leukaemia, CNS tumour or malignant lymphoma during 1968-2003 recorded in the Danish Cancer Registry and 9129 controls randomly selected from the Danish childhood population. ELF-MF from 50 to 400 kV facilities were calculated at the residences. For recently diagnosed cases (1987-2003), the relative risk (RR) was 0.88 (95% confidence interval (CI): 0.32-2.42), while for the total period (1968-2003) it was 1.63 (95% CI: 0.77-3.46) for leukaemia, CNS tumour and malignant lymphoma combined for exposures ⩾0.4 μT compared with <0.1 μT. These results were based on five cases (recent period) and 11 cases (total period) in the highest exposure group. We did not confirm the previous finding of a five- to six-fold higher risk for leukaemia, CNS tumour and malignant lymphoma when including data from the more recent time period. For the total time period, the results for childhood leukaemia were in line with large pooled analyses showing RRs between 1.5 and 2.

  18. An 18-26 GHz Segmented Chirped Pulse Fourier Transform Microwave Spectrometer for Astrochemical Applications

    NASA Astrophysics Data System (ADS)

    Steber, Amanda; Fatima, Mariyam; Perez, Cristobal; Schnell, Melanie

    2017-06-01

    In the past decade, astrochemistry has seen an increase in interest. As higher throughput and increased resolution radio astronomy facilities come online, faster laboratory instrumentation that directly covers the frequency ranges of these facilities is needed. The 18-26 GHz region is of interest astronomically as many cold organic molecules have their peak intensity in this region. We present here a new segmented chirped pulse Fourier transform microwave (CP-FTMW) spectrometer operating between 18-26 GHz. Using state-of-the-art digital electronics and the segmented approach[1], this design has the potential to be faster and cheaper than the previously presented broadband design. Characterization of the instrument using OCS will be presented, along with a comparison to the previously built and optimized 18-26 CP-FTMW built at the University of Virginia. It will be coupled with a discharge nozzle[2], and its applications to astrochemistry will be explored in this talk. [1] Neill, J.L., Harris, B.J., Steber, A.L., Douglass, K.O., Plusquellic, D.F., Pate, B.H. Opt. Express, 21, 19743-19749, 2013. [2] McCarthy, M.C., Chen, W., Travers, M.J., Thaddeus, P. Astrophys. J. Suppl. Ser., 129, 611-623 , 2000.

  19. Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

    PubMed Central

    Rushton, L; Schnatter, A R; Tang, G; Glass, D C

    2014-01-01

    Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

  20. Acute lymphoblastic leukaemia

    PubMed Central

    Inaba, Hiroto; Greaves, Mel; Mullighan, Charles G.

    2013-01-01

    Summary Acute lymphoblastic leukaemia (ALL) is seen in both children and adults, but its incidence peaks between ages 2 and 5 years. The causation of ALL is considered to be multi-factorial, including exogenous or endogenous exposures, genetic susceptibility, and chance. The survival rate of paediatric ALL has improved to approximately 90% in recent trials with risk stratification by biologic features of leukaemic cells and response to therapy, therapy modification based on patient pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. While most children can be cured, the prognosis of infants and adults with ALL remains poor. Recent genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic alterations and sequence mutations that contribute to leukaemogenesis, define new ALL subtypes, influence responsiveness to treatment, and may provide novel prognostic markers and therapeutic targets for personalized medicine. PMID:23523389

  1. How I treat children and adolescents with acute promyelocytic leukaemia.

    PubMed

    Abla, Oussama; Ribeiro, Raul C

    2014-01-01

    Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all-trans retinoic acid (ATRA) is given with anthracycline-based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA-related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk-adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high-dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy. © 2013 John Wiley & Sons Ltd.

  2. How I Treat Children and Adolescents with Acute Promyelocytic Leukaemia

    PubMed Central

    Abla, Oussama; Ribeiro, Raul C.

    2016-01-01

    Summary Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all-trans retinoic acid (ATRA) is given with anthracycline-based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA-related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk-adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high-dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy. PMID:24117210

  3. 26 CFR 1.927(e)-1 - Special sourcing rule.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 10 2010-04-01 2010-04-01 false Special sourcing rule. 1.927(e)-1 Section 1.927(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX... sale of export property giving rise to foreign trading gross receipts of a FSC that is treated as from...

  4. Geographical variation in mortality from leukaemia and other cancers in England and Wales in relation to proximity to nuclear installations, 1969-78.

    PubMed Central

    Cook-Mozaffari, P. J.; Darby, S. C.; Doll, R.; Forman, D.; Hermon, C.; Pike, M. C.; Vincent, T.

    1989-01-01

    The distribution of mortality from 11 causes of death (lymphoid leukaemia, other leukaemia, leukaemia of all types, Hodgkin's disease, other lymphomas, all lymphomas, multiple myeloma, lung cancer, other malignancies, all malignancies and all other causes) has been examined in three age groups throughout England and Wales over the period 1969-78. The reorganisation of local authority administration in 1974 meant that the smallest areas that could be examined were 400 county districts or (in some cases) approximate county districts formed by aggregating pre-1974 local authority areas. The variation in the numbers of deaths observed about the numbers expected was assessed using log-linear models to estimate the effect on the relative risk in each district associated with social class, rural status, population size, health authority region and proximity to one of 15 nuclear installations. Trends in risk with increasing proximity to an installation (as judged by the proportion of the population resident within 10 miles) were examined after adjustment for the other four variables. The results showed that in districts near to an installation there were significant excess mortalities in persons under 25 years of age from leukaemia (RR = 1.15, P = 0.01) and especially from lymphoid leukaemia (RR 1.21, P = 0.01) and from Hodgkin's disease (RR 1.24, P = 0.05) and a significant deficiency of mortality from lymphoid leukaemia in persons aged 25-64 years. No significant trends were observed with an increasing proportion of the population near to the installations and the greatest excess mortality from lymphoid leukaemia in young persons was observed in the districts with the intermediate proportion of the population (10.0-65.9%) near an installation. PMID:2930718

  5. 26 CFR 1.367(e)-0 - Outline of §§ 1.367(e)-1 and 1.367(e)-2.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 4 2011-04-01 2011-04-01 false Outline of §§ 1.367(e)-1 and 1.367(e)-2. 1.367(e)-0 Section 1.367(e)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Effects on Corporation § 1.367(e)-0 Outline of §§ 1.367(e)-1...

  6. 26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

  7. 26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 17 2012-04-01 2012-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

  8. 26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 17 2013-04-01 2013-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

  9. 26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 17 2011-04-01 2011-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

  10. 26 CFR 53.4941(d)-2 - Specific acts of self-dealing.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 17 2014-04-01 2014-04-01 false Specific acts of self-dealing. 53.4941(d)-2...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(d)-2 Specific acts of self-dealing. Except as provided in § 53.4941(d)-3 or § 53.4941(d)-4: (a) Sale or exchange...

  11. Electrochemotherapy treatment of a recalcitrant earlobe keloid scar with chronic lymphocytic leukaemia infiltration.

    PubMed

    Sainsbury, D C G; Allison, K P; Muir, T

    2010-10-01

    Electrochemotherapy, a tumour ablation modality, which facilitates intracellular delivery of poorly-permeable cytotoxic drugs, such as bleomycin, has shown promising results in the treatment of cutaneous and subcutaneous melanomatous and non-melanomatous metastases. We report the case of a 52-year-old Caucasian gentleman with a keloid scar to his left earlobe that developed following a piercing. Despite multiple intralesional steroidal injections, five intralesional excisions and a course of superficial radiotherapy the keloid scar remained over nine years later. For 15 years the patient had also suffered chronic lymphocytic leukaemia with no nodal disease or systemic involvement. However, histological analysis of the final surgical excision specimen showed chronic lymphocytic leukaemia infiltration of the keloid scar. Further surgical excision seemed unwise considering the recalcitrance of the keloid scar. Additionally, no systemic chemotherapy treatment options were feasible. Electrochemotherapy was performed under local anaesthesia with the aim of eradicating the chronic lymphocytic leukaemia deposit within the keloid lesion. Four sessions of electrochemotherapy using bleomycin were deployed over 11 months. A deep core biopsy of the treated keloid performed three months following the last electrochemotherapy session showed no evidence of chronic lymphocytic leukaemia. Serendipitously, following the initial electrochemotherapy treatment no further growth of the keloid scar was observed. Furthermore, subsequent electrochemotherapy led to a substantial reduction in size of the keloid sustained for 14 months at last follow-up. This report highlights the exciting potential of electrochemotherapy and bleomycin in the treatment of recalcitrant scars. Larger, well-designed clinical and in-vitro studies are required to further elucidate the exact role, mechanism and cost-effectiveness of electrochemotherapy in this area. Copyright 2010 British Association of Plastic

  12. [A case of de novo acute basophilic leukaemia: diagnostic criteria and review of the literature].

    PubMed

    Staal-Viliare, A; Latger-Cannard, V; Rault, J P; Didion, J; Grégoire, M J; Bologna, S; Witz, B; Jonveaux, P; Lecompte, T; Rio, Y

    2006-01-01

    We report a case of a de novo acute basophilic leukaemia, revealed by an infectious pneumopathy in a 73 year old man. The full blood count revealed an hyperleucocytosis associated with an unregenerative normocytic normochrom anaemia and a thrombocytopenia. The blood and bone marrow smears showed a mixture of undifferentiated blast cells and basophiloblasts (high nucleo-cytoplasmic ratio, coarse basophilic cytoplasmic granules), along with basophilic precursors and basophilic polymorphonuclears. All the blasts were MPO negative but positive for the toluidine blue metachromatic coloration, which is considered as consistent with basophilic lineage. Immunophenotypic studies showed myeloid blasts, without maturity marker, CD 117 negative and CD203 cytoplasmic positive, the latter known to be highly representative of the basophilic lineage. This very clear-cut phenotype, associated with the morphology of cells, were arguments to ascertain the basophilic lineage of the blasts without the need of electron microscopic study. Cytogenetic and RNA analysis revealed the presence of a Philadelphia chromosome and of a BCR-ABL transcript with the unusual junction e6a2. Thus, imatinib was added to the conventional chimiotherapy and the patient is currently in complete remission. This clinical prompted allows us to review the literature on acute basophilic leukaemia and to state on the different diagnostic criteria of this rare disorder.

  13. 26 CFR 1.167(e)-1 - Change in method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Change in method. 1.167(e)-1 Section 1.167(e)-1... method. (a) In general. (1) Any change in the method of computing the depreciation allowances with respect to a particular account (other than a change in method permitted or required by reason of the...

  14. Spatial variation of natural radiation and childhood leukaemia incidence in Great Britain.

    PubMed

    Richardson, S; Monfort, C; Green, M; Draper, G; Muirhead, C

    This paper describes an analysis of the geographical variation of childhood leukaemia incidence in Great Britain over a 15 year period in relation to natural radiation (gamma and radon). Data at the level of the 459 district level local authorities in England, Wales and regional districts in Scotland are analysed in two complementary ways: first, by Poisson regressions with the inclusion of environmental covariates and a smooth spatial structure; secondly, by a hierarchical Bayesian model in which extra-Poisson variability is modelled explicitly in terms of spatial and non-spatial components. From this analysis, we deduce a strong indication that a main part of the variability is accounted for by a local neighbourhood 'clustering' structure. This structure is furthermore relatively stable over the 15 year period for the lymphocytic leukaemias which make up the majority of observed cases. We found no evidence of a positive association of childhood leukaemia incidence with outdoor or indoor gamma radiation levels. There is no consistent evidence of any association with radon levels. Indeed, in the Poisson regressions, a significant positive association was only observed for one 5-year period, a result which is not compatible with a stable environmental effect. Moreover, this positive association became clearly non-significant when over-dispersion relative to the Poisson distribution was taken into account.

  15. [Hospital at home care for children with leukaemia].

    PubMed

    Justin, Manuela

    2015-01-01

    The care pathway of a child with leukaemia is long and often difficult. The different professionals work together to ensure optimal care management. Hospital at home forms part of this pathway in partnership with the inhospital departments, the general practitioner and the day hospital. This link between the different professionals is assured by the hospital at home child health nurse coordinator. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine‑induced death of leukaemia cells.

    PubMed

    Palmeira dos Santos, Caroline; Pereira, Gustavo J S; Barbosa, Christiano M V; Jurkiewicz, Aron; Smaili, Soraya S; Bincoletto, Claudia

    2014-06-01

    As the molecular mechanisms of Cytarabine,one of the most important drugs used in the leukaemia’s treatment, are only partially understood and the role of autophagy on leukaemia development and treatment is only recently being investigated, in this study, by using Chloroquine (CQ) and 3-methyladenine (3MA) as autophagy inhibitors, we aim to evaluate the contribution of an autophagic mechanism to Cytarabine (AraC)-induced death of HL60 leukaemia cells. Trypan blue exclusion and AnnexinV/PI assays were used to evaluate HL60 cell death under AraC treatment in the presence or absence of 3MA and CQ. Western blotting and immunofluorescence experiments were performed to show the involvement of apoptosis and autophagy protein expressions. Phenotypic characterization of HL60-treated cells was performed by using immunophenotyping. Clonogenic assays were applied to analyse clonal function of HL60-treated cells. We observed that although autophagy inhibition by 3MA, but not CQ, increased the death of HL60 AraC cells after 24 h of treatment, no significant differences between AraC and AraC + 3MA-treated groups were observed by using clonogenic assay. In addition, increased number of immature (CD34(+)/CD38(−)Lin(−/low)) HL60 cells was found in AraC and AraC-3MA groups when compared with control untreated cells. Although AraC anti-leukaemia effects could be potentiated by 3MA autophagy inhibition after 24 h of exposure, leukaemia cell resistance, the main causes of treatment failure, is also promoted by autophagy initial stage impairment by 3MA, denoting the complex role of autophagy in leukaemia cells’ response to chemotherapy.

  17. Durable graft-versus-leukaemia effects without donor lymphocyte infusions - results of a phase II study of sequential T-replete allogeneic transplantation for high-risk acute myeloid leukaemia and myelodysplasia.

    PubMed

    Davies, Jeff K; Hassan, Sandra; Sarker, Shah-Jalal; Besley, Caroline; Oakervee, Heather; Smith, Matthew; Taussig, David; Gribben, John G; Cavenagh, Jamie D

    2018-02-01

    Allogeneic haematopoietic stem-cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high-risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T-cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft-versus-leukaemia effects. T-replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single-arm prospective Phase II clinical trial of sequential chemotherapy and T-replete transplantation using reduced-intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty-seven patients with relapsed/refractory AML or high-risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment-related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late-onset graft-versus-host disease protected against relapse. In conclusion, a T-replete sequential transplantation using reduced-intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft-versus-leukaemia effects without DLI. © 2017 John Wiley & Sons Ltd.

  18. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.

    PubMed

    Etchin, Julia; Sanda, Takaomi; Mansour, Marc R; Kentsis, Alex; Montero, Joan; Le, Bonnie T; Christie, Amanda L; McCauley, Dilara; Rodig, Scott J; Kauffman, Michael; Shacham, Sharon; Stone, Richard; Letai, Anthony; Kung, Andrew L; Thomas Look, A

    2013-04-01

    This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T-ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T-ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T-ALL and AML. © 2013 Blackwell Publishing Ltd.

  19. Acute promyelocytic leukaemia is highly frequent among acute myeloid leukaemias in Brazil: a hospital-based cancer registry study from 2001 to 2012.

    PubMed

    Thuler, Luiz Claudio Santos; Pombo-de-Oliveira, Maria S

    2017-03-01

    The WHO classification that defines subtypes of acute myeloid leukaemias (AMLs) is relatively unexplored at the population-based level. This study aimed to examine the frequency of acute promyelocytic leukaemia (APL or AML-M3) in Brazil. Data were extracted from 239 cancer centres (2001-2012) and categorized according to the International Classification of Diseases for Oncology (CID-O 3.0) and WHO classification (n = 9116). CID-O3 code 9866 identified 614 APL patients. AML not otherwise specified (NOS) was frequent, and the APL group represented the main subtype specified. The mean age of APL was lower than that of other AMLs (31.5, standard deviation (SD) 18.6 versus 40.9, SD 24.6; p < 0.001); there was a high frequency of APL in the 13-21-year-old (11.8 %) and ≤12.9-year-old (6.4 %) age groups. Time taken to begin treatment (as ≤14 days versus >14 days) and induction death rate were lower in APL than in other AML subtypes (p < 0.001). This report provides additional evidence on the distribution of APL among cases of AML in Brazil.

  20. Preventing relapse after haematopoietic stem cell transplantation for acute leukaemia: the role of post-transplantation minimal residual disease (MRD) monitoring and MRD-directed intervention.

    PubMed

    Mo, Xiao-Dong; Lv, Meng; Huang, Xiao-Jun

    2017-10-01

    Relapse is the main cause of treatment failure after allogeneic haematopoietic stem cell transplantation (allo-HSCT) for acute leukaemia (AL). Post-transplantation minimal residual disease (MRD) monitoring enables risk stratification and identifies AL patients at higher risk of relapse. MRD assessment primarily involves the determination of leukaemia-associated immunophenotypic patterns using multiparameter flow cytometry, and the polymerase chain reaction (PCR)-based evaluation of expression levels of leukaemia-related genes (specific reciprocal gene rearrangements and other mutation types). In addition, next generation sequencing and digital PCR may further enrich current MRD detection. Several MRD-directed interventions have demonstrated the ability to reduce the risk of relapse with acceptable treatment-related toxicities. Donor lymphocyte infusion (DLI) is the most important intervention for MRD-positive patients, while several modified strategies, such as granulocyte colony-stimulating factor-mobilized peripheral blood cells followed by short term immune suppression and escalating dose regimen, further improve the safety and efficacy of DLI. Interferon therapy, targeted drugs, and hypomethylating agents have also been introduced for MRD-directed interventions. Referring to the issues of whether and who would benefit from pre-emptive intervention according to MRD, in this review, we summarized this rapidly evolving area of MRD monitoring and MRD-directed interventions in AL patients after allo-HSCT. © 2017 John Wiley & Sons Ltd.

  1. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

    PubMed Central

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-01-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan–Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID:23929599

  2. Changes in cell surface structure by viral transformation studied by binding of lectins differing in sugar specificity.

    PubMed

    Tsuda, M; Kurokawa, T; Takeuchi, M; Sugino, Y

    1975-10-01

    Changes in cell surface structure by viral transformation were studied by examining changes in the binding of various lectins differing in carbohydrate specificities. Binding of lectins was assayed directly using cells grown in coverslips. The following 125I-lectins were used: Concanavalin-A (specific for glucose and mannose), wheat germ agglutinin (specific for N-acetylglucosamine), castor bean agglutinin (specific for galactose), Wistaria floribunda agglutinin (specific for N-acetylgalactosamine), and soybean agglutinin (specific for N-acetyl-galactosamine). Cells for a clone, SS7, transformed by bovine adenovirus type-3, were found to bind 5 to 6 times more Wistaria floribunda agglutinin than the normal counterpart cells (clone C31, from C3H mouse kidney). In contrast, the binding of soybean agglutinin, which has a sugar specificity similar to Wistaria floribunda agglutinin, to normal and transformed cells was similar. The binding of wheat germ agglutinin and castor bean agglutinin, respectively, to normal and transformed cells was also similar. However, normal cells bound twice as much concanavalin-A as transformed cells. Only half as much Wistaria floribunda agglutinin was bound to transformed cells when they had been dispersed with EDTA. These changes in the number of lectin binding sites on transformation are thought to reflect alteration of the cell surface structure. The amount of lectins bound per cell decreased with increase in cell density, especially in the case of binding of Wistaria floribunda agglutinin to normal cells.

  3. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes.

    PubMed

    Schmiegelow, Kjeld

    2016-12-01

    Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments. Copyright © 2016. Published by Elsevier Masson SAS.

  4. Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

    PubMed

    Nikula, P; Ruohola, H; Alhonen-Hongisto, L; Jänne, J

    1985-06-01

    We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations.

  5. Importance of 6-mercaptopurine dose in lymphoblastic leukaemia.

    PubMed Central

    Hale, J P; Lilleyman, J S

    1991-01-01

    To explore the possibility that higher total dosage of 'maintenance' treatment may have contributed to the recent improvement in outlook of children in the United Kingdom with lymphoblastic leukaemia, details of the amount of 6-mercaptopurine prescribed during the first two years of treatment were studied in an unselected cohort of children diagnosed between 1973 and 1987. Eighty five patients were studied, 30 diagnosed before and 55 after 1980. The group diagnosed after 1980 showed an 18% improvement in relapse free survival at five years. Their median total dose of 6-mercaptopurine had increased by 22%, whereas according to the protocol it should have risen by an average of only 9%. After 1980 boys were prescribed significantly more 6-mercaptopurine than girls, and had fewer dose reductions because of myelosuppression. These findings support the clinical impression that after 1980 an important therapeutic difference resulting from the new United Kingdom acute lymphoblastic leukaemia protocols was an increase in the amount of 6-mercaptopurine that children actually received as a result of changes in prescribing guidelines rather than dose. They also provide further evidence that boys tolerate 6-mercaptopurine better than girls, which may be related to the still unexplained difference in prognosis between the sexes. PMID:2031601

  6. Fever without a source: evolution of a diagnosis from Kawasaki disease to acute myelogenous leukaemia.

    PubMed

    Lee, Begem; Kofman, Christine D; Tremoulet, Adriana H; Kuo, Dennis John

    2017-05-06

    A previously healthy 11-month-old male patient presented with fever, abdominal pain and irritability. As part of an extensive evaluation for the cause of his fevers, an echocardiogram was performed and showed mildly dilated coronary arteries, leading to a diagnosis of incomplete Kawasaki disease (KD). He was treated with intravenous immunoglobulin (IVIG), defervesced and was discharged home. Two weeks later, he presented with anaemia initially attributed to haemolytic anaemia secondary to IVIG and received a red blood cell transfusion. However, his anaemia recurred 2  weeks later with leucocytosis, prompting a bone marrow aspirate 4  weeks after his diagnosis of KD. This demonstrated acute myelogenous leukaemia most consistent with acute megakaryocytic leukaemia. This case highlights the potentially subtle presentation of acute leukaemia and the need to keep an open mind and reconsider the initial diagnosis as new information comes to light in the care of an ill child. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  7. Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia.

    PubMed

    Elder, A; Bomken, S; Wilson, I; Blair, H J; Cockell, S; Ponthan, F; Dormon, K; Pal, D; Heidenreich, O; Vormoor, J

    2017-12-01

    High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However, it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate mapping tool to track primograft ALL blasts in vivo. Our results show that high numbers of ALL founder cells contribute at similar frequencies to leukaemic propagation over serial transplants, without any clear evidence of clonal succession. These founder cells also exhibit equal capacity to home and engraft to different organs, although stochastic processes may alter the composition in restrictive niches. Our findings enhance the stochastic stem cell model of ALL by demonstrating equal functional abilities of singular ALL blasts and show that successful treatment strategies must eradicate the entire leukaemic cell population.

  8. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War.

    PubMed

    Kinlen, L

    2006-07-03

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1-14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1-4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural-urban population mixing

  9. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War

    PubMed Central

    Kinlen, L

    2006-01-01

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1–14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1–4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural–urban population

  10. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

  11. Population mixing for leukaemia, lymphoma and CNS tumours in teenagers and young adults in England, 1996-2005.

    PubMed

    van Laar, Marlous; Stark, Daniel P; McKinney, Patricia; Parslow, Roger C; Kinsey, Sally E; Picton, Susan V; Feltbower, Richard G

    2014-09-23

    Little aetiological epidemiological research has been undertaken for major cancers occurring in teenagers and young adults (TYA). Population mixing, as a possible proxy for infectious exposure, has been well researched for childhood malignancies. We aimed to investigate effects of population mixing in this older age group using an English national cancer dataset. Cases of leukaemia, lymphoma and central nervous system (CNS) tumours amongst 15-24 year olds in England (diagnosed 1996-2005) were included in the study. Data were obtained by ward of diagnosis and linked to 1991 census variables including population mixing (Shannon index); data on person-weighted population density and deprivation (Townsend score) were also used and considered as explanatory variables. Associations between TYA cancer incidence and census variables were investigated using negative binomial regression, and results presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). A total of 6251 cases of leukaemia (21%), lymphoma (49%) and CNS tumours (30%) were analysed. Higher levels of population mixing were associated with a significant decrease in the incidence of CNS tumours (IRR=0.83, 95% CI=0.75-0.91), accounted for by astrocytomas and 'other CNS tumours'; however, there was no association with leukaemia or lymphoma. Incidence of CNS tumours and lymphoma was 3% lower in more deprived areas (IRR=0.97, 95% CI=0.96-0.99 and IRR=0.97, 95% CI=.96-0.98 respectively). Population density was not associated with the incidence of leukaemia, lymphoma or CNS tumours. Our results suggest a possible role for environmental risk factors with population correlates in the aetiology of CNS tumours amongst TYAs. Unlike studies of childhood cancer, associations between population mixing and the incidence of leukaemia and lymphoma were not observed.

  12. Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

    PubMed

    Irving, Julie A E

    2016-03-01

    Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. © 2015 John Wiley & Sons Ltd.

  13. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For rules...

  14. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For rules...

  15. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For rules...

  16. 26 CFR 31.3231(e)-2 - Contribution base.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For rules...

  17. Genomic Characterization of Paediatric Acute Lymphoblastic Leukaemia: an Opportunity for Precision Medicine Therapeutics

    PubMed Central

    Tasian, Sarah K; Hunger, Stephen P

    2016-01-01

    Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia-associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (1) underlying biological and clinical characteristics and (2) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies. PMID:27984637

  18. Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics.

    PubMed

    Tasian, Sarah K; Hunger, Stephen P

    2017-03-01

    Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia-associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (i) underlying biological and clinical characteristics, and (ii) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies. © 2016 John Wiley & Sons Ltd.

  19. Engineered catalytic biofilms: Site-specific enzyme immobilization onto E. coli curli nanofibers.

    PubMed

    Botyanszki, Zsofia; Tay, Pei Kun R; Nguyen, Peter Q; Nussbaumer, Martin G; Joshi, Neel S

    2015-10-01

    Biocatalytic transformations generally rely on purified enzymes or whole cells to perform complex transformations that are used on industrial scale for chemical, drug, and biofuel synthesis, pesticide decontamination, and water purification. However, both of these systems have inherent disadvantages related to the costs associated with enzyme purification, the long-term stability of immobilized enzymes, catalyst recovery, and compatibility with harsh reaction conditions. We developed a novel strategy for producing rationally designed biocatalytic surfaces based on Biofilm Integrated Nanofiber Display (BIND), which exploits the curli system of E. coli to create a functional nanofiber network capable of covalent immobilization of enzymes. This approach is attractive because it is scalable, represents a modular strategy for site-specific enzyme immobilization, and has the potential to stabilize enzymes under denaturing environmental conditions. We site-specifically immobilized a recombinant α-amylase, fused to the SpyCatcher attachment domain, onto E. coli curli fibers displaying complementary SpyTag capture domains. We characterized the effectiveness of this immobilization technique on the biofilms and tested the stability of immobilized α-amylase in unfavorable conditions. This enzyme-modified biofilm maintained its activity when exposed to a wide range of pH and organic solvent conditions. In contrast to other biofilm-based catalysts, which rely on high cellular metabolism, the modified curli-based biofilm remained active even after cell death due to organic solvent exposure. This work lays the foundation for a new and versatile method of using the extracellular polymeric matrix of E. coli for creating novel biocatalytic surfaces. © 2015 Wiley Periodicals, Inc.

  20. A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom.

    PubMed Central

    Rushton, L; Romaniuk, H

    1997-01-01

    OBJECTIVES: To investigate the risk of leukaemia in workers in the petroleum distribution industry who were exposed to low levels of benzene. METHODS: From the cohort of distribution workers, 91 cases were identified as having leukaemia on either a death certificate or on cancer registration. These cases were compared with controls (four per case) randomly selected from the cohort, who were from the same company as the respective case, matched for age, and alive and under follow up at the time of case occurrence. Work histories were collected for the cases and controls, together with information about the terminals at which they had worked, fuel compositions, and occupational hygiene measurements of benzene. These data were used to derive quantitative estimates of personal exposure to benzene. Odds ratios (OR) were calculated conditional on the matching, to identify those variables in the study which were associated with risk of leukaemia. Examination of the potential effects of confounding and other variables was carried out with conditional logistic regression. Analyses were carried out for all leukaemia and separately for acute lymphoblastic, chronic lymphocytic, acute myeloid and monocytic, and chronic myeloid leukaemias. RESULTS: There was no significant increase in the overall risk of all leukaemias with higher cumulative exposure to benzene or with intensity of exposure, but risk was consistently doubled in subjects employed in the industry for > 10 years. Acute lymphoblastic leukaemia tended to occur in workers employed after 1950, who started work after the age of 30, worked for a short duration, and experienced low cumulative exposure with few peaks. The ORs did not increase with increasing cumulative exposure. The risk of chronic lymphocytic leukaemia seemed to be related most closely to duration of employment and the highest risk occurred in white collar workers with long service. These workers had only background levels of benzene exposure. There was

  1. Historical data decrease complete blood count reflex blood smear review rates without missing patients with acute leukaemia.

    PubMed

    Rabizadeh, Esther; Pickholtz, Itay; Barak, Mira; Froom, Paul

    2013-08-01

    The availability of historical data decreases the rate of blood smear review rates in outpatients, but we are unaware of studies done at referral centres. In the following study, we determined the effect of historical data on the rates of peripheral blood smears over a 3-month period and then the detection rate of patients with acute leukaemia. All results of complete blood counts (CBCs) tested on three ADVIA 120 analyzers at the regional Rabin Medical Centre, Beilinson Campus over a 3-month period were accessed on a computerised laboratory information system. Over a 3-month period, we determined the proportion of total CBC and patients with criteria for a manual differential count and the actual number of peripheral blood smears done. Finally, we determined the proportion of 100 consecutive patients with acute leukaemia detected using our criteria that included limiting reflex testing according to historical data. Over the 3-month period, there were 34,827 tests done in 12,785 patients. Without historical data, our smear rate would have been 24.5%, but with the availability of historical data, the blood smear review rate was 5.6%. The detection rate for cases of acute leukaemia was 100%. We conclude that the availability of previous test results significantly reduces the need for blood smear review without missing any patients with acute leukaemia.

  2. Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children.

    PubMed

    Brix, Ninna; Rosthøj, Steen; Herlin, Troels; Hasle, Henrik

    2015-09-01

    At disease onset, children with acute lymphoblastic leukaemia (ALL) may present with arthralgia or even signs of arthritis. This might cause misdiagnosis and thereby lead to prolonged diagnostic delay. The present study aimed to identify children with ALL with joint involvement and to compare their characteristics and outcome with children with ALL without joint involvement. Case records of 286 children diagnosed with ALL between 1992 and 2013 were reviewed and analysed in this retrospective, descriptive study. Fifty-three (18.5%) children with ALL presented with localised joint pain, and half of them had objective signs of arthritis. The mean number of joints involved was 2.5, most frequently presenting as asymmetric oligoarthritis. The suspected misdiagnosis were reactive arthritis (19/53), osteomyelitis (9/53) and juvenile idiopathic arthritis (8/53). Children with joint involvement had less objective signs of haematological disease. Cytopenia was absent in 24% in children with joint involvement (vs 8% without, p=0.001), 50% had only one cell line affected (vs 21%, p=0.0005) and 44% had no organomegaly (vs 29%, p=0.05). Median diagnostic delay was 4 vs 2 weeks. The 5-year event-free and overall survival was superior for children with joint involvement: 94% vs 87% (p=0.049), and 96% vs 83% (p=0.044). ALL with joint involvement is a frequent finding (18.5%). The clinical signs of leukaemia are less prominent, but non-articular pain should alert the clinician of a possible diagnosis of leukaemia. The overall and event-free survivals were superior compared with the children without joint involvement. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Resilience factors play an important role in the mental health of parents when children survive acute lymphoblastic leukaemia.

    PubMed

    Eilertsen, Mary-Elizabeth; Hjemdal, Odin; Le, Thien Thanh; Diseth, Trond H; Reinfjell, Trude

    2016-01-01

    Childhood cancer is a tremendous stressor that requires parents to adapt to new challenges, and research has mainly focused on psychopathology and rarely on a resource-oriented perspective, such as resilience. This study assessed resilience factors among parents of children surviving acute lymphoblastic leukaemia and parents of healthy children. We also explored the association between parental resilience and mental health. The study compared 57 parents of 40 children from eight to 15 years of age in remission from acute lymphoblastic leukaemia and 63 parents of 42 healthy children. The Resilience Scale for Adults and the General Health Questionnaire were used to assess parental resilience and mental health. Parents of children surviving acute lymphoblastic leukaemia showed significantly lower levels of resilience than parents of healthy children, but no significant difference was found for mental health. Certain resilience factors were positively associated with mental health, especially for mothers, such as family cohesion, good perception of self and being able to plan their future. Resilience factors may help to protect parents' mental health, especially mothers, when their child has survived acute lymphoblastic leukaemia and should be considered in a clinical setting. Further research on resilience factors for fathers is needed. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  4. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?

    PubMed Central

    Grove, Carolyn S.; Vassiliou, George S.

    2014-01-01

    Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers. PMID:25056697

  5. Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

    PubMed

    Aguirre Palma, Luis Mario; Gehrke, Iris; Kreuzer, Karl-Anton

    2015-03-01

    The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Cytogenetic analysis in acute myeloid leukaemia.

    PubMed

    Campbell, Lynda J; White, Joanne S

    2011-01-01

    Cytogenetic analysis is an integral part of the diagnostic work-up of the patient with acute myeloid leukaemia. Conventional cytogenetic analysis relies on obtaining a good quality bone marrow specimen in a timely fashion and setting up at least two short-term cultures. A 15-24-h culture and a 48-h synchronised culture are routinely set up but as the cytogenetics result is often required urgently to determine the type of therapy to be administered, analysis is undertaken using the overnight culture in the first instance. Rapid and accurate analysis relies on obtaining high-quality G-banding. Knowledge of the conditions affecting banding is therefore essential.

  7. Chronic myelocytic leukaemia with unusual (27 years) complete remission terminating in acute undifferentiated leukaemia: a clinical and karyotypic study.

    PubMed

    Najean, Y; Miclea, M; Tanzer, J; Lessard, M; Sigaux, F

    1991-07-01

    A case of clinically typical CML (300 x 10(6)/l leukocytes, 400 x 10(6)/l platelets, splenomegaly) is presented. After complete remission induced by busulphan, no clinical or haematological abnormalities were observed for 27 years until the development of acute leukaemia (type M1), which was rapidly fatal after a brief chemotherapy-induced remission. The cytogenetic findings were also original: no chromosome Ph1 (during remission 3 years after the onset of the disease), no translocation (banding study 5 years later), and no bcr/abl rearrangement (during the terminal phase).

  8. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia.

    PubMed

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; Del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-06-11

    Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). A case-control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47-11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20-0.91). Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS.

  9. Childhood Acute Myeloid Leukaemia

    PubMed Central

    Rubnitz, Jeffrey E.; Inaba, Hiroto

    2012-01-01

    Summary Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation. PMID:22966788

  10. Promyelocytic leukaemia zinc finger maintains self-renewal of male germline stem cells (mGSCs) and its expression pattern in dairy goat testis.

    PubMed

    Song, W; Zhu, H; Li, M; Li, N; Wu, J; Mu, H; Yao, X; Han, W; Liu, W; Hua, J

    2013-08-01

    Previous studies have shown that promyelocytic leukaemia zinc finger (PLZF) is a spermatogonia-specific transcription factor in the testis, required to regulate self-renewal and maintenance of the spermatogonia stem cell. Up to now, expression and function of PLZF in the goat testis has not been known. The objectives of this study were to investigate PLZF expression pattern in the dairy goat and its effect on male goat germline stem cell (mGSC) self-renewal and differentiation. Testis development and expression patterns of PLZF in the dairy goat were analysed by haematoxylin and eosin staining, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, effects of PLZF overexpression on mGSC self-renewal and differentiation were evaluated by quantitative RT-PCR (QRT-PCR), immunofluorescence and BrdU incorporation assay. Promyelocytic leukaemia zinc finger was essential for dairy goat testis development and expression of several proliferation and pluripotency-associated proteins including OCT4, C-MYC were upregulated by PLZF overexpression. The study demonstrated that PLZF played a key role in maintaining self-renewal of mGSCs and its overexpression enhanced expression of proliferation-associated genes. Promyelocytic leukaemia zinc finger could function in the dairy goat as well as in other species in maintaining self-renewal of germline stem cells and this study provides a model to study the mechanism on self-renewal and differentiation of mGSCs in livestock. © 2013 John Wiley & Sons Ltd.

  11. Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells.

    PubMed

    Bejarano, Ignacio; Godoy-Cancho, Belén; Franco, Lourdes; Martínez-Cañas, Manuel A; Tormo, María A

    2015-08-01

    Quercus suber L. cork contains a diversity of phenolic compounds, mostly low molecular weight phenols. A rising number of reports support with convergent findings that polyphenols evoke pro-apoptotic events in cancerous cells. However, the literature related to the anti-cancer bioactivity of Q. suber L. cork extractives (QSE) is still limited. Herein, we aim to describe the antitumor potential displayed by cork extractives obtained by different extraction methods in the human promyelocytic leukaemia cells. In order to quantify the effects of QSE on cancer cells viability, phosphatidylserine exposure, caspase-3 activity, mitochondrial membrane potential and cell cycle were evaluated. The results indicated that the QSE present a time-dependent and dose-dependent cytotoxicity in the human promyelocytic leukaemia cells. Such a noxious effect leads these leukaemia cells to their death through apoptotic processes by altering the mitochondrial outer membrane potential, activating caspase-3 and externalizing phosphatidylserine. However, cells cycle progression was not affected by the treatments. This study contributes to open a new way to use this natural resource by exploiting its anti-cancer properties. Moreover, it opens new possibilities of application of cork by-products, being more efficient in the sector of cork-based agriculture. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.

    PubMed

    Ferret, Yann; Caillault, Aurélie; Sebda, Shéhérazade; Duez, Marc; Grardel, Nathalie; Duployez, Nicolas; Villenet, Céline; Figeac, Martin; Preudhomme, Claude; Salson, Mikaël; Giraud, Mathieu

    2016-05-01

    High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients. © 2016 John Wiley & Sons Ltd.

  13. Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

    PubMed Central

    Nikula, P; Ruohola, H; Alhonen-Hongisto, L; Jänne, J

    1985-01-01

    We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations. Images Fig. 1. PMID:3837667

  14. Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

    PubMed Central

    2011-01-01

    Background The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. Results The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as

  15. Trib2 expression in granulocyte-monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2

    PubMed Central

    O’Connor, Caitriona; Yalla, Krishna; Salomé, Mara; Moka, Hothri Ananyambica; Castañeda, Eduardo Gómez; Eyers, Patrick A.; Keeshan, Karen

    2018-01-01

    Trib2 pseudokinase has oncogenic and tumour suppressive functions depending on the cellular context. We investigated the ability of Trib2 to transform different haemopoietic stem and progenitor cells (HSPCs). Our study identified the granulocyte-macrophage progenitor (GMP) subpopulation as a potent leukaemia initiating cell of Trib2-driven AML in vivo. Trib2 transformed GMPs generated a fully penetrant and short latency AML. AML cells expressing elevated Trib2 led to a chemoresistant phenotype following chemotherapy treatment. We show that Trib2 overexpression results in an increase in BCL2 expression, and high Trib2 expressing cells are highly sensitive to cell killing by BCL2 inhibition (ABT199). Combined treatment with chemotherapeutic agents and BCL2 inhibition resulted in synergistic killing of Trib2+ AML cells. Trib2 transformed GMP AML cells showed more chemoresistance compared with HSPC derived Trib2 AML cells associated with higher Bcl2 expression. There is significant correlation of high TRIB2 and BCL2 expression in patient derived human AML cells. These data demonstrate that the cell of origin influences the leukaemic profile and chemotherapeutic response of Trib2+ AML. Combined TRIB2 and BCL2 expression in AML cells may have clinical utility relevant for monitoring drug resistance and disease relapse. PMID:29599919

  16. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

    PubMed

    Kantarjian, Hagop M; Roboz, Gail J; Kropf, Patricia L; Yee, Karen W L; O'Connell, Casey L; Tibes, Raoul; Walsh, Katherine J; Podoltsev, Nikolai A; Griffiths, Elizabeth A; Jabbour, Elias; Garcia-Manero, Guillermo; Rizzieri, David; Stock, Wendy; Savona, Michael R; Rosenblat, Todd L; Berdeja, Jesus G; Ravandi, Farhad; Rock, Edwin P; Hao, Yong; Azab, Mohammad; Issa, Jean-Pierre J

    2017-10-01

    , 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m 2 and 28 to 90 mg/m 2 ) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m 2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m 2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m 2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m 2 in a 5-day schedule. A phase

  17. A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.

    PubMed

    Duong, Janna K; Griffin, Melanie J; Hargrave, Darren; Vormoor, Josef; Edwards, David; Boddy, Alan V

    2017-08-01

    AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. Data from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children. The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h -1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg -1  72 h -1 . For adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg -1  72 h -1 children with leukaemia. © 2017 The British Pharmacological Society.

  18. Role of Glutamine 17 of the Bovine Papillomavirus E5 Protein in Platelet-Derived Growth Factor β Receptor Activation and Cell Transformation

    PubMed Central

    Klein, Ophir; Polack, Glenda W.; Surti, Toral; Kegler-Ebo, Deena; Smith, Steven O.; DiMaio, Daniel

    1998-01-01

    The bovine papillomavirus E5 protein is a small, homodimeric transmembrane protein that forms a stable complex with the cellular platelet-derived growth factor (PDGF) β receptor through transmembrane and juxtamembrane interactions, resulting in receptor activation and cell transformation. Glutamine 17 in the transmembrane domain of the 44-amino-acid E5 protein is critical for complex formation and receptor activation, and we previously proposed that glutamine 17 forms a hydrogen bond with threonine 513 of the PDGF β receptor. We have constructed and analyzed mutant E5 proteins containing all possible amino acids at position 17 and examined the ability of these proteins to transform C127 fibroblasts, which express endogenous PDGF β receptor. Although several position 17 mutants were able to transform cells, mutants containing amino acids with side groups that were unable to participate in hydrogen bonding interactions did not form a stable complex with the PDGF β receptor or transform cells, in agreement with the proposed interaction between position 17 of the E5 protein and threonine 513 of the receptor. The nature of the residue at position 17 also affected the ability of the E5 proteins to dimerize. Overall, there was an excellent correlation between the ability of the various E5 mutant proteins to bind the PDGF β receptor, lead to receptor tyrosine phosphorylation, and transform cells. Similar results were obtained in Ba/F3 hematopoietic cells expressing exogenous PDGF β receptor. In addition, treatment of E5-transformed cells with a specific inhibitor of the PDGF receptor tyrosine kinase reversed the transformed phenotype. These results confirm the central importance of the PDGF β receptor in mediating E5 transformation and highlight the critical role of the residue at position 17 of the E5 protein in the productive interaction with the PDGF β receptor. On the basis of molecular modeling analysis and the known chemical properties of the amino acids, we

  19. Role of glutamine 17 of the bovine papillomavirus E5 protein in platelet-derived growth factor beta receptor activation and cell transformation.

    PubMed

    Klein, O; Polack, G W; Surti, T; Kegler-Ebo, D; Smith, S O; DiMaio, D

    1998-11-01

    The bovine papillomavirus E5 protein is a small, homodimeric transmembrane protein that forms a stable complex with the cellular platelet-derived growth factor (PDGF) beta receptor through transmembrane and juxtamembrane interactions, resulting in receptor activation and cell transformation. Glutamine 17 in the transmembrane domain of the 44-amino-acid E5 protein is critical for complex formation and receptor activation, and we previously proposed that glutamine 17 forms a hydrogen bond with threonine 513 of the PDGF beta receptor. We have constructed and analyzed mutant E5 proteins containing all possible amino acids at position 17 and examined the ability of these proteins to transform C127 fibroblasts, which express endogenous PDGF beta receptor. Although several position 17 mutants were able to transform cells, mutants containing amino acids with side groups that were unable to participate in hydrogen bonding interactions did not form a stable complex with the PDGF beta receptor or transform cells, in agreement with the proposed interaction between position 17 of the E5 protein and threonine 513 of the receptor. The nature of the residue at position 17 also affected the ability of the E5 proteins to dimerize. Overall, there was an excellent correlation between the ability of the various E5 mutant proteins to bind the PDGF beta receptor, lead to receptor tyrosine phosphorylation, and transform cells. Similar results were obtained in Ba/F3 hematopoietic cells expressing exogenous PDGF beta receptor. In addition, treatment of E5-transformed cells with a specific inhibitor of the PDGF receptor tyrosine kinase reversed the transformed phenotype. These results confirm the central importance of the PDGF beta receptor in mediating E5 transformation and highlight the critical role of the residue at position 17 of the E5 protein in the productive interaction with the PDGF beta receptor. On the basis of molecular modeling analysis and the known chemical properties of the

  20. 26 CFR 31.3402(e)-1 - Included and excluded wages.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Included and excluded wages. 31.3402(e)-1... SOURCE Collection of Income Tax at Source § 31.3402(e)-1 Included and excluded wages. (a) If a portion of... not more than 31 consecutive days constitutes wages, and the remainder does not constitute wages, all...

  1. MLL-ENL cooperates with SCF to transform primary avian multipotent cells.

    PubMed

    Schulte, Cathleen E; von Lindern, Marieke; Steinlein, Peter; Beug, Hartmut; Wiedemann, Leanne M

    2002-08-15

    The MLL gene is targeted by chromosomal translocations, which give rise to heterologous MLL fusion proteins and are associated with distinct types of acute lymphoid and myeloid leukaemia. To determine how MLL fusion proteins alter the proliferation and/or differentiation of primary haematopoietic progenitors, we introduced the MLL-AF9 and MLL-ENL fusion proteins into primary chicken bone marrow cells. Both fusion proteins caused the sustained outgrowth of immature haematopoietic cells, which was strictly dependent on stem cell factor (SCF). The renewing cells have a long in vitro lifespan exceeding the Hayflick limit of avian cells. Analysis of clonal cultures identified the renewing cells as immature, multipotent progenitors, expressing erythroid, myeloid, lymphoid and stem cell surface markers. Employing a two-step commitment/differentiation protocol involving the controlled withdrawal of SCF, the MLL-ENL-transformed progenitors could be induced to terminal erythroid or myeloid differentiation. Finally, in cooperation with the weakly leukaemogenic receptor tyrosine kinase v-Sea, the MLL-ENL fusion protein gave rise to multilineage leukaemia in chicks, suggesting that other activated, receptor tyrosine kinases can substitute for ligand-activated c-Kit in vivo.

  2. IFN-β antiproliferative effect and miRNA regulation in Human Papilloma Virus E6- and E7-transformed keratinocytes.

    PubMed

    Chiantore, Maria Vincenza; Mangino, Giorgio; Iuliano, Marco; Zangrillo, Maria Simona; De Lillis, Ilaria; Vaccari, Gabriele; Accardi, Rosita; Tommasino, Massimo; Fiorucci, Gianna; Romeo, Giovanna

    2017-01-01

    Human Papilloma Viruses (HPVs) are the causative agents of cervical cancer although other types of cancers are associated with HPV infection. Type I Interferons can interfere with HPV E6- and/or E7-dependent transformation and can affect microRNA (miRNA) expression. Cancer cells show a specific pattern of miRNA expression and HPVs are able to modulate miRNAs expressed in infected cells. Keratinocytes transduced with E6 and E7 from mucosal HPV-16 or cutaneous HPV-38 (K16 and K38) were studied to analyze the involvement of HPV oncoproteins in the anti-proliferative activity of IFN-β. In view of our previous data showing senescence induction by the cytokine in K38 cells, we observe that IFN-β treatment leads to p53-indipendent apoptosis in K16 cells whereas induces senescence in K16 cells if E6 is silenced and p53 expression is restored. The levels of selected miRNAs, deregulated in K16 and K38 cells, can be modulated by IFN-β when E6 and E7 proteins of HPV-16, but not HPV-38, are expressed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Managing the Transformation to an E-Learning Organisation.

    ERIC Educational Resources Information Center

    Simpson, Janet

    The Douglas Mawson Institute (DMI) of TAFE (technical and further education), which operates more than four campuses in Australia with a diverse student body numbering approximately 17,000 (78 percent studying part-time), has initiated strategies to support the transformation to an e-learning organization. Major elements in the change model are…

  4. Investigation of the inhibitors of histone-lysine N-methyltransferase SETD2 for acute lymphoblastic leukaemia from traditional Chinese medicine.

    PubMed

    Chang, Y-L; Chen, H-Y; Chen, K-B; Chen, K-C; Chang, K-L; Chang, P-C; Chang, T-T; Chen, Y-C

    2016-07-01

    Leukaemia is the leading cause of childhood malignancies. Recent research indicates that the SETD2 gene is associated with acute lymphoblastic leukaemia. This study aims to identify potential lead compounds from traditional Chinese medicine (TCM) using virtual screening for SET domain containing 2 (SETD2) protein against acute lymphoblastic leukaemia. Docking simulation was performed to determine potential candidates which obtain suitable docking poses in the binding domain of the SETD2 protein. We also performed molecular dynamics (MD) simulation to investigate the stability of docking poses of SETD2 protein complexes with the top three TCM candidates and a control. According to the results of docking and MD simulation, coniselin and coniferyl ferulate have high binding affinity and stable interactions with the SETD2 protein. Coniselin is isolated from the alcoholic extract of Comiselinum vaginatum Thell. Coniferyl ferulate can be isolated from Angelica sinensis, Poria cocos (Schw.) Wolf, and Notopterygium forbesii. Although S-adenosyl-L-homocysteine has more stable interactions with key residues in the binding domain than coniselin and coniferyl ferulate during MD simulation, the TCM compounds coniselin and coniferyl ferulate are still potential candidates as lead compounds for further study in the drug development process with the SETD2 protein against acute lymphoblastic leukaemia.

  5. Effects of incomplete residential histories on studies of environmental exposure with application to childhood leukaemia and background radiation.

    PubMed

    Nikkilä, Atte; Kendall, Gerald; Raitanen, Jani; Spycher, Ben; Lohi, Olli; Auvinen, Anssi

    2018-06-22

    When evaluating environmental exposures, residential exposures are often most relevant. In most countries, it is impossible to establish full residential histories. In recent publications, childhood leukaemia and background radiation have been studied with and without full residential histories. This paper investigates the consequences of lacking such full data. Data from a nationwide Finnish Case-Control study of Childhood Leukaemia and gamma rays were analysed. This included 1093 children diagnosed with leukaemia in Finland in 1990-2011. Each case was matched by gender and year of birth to three controls. Full residential histories were available. The dose estimates were based on outdoor background radiation measurements. The indoor dose rates were obtained with a dwelling type specific conversion coefficient and the individual time-weighted mean red bone marrow dose rates were calculated using age-specific indoor occupancy and the age and gender of the child. Radiation from Chernobyl fallout was included and a 2-year latency period assumed. The median separation between successive dwellings was 3.4 km and median difference in red bone marrow dose 2.9 nSv/h. The Pearson correlation between the indoor red bone marrow dose rates of successive dwellings was 0.62 (95% CI 0.60, 0.64). The odds ratio for a 10 nSv/h increase in dose rate with full residential histories was 1.01 (95% CI 0.97, 1.05). Similar odds ratios were calculated with dose rates based on only the first dwelling (1.02, 95% CI 0.99, 1.05) and only the last dwelling (1.00, 95% CI 0.98, 1.03) and for subjects who had lived only in a single dwelling (1.05, 95% CI 0.98, 1.10). Knowledge of full residential histories would always be the option of choice. However, due to the strong correlation between exposure estimates in successive dwellings and the uncertainty about the most relevant exposure period, estimation of overall exposure level from a single address is also informative. Error in dose

  6. Common acute lymphoblastic leukaemia-lymphoma expressing cytokeratin: a case report.

    PubMed

    Menestrina, F; Lestani, M; Scarpa, A; Viale, G; Bonetti, F; Pizzolo, G; Chilosi, M

    1994-01-01

    This report presents a case of common acute lymphoblastic leukaemia-lymphoma expressing low molecular weight cytokeratin but no leukocyte common antigen (CD45) in a 57-year-old man. The unusual morphology and clinical course together with the aberrant immunohistochemical results suggested a diagnosis of undifferentiated carcinoma. A detailed immunohistochemistry study on frozen and paraffin sections and molecular analysis prevented a diagnostic mistake.

  7. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia

    PubMed Central

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-01-01

    Background: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). Methods: A case–control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Results: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47–11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20–0.91). Conclusion: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS. PMID:23695017

  8. Transformation of Topic-Specific Professional Knowledge into Personal Pedagogical Content Knowledge through Lesson Planning

    ERIC Educational Resources Information Center

    Stender, Anita; Brückmann, Maja; Neumann, Knut

    2017-01-01

    This study investigates the relationship between two different types of pedagogical content knowledge (PCK): the topic-specific professional knowledge (TSPK) and practical routines, so-called teaching scripts. Based on the Transformation Model of Lesson Planning, we assume that teaching scripts originate from a transformation of TSPK during lesson…

  9. Factors influencing the specific interaction of Neisseria gonorrhoeae with transforming DNA.

    PubMed Central

    Goodman, S D; Scocca, J J

    1991-01-01

    The specific interaction of transformable Neisseria gonorrhoeae with DNA depends on the recognition of specific 10-residue target sequences. The relative affinity for DNA between 3 and 17 kb in size appears to be linearly related to the frequency of targets on the segment and is unaffected by absolute size. The average frequency of targets in chromosomal DNA of N. gonorrhoeae appears to be approximately one per 1,000 bp. PMID:1909325

  10. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.

    PubMed

    Castaigne, Sylvie; Pautas, Cécile; Terré, Christine; Raffoux, Emmanuel; Bordessoule, Dominique; Bastie, Jean-Noel; Legrand, Ollivier; Thomas, Xavier; Turlure, Pascal; Reman, Oumedaly; de Revel, Thierry; Gastaud, Lauris; de Gunzburg, Noémie; Contentin, Nathalie; Henry, Estelle; Marolleau, Jean-Pierre; Aljijakli, Ahmad; Rousselot, Philippe; Fenaux, Pierre; Preudhomme, Claude; Chevret, Sylvie; Dombret, Hervé

    2012-04-21

    The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control

  11. Enhancement of chemosensitivity by simultaneously silencing of Mcl-1 and Survivin genes using small interfering RNA in human myelomonocytic leukaemia.

    PubMed

    Jafarlou, Mahdi; Shanehbandi, Dariush; Dehghan, Parvin; Mansoori, Behzad; Othman, F; Baradaran, Behzad

    2017-11-07

    Acute myeloid leukaemia (AML) is a genetically heterogeneous, severe and rapidly progressing disease triggered by blocking granulocyte or monocyte differentiation and maturation. Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers. In the present study, we examined the combined effect of etoposide and dual siRNA-mediated silencing of Mcl-1 and Survivin on U-937 AML cells. The AML cells were co-transfected with Mcl-1 and Survivin-specific siRNAs and genes silencing were confirmed by quantitative real-time PCR and Western blotting. Subsequently, MTT assay was used for the evaluation of cytotoxic effects by dual siRNA and etoposide on their own and in combination. For the studying of apoptosis, DNA-histone ELISA and annexin-V/FITC assays were performed. Co-transfection of Mcl-1 and Survivin siRNA significantly blocked their expression at the mRNA and protein levels, leading to the induction of apoptosis and strong inhibition of growth (p < .05). Besides, combined treatment of etoposide with Mcl-1 and Survivin siRNAs co-transfection leads to synergistically enhance etoposide-induced cytotoxic and apoptotic effects (p < .05). The results showed that Mcl-1 and Survivin play a major role in the U937 cells survival and their resistance relative to etoposide. Thus, Mcl-1 and Survivin can be considered as promising molecular targets for the treatment of AML. The combination treatment with etoposide, and siRNA-mediated silencing of corresponding genes may be a novel strategy in chemoresistance AML treatment.

  12. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

    PubMed Central

    Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Craft, Alan W; Parker, Louise; de González, Amy Berrington

    2012-01-01

    Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain

  13. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study.

    PubMed

    Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Sir Craft, Alan W; Parker, Louise; Berrington de González, Amy

    2012-08-04

    Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. During follow-up, 74 of 178,604 patients were diagnosed with leukaemia and 135 of 176,587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005-0·120; p=0·0097) and brain tumours (0·023, 0·010-0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46-6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50-74 mGy (mean dose 60·42 mGy) was 2·82 (1·33-6·03). Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative

  14. Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.

    PubMed

    Bleckmann, Kirsten; Schrappe, Martin

    2016-03-01

    The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity. © 2016 John Wiley & Sons Ltd.

  15. Ajoene, a garlic-derived natural compound, enhances chemotherapy-induced apoptosis in human myeloid leukaemia CD34-positive resistant cells.

    PubMed

    Ahmed, N; Laverick, L; Sammons, J; Zhang, H; Maslin, D J; Hassan, H T

    2001-01-01

    The reputation of garlic as an effective remedy for tumours extends back to the Egyptian Codex Ebers of 1550 BC. Several garlic compounds, including allicin and its corresponding sulfide, inhibit the proliferation of several human malignant cells. Ajoene is a garlic-derived compound produced most efficiently from pure allicin and has the advantage of a greater chemical stability than allicin. Recently, ajoene was shown to inhibit proliferation and induce apoptosis of human leukaemia CD34-negative cells including HL-60, U937, HEL and OCIM-I. More significantly, ajoene was shown to induce 30% apoptosis in myeloblasts from a chronic myeloid leukaemia patient in blastic crisis. Acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease progression at the level of CD34-positive cells has a major impact on resistance to chemotherapy and relapse. The aim of the present study was to investigate the effect of ajoene on changes in the expression of apoptosis-related proteins: bcl-2 and caspase-3, induced by two principal drugs used in treatment of AML, cytarabine and fludarabine, in KGI human myeloid leukaemia CD34-positive-resistant cells. Both quantitative ELISA measurement of bcl-2 and colourimetric measurement of active caspase-3 were used. Quantitative ELISA measurement of bcl-2 (units per million cells) showed treatment of KG1-resistant leukaemia cells with 40 microM ajoene alone to significantly reduce the bcl-2-expression from 239.5 +/- 1.5 in control cultures to only 22.0 +/- 4.0 in ajoene-treated cultures. Fludarabine had significantly more inhibitory effect on bcl-2-expression than cytarabine in KGI-resistant myeloid leukaemia cells. Ajoene significantly enhanced the inhibitory effect of the two chemotherapeutic drugs, cytarabine and fludarabine, on bcl-2-expression in KGI cells. Bcl-2-expression could not be detected in fludarabine + ajoene-treated cultures. The Western blot of bcl-2-expression in KGI control and treated cells confirmed

  16. Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

    PubMed

    January

    2016-04-01

    codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile.

  17. 26. Historic American Buildings Survey E. W. Russell, Photographer, May ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    26. Historic American Buildings Survey E. W. Russell, Photographer, May 7, 1936 EXTERIOR VIEW OF WINDOW IN REAR S. WALL, 1st FLOOR - Spring Hill College, Main Building, Old Shell Road, Spring Hill, Mobile County, AL

  18. Application of oncoproteomics to aberrant signalling networks in changing the treatment paradigm in acute lymphoblastic leukaemia.

    PubMed

    López Villar, Elena; Wang, Xiangdong; Madero, Luis; Cho, William C

    2015-01-01

    Oncoproteomics is an important innovation in the early diagnosis, management and development of personalized treatment of acute lymphoblastic leukaemia (ALL). As inherent factors are not completely known - e.g. age or family history, radiation exposure, benzene chemical exposure, certain viral exposures such as infection with the human T-cell lymphoma/leukaemia virus-1, as well as some inherited syndromes may raise the risk of ALL - each ALL patient may modify the susceptibility of therapy. Indeed, we consider these unknown inherent factors could be explained via coupling cytogenetics plus proteomics, especially when proteins are the ones which play function within cells. Innovative proteomics to ALL therapy may help to understand the mechanism of drug resistance and toxicities, which in turn will provide some leads to improve ALL management. Most important of these are shotgun proteomic strategies to unravel ALL aberrant signalling networks. Some shotgun proteomic innovations and bioinformatic tools for ALL therapies will be discussed. As network proteins are distinctive characteristics for ALL patients, unrevealed by cytogenetics, those network proteins are currently an important source of novel therapeutic targets that emerge from shotgun proteomics. Indeed, ALL evolution can be studied for each individual patient via oncoproteomics. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  19. Carfilzomib induces leukaemia cell apoptosis via inhibiting ELK1/KIAA1524 (Elk-1/CIP2A) and activating PP2A not related to proteasome inhibition.

    PubMed

    Liu, Chun-Yu; Hsieh, Feng-Shu; Chu, Pei-Yi; Tsai, Wen-Chun; Huang, Chun-Teng; Yu, Yuan-Bin; Huang, Tzu-Ting; Ko, Po-Shen; Hung, Man-Hsin; Wang, Wan-Lun; Shiau, Chung-Wai; Chen, Kuen-Feng

    2017-06-01

    Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment. © 2017 John Wiley & Sons Ltd.

  20. A case of hypotriploid chromosome in a patient with acute lymphoblastic leukaemia.

    PubMed

    Khan, Bilal Ahmed; Ali Baig, Mirza Faris; Siddiqui, Nadir

    2017-11-01

    TA 58-61, XXXX, hypotriploid chromosome was detected in the cytogenetics report of a 28 years old female patient, known case of B-cell Acute Lymphoblastic Leukaemia. On admission, the patient had normal physical examination findings and mental status, except history of fever spikes and generalized bone pains. The patient was admitted for induction of chemotherapy. Bone Marrow/Trephine biopsy report showed diffuse infiltration with blast cells with overall cellularity around 80-85% and suppressed normal haematopoiesis. Hypotriploid chromosome number in patients with B-cell Acute Lymphoblastic Leukaemia is a unique finding which, according to WHO classification of ALL, is an important prognostic factor itself and these cases have a favourable prognosis. There are only a few medical reports published about cases with similar presentations in Pakistan. Therefore, this case is very unique and further work should be done for better understanding of similar presentations and to find out more about its epidemiology.

  1. The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.

    PubMed

    Furness, Caroline L; Mansur, Marcela B; Weston, Victoria J; Ermini, Luca; van Delft, Frederik W; Jenkinson, Sarah; Gale, Rosemary; Harrison, Christine J; Pombo-de-Oliveira, Maria S; Sanchez-Martin, Marta; Ferrando, Adolfo A; Kearns, Pamela; Titley, Ian; Ford, Anthony M; Potter, Nicola E; Greaves, Mel

    2018-03-20

    Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

  2. Acute Myeloid Leukaemia

    PubMed Central

    Villela, Luis; Bolaños-Meade, Javier

    2013-01-01

    The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30–40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients’ outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used ‘7+3’ regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients. PMID:21861539

  3. Experience and nursing needs of school-age children undergoing lumbar puncture during the treatment of acute lymphoblastic leukaemia: a descriptive and qualitative study.

    PubMed

    Xie, Anwei; Shan, Yuying; Niu, Mei E; Chen, Yi; Wang, Xiya

    2017-11-01

    To describe experiences and nursing needs of school-age Chinese children undergoing lumbar puncture for the treatment of acute lymphoblastic leukaemia. Lumbar puncture is an invasive procedure, causing psychological changes and physical discomfort in patients. In a previous study, it was proved that distraction intervention, such as music therapy, relieves pain and anxiety. There is limited evidence regarding the experience and needs of school-age children during lumbar puncture after being diagnosed with acute lymphoblastic leukaemia. To minimise their anxiety and pain during the procedure, it is important to collect information directly from these children. A descriptive qualitative research. Twenty-one school-age children with acute lymphoblastic leukaemia participated in semi-structured interviews at a Children's Hospital in China. Data were collected by an experienced and trained interviewer. Qualitative content analysis was chosen to describe experiences of children undergoing lumbar puncture. While undergoing lumbar puncture for the treatment of acute lymphoblastic leukaemia, school-age Chinese children experienced complex psychological feelings (fear, tension, helplessness, sadness and anxiety). They also experienced physical discomfort. They had multipolar needs, such as information, communication, respect, self-actualisation, environment and equipment. This study identified important areas that must be closely monitored by healthcare staff, performing lumbar puncture on acute lymphoblastic leukaemia children. Thus, a successful and smooth procedure can be performed on these patients, and their quality of life can be improved. The experiences described in this study contribute to a better understanding of the needs of acute lymphoblastic leukaemia children undergoing lumbar puncture. They also provide valuable information to professional medical care staff that develops future nursing assessments. © 2016 John Wiley & Sons Ltd.

  4. Prevalence of feline immunodeficiency virus and feline leukaemia virus infection in Malaysia: a retrospective study.

    PubMed

    Sivagurunathan, Amilan; Atwa, Asem M; Lobetti, Remo

    2018-01-01

    Feline ownership is popular and represents the largest segment of the pet population in Malaysia. Most feline owners own, on average, 2-3 cats, with some having >10 cats per household. Feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) are two clinically important viral infections in cats. Documenting the prevalence of these diseases in the feline population is important for both veterinarians and the public. This was a retrospective study, using data collected from the domestic cat population seen at a 24 h private veterinary hospital in Malaysia, to determine the prevalence of FIV and FeLV in an urban area and risk factors associated with these infections. Between 2010 and 2016, 2230 blood samples were collected and tested for FIV antibodies and FeLV antigen using commercially available ELISA test kits. In total, 10.0% (n = 224; 95% confidence interval [CI] 8.80-11.26) were seropositive for FIV; 12.0% (n = 267; 95% CI 10.62-13.32) were seropositive for FeLV; and 2.6% (n = 58; 95% CI 2.01-3.17) were seropositive for both. The prevalence of FIV is lower and FeLV higher than previously documented for this region. Because of the immunosuppressive potential of both viruses, client education and use of appropriate control strategies such as routine screening, vaccination and eradication should be considered.

  5. Cell markers in the recognition of acute myeloblastic leukaemia subtypes.

    PubMed

    Andoljsek, Dusan; Preloznik Zupan, Irena; Zontar, Darja; Cernelc, Peter; Mlakar, Uros; Modic, Mojca; Pretnar, Joze; Zver, Samo

    2002-01-01

    The diagnosis of acute myeloblastic leukaemia (AML) is based on cell morphology, cytogenetic and molecular changes, cell markers and clinical data. Our aim was to establish whether morphology and cell markers are comparable in the evaluation of AML. Bone marrow smears were analysed, and flow cytometry and monoclonal antibodies were used to determine cell type and maturity. Morphology and cell markers correlated differently in different AML subtypes.

  6. Assessment of the utility of the tomato fruit-specific E8 promoter for driving vaccine antigen expression.

    PubMed

    He, Zhu-Mei; Jiang, Xiao-Ling; Qi, Yu; Luo, Di-Qing

    2008-06-01

    To assess the utility of the tomato fruit-specific E8 gene's promoter for driving vaccine antigen expression in plant, the 2.2 kb and 1.1 kb E8 promoters were isolated and sequenced from Lycopersicon esculentum cv. Jinfeng #1. The 1.1 kb promoter was fused to vaccine antigen HBsAg M gene for the transfer to Nicotiana tabacum, and the CaMV 35S promoter was used for comparison. Cholera toxin B (ctb) gene under the control of the 1.1 kb promoter was transformed into both N. tabacum and L. esculentum. Southern blot hybridization confirmed the stable integration of the target genes into the tomato and tobacco genomes. ELISA assay showed that the expression product of HBsAg M gene under the control of the 1.1 kb E8 promoter could not be detected in transgenic tobacco tissues such as leaves, flowers, and seeds. In contrast, the expression of HBsAg M gene driven by CaMV 35S promoter could be detected in transgenic tobacco. ELISA assay for CTB proved that the 1.1 kb E8 promoter was able to direct the expression of exotic gene in ripe fruits of transgenic tomato, but expression was absent in leaf, flower, and unripe fruit of tomato, and CTB protein was not detected in transgenic tobacco tissues such as leaves, flowers, and seeds when the gene was under the control of the 1.1 kb E8 promoter. The results indicated that the E8 promoter acted not only in an organ-specific, but also in a species-specific fashion in plant transformation.

  7. Low CREBBP expression is associated with adverse long-term outcomes in paediatric acute lymphoblastic leukaemia.

    PubMed

    Gao, Chao; Zhang, Rui-Dong; Liu, Shu-Guang; Zhao, Xiao-Xi; Cui, Lei; Yue, Zhi-Xia; Li, Wei-Jing; Chen, Zhen-Ping; Li, Zhi-Gang; Rao, Qing; Wang, Min; Zheng, Hu-Yong; Wang, Jian-Xiang

    2017-08-01

    CREBBP alterations are associated with many diseases including leukaemia. However, CREBBP expression and its clinical relevance in paediatric acute lymphoblastic leukaemia have not been elucidated. We studied CREBBP mRNA expression in 349 patients treated with either the BCH-2003 or CCLG-2008 protocol. Using a receiver operating characteristic curve, patients were divided into low- or high-CREBBP. The association among clinicobiological characteristics, outcomes and CREBBP level was analysed. Low expression of CREBBP (<1.0) at diagnosis was found in 97.7% of patients and increased significantly after complete remission. Low-CREBBP patients were associated with unfavourable clinical presentations, poor prednisone response and high minimal residual disease (>10 -2 ) after induction. We found significantly poorer event-free survival (EFS) and overall survival (OS) in low-CREBBP group whether administered BCH-2003 or CCLG-2008. Low-CREBBP was an inferior independent prognostic factor in BCH-2003; patients with low-CREBBP had better outcomes on an intermediate-risk regimen than a standard-risk regimen involving the CCLG-2008 protocol. Patients stratified to high-risk with low-CREBBP had the worst EFS and OS. These findings indicate that low-CREBBP is predictive of unfavourable outcomes; thus, a more intensive treatment protocol is necessitated for standard-risk patients with insufficient CREBBP and that a specific target therapy is necessitated for high-risk patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy.

    PubMed

    Forastiere, F; Sperati, A; Cherubini, G; Miceli, M; Biggeri, A; Axelson, O

    1998-02-01

    To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses--that might need further consideration.

  9. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy

    PubMed Central

    Forastiere, F.; Sperati, A.; Cherubini, G.; Miceli, M.; Biggeri, A.; Axelson, O.

    1998-01-01

    OBJECTIVES: To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. METHODS: For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. RESULTS: The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. CONCLUSIONS: In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses-- that might need further consideration.   PMID:9614394

  10. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

    PubMed Central

    Minici, Claudia; Gounari, Maria; Übelhart, Rudolf; Scarfò, Lydia; Dühren-von Minden, Marcus; Schneider, Dunja; Tasdogan, Alpaslan; Alkhatib, Alabbas; Agathangelidis, Andreas; Ntoufa, Stavroula; Chiorazzi, Nicholas; Jumaa, Hassan; Stamatopoulos, Kostas; Ghia, Paolo; Degano, Massimo

    2017-01-01

    Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR–BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies. PMID:28598442

  11. Femoral diaphyseal stress fracture as the initial presentation of acute leukaemia in an adolescent.

    PubMed

    Chase, Helen Emily; Pang, Joe Hwong; Sanghrajka, Anish Pradip

    2016-06-28

    A 14-year-old boy was referred to the orthopaedic clinic by his general practitioner, reporting of a 6-week history of left thigh pain. Clinical examination was unremarkable. Radiographs demonstrated a periosteal reaction at the proximal femur. MRI scans demonstrated a stress fracture of the femur, with no associated sinister features and no evidence of a pathological lesion. As the fracture healed and symptoms improved, the patient became unwell with weight loss, lethargy, chest and jaw pain and fevers. After multiple blood tests over a 25-day period, including five full blood counts and two normal blood films, a third blood film finally demonstrated blasts in keeping with acute leukaemia. We discuss a literature review of musculoskeletal manifestations of leukaemia and the often atypical presentations found. 2016 BMJ Publishing Group Ltd.

  12. Specific oral desensitization in children with IgE-mediated cow's milk allergy. Evolution in one year.

    PubMed

    Alvaro, Montserrat; Giner, Ma Teresa; Vázquez, Marta; Lozano, Jaime; Domínguez, Olga; Piquer, Mónica; Días, Marcia; Jiménez, Rosa; Martín, Ma Anunciación; Alsina, Laia; Plaza, Ana Ma

    2012-09-01

    Cow's milk allergy is the most frequent childhood food allergy. Children older than 5 who have not become tolerant have less probabilities of natural tolerance. Specific oral desensitization methods are being investigated in reference centres. The aims of our study were to assess the efficacy of our guideline of specific oral desensitization to cow's milk in children and to know its suitability for anaphylactic children. Both clinical and specific IgE outcomes were evaluated. Eighty-seven children aged 5 to 16 years with a history of cow's milk allergy were included. Prior to desensitization, skin prick test, specific IgE to cow's milk proteins and a double-blind placebo control food challenge were performed in all. Of the 87 patients, 21 had a negative challenge; they were considered tolerant, and they were told to follow a free diet. Of the positive, 44 were anaphylactic and 22 non-anaphylactic. All of them were included. In non-anaphylactic patients, 6 achieved partial and 16 maximum desensitization after 23.1 weeks. In the anaphylactic group, 7 achieved partial and 35 maximum desensitization after 26.4 weeks. Cow's milk-specific IgE levels and casein-specific IgE levels were significantly lower in the tolerant patients at baseline. One year after desensitization, the medium specific cow's milk levels and casein IgE levels had dropped significantly. Our guideline for specific oral desensitization to cow's milk is efficacious even in patients with anaphylactic reactions to cow's milk and represents a significant life change. Immunological changes in 1 year show a drop in cow's milk protein-specific IgE.

  13. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

    PubMed Central

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

    2012-01-01

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

  14. 26 CFR 1.1031(e)-1 - Exchange of livestock of different sexes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 11 2012-04-01 2012-04-01 false Exchange of livestock of different sexes. 1.1031(e)-1 Section 1.1031(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Exchange of livestock of different sexes. Section 1031(e) provides that livestock of different sexes are...

  15. 26 CFR 1.1031(e)-1 - Exchange of livestock of different sexes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 11 2013-04-01 2013-04-01 false Exchange of livestock of different sexes. 1.1031(e)-1 Section 1.1031(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Exchange of livestock of different sexes. Section 1031(e) provides that livestock of different sexes are...

  16. 26 CFR 1.1031(e)-1 - Exchange of livestock of different sexes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 11 2011-04-01 2011-04-01 false Exchange of livestock of different sexes. 1.1031(e)-1 Section 1.1031(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Exchange of livestock of different sexes. Section 1031(e) provides that livestock of different sexes are...

  17. 26 CFR 1.1031(e)-1 - Exchange of livestock of different sexes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 11 2014-04-01 2014-04-01 false Exchange of livestock of different sexes. 1.1031(e)-1 Section 1.1031(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Exchange of livestock of different sexes. Section 1031(e) provides that livestock of different sexes are...

  18. Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway.

    PubMed

    Zhang, Xueyan; Ai, Ziying; Chen, Jing; Yi, Juan; Liu, Zhuan; Zhao, Huaishun; Wei, Hulai

    2017-04-01

    In human leukaemia, resistance to chemotherapy leads to treatment ineffectiveness or failure. Previous studies have indicated that cancers with increased levels of aerobic glycolysis are insensitive to numerous forms of chemotherapy and respond poorly to radiotherapy. Whether glycolysis serves a key role in drug resistance of leukaemia cells remains unclear. The present study systematically investigated aerobic glycolytic alterations and regulation in K562/adriamycin (ADM) multidrug‑resistant (MDR) and ADM‑sensitive K562 leukaemia cells in normoxia, and the association between drug resistance and improper glycometabolism. The cell proliferating activity was assessed with an MTT colorimetric assay, glycolysis, including glucose consumption, lactate export and key‑enzyme activity was determined by corresponding commercial testing kits. The expression levels of hexokinase‑II (HK‑II), lactate dehydrogenase A (LDHA), glucose transporter‑4 (GLUT‑4), AKT, p‑AKT473/308, mammalian target of rapamycin (mTOR), p‑mTOR, c‑Myc and hypoxia‑inducible factor‑1α (HIF‑1α) were analyzed by western blot or reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). K562/ADM cells exhibited increased glucose consumption and lactate accumulation, increased lactate dehydrogenase, hexokinase and pyruvate kinase activities, and reduced phosphofructokinase activity. In addition, K562/ADM cells expressed significantly more HK‑II and GLUT‑4. Notably, inhibition of glycolysis effectively killed sensitive and resistant leukaemia cells and potently restored the sensitivity of MDR cells to the anticancer agent ADM. The AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway, a crucial regulator of glycometabolic homeostasis, mediated over‑activation and upregulation of c‑Myc expression levels in K562/ADM cells, which directly stimulated glucose consumption and enhanced glycolysis. In conclusion, the present

  19. FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p

    PubMed Central

    Helliwell, Stephen B.; Karkare, Shantanu; Bergdoll, Marc; Rahier, Alain; Leighton-Davis, Juliet R.; Fioretto, Celine; Aust, Thomas; Filipuzzi, Ireos; Frederiksen, Mathias; Gounarides, John; Hoepfner, Dominic; Hofmann, Andreas; Imbert, Pierre-Eloi; Jeker, Rolf; Knochenmuss, Richard; Krastel, Philipp; Margerit, Anais; Memmert, Klaus; Miault, Charlotte V.; Rao Movva, N.; Muller, Alban; Naegeli, Hans-Ulrich; Oberer, Lukas; Prindle, Vivian; Riedl, Ralph; Schuierer, Sven; Sexton, Jessica A.; Tao, Jianshi; Wagner, Trixie; Yin, Hong; Zhang, Juan; Roggo, Silvio; Reinker, Stefan; Parker, Christian N.

    2015-01-01

    FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae—Erg26p, Homo sapiens—NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound. PMID:26456460

  20. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    PubMed

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature. © 2015 by the Association of Clinical Scientists, Inc.

  1. Self-Esteem and Academic Difficulties in Preadolescents and Adolescents Healed from Paediatric Leukaemia

    PubMed Central

    Tremolada, Marta; Taverna, Livia; Bonichini, Sabrina; Basso, Giuseppe; Pillon, Marta

    2017-01-01

    Adolescents with cancer may demonstrate problems in their self-esteem and schooling. This study aims to screen the preadolescents and adolescents more at risk in their self-esteem perception and schooling difficulties post-five years from the end of therapy. Twenty-five paediatric ex-patients healed from leukaemia were recruited at the Haematology-Oncologic Clinic (University of Padua). The mean age of the children was 13.64 years (Standard Deviation (SD)) = 3.08, range = 10–19 years), most were treated for acute lymphoblastic leukaemia (ALL) (84%) and relatively equally distributed by gender. They filled in the Multidimensional Self-Esteem Test, while parents completed a questionnaire on their child’s schooling. Global self-esteem was mostly below the 50 percentile (58.5%), especially regarding interpersonal relationships (75%). An independent sample t-test showed significant mean differences on the emotionality scale (t = 2.23; degree of freedom (df) = 24; p = 0.03) and in the bodily experience scale (t = 3.02; df = 24; p = 0.006) with survivors of Acute Myeloid Leukaemia (AML) having lower scores. An Analysis of Variance (ANOVA) showed significant mean differences in the bodily experience scale (F = 12.31; df = 2, p = 0.0001) depending on the survivors’ assigned risk band. The parent reports showed that 43.5% of children had difficulties at school. Childhood AML survivors with a high-risk treatment were more at risk in their self-esteem perceptions. Preventive interventions focusing on self-esteem and scholastic wellbeing are suggested in order to help their return to their normal schedules. PMID:28538707

  2. Self-Esteem and Academic Difficulties in Preadolescents and Adolescents Healed from Paediatric Leukaemia.

    PubMed

    Tremolada, Marta; Taverna, Livia; Bonichini, Sabrina; Basso, Giuseppe; Pillon, Marta

    2017-05-24

    Adolescents with cancer may demonstrate problems in their self-esteem and schooling. This study aims to screen the preadolescents and adolescents more at risk in their self-esteem perception and schooling difficulties post-five years from the end of therapy. Twenty-five paediatric ex-patients healed from leukaemia were recruited at the Haematology-Oncologic Clinic (University of Padua). The mean age of the children was 13.64 years (Standard Deviation (SD)) = 3.08, range = 10-19 years), most were treated for acute lymphoblastic leukaemia (ALL) (84%) and relatively equally distributed by gender. They filled in the Multidimensional Self-Esteem Test, while parents completed a questionnaire on their child's schooling. Global self-esteem was mostly below the 50 percentile (58.5%), especially regarding interpersonal relationships (75%). An independent sample t -test showed significant mean differences on the emotionality scale ( t = 2.23; degree of freedom (df) = 24; p = 0.03) and in the bodily experience scale ( t = 3.02; df = 24; p = 0.006) with survivors of Acute Myeloid Leukaemia (AML) having lower scores. An Analysis of Variance (ANOVA ) showed significant mean differences in the bodily experience scale ( F = 12.31; df = 2, p = 0.0001) depending on the survivors' assigned risk band. The parent reports showed that 43.5% of children had difficulties at school. Childhood AML survivors with a high-risk treatment were more at risk in their self-esteem perceptions. Preventive interventions focusing on self-esteem and scholastic wellbeing are suggested in order to help their return to their normal schedules.

  3. 26 CFR 1.1031(e)-1 - Exchange of livestock of different sexes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Exchange of livestock of different sexes. 1.1031(e)-1 Section 1.1031(e)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... livestock of different sexes. Section 1031(e) provides that livestock of different sexes are not property of...

  4. Violacein Induces Death of Resistant Leukaemia Cells via Kinome Reprogramming, Endoplasmic Reticulum Stress and Golgi Apparatus Collapse

    PubMed Central

    Queiroz, Karla C. S.; Milani, Renato; Ruela-de-Sousa, Roberta R.; Fuhler, Gwenny M.; Justo, Giselle Z.; Zambuzzi, Willian F.; Duran, Nelson; Diks, Sander H.; Spek, C. Arnold; Ferreira, Carmen V.; Peppelenbosch, Maikel P.

    2012-01-01

    It is now generally recognised that different modes of programmed cell death (PCD) are intimately linked to the cancerous process. However, the mechanism of PCD involved in cancer chemoprevention is much less clear and may be different between types of chemopreventive agents and tumour cell types involved. Therefore, from a pharmacological view, it is crucial during the earlier steps of drug development to define the cellular specificity of the candidate as well as its capacity to bypass dysfunctional tumoral signalling pathways providing insensitivity to death stimuli. Studying the cytotoxic effects of violacein, an antibiotic dihydro-indolone synthesised by an Amazon river Chromobacterium, we observed that death induced in CD34+/c-Kit+/P-glycoprotein+/MRP1+ TF1 leukaemia progenitor cells is not mediated by apoptosis and/or autophagy, since biomarkers of both types of cell death were not significantly affected by this compound. To clarify the working mechanism of violacein, we performed kinome profiling using peptide arrays to yield comprehensive descriptions of cellular kinase activities. Pro-death activity of violacein is actually carried out by inhibition of calpain and DAPK1 and activation of PKA, AKT and PDK, followed by structural changes caused by endoplasmic reticulum stress and Golgi apparatus collapse, leading to cellular demise. Our results demonstrate that violacein induces kinome reprogramming, overcoming death signaling dysfunctions of intrinsically resistant human leukaemia cells. PMID:23071514

  5. 26. "TEST STAND, STRUCTURAL, FOUNDATION PLAN." Specifications No. ENG043535572; Drawing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    26. "TEST STAND, STRUCTURAL, FOUNDATION PLAN." Specifications No. ENG-04-353-55-72; Drawing No. 60-0912; sheet 25 of 148; file no. 1320/76. Stamped: RECORD DRAWING - AS CONSTRUCTED. Below stamp: Contract no. 4338, no change. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Test Stand 1-A, Test Area 1-120, north end of Jupiter Boulevard, Boron, Kern County, CA

  6. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.

    PubMed

    Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Coutre, Steven; Seymour, John F; Munir, Talha; Puvvada, Soham D; Wendtner, Clemens-Martin; Roberts, Andrew W; Jurczak, Wojciech; Mulligan, Stephen P; Böttcher, Sebastian; Mobasher, Mehrdad; Zhu, Ming; Desai, Monali; Chyla, Brenda; Verdugo, Maria; Enschede, Sari Heitner; Cerri, Elisa; Humerickhouse, Rod; Gordon, Gary; Hallek, Michael; Wierda, William G

    2016-06-01

    Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their

  7. Risk of leukaemia and residential exposure to air pollution in an industrial area in Northern Italy: a case-control study.

    PubMed

    Parodi, Stefano; Santi, Irene; Casella, Claudia; Puppo, Antonella; Montanaro, Fabio; Fontana, Vincenzo; Pescetto, Massimiliano; Stagnaro, Emanuele

    2015-01-01

    Leukaemia risk in adult populations exposed to environmental air pollution is poorly investigated. We have carried out a population-based case-control study in an area that included a fossil fuel power plant, a coke oven and two big chemical industries. Information on residential history and several risk factors for leukaemia was obtained from 164 cases, diagnosed between 2002 and 2005, and 279 controls. A higher risk for subjects residing in polluted areas was observed, but statistical significance was not reached (adjusted OR = 1.11 and 1.56 for subjects living in moderately and in heavily polluted zones, respectively, p = 0.190). Results suggest a possible aetiological role of residential air pollution from industrial sites on the risk of developing leukaemia in adult populations. However, the proportion of eligible subjects excluded from the study and the lack of any measure of air pollution prevent definitive conclusions from being drawn.

  8. 26 CFR 31.3121(e)-1 - State, United States, and citizen.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 15 2013-04-01 2013-04-01 false State, United States, and citizen. 31.3121(e)-1... § 31.3121(e)-1 State, United States, and citizen. (a) When used in the regulations in this subpart, the..., the term “United States”, when used in a geographical sense, means the several states (including the...

  9. 26 CFR 31.3121(e)-1 - State, United States, and citizen.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false State, United States, and citizen. 31.3121(e)-1... § 31.3121(e)-1 State, United States, and citizen. (a) When used in the regulations in this subpart, the..., the term “United States”, when used in a geographical sense, means the several states (including the...

  10. 26 CFR 31.3121(e)-1 - State, United States, and citizen.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false State, United States, and citizen. 31.3121(e)-1... § 31.3121(e)-1 State, United States, and citizen. (a) When used in the regulations in this subpart, the..., the term “United States”, when used in a geographical sense, means the several states (including the...

  11. Adenovirus type 5 E1A and E6 proteins of low-risk cutaneous beta-human papillomaviruses suppress cell transformation through interaction with FOXK1/K2 transcription factors.

    PubMed

    Komorek, Jessica; Kuppuswamy, Mohan; Subramanian, T; Vijayalingam, S; Lomonosova, Elena; Zhao, Ling-Jun; Mymryk, Joe S; Schmitt, Kimberly; Chinnadurai, G

    2010-03-01

    The adenovirus (Adv) oncoprotein E1A stimulates cell proliferation and inhibits differentiation. These activities are primarily linked to the N-terminal region (exon 1) of E1A, which interacts with multiple cellular protein complexes. The C terminus (exon 2) of E1A antagonizes these processes, mediated in part through interaction with C-terminal binding proteins 1 and 2 (CtBP1/2). To identify additional cellular E1A targets that are involved in the modulation of E1A C-terminus-mediated activities, we undertook tandem affinity purification of E1A-associated proteins. Through mass spectrometric analysis, we identified several known E1A-interacting proteins as well as novel E1A targets, such as the forkhead transcription factors, FOXK1/K2. We identified a Ser/Thr-containing sequence motif in E1A that mediated interaction with FOXK1/K2. We demonstrated that the E6 proteins of two beta-human papillomaviruses (HPV14 and HPV21) associated with epidermodysplasia verruciformis also interacted with FOXK1/K2 through a motif similar to that of E1A. The E1A mutants deficient in interaction with FOXK1/K2 induced enhanced cell proliferation and oncogenic transformation. The hypertransforming activity of the mutant E1A was suppressed by HPV21 E6. An E1A-E6 chimeric protein containing the Ser/Thr domain of the E6 protein in E1A interacted efficiently with FOXK1/K2 and inhibited cell transformation. Our results suggest that targeting FOXK1/K2 may be a common mechanism for certain beta-HPVs and Adv5. E1A exon 2 mutants deficient in interaction with the dual-specificity kinases DYRK1A/1B and their cofactor HAN11 also induced increased cell proliferation and transformation. Our results suggest that the E1A C-terminal region may suppress cell proliferation and oncogenic transformation through interaction with three different cellular protein complexes: FOXK1/K2, DYRK(1A/1B)/HAN11, and CtBP1/2.

  12. Molecular techniques for the personalised management of patients with chronic myeloid leukaemia.

    PubMed

    Alikian, Mary; Gale, Robert Peter; Apperley, Jane F; Foroni, Letizia

    2017-03-01

    Chronic myeloid leukemia (CML) is the paradigm for targeted cancer therapy. RT-qPCR is the gold standard for monitoring response to tyrosine kinase-inhibitor (TKI) therapy based on the reduction of blood or bone marrow BCR-ABL1 . Some patients with CML and very low or undetectable levels of BCR-ABL1 transcripts can stop TKI-therapy without CML recurrence. However, about 60 percent of patients discontinuing TKI-therapy have rapid leukaemia recurrence. This has increased the need for more sensitive and specific techniques to measure residual CML cells. The clinical challenge is to determine when it is safe to stop TKI-therapy. In this review we describe and critically evaluate the current state of CML clinical management, different technologies used to monitor measurable residual disease (MRD) focus on comparingRT-qPCR and new methods entering clinical practice. We discuss advantages and disadvantages of new methods.

  13. Long survival in acute myelogenous leukaemia: an international collaborative study.

    PubMed Central

    Whittaker, J A; Reizenstein, P; Callender, S T; Cornwell, G G; Delamore, I W; Gale, R P; Gobbi, M; Jacobs, P; Lantz, B; Maiolo, A T; Rees, J K; Van Slyck, E J; Van, H V

    1981-01-01

    A group of 82 adult patients with acute myelogenous leukaemia had survived in continuous first remission for more than three years was studied. These long-surviving patients were being treated at 12 referral centres in Europe and the USA, and they were compared with other patients with acute myelogenous leukaemia from 10 of these centres. There was no clear difference in the amount of induction chemotherapy or the time taken to achieve remission. Immunotherapy was not found to improve chances of long-term survival. The 82 patients were also compared with a group of 115 patients who had no appreciable difference in the number of blood or marrow myeloblasts between these two groups at presentation, but the long survivors had significantly higher initial platelet counts and were slightly younger. The long survivors also tended to have a lower total white cell count at presentation and lower granulocyte counts; there was no obvious explanation for these differences. Eight of the 82 patients relapsed from three to four years after remission and two (of 69 patients) after four to five year. Thereafter relapse was rare, and it seems likely that some of the 40 patients who have survived for five years or more are cured. PMID:6781618

  14. 12 CFR 563e.26 - Small savings association performance standards.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Small savings association performance standards... COMMUNITY REINVESTMENT Standards for Assessing Performance § 563e.26 Small savings association performance standards. (a) Performance criteria—(1) Small savings associations that are not intermediate small savings...

  15. 12 CFR 563e.26 - Small savings association performance standards.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 5 2011-01-01 2011-01-01 false Small savings association performance standards... COMMUNITY REINVESTMENT Standards for Assessing Performance § 563e.26 Small savings association performance standards. (a) Performance criteria—(1) Small savings associations that are not intermediate small savings...

  16. Dedicated cytogenetics factor is critical for improving karyotyping results for childhood leukaemias - experience in the National University Hospital, Singapore 1989-2006.

    PubMed

    Heng, J L; Chen, Y C; Quah, T C; Liu, T C; Yeoh, A E J

    2010-02-01

    Childhood leukaemia accounts for more than 40% of new childhood cancer cases. Karyotyping of cytogenetic abnormalities in such cases continues to provide critical prognostic information which allows the delivery of an appropriate intensity of treatment. Unfortunately, karyotyping of childhood leukaemia is difficult, laborious and often unsuccessful. Banding resolution tends to be poor unlike routine antenatal cytogenetics. The aim of the study is to highlight the benefit of dedicated cytogenetics in improving karyotyping results. We analysed the impact of setting up a team of cytogeneticists in the National University Hospital (NUH) on the success of karyotyping, evaluating cytogenetic data collected from 1989 to 2006. From 1989 to 2006, 4789 cases have been processed. Among them, 369 newly diagnosed and relapsed childhood acute leukaemia cases [281 acute lymphoblastic leukaemia (ALL) and 88 acute myeloid leukaemia (AML)] have been diagnosed at NUH. A dedicated cytogenetics laboratory with clearly defined standard operating procedures and quality control was set up in 2002. It used the established recommendation of a complete analysis of at least 20 metaphases per analysis. Overall, the frequency of successful karyotyping was significantly higher (P = 0.002) at 90.7% (185/204) from 2002-2006 compared to 79.4% (131/165) from 1989-2001. For ALL cases, the success rate improved from 77.6% (97/125) in 1989 to 2001 to 89.1% (139/156) in the 2002 to 2006 cohort. For AML, the success rate also was significantly improved (P = 0.04) from 85% (34/40) to 95.8% (46/48). Significantly, this high rate of success is still maintained despite a yearly increase in volume. The establishment of a dedicated cytogenetics service leads to an improvement in results.

  17. Deoxycytidine kinase is downregulated under hypoxic conditions and confers resistance against cytarabine in acute myeloid leukaemia.

    PubMed

    Degwert, Nicole; Latuske, Emily; Vohwinkel, Gabi; Stamm, Hauke; Klokow, Marianne; Bokemeyer, Carsten; Fiedler, Walter; Wellbrock, Jasmin

    2016-09-01

    Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 α in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML). In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia-inducible factor 1 α as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions. In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Correlations Between Allergen-Specific IgE Serum Levels in Patients With Ocular Allergy.

    PubMed

    Polido, Júlia Gomes Fernandes; Cabral, Thiago; Perini, Paula de Resende Campos; Fernandes, Maria de Fátima Marcelos; de Freitas, Denise; dos Santos Araújo, Maria Emília Xavier; Serracarbassa, Pedro Durães

    2015-09-01

    To evaluate ocular allergies in patients at the Hospital do Servidor Publico Estadual de Sao Paulo (HSPE) and the correlations with serum allergen-specific immunoglobulin E levels. We performed a longitudinal study of patients with ocular allergies who were treated at the Cornea and Immunology and Allergy Department. Patients underwent an ophthalmologic examination to identify their primary presenting signs and symptoms. The allergy types were divided into 4 groups. We conducted the following laboratory tests and measurements: blood count, eosinophil count, total serum IgE, and specific IgE. Among 61 patients, 16 (26.2%) had a clinical diagnosis of seasonal allergic conjunctivitis, 23 (37.7%) had perennial allergic conjunctivitis, 19 (31.1%) had vernal keratoconjunctivitis, and 3 (4.9%) had atopic keratoconjunctivitis. Mixed dust mites were positive in 94.9% of patients. Dermatophagoides pteronyssinus (dp) and Dermatophagoides farinae (df) antigens were positive in 93.2% of patients followed by Blattella germanica, Blomia tropicalis, and mixed animal epithelia (81%, 75.9%, and 25.8%, respectively). Perennial allergic conjunctivitis was the most prevalent disorder and demonstrated higher positivity in class V/VI for specific antigens (mixed dust mites, dp, and df), indicating high antigenicity. Dust mites, D. pteronyssinus, D. farinae, B. germanica, and B. tropicalis were the primary triggers of the studied ocular allergies.

  19. Promoting safety voice with safety-specific transformational leadership: the mediating role of two dimensions of trust.

    PubMed

    Conchie, Stacey M; Taylor, Paul J; Donald, Ian J

    2012-01-01

    Although safety-specific transformational leadership is known to encourage employee safety voice behaviors, less is known about what makes this style of leadership effective. We tested a model that links safety-specific transformational leadership to safety voice through various dimensions of trust. Data from 150 supervisor-employee dyads from the United Kingdom oil industry supported our predictions that the effects of safety-specific transformational leadership are sequentially mediated by affect-based trust beliefs and disclosure trust intentions. Moreover, we found that reliance trust intentions moderated the effect of disclosure: employees' disclosure intentions mediated the effects of affect-based trust on safety voice behaviors only when employees' intention to rely on their leader was moderate to high. These findings suggest that leaders seeking to encourage safety voice behaviors should go beyond "good reason" arguments and develop affective bonds with their employees.

  20. Highly efficient focus formation by Rous sarcoma virus on adenovirus type 12 E1A-transformed rat 3Y1 cells.

    PubMed Central

    Shiroki, K; Hamaguchi, M; Kawai, S

    1992-01-01

    When rat 3Y1 cells were infected with Rous sarcoma virus (RSV) variant SR-RSV-D(H), many 3Y1 cells acquired a stable provirus but only few of them formed transformed foci. In contrast, 12E1AY cells (3Y1 cells expressing the adenovirus type 12 [Ad12] E1A protein) formed transformed foci upon RSV infection with the same high frequency as did chicken embryo fibroblast cells. This enhancement of focus-forming efficiency was specifically observed in 3Y1 cells expressing Ad12 E1A protein but was not observed in 3Y1 cells expressing simian virus 40 T, c-myc, p53, c-fos, or v-fos protein. This enhancement was not evident in 5E1AY cells (3Y1 cells expressing the Ad5 E1A protein). Judging from the experiment using Ad12-Ad5 hybird E1A DNAs, the N-terminal half of the Ad12 E1A protein was responsible for this enhancement. The promoter activity of the RSV long terminal repeat measured by pLTR-CAT did not correlate to the efficiency of focus formation by RSV in these 3Y1 cells. Moreover, RSV containing the neo gene instead of the src gene produced G418-resistant cells equally efficiently among 3Y1, E1AY, and chicken embryo fibroblast cells. These results suggest that the enhancement of focus formation by RSV is not due to the increased expression of the src gene by the E1A protein. src mRNA and src protein were lower in RSV-transformed E1AY (RSVE1AY) cells than in RSV-transformed 3Y1 (RSV3Y1) cells. The phosphotyrosine-containing proteins were also less abundant in RSVE1AY cells than in RSV3Y1 cells, suggesting that E1AY cells require a lower threshold dose of p60v-src for transformation than do 3Y1 cells. E1AY cells were found to be more sensitive to lysis by detergents. The results suggest that the enhancement is due to changes in membrane structures in E1AY cells. Images PMID:1310757

  1. The Toxoplasma gondii ME-49 strain upregulates levels of A20 that inhibit NF-κB activation and promotes apoptosis in human leukaemia T-cell lines.

    PubMed

    Chen, Qian; Pang, Min-Hui; Ye, Xiao-Hong; Yang, Guang; Lin, Chen

    2018-05-18

    Acute T-lymphocyte leukaemia is a form of haematological malignancy with abnormal activation of NF-κB pathway, which results in high expression of A20 and ABIN1, which constitute a negative feedback mechanism for the regulation of NF-κB activation. Clinical studies have found that acute T-lymphocyte leukaemia patients are susceptible to Toxoplasma gondii infection; however, the effect of T. gondii on the proliferation and apoptosis of human leukaemia T-cells remains unclear. Here, we used the T. gondii ME-49 strain to infect human leukaemia T-cell lines Jurkat and Molt-4, to explore the effect of T. gondii on proliferation and apoptosis, which is mediated by NF-κB in human leukaemia T-cells. The Tunel assay was used to detect cell apoptosis. Cell Counting Kit-8 was used to detect cell proliferation viability. The apoptosis level and the expression level of NF-κB related proteins in human leukaemia T-cells were detected by flow cytometry and Western blotting. Western blotting analyses revealed that the T. gondii ME-49 strain increased the expression of A20 and decreased both ABIN1 expression and NF-κB p65 phosphorylation. By constructing a lentiviral-mediated shRNA to knockdown the A20 gene in Jurkat T-cells and Molt-4 T-cells, the apoptosis levels of the two cell lines decreased after T. gondii ME-49 infection, and levels of NF-κB p65 phosphorylation and ABIN1 were higher than in the non-konckdown group. After knockingdown ABIN1 gene expression by constructing the lentiviral-mediated shRNA and transfecting the recombinant expression plasmid containing the ABIN1 gene into two cell lines, apoptosis levels and cleaved caspase-8 expression increased or decreased in response to T. gondii ME-49 infection, respectively. Our data suggest that ABIN1 protects human leukaemia T-cells by allowing them to resist the apoptosis induced by T. gondii ME-49 and that the T. gondii ME-49 strain induces the apoptosis of human leukaemia T-cells via A20-mediated downregulation of

  2. A case-control study to investigate the association between exposure to benzene and deaths from leukaemia in oil refinery workers.

    PubMed

    Rushton, L; Alderson, M R

    1981-01-01

    All deaths with a mention of leukaemia on the death certificate, in men employed over a period of 25 years of 8 oil refineries in the U.K. were identified. The potential benzene exposure of these cases was compared with that of two sets of controls selected from the total refinery population. One set of controls was matched for refinery and year of birth, the other set was matched for refinery, year of birth nd length of service. No information was available on measurement of benzene in the work environment but a job history was obtained from refinery personnel records for all cases and controls. This was used to allocate each man to a benzene exposure level of "low", "medium", or "high". There was no overall excess of deaths from leukaemia when compared with the expectation from national rates. There was also no excess of cytological types of leukaemia which have been shown to be particularly associated with benzene exposure. However, the risk for those men with medium or high exposure relative to the risk for those with low benzene exposure approached a significance (P=0.05) when length of service was taken into account. If there were an increased risk of leukaemia due to benzene exposure, it could have only been one that affected a very small proportion of men within the refinery workforce.

  3. Crystalline inclusions in the cytoplasm and nuclei of cells of acute myeloid leukaemia.

    PubMed

    Pearson, E C

    1989-01-01

    In a survey by electron microscopy of peripheral blood and/or bone marrow from 230 adult patients with acute myeloid leukaemia, five were observed to contain crystalline inclusions in the cytoplasm of the leukaemic cells and a sixth contained crystals in the nuclei. In four cases, two of FAB type M2 and two of M4, the cytoplasmic crystals were hexagonal in section and 1-2 micron long. Two examples showed internal periodicities in the range 3.3-4.0 nm when the electronmicrographs were analysed by optical diffractometry. A single case of M1 contained smaller trapezoidal crystals with a 4.9nm periodicity. The sixth patient, with unusual cytological abnormalities and a rare t(3; 6) chromosomal translocation, contained six-sided crystals in the nuclei of some relatively undifferentiated cells. To the best of our knowledge such intranuclear crystals have not previously been reported in leukaemia. The relevance of the crystals to the leukaemic process is discussed.

  4. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

    PubMed

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-08-18

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.

  5. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes.

    PubMed

    Krug, Utz; Röllig, Christoph; Koschmieder, Anja; Heinecke, Achim; Sauerland, Maria Cristina; Schaich, Markus; Thiede, Christian; Kramer, Michael; Braess, Jan; Spiekermann, Karsten; Haferlach, Torsten; Haferlach, Claudia; Koschmieder, Steffen; Rohde, Christian; Serve, Hubert; Wörmann, Bernhard; Hiddemann, Wolfgang; Ehninger, Gerhard; Berdel, Wolfgang E; Büchner, Thomas; Müller-Tidow, Carsten

    2010-12-11

    About 50% of patients (age ≥60 years) who have acute myeloid leukaemia and are otherwise medically healthy (ie, able to undergo intensive chemotherapy) achieve a complete remission (CR) after intensive chemotherapy, but with a substantially increased risk of early death (ED) compared with younger patients. We verified the association of standard clinical and laboratory variables with CR and ED and developed a web-based application for risk assessment of intensive chemotherapy in these patients. Multivariate regression analysis was used to develop risk scores with or without knowledge of the cytogenetic and molecular risk profiles for a cohort of 1406 patients (aged ≥60 years) with acute myeloid leukaemia, but otherwise medically healthy, who were treated with two courses of intensive induction chemotherapy (tioguanine, standard-dose cytarabine, and daunorubicin followed by high-dose cytarabine and mitoxantrone; or with high-dose cytarabine and mitoxantrone in the first and second induction courses) in the German Acute Myeloid Leukaemia Cooperative Group 1999 study. Risk prediction was validated in an independent cohort of 801 patients (aged >60 years) with acute myeloid leukaemia who were given two courses of cytarabine and daunorubicin in the Acute Myeloid Leukaemia 1996 study. Body temperature, age, de-novo leukaemia versus leukaemia secondary to cytotoxic treatment or an antecedent haematological disease, haemoglobin, platelet count, fibrinogen, and serum concentration of lactate dehydrogenase were significantly associated with CR or ED. The probability of CR with knowledge of cytogenetic and molecular risk (score 1) was from 12% to 91%, and without knowledge (score 2) from 21% to 80%. The predicted risk of ED was from 6% to 69% for score 1 and from 7% to 63% for score 2. The predictive power of the risk scores was confirmed in the independent patient cohort (CR score 1, from 10% to 91%; CR score 2, from 16% to 80%; ED score 1, from 6% to 69%; and ED score 2

  6. Treatment for childhood acute lymphoblastic leukaemia: the fathers' perspective.

    PubMed

    McGrath, P

    2001-01-01

    Research on parental adaptation to a child's chronic illness is still scant, and this is particularly so in relation to the experience of treatment for paediatric Acute Lymphoblastic Leukaemia (ALL). The work that does exist on parental reactions tends to conflate maternal responses with paternal responses, as fathers are usually seen as having a secondary role. Consequently, little is known about how fathers cope with treatment for childhood ALL. The present discussion seeks to make a contribution to this area by presenting findings on the paternal experience of treatment for paediatric ALL from a longitudinal study conducted at Royal Children's Hospital in Brisbane, Queensland. The findings from this research clearly indicate the emotional pain that fathers face in their struggle to accept the diagnosis of a serious, life-threatening illness such as ALL in their child. The findings challenge the notion of the make stereotype by showing that the shock of diagnosis, the emotional pain of coping with the illness, the expression of pain through tears, the desire to be with the child, the struggle to cope with the medical interventions, and concerns about other family members are not gender specific, but are rather issues common to both parents.

  7. The Effects of Herbs and Fruits on Leukaemia

    PubMed Central

    Saedi, Tayebeh Azam; Md Noor, Sabariah; Ismail, Patimah; Othman, Fauziah

    2014-01-01

    In developing countries, herbal therapy is the first and basis form of treatment for most types of diseases. About 75–80% of the world's population prefers herbal therapy as a major treatment due to its better adequacy and satisfactoriness, which enhance human body's symmetry with minimal side effects. Fruits and plants have been presented from the past as promising tools in becoming a natural anticancer agents. Many of these plant extracts are currently used in cancer therapy and prevention. This review paper will particularly explore and emphasize on herbs and fruits used in the treatment of the leukaemia. PMID:25250054

  8. Interferon in chronic myeloid leukaemia: past and future.

    PubMed

    Guilhot, François; Roy, Lydia; Saulnier, Pierre-Jean; Guilhot, Joëlle

    2009-09-01

    Imatinib has revolutionized the therapy of chronic myeloid leukaemia. However the complete eradication of leukaemic stem cells is still a matter of discussion. Interferon (IFN) has been used in the past with success. However the proportion of patients who achieved sustained complete cytogenetic response was small. Recently, in addition to its direct antineoplastic effect and immunomodulatory activity, IFN has been shown to stimulate the quiescent leukaemic stem cells. Thus there is now a rational for combining Imatinib and IFN. Large prospective phase III trials are in good progress to demonstrate in humans the usefullness of a combination therapy using Imatinib and IFN.

  9. Bloodstream infection in paediatric cancer centres--leukaemia and relapsed malignancies are independent risk factors.

    PubMed

    Ammann, R A; Laws, H J; Schrey, D; Ehlert, K; Moser, O; Dilloo, D; Bode, U; Wawer, A; Schrauder, A; Cario, G; Laengler, A; Graf, N; Furtwängler, R; Simon, A

    2015-05-01

    In a prospective multicentre study of bloodstream infection (BSI) from November 01, 2007 to July 31, 2010, seven paediatric cancer centres (PCC) from Germany and one from Switzerland included 770 paediatric cancer patients (58% males; median age 8.3 years, interquartile range (IQR) 3.8-14.8 years) comprising 153,193 individual days of surveillance (in- and outpatient days during intensive treatment). Broviac catheters were used in 63% of all patients and Ports in 20%. One hundred forty-two patients (18%; 95% CI 16 to 21%) experienced at least one BSI (179 BSIs in total; bacteraemia 70%, bacterial sepsis 27%, candidaemia 2%). In 57%, the BSI occurred in inpatients, in 79% after conventional chemotherapy. Only 56 % of the patients showed neutropenia at BSI onset. Eventually, patients with acute lymphoblastic leukaemia (ALL) or acute myeloblastic leukaemia (AML), relapsed malignancy and patients with a Broviac faced an increased risk of BSI in the multivariate analysis. Relapsed malignancy (16%) was an independent risk factor for all BSI and for Gram-positive BSI. This study confirms relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. On a unit level, data on BSIs in this high-risk population derived from prospective surveillance are not only mandatory to decide on empiric antimicrobial treatment but also beneficial in planning and evaluating preventive bundles. • Paediatric cancer patients face an increased risk of nosocomial bloodstream infections (BSIs). • In most cases, these BSIs are associated with the use of a long-term central venous catheter (Broviac, Port), severe and prolonged immunosuppression (e.g. neutropenia) and other chemotherapy-induced alterations of host defence mechanisms (e.g. mucositis). What is New: • This study is the first multicentre study confirming relapsed malignancy as an independent risk factor for BSIs in paediatric cancer patients. • It describes the epidemiology of nosocomial BSI in

  10. Naja nigricollis CMS-9 enhances the mitochondria-mediated death pathway in adaphostin-treated human leukaemia U937 cells.

    PubMed

    Chen, Ying-Jung; Wang, Jeh-Jeng; Chang, Long-Sen

    2011-11-01

    1. The aim of the present study was to explore the effect of the Naja nigricollis phospholipase A(2) CMS-9 on adaphostin-induced death of human leukaemia U937 cells. 2. Leukaemia U937 cells (Bcr/Abl-negative cells) were treated with adaphostin (0-10 μmol/L) and CMS-9 (0-1 μmol/L). The effects of CMS-9, adaphostin and their combination on cell viability, the generation reactive oxygen species (ROS), [Ca(2+) ](i) , p38 mitogen-activated protein kinase (MAPK) activation, Akt and extracellular signal-regulated kinase (ERK) inactivation, mitochondrial membrane potential (ΔΨ(m) ) and Bcl-2 family proteins were analysed. 3. Both adaphostin and CMS-9 induced U937 cell apoptosis, characterized by dissipation of ΔΨ(m) and ROS generation. Combined treatment further increased ΔΨ(m) loss and reduced the viability of adaphostin-treated cells. Unlike in CMS-9-treated cells, in adaphostin-treated cells ROS-induced increases in [Ca(2+) ](i) were observed. CMS-9-induced ROS generation resulted in p38 MAPK activation, whereas adaphostin treatment elicited ROS/Ca(2+) -mediated inactivation of Akt and ERK. Moreover, Akt was found to be involved in ERK phosphorylation. Suppression of p38 MAPK activation blocked CMS-9-induced ΔΨ(m) loss and Bcl-xL downregulation. Overexpression of constitutively active Akt and mitogen-activated protein kinase kinase (MEK) 1 rescued adaphostin-induced ΔΨ(m) loss and Bcl-2 downregulation. Similarly, CMS-9 augmented adaphostin toxicity in human leukaemia K562 cells via increased mitochondrial alterations. 4. The results suggest that two distinct pathways mediate adaphostin- and CMS-9-induced mitochondrial damage (i.e. the ROS-Ca(2+) -Akt-ERK and ROS-p38 MAPK pathways, respectively). These distinct pathway explain the augmentation by CMS-9 of ΔΨ(m) loss and apoptosis in adaphostin-treated U937 cells. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

  11. 5'-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells.

    PubMed

    Li, Dengzhe; Gale, Robert Peter; Liu, Yanfeng; Lei, Baoxia; Wang, Yuan; Diao, Dongmei; Zhang, Mei

    2017-07-01

    Multi-drug resistance (MDR), immune suppression and decreased apoptosis are important causes of therapy-failure in leukaemia. Short interfering RNAs (siRNAs) down-regulate gene transcription, have sequence-independent immune-stimulatory effects and synergize with other anti-cancer therapies in some experimental models. We designed a siRNA targeting MDR1 with 5'-triphosphate ends (3p-siRNA-MDR1). Treatment of leukaemia cells with 3p-siRNA-MDR1 down-regulated MDR1 expression, reduced-drug resistance and induced immune and pro-apoptotic effects in drug-resistant HL-60/Adr and K562/Adr human leukaemia cell lines. We show mechanisms-of-action of these effects involve alterations in the anti-viral cytosolic retinoic acid-inducible protein-I (RIG-I; encoded by RIG-I or DDX58) mediated type-I interferon signal induction, interferon-gamma-inducible protein 10 (IP-10; encoded by IP10 or CXCL10) secretion, major histocompatibility complex-I expression (MHC-I) and caspase-mediated cell apoptosis. 3p-siRNA-MDR1 transfection also enhanced the anti-leukaemia efficacy of doxorubicin. These data suggest a possible synergistic role for 3p-siRNA-MDR1 in anti-leukaemia therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Prevalence of feline immunodeficiency virus and feline leukaemia virus infection in Malaysia: a retrospective study

    PubMed Central

    Sivagurunathan, Amilan; Atwa, Asem M; Lobetti, Remo

    2018-01-01

    Objectives Feline ownership is popular and represents the largest segment of the pet population in Malaysia. Most feline owners own, on average, 2–3 cats, with some having >10 cats per household. Feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) are two clinically important viral infections in cats. Documenting the prevalence of these diseases in the feline population is important for both veterinarians and the public. Methods This was a retrospective study, using data collected from the domestic cat population seen at a 24 h private veterinary hospital in Malaysia, to determine the prevalence of FIV and FeLV in an urban area and risk factors associated with these infections. Between 2010 and 2016, 2230 blood samples were collected and tested for FIV antibodies and FeLV antigen using commercially available ELISA test kits. Results In total, 10.0% (n = 224; 95% confidence interval [CI] 8.80–11.26) were seropositive for FIV; 12.0% (n = 267; 95% CI 10.62–13.32) were seropositive for FeLV; and 2.6% (n = 58; 95% CI 2.01–3.17) were seropositive for both. Conclusions and relevance The prevalence of FIV is lower and FeLV higher than previously documented for this region. Because of the immunosuppressive potential of both viruses, client education and use of appropriate control strategies such as routine screening, vaccination and eradication should be considered. PMID:29568541

  13. Embryo-specific expression of a visual reporter gene as a selection system for citrus transformation

    PubMed Central

    Zambon, Flavia T.; Erpen, Lígia; Soriano, Leonardo; Grosser, Jude

    2018-01-01

    The embryo-specific Dc3 gene promoter driving the VvMybA1 anthocyanin regulatory gene was used to develop a visual selection system for the genetic transformation of citrus. Agrobacterium-mediated transformation of cell suspension cultures resulted in the production of purple transgenic somatic embryos that could be easily separated from the green non-transgenic embryos. The somatic embryos produced phenotypically normal plants devoid of any visual purple coloration. These results were also confirmed using protoplast transformation. There was minimal gene expression in unstressed one-year-old transgenic lines. Cold and drought stress did not have any effect on gene expression, while exogenous ABA and NaCl application resulted in a minor change in gene expression in several transgenic lines. When gas exchange was measured in intact leaves, the transgenic lines were similar to controls under the same environment. Our results provide conclusive evidence for the utilization of a plant-derived, embryo-specific visual reporter system for the genetic transformation of citrus. Such a system could aid in the development of an all-plant, consumer-friendly GM citrus tree. PMID:29293649

  14. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

    PubMed

    Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun

    2015-05-01

    Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. © 2015 John Wiley & Sons Ltd.

  15. E-Referencer: Transforming Boolean OPACs to Web Search Engines.

    ERIC Educational Resources Information Center

    Khoo, Christopher S. G.; Poo, Danny C. C.; Toh, Teck-Kang; Hong, Glenn

    E-Referencer is an expert intermediary system for searching library online public access catalogs (OPACs) on the World Wide Web. It is implemented as a proxy server that mediates the interaction between the user and Boolean OPACs. It transforms a Boolean OPAC into a retrieval system with many of the search capabilities of Web search engines.…

  16. [Chronic lymphocytic leukaemia: current management].

    PubMed

    Aurran-Schleinitz, T; Arnoulet, C; Ivanov, V; Coso, D; Rey, J; Schiano, J-M; Stoppa, A-M; Bouabdallah, R; Gastaut, J-A

    2008-05-01

    Chronic lymphocytic leukemia (CLL) is the most common leukaemia in the Western world. Recent advancement in the aetiology, pathophysiology and the development of new therapeutics tools have significantly modified the current management of CLL. The cellular origin of CLL is still unknown. The current main hypothesis will be first briefly described. This review will then focus on the newly defined prognostic factors and the development and use of new drugs for the treatment of CLL. To describe the modern and practical management of CLL, we will compare classical and new prognostic markers. Then, we will discuss the various therapeutic options including chemotherapy and immunotherapy (monoclonal antibodies, allogenic transplantation), and define their current respective indications. These new diagnostic and prognostic markers will allow the characterization of new prognostic subgroups of patients. This will lead to a targeted and individualized therapeutic approach. We will present the first results of clinical trials and the on-going studies conducted in this disease.

  17. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013

    PubMed Central

    Yeoh, Allen EJ; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2014-01-01

    The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region. PMID:24176570

  18. Genetic polymorphisms of Th2 interleukins, history of asthma or eczema and childhood acute lymphoid leukaemia: Findings from the ESCALE study (SFCE).

    PubMed

    Bonaventure, A; Orsi, L; Rudant, J; Goujon-Bellec, S; Leverger, G; Baruchel, A; Bertrand, Y; Nelken, B; Pasquet, M; Michel, G; Sirvent, N; Chastagner, P; Ducassou, S; Thomas, C; Besse, C; Hémon, D; Clavel, J

    2018-06-05

    Previous studies on the putative role of allergy in the aetiology of childhood leukaemia have reported contradictory results. The present study aimed to analyse the relation between a medical history of asthma or eczema and childhood acute lymphoid leukaemia (ALL) in light of potential candidate gene-environment interactions. Analyses were based on a subset of 434 cases of ALL and 442 controls successfully genotyped and of European ancestry children enrolled in a French population-based case-control study conducted in 2003-2004. Information about medical history was obtained during a standardized interview with the mothers. Candidate polymorphisms in genes of the Th2 cytokines IL4, IL10, IL13 and IL4-receptor, were genotyped or imputed. None of the variant alleles were directly associated with childhood acute lymphoid leukaemia. A medical history of asthma or eczema was reported more often in the control group (OR = 0.7 [0.5-1.0]). This association was mostly seen in the group of children not carrying the IL13-rs20541 variant allele (Interaction Odds Ratio IOR 1.9, p-interaction = 0.07) and in those carrying the IL10 triple variant haplotype (IOR 0.5, p-interaction = 0.04). No interaction was observed with the candidate polymorphisms in IL4 and IL4R. This study provides a new insight into the relationship between allergic symptoms and childhood acute lymphoid leukaemia, by suggesting this inverse association could be limited to children carrying certain genetic polymorphisms. If confirmed, these results could help better understand the biological mechanisms involved in the development of childhood acute lymphoid leukaemia. Copyright © 2018. Published by Elsevier Ltd.

  19. Correlation between preferentially expressed antigen of melanoma and tumour necrosis factor-related apoptosis-inducing ligand gene expression in different types of leukaemia patients.

    PubMed

    Zhang, Wenhui; Chi, Kaikai; Zhang, Yin; Ma, Baogen; Shi, Jie; Chen, Yuqing; Lei, Pingchong; Li, Yulong; Sun, Kai

    2013-01-01

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) down-regulation by preferentially expressed antigen of melanoma (PRAME) is a general phenomenon in different types of solid tumours, but research on the correlation between PRAME and TRAIL gene expression in leukaemia patients is rare. PRAME and TRAIL expression was detected in bone marrow samples from 80 newly diagnosed acute leukaemia (AL) patients and 40 chronic myeloid leukaemia (CML) patients using TaqMan-based real-time quantitative PCR methods, and a linear correlation analysis was performed on their levels of expression. A total of 15 normal bone marrow samples from individuals with non-malignant haematological diseases served as normal controls. PRAME expression was higher in both AL and CML patients compared to controls (both p < 0.001). CML patients in both blast crisis (BC) and the accelerated phase (AP) had significantly higher PRAME levels than CML patients in the chronic phase (CP) (p = 0.006 and 0.0461, respectively). TRAIL expression was higher in both the acute myeloid leukaemia (AML) group and the acute lymphoblastic leukaemia (ALL) group than in the controls (p = 0.039 and 0.047, respectively). In contrast, CML patients had lower TRAIL levels than controls (p = 0.043), and TRAIL expression in CML patients in the advanced phases (BC and AP) was significantly lower than in CML-CP patients (p = 0.006). In CML patients, there was a significant inverse correlation (Spearman's R = -0.6669, p < 0.0001) between PRAME and TRAIL gene expression, while a greater significant inverse correlation was found in patients in the advanced phases (BC and AP) (R = -0.6764). In addition, no correlation was observed in AML and ALL patients. The simultaneous detection of PRAME and TRAIL gene expression may be helpful to monitor condition changes in leukaemia patients and evaluate therapeutic effects in clinical practice, particularly in CML patients. © 2013 S. Karger AG, Basel.

  20. Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

    PubMed Central

    Makropoulos , Vassilios; Alexopoulos, Evangelos C

    2006-01-01

    Background Exposures to high doses of irradiation, to chemotherapy, benzene, petroleum products, paints, embalming fluids, ethylene oxide, herbicides, pesticides, and smoking have been associated with an increased risk of acute myelogenous leukemia (AML). Although there in no epidemiological evidence of relation between X-ray developer, fixer and replenisher liquids and AML, these included glutaraldehyde which has weakly associated with lymphocytic leukemia in rats and hydroquinone has been increasingly implicated in producing leukemia, causing DNA and chromosomal damage, inhibits topo-isomerase II, alter hematopoiesis and inhibit apoptosis of neoplastic cells. Case presentation Two white females (A and B) hired in 1985 as medical radiation technologists in a primary care center, in Greece. In July 2001, woman A, 38-years-old, was diagnosed as having acute monocytic leukaemia (FAB M5). The patient did not respond to therapy and died threeweeks later. In August 2001, woman B, 35-year-old, was diagnosed with acute promyelocytic leukaemia (FAB M3). Since discharge, she is in continuous complete remission. Both women were non smokers without any medical history. Shortly after these incidents official inspectors and experts inspected workplace, examined equipment, archives of repairs, notes, interviewed and monitored employees. They concluded that shielding was inadequate for balcony's door but personal monitoring did not show any exceeding of TLV of 20 mSv yearly and cytogenetics analysis did not reveal findings considered to be characteristics of ionizing exposure. Equipment for developing photos had a long list of repairs, mainly leakages of liquids and increases of temperature. On several occasions the floor has been flooded especially during 1987–1993 and 1997–2001. Inspection confirmed a complete lack of ventilation and many spoiled medical x-ray films. Employees reported that an "osmic" level was continuously evident and frequently developed symptoms of

  1. Effectiveness of environmental control measures to decrease the risk of invasive aspergillosis in acute leukaemia patients during hospital building work.

    PubMed

    Combariza, J F; Toro, L F; Orozco, J J

    2017-08-01

    Invasive aspergillosis (IA) is a significant problem in acute leukaemia patients. Construction work near hospital wards caring for immunocompromised patients is one of the main risk factors for developing invasive pulmonary aspergillosis (IPA). To assess the impact of environmental control measures used during hospital construction for the prevention of IA in acute leukaemia patients. A retrospective cohort study was developed to evaluate the IA incidence in acute leukaemia patients with different environmental control measures employed during hospital construction. We used European Organisation for the Research and Treatment of Cancer (EORTC) criterial diagnosis parameters for definition of IA. A total of 175 episodes of inpatient care were evaluated, 62 of which did not have any environmental control measures (when an outbreak occurred), and 113 that were subject to environmental control measures directed to preventing IA. The study showed an IA incidence of 25.8% for the group without environmental control measures vs 12.4% for those who did receive environmental control measures (P=0.024). The relative risk for IA was 0.595 (95% confidence interval: 0.394-0.897) for the group with environmental control measures. The current study suggests that the implementation of environmental control measures during a hospital construction has a positive impact for prevention of IA in patients hospitalized with acute leukaemia. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  2. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

    PubMed

    Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy Te; Basso, Giuseppe

    2016-10-04

    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. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.

  3. Acute myeloid leukaemia at an early age: Reviewing the interaction between pesticide exposure and KMT2A-rearrangement

    PubMed Central

    Pombo-de-Oliveira, Maria S; Andrade, Francianne Gomes; Brisson, Gisele Dallapicola; dos Santos Bueno, Filipe Vicente; Cezar, Ingrid Sardou; Noronha, Elda Pereira

    2017-01-01

    Acute myeloid leukaemia (AML) in early childhood is characterised by a high frequency of recurrent genomic aberrations associated with distinct myeloid subtypes, clinical outcomes and pathogenesis. Genomic instability is the first step of pathogenic mechanism in early childhood AML. A sum of adverse events is necessary to the development of infant AML (i-AML), which includes latency of biochemical-molecular and cellular effects. Inherited genetic susceptibility associated with exposures to biotransformation substances can modulate the risk of DNA damage and it is a very important piece in the pathogenic puzzle. In this review, we have aimed to explore the chain of events in the time-points of the natural history of i-AML, which includes maternal exposures during pregnancy, the speculations about the formation of somatic mutations during foetal life and the secondary genomic aberrations associated with i-AML. The modulation of risk conferred by xenobiotic metabolism´s genes variants is the bottom line of the pathogenic process. Since we have conducted observational and molecular investigations in early childhood leukaemia, the data focused here is based on Brazilian findings with summarised results of our experience with epidemiological and molecular studies in early-age leukaemia. PMID:29225689

  4. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study.

    PubMed

    Wolthers, Benjamin O; Frandsen, Thomas L; Baruchel, André; Attarbaschi, Andishe; Barzilai, Shlomit; Colombini, Antonella; Escherich, Gabriele; Grell, Kathrine; Inaba, Hiroto; Kovacs, Gábor; Liang, Der-Cherng; Mateos, Marion; Mondelaers, Veerle; Möricke, Anja; Ociepa, Tomasz; Samarasinghe, Sujith; Silverman, Lewis B; van der Sluis, Inge M; Stanulla, Martin; Vrooman, Lynda M; Yano, Michihiro; Zapotocka, Ester; Schmiegelow, Kjeld

    2017-09-01

    Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients

  5. The effect of dietary intake changes on nutritional status in acute leukaemia patients after first induction chemotherapy.

    PubMed

    Malihi, Z; Kandiah, M; Chan, Y M; Esfandbod, M; Vakili, M; Hosseinzadeh, M; Zarif Yeganeh, M

    2015-07-01

    This study aimed to evaluate how changes in dietary intake among acute lymphoblastic and acute myeloid leukaemia (ALL and AML) patients affect nutritional status after the first induction chemotherapy. Dietary intake was assessed using 24-h recall and a 136-item food frequency questionnaire. Nutritional status was assessed by Patients Subjective Global Assessment questionnaire before starting induction therapy and again after 1 month. All newly diagnosed acute leukaemia patients aged 15 years old and older who attended three referral hospitals for initiation of their induction chemotherapy were included in the sample selection provided that they gave informed consent. A total of 30 AML and 33 ALL patients participated in the study. Dietary intake and nutritional status worsened after the chemotherapy treatment. Dietary intake in terms of macronutrients, micronutrients, food variety and diet diversity score changed significantly after the induction chemotherapy. No significant relationship was found between the changes in dietary indices and nutritional status. Chemotherapy-related side effects as an additional factor to cancer itself could affect dietary intake of leukaemia patients. The effectiveness of an early assessment of nutritional status and dietary intake should be further investigated in order to deter further deterioration. © 2014 The Authors. European Journal of Cancer Care Published by John Wiley & Sons Ltd.

  6. Iowa radon leukaemia study: a hierarchical population risk model for spatially correlated exposure measured with error.

    PubMed

    Smith, Brian J; Zhang, Lixun; Field, R William

    2007-11-10

    This paper presents a Bayesian model that allows for the joint prediction of county-average radon levels and estimation of the associated leukaemia risk. The methods are motivated by radon data from an epidemiologic study of residential radon in Iowa that include 2726 outdoor and indoor measurements. Prediction of county-average radon is based on a geostatistical model for the radon data which assumes an underlying continuous spatial process. In the radon model, we account for uncertainties due to incomplete spatial coverage, spatial variability, characteristic differences between homes, and detector measurement error. The predicted radon averages are, in turn, included as a covariate in Poisson models for incident cases of acute lymphocytic (ALL), acute myelogenous (AML), chronic lymphocytic (CLL), and chronic myelogenous (CML) leukaemias reported to the Iowa cancer registry from 1973 to 2002. Since radon and leukaemia risk are modelled simultaneously in our approach, the resulting risk estimates accurately reflect uncertainties in the predicted radon exposure covariate. Posterior mean (95 per cent Bayesian credible interval) estimates of the relative risk associated with a 1 pCi/L increase in radon for ALL, AML, CLL, and CML are 0.91 (0.78-1.03), 1.01 (0.92-1.12), 1.06 (0.96-1.16), and 1.12 (0.98-1.27), respectively. Copyright 2007 John Wiley & Sons, Ltd.

  7. The Anti-cancer Activity of Vernonia divaricata Sw against Leukaemia, Breast and Prostate Cancers In Vitro

    PubMed Central

    Lowe, HIC; Daley-Beckford, D; Toyang, NJ; Watson, C; Hartley, S; Bryant, J

    2014-01-01

    Background: Vernonia divaricata is one of five endemic Vernonia species of Jamaica. The ethnomedicinal uses of other species have been established, however, scientific validation of this species has not yet been done and as such this paper is aimed at identifying the anti-cancer activity of V divaricata against leukaemia, breast and prostate cancer cell lines. Methods: Leaves and stems of V divaricata were dried and milled into powder. The crude hexane and methanol extracts of the leaves and stems were obtained and bio-assayed using WST-1 cell proliferation assay against leukaemia, breast and prostate cancer cell lines. Results: The crude hexane and methanol extracts of V divaricata were able to significantly retard the growth of the MCF-7 (breast), HL-60 (leukaemia) and the PC-3 (prostate) cancer cell lines. The crude methanol extract of the stem was the strongest, exhibiting anti-proliferation activity with IC50 values of 10.14, 12.63 and 9.894 μg/ml for the HL-60, MCF-7 and PC-3 cancer cell lines, respectively, with the most potent toward prostate cancer. Conclusion: The medicinal use of V divaricata as an anti-cancer agent was corroborated as the crude hexane and methanol extracts demonstrated potent anti-proliferation activity and as such hold potential for further research and development into a drug to prevent or treat various cancers. PMID:25429469

  8. Escherichia coli O26 in feedlot cattle: fecal prevalence, isolation, characterization, and effects of an E. coli O157 vaccine and a direct-fed microbial.

    PubMed

    Paddock, Zac D; Renter, David G; Cull, Charley A; Shi, Xiarong; Bai, Jianfa; Nagaraja, Tiruvoor G

    2014-03-01

    Escherichia coli O26 is second only to O157 in causing foodborne, Shiga toxin-producing E. coli (STEC) infections. Our objectives were to determine fecal prevalence and characteristics of E. coli O26 in commercial feedlot cattle (17,148) that were enrolled in a study to evaluate an E. coli O157:H7 siderophore receptor and porin (SRP(®)) vaccine (VAC) and a direct-fed microbial (DFM; 10(6) colony-forming units [CFU]/animal/day of Lactobacillus acidophilus and 10(9) CFU/animal/day of Propionibacterium freudenreichii). Cattle were randomly allocated to 40 pens within 10 complete blocks; pens were randomly assigned to control, VAC, DFM, or VAC+DFM treatments. Vaccine was administered on days 0 and 21, and DFM was fed throughout the study. Pen-floor fecal samples (30/pen) were collected weekly for the last 4 study weeks. Samples were enriched in E. coli broth and subjected to a multiplex polymerase chain reaction (PCR) designed to detect O26-specific wzx gene and four major virulence genes (stx1, stx2, eae, and ehxA) and to a culture-based procedure that involved immunomagnetic separation and plating on MacConkey agar. Ten presumptive E. coli colonies were randomly picked, pooled, and tested by the multiplex PCR. Pooled colonies positive for O26 serogroup were streaked on sorbose MacConkey agar, and 10 randomly picked colonies per sample were tested individually by the multiplex PCR. The overall prevalence of E. coli O26 was higher (p<0.001) by the culture-based method compared to the PCR assay (22.7 versus 10.5%). The interventions (VAC and or DFM) had no impact on fecal shedding of O26. Serogroup O26 was recovered in pure culture from 23.9% (260 of 1089) of O26 PCR-positive pooled colonies. Only 7 of the 260 isolates were positive for the stx gene and 90.1% of the isolates possessed an eaeβ gene that codes for intimin subtype β, but not the bfpA gene, which codes for bundle-forming pilus. Therefore, the majority of the O26 recovered from feedlot cattle feces was

  9. Synergism of herpes simplex virus and tobacco-specific N'-nitrosamines in cell transformation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, N.H.; Dokko, H.; Li, S.L.

    1991-03-01

    Previous studies indicate that herpes simplex virus (HSV) enhances the carcinogenic activity of smokeless tobacco and tobacco-related chemical carcinogens in animals. Since tobacco-specific N'-nitrosamines (TSNAs) such as N'-nitrosonornicotine (NNN) and 4-(N-methyl-N'-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major chemical carcinogens of smokeless tobacco and are known to be responsible for the development of oral cancers in smokeless tobacco users, the combined effects of TSNAs and HSV in cell transformation were investigated. Exposure of cells to NNN or NNK followed by virus infection resulted in a significant enhancement of transformation frequency when compared with that observed with chemical carcinogens or virus alone. This study suggestsmore » that TSNAs and HSV can interact together and show synergism in cell transformation.« less

  10. The path to cost transformation.

    PubMed

    Hill-Mischel, Jody; Morrissey, Walter W; Neese, Kimberly; Shoger, Timothy R

    2016-06-01

    A healthcare organization's efforts to strategically transform its cost structure in preparation for value-based payment invariably must begin with a systemwide assessment of cost and quality. Such an assessment should focus on three categories of performance improvement activities: margin improvement, business restructuring, and clinical transformation. A work-team approach is recommended, where teams with multidisciplinary representation assume responsibility for assessing specific areas (e.g., acute care enterprise, physician enterprise, business restructuring).

  11. Spontaneous Transformation of Murine Epithelial Cells Requires the Early Acquisition of Specific Chromosomal Aneuploidies and Genomic Imbalances

    PubMed Central

    Padilla-Nash, Hesed M.; Hathcock, Karen; McNeil, Nicole E.; Mack, David; Hoeppner, Daniel; Ravin, Rea; Knutsen, Turid; Yonescu, Raluca; Wangsa, Danny; Dorritie, Kathleen; Barenboim, Linda; Hu, Yue; Ried, Thomas

    2011-01-01

    Human carcinomas are defined by recurrent chromosomal aneuploidies, which result in tissue-specific distribution of genomic imbalances. In order to develop models for these genome mutations and determine their role in tumorigenesis, we generated 45 spontaneously transformed murine cell lines from normal epithelial cells derived from bladder, cervix, colon, kidney, lung, and mammary gland. Phenotypic changes, chromosomal aberrations, centrosome number, and telomerase activity were assayed in control uncultured cells and in three subsequent stages of transformation. Supernumerary centrosomes, bi-nucleate cells, and tetraploidy were observed as early as 48 hr after explantation. In addition, telomerase activity increased throughout progression. Live-cell imaging revealed that failure of cytokinesis, not cell fusion, promoted genome duplication. Spectral karyotyping demonstrated that aneuploidy preceded immortalization, consisting predominantly of whole chromosome losses (4, 9, 12, 13, 16, and Y) and gains (1, 10, 15, and 19). After transformation, focal amplifications of the oncogenes Myc and Mdm2 were frequently detected. Fifty percent of the transformed lines resulted in tumors upon injection into immuno-compromised mice. The phenotypic and genomic alterations observed in spontaneously transformed murine epithelial cells recapitulated the aberration pattern observed during human carcinogenesis. The dominant aberration of these cell lines was the presence of specific chromosomal aneuploidies. We propose that our newly derived cancer models will be useful tools to dissect the sequential steps of genome mutations during malignant transformation, and also to identify cancer-specific genes, signaling pathways, and the role of chromosomal instability in this process. PMID:22161874

  12. Chronic lymphocytic leukaemia

    PubMed Central

    Kipps, Thomas J.; Stevenson, Freda K.; Wu, Catherine J.; Croce, Carlo M.; Packham, Graham; Wierda, William G.; O’Brien, Susan; Gribben, John; Rai, Kanti

    2017-01-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. PMID:28102226

  13. BK virus induced nephritis in a boy with acute myeloid leukaemia undergoing bone marrow transplantation

    PubMed Central

    Hoefele, Julia; Rüssmann, Despina; Klein, Barbara; Weber, Lutz T.; Führer, Monika

    2008-01-01

    BK virus (BKV) is a human polyomavirus. The primary infection occurs typically without specific signs or symptoms. Almost 80% of adults are seropositive. Clinically relevant infections are usually limited to individuals who are immunosuppressed. After primary infection, BKV remains latent in the kidneys and can be reactivated in the setting of immunosuppression. BKV is associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients. Furthermore, BKV-induced haemorrhagic cystitis (HC) is a severe complication of bone marrow transplantation (BMT) in children and adults. A combination of HC and tubulointerstitial nephritis in a patient has not been reported so far. We report on an 11-year-old boy with acute myeloid leukaemia undergoing BMT. BKV infection was reactivated during post-transplant immunosuppressive therapy causing HC associated with tubulointerstitial nephritis. PMID:25983928

  14. Primary angiocentric/angioinvasive T-cell lymphoma of the tympanic bulla in a feline leukaemia virus-positive cat.

    PubMed

    Santagostino, Sara F; Mortellaro, Carlo M; Buchholz, Julia; Lugli, Margherita; Forlani, Annalisa; Ghisleni, Gabriele; Roccabianca, Paola

    2015-01-01

    Case summary A 5-year-old neutered female feline leukaemia virus (FeLV)-positive domestic shorthair cat with a 5 month history of otitis media was referred for head tilt, stertor and dyspnoea. Computed tomography scan revealed soft tissue opacities inside the right tympanic bulla, with bone remodelling, and concurrent nasopharyngeal and intracranial invasion. Endoscopically guided bioptic samples were collected from the nasopharynx and middle ear. Histology revealed dense sheets of round, large, neoplastic cells, often surrounding or invading vascular walls. Neoplastic cells expressed CD3, FeLV p27 and gp70 antigens. A middle ear angiocentric/angioinvasive T-cell lymphoma was diagnosed. After improvement of clinical conditions following radiation therapy, the cat died unexpectedly. At necropsy, hepatic and splenic spread was detected. Relevance and novel information Primary middle ear tumours are rare and their diagnosis is often delayed as clinical signs mimic more common otological conditions. Multiple bioptic specimens are pivotal for a definitive diagnosis. The young age of the cat, serology and immunohistochemistry revealed a possible transforming role of FeLV.

  15. Nutritional status and dietary intake of children with acute leukaemia during induction or consolidation chemotherapy.

    PubMed

    Tan, S Y; Poh, B K; Nadrah, M H; Jannah, N A; Rahman, J; Ismail, M N

    2013-07-01

    The assessment of nutritional status among paediatric patients is important for the planning and execution of nutritional strategies that strive to optimise the quality of life and growth among sick children. The present study aimed to evaluate the nutritional status and dietary intake among children with acute leukaemia. This cross-sectional study included 53 paediatric patients aged 3-12 years old, who were diagnosed with either acute lymphoblastic leukaemia or acute myelogenous leukaemia and were undergoing chemotherapy treatments (induction or consolidation phase). Patients were matched for sex, age (±6 months) and ethnicity with healthy children as controls. Weight, height, body mass index, waist circumference, mid-upper arm circumference, triceps skinfold thickness, mid-upper arm muscle area and fat area were determined. Dietary intake was assessed using 3-day food records. Anthropometric variables were generally higher among patients compared to controls, although the differences were not statistically significant (P > 0.05). The prevalence of overnutrition among patients according to body mass index-for-age, waist circumference-for-age, mid-upper arm circumference-for-age and triceps skinfold-for-age were 24.5%, 29.1%, 17.0% and 30.2%, respectively. Mean energy [5732 ± 1958 kJ (1370 ± 468 kcal) versus 6945 ± 1970 kJ (1660 ± 471 kcal), P < 0.01], protein (50.0 ± 19.7 g versus 62.3 ± 22.3 g, P < 0.01) and fat (43.6 ± 18.9 g versus 58.3 ± 16.7, P < 0.001) intakes of patients were significantly lower than controls. The prevalence of being overweight and obesity in children with acute leukaemia was higher despite lower energy intake compared to controls. Studies assessing physical activity, the complex interaction and the effects of treatment drugs are warranted to better manage malnutrition among paediatric patients. © 2013 The Authors Journal of Human Nutrition and Dietetics © 2013 The British Dietetic Association

  16. Sesame allergy: role of specific IgE and skin-prick testing in predicting food challenge results.

    PubMed

    Permaul, Perdita; Stutius, Lisa M; Sheehan, William J; Rangsithienchai, Pitud; Walter, Jolan E; Twarog, Frank J; Young, Michael C; Scott, Jordan E; Schneider, Lynda C; Phipatanakul, Wanda

    2009-01-01

    There are conflicting data regarding the diagnostic value of sesame-specific IgE and sesame skin test. Currently, there are no established thresholds that predict clinical reactivity. We examined the correlation of sesame ImmunoCAP and skin-prick test (SPT) results with oral challenge outcomes in children suspected of having a sesame food allergy. We conducted a retrospective chart review of children, aged 2-12 years, receiving a sesame ImmunoCAP level, SPT, and food challenge from January 2004 to August 2008 at Children's Hospital Boston and affiliated allergy clinics. Food challenges were conducted in cases of questionable clinical history or a negative ImmunoCAP and/or negative SPT despite a convincing history. Thirty-three oral sesame challenges were conducted. Of the 33 challenges performed, 21% (n = 7) failed and 79% (n = 26) passed. A sesame-specific IgE level of > or = 7 kU(A)/L showed specificity of >90%. An SPT wheal size of > or = 6 mm showed specificity of >90%. Receiver operator characteristic (ROC) curve analysis for sesame-specific IgE revealed an area under the curve (AUC) of 0.56. ROC curve analysis for SPT wheal size revealed an AUC of 0.67. To our knowledge, this study represents the largest number of sesame challenges performed to evaluate the diagnostic value of both sesame-specific IgE and SPT. Based on our sample, both tests are not good predictors of true sesame allergy as determined by an oral challenge. We were unable to establish a threshold with a 95% positive predictive value for both sesame-specific IgE and SPT.

  17. Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy.

    PubMed

    Karol, Seth E; Coustan-Smith, Elaine; Cao, Xueyuan; Shurtleff, Sheila A; Raimondi, Susana C; Choi, John K; Ribeiro, Raul C; Dahl, Gary V; Bowman, William Paul; Taub, Jeffrey W; Degar, Barbara; Leung, Wing; Downing, James R; Pui, Ching-Hon; Rubnitz, Jeffrey E; Campana, Dario; Inaba, Hiroto

    2015-01-01

    Minimal residual disease (MRD) is a strong prognostic factor in children and adolescents with acute myeloid leukaemia (AML) but nearly one-quarter of patients who achieve MRD-negative status still relapse. The adverse prognostic factors among MRD-negative patients remain unknown. We analysed the AML02 study cohort to identify demographic and genetic prognostic factors. Among the presenting features, certain 11q23 abnormalities, such as t(6;11) and t(10;11), acute megakaryoblastic leukaemia without the t(1;22), and age ≥10 years were associated with inferior outcome in patients who had MRD-negative status after either remission induction I or II. By contrast, those with rearrangement of CBF genes had superior outcome. Our study identifies patient populations for whom close post-remission MRD monitoring to detect and treat emerging relapse and adjustment in treatment intensity might be indicated. © 2014 John Wiley & Sons Ltd.

  18. Staphylococcal enterotoxin-specific IgE antibodies in atopic dermatitis.

    PubMed

    Ide, Fumihito; Matsubara, Tomoyo; Kaneko, Miho; Ichiyama, Takashi; Mukouyama, Tokuko; Furukawa, Susumu

    2004-06-01

    The authors clarified the clinical significance of the measurement of serum concentrations of specific IgE antibodies to staphylococcal enterotoxin (SE) A- and SEB in atopic dermatitis (AD). The serum concentrations of SEA- and SEB-specific IgE antibodies in 140 pediatric patients with AD were measured with an immuno CAP -radioallergosorbent test system (RAST). To check the cross-reaction of specific IgE antibodies to SEA/SEB and other allergens, the CAP RAST fluorescent enzyme immunoassay inhibition test was performed. Forty-seven patients (33.6%) tested positive for either SEA- or SEB-specific IgE antibodies. School children showed higher positive rates of SEA/SEB-specific IgE antibodies than infants or young children. The patients with severe AD and those with exacerbation of symptoms in summer, had higher positive rates of SEA/SEB-specific IgE antibodies than patients with mild AD or those with exacerbation in winter. In addition, the positive rates of specific IgE antibodies to both dog-dander and cat-dander were higher in patients with positive SEA/SEB-specific IgE antibodies than in patients with negative ones. No cross-reactions occurred among specific IgE antibodies to SEA/SEB and dog/cat dander with one patient's serum, which had positive IgE-specific antibodies against cat/dog dander and SEA/SEB. The positive rate of SEA/SEB-specific IgE antibodies in the patients with dogs and/or cats as pets was 48.4%, which was higher than in those with no pets. Atopic dermatitis patients who exhibit high positive rates of SEA/SEB-specific IgE antibodies were found to be school children, severe cases, cases with high serum concentrations of total IgE, cases with exacerbation in summer, and cases with dogs and/or cats as pets. The measurement of serum concentrations of specific IgE antibodies to SEA and SEB, thus has some value for evaluating AD patients.

  19. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial.

    PubMed

    Saussele, Susanne; Richter, Johan; Guilhot, Joelle; Gruber, Franz X; Hjorth-Hansen, Henrik; Almeida, Antonio; Janssen, Jeroen J W M; Mayer, Jiri; Koskenvesa, Perttu; Panayiotidis, Panayiotis; Olsson-Strömberg, Ulla; Martinez-Lopez, Joaquin; Rousselot, Philippe; Vestergaard, Hanne; Ehrencrona, Hans; Kairisto, Veli; Machová Poláková, Katerina; Müller, Martin C; Mustjoki, Satu; Berger, Marc G; Fabarius, Alice; Hofmann, Wolf-Karsten; Hochhaus, Andreas; Pfirrmann, Markus; Mahon, Francois-Xavier

    2018-06-01

    Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer

  20. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.

    PubMed

    Prost, Stéphane; Relouzat, Francis; Spentchian, Marc; Ouzegdouh, Yasmine; Saliba, Joseph; Massonnet, Gérald; Beressi, Jean-Paul; Verhoeyen, Els; Raggueneau, Victoria; Maneglier, Benjamin; Castaigne, Sylvie; Chomienne, Christine; Chrétien, Stany; Rousselot, Philippe; Leboulch, Philippe

    2015-09-17

    Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally

  1. Current approach to the treatment of chronic myeloid leukaemia.

    PubMed

    Pasic, Ivan; Lipton, Jeffrey H

    2017-04-01

    Of all the cancers, chronic myeloid leukaemia (CML) has witnessed the most rapid evolution of the therapeutic milieu in recent decades. The introduction of tyrosine kinase inhibitors (TKIs) as a therapeutic option has profoundly changed patient experience and outcome. The availability of multiple new highly effective therapies has increasingly underscored the importance of a good understanding of the underlying pathophysiological basis in CML, as well as patient-specific factors in choosing the right treatment for every individual. The treatment of CML has migrated in many jurisdictions from the office of a highly specialized malignant hematologist to the general hematologist or even a general practitioner. The goal of this review is to offer an overview of the modern approach to the treatment of CML, with an emphasis on chronic phase (CP) CML, including both TKI-based therapies such as imatinib, dasatinib, nilotinib, bosutinib and ponatinib, and non-TKI medications, such as omacetaxine. We discuss evidence behind each drug, most common and material adverse reactions and outline how this information can be used in selecting the right drug for the right patient. We also discuss evidence as it relates to other therapies, including stem cell transplant (SCT), and patients in accelerated (AP) and blastic phase (BP). Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

    PubMed

    Walker, Logan C; Stevens, Jane; Campbell, Hamish; Corbett, Rob; Spearing, Ruth; Heaton, David; Macdonald, Donald H; Morris, Christine M; Ganly, Peter

    2002-06-01

    The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).

  3. Cooperative transformation and coexpression of bovine papillomavirus type 1 E5 and E7 proteins.

    PubMed

    Bohl, J; Hull, B; Vande Pol, S B

    2001-01-01

    Productively infected bovine fibropapillomas were examined for bovine papillomavirus type 1 (BPV-1) E7 localization. BPV-1 E7 was observed in the cytoplasm of basal and lower spinous epithelial cells, coexpressed in the cytoplasm of basal cells with the E5 oncoprotein. E7 was also observed in nucleoli throughout the basal and spinous layers but not in the granular cell layer. Ectopic expression of E7 in cultured epithelial cells gave rise to localization similar to that seen in productive fibropapillomas, with cytoplasmic and nucleolar expression observed. Consistent with the coexpression of E7 and E5 in basal keratinocytes, BPV-1 E7 cooperated with E5 as well as E6 in an anchorage independence transformation assay. While E5 is expressed in both basal and superficial differentiating keratinocytes, BPV-1 E7 is only observed in basal and lower spinous epithelial cells. Therefore, BPV-1 E7 may serve to modulate the cellular response of basal epithelial cells to E5 expression.

  4. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation.

    PubMed

    Steffen, Leta S; Bacher, Jeffery W; Peng, Yuanlin; Le, Phuong N; Ding, Liang-Hao; Genik, Paula C; Ray, F Andrew; Bedford, Joel S; Fallgren, Christina M; Bailey, Susan M; Ullrich, Robert L; Weil, Michael M; Story, Michael D

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.

  5. Allergen-specific IgE measurement with the IMMULITE 2000 system: intermethod comparison of detection performance for allergen-specific IgE antibodies from Korean allergic patients.

    PubMed

    Lee, Yong Won; Sohn, Jung Ho; Lee, Jae-Hyun; Hong, Chein-Soo; Park, Jung-Won

    2009-03-01

    Intermethod comparison between IMMULITE 2000 chemiluminescent enzyme immunoassay (CLEIA) and the established CAP test for allergen-specific IgE (sIgE) has only been evaluated by a few studies. We performed such an interassay comparison using 283 Korean allergic patients with the following: asthma (18.4%), allergic rhinitis (18.4%), both asthma and allergic rhinitis (14.5%), atopic dermatitis (21.9%), and others (26.8%). We compared the sIgE detection performance of both systems for 10 major inhalant allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blattela germanica, cat dander, dog hair, alder, birch, oak, ragweed, and mugwort) and four food allergens (egg white, cow milk, peanut, and shrimp). After 645 paired comparison tests, close association and significant correlation were observed between the results of both assays for most of these allergens (r=0.525-0.979, p<0.05, respectively), except for shrimp. Intermethod agreement based on sIgE detection was fair to good (74.1-100%, kappa=0.514-1.000, p<0.05, respectively) for most allergens except for B. germanica, ragweed, and shrimp. Although both assays showed good accuracy in ROC curve analysis, some minor differences were noted. IMMULITE 2000 CLEIA for sIgE detection showed fair to good intermethod correlation, association, agreement, and accuracy in comparison to the established CAP assay among Korean allergic patients. However, we should take into account the intermethod differences between both assays for clinical applications.

  6. Acute myeloid leukaemia: challenges and real world data from India.

    PubMed

    Philip, Chepsy; George, Biju; Ganapule, Abhijeet; Korula, Anu; Jain, Punit; Alex, Ansu Abu; Lakshmi, Kavitha M; Sitaram, Usha; Abubacker, Fouzia N; Abraham, Aby; Viswabandya, Auro; Srivastava, Vivi M; Srivastava, Alok; Balasubramanian, Poonkuzhali; Mathews, Vikram

    2015-07-01

    The management of acute myeloid leukaemia (AML) in India remains a challenge. In a two-year prospective study at our centre there were 380 newly diagnosed AML (excluding acute promyelocytic leukaemia, AML-M3) patients. The median age of newly diagnosed patients was 40 years (range: 1-79; 12.3% were ≤ 15 years, 16.3% were ≥ 60 years old) and there were 244 (64.2%) males. The median duration of symptoms prior to first presentation at our hospital was 4 weeks (range: 1-52). The median distance from home to hospital was 580 km (range: 6-3200 km). 109 (29%) opted for standard of care and were admitted for induction chemotherapy. Of the 271 that did not take treatment the major reason was lack of financial resources in 219 (81%). There were 27 (24.7%) inductions deaths and of these, 12 (44.5%) were due to multidrug-resistant gram-negative bacilli and 12 (44.5%) showed evidence of a fungal infection. The overall survival at 1 year was 70.4% ± 10.7%, 55.6% ± 6.8% and 42.4% ± 15.6% in patients aged ≤ 15 years, 15 - 60 years and ≥ 60 years, respectively. In conclusion, the biggest constraint is the cost of treatment and the absence of a health security net to treat all patients with this diagnosis. © 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

  7. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    PubMed Central

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  8. Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic.

    PubMed

    Uckun, Fatih M; Ek, Rauf O; Jan, Shyi-Tai; Chen, Chun-Lin; Qazi, Sanjive

    2010-05-01

    The present study found that the pentapeptide mimic C-61, targeting the substrate binding P-site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy-resistant SYK-expressing primary leukemic B-cell precursors taken directly from relapsed B-precursor leukaemia (BPL) patients (but not SYK-deficient infant pro-B leukaemia cells), exhibited favourable pharmacokinetics in mice and non-human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy-resistant human BPL at dose levels non-toxic to mice and non-human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy-resistant BPL by targeting SYK-dependent anti-apoptotic blast cell survival machinery with a SYK P-Site inhibitor. Further development of C-61 may provide the foundation for therapeutic innovation against chemotherapy-resistant BPL.

  9. Tetraploidy acute myeloid leukaemia after chromosome 16 inversion.

    PubMed

    Vilches, Alba Sara; Díaz de Bustamante, Aranzazu; Sanchez-Calero, Jorge; Darnaude, María Teresa

    2017-03-22

    Our patient is a 36-year-old man referred by his general physician to the Department of Hematology because of mild neutropenia in a routine analysis at work. There was no history of previous diseases, and examination was normal. Blood investigations confirmed the neutropenia and showed elongation of prothrombin time. A bone marrow examination was performed revealing about 10% of myeloblasts on the aspirate smears. A cytogenetic study showed chromosome 16 inversion in all of these cells and tetraploidy only in some of them, which were extremely large in size. According to the revised WHO classification of tumours (2008), the patient was diagnosed as a case of acute myeloid leukaemia with chromosome 16 inversion. 2017 BMJ Publishing Group Ltd.

  10. Prevalence of multi-drug resistant organisms in stool of paediatric patients with acute leukaemia and correlation with blood culture positivity: A single institution experience.

    PubMed

    Shankar, Krupa; Radhakrishnan, Venkatraman; Vijayakumar, Varalakskmi; Ramamoorthy, Jaikumar; Ganesan, Prasanth; Dhanushkodi, Manikandan; Ganesan, T S; Sagar, T G

    2018-01-01

    Multi-drug resistant (MDR) bacteria are associated with increased morbidity and mortality in children with acute leukaemia. The present study was conducted to assess the prevalence of MDR bacteria in stool cultures of patients with acute leukaemia at presentation to the hospital. The results were then correlated with blood cultures when patients developed septicaemia. The study involved analysis of case records of patients with newly diagnosed acute leukaemia less than 18 years of age treated at our centre from January 2015 to December 2015. Stool cultures were sent within 72 hr of hospital admission and blood cultures were sent when clinically indicated. MDR was defined as resistance to at least one antibiotic in three or more following antimicrobial groups: cephalosporins, β-lactam/β-lactamase inhibitor, carbapenems, fluoroquinolones and aminoglycosides. The analysis included 85 patients with acute leukaemia, among whom 48 of 85 (56%) patients had positive stool cultures and 42 of 85 (50%) patients were positive for MDR bacteria. Blood cultures were positive in 13 of 48 patients (27%, seven MDR and six non-MDR) with positive stool cultures and three of 37 patients (8%, one MDR and two non-MDR) with negative stool cultures (P = 0.01). The concordance between stool and blood culture for similar organism was 61%. There were seven deaths in 48 stool culture positive patients and two deaths in 37 stool culture negative patients. This study shows the high prevalence of MDR bacteria in newly diagnosed children with acute leukaemia. Colonisation with MDR bacteria in stools is associated with increased positivity of blood cultures and mortality. © 2017 Wiley Periodicals, Inc.

  11. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line

    PubMed Central

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-01-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  12. Cell Specific eQTL Analysis without Sorting Cells

    PubMed Central

    Esko, Tõnu; Peters, Marjolein J.; Schurmann, Claudia; Schramm, Katharina; Kettunen, Johannes; Yaghootkar, Hanieh; Fairfax, Benjamin P.; Andiappan, Anand Kumar; Li, Yang; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Weersma, Rinse K.; Kasela, Silva; Milani, Lili; Tserel, Liina; Peterson, Pärt; Reinmaa, Eva; Hofman, Albert; Uitterlinden, André G.; Rivadeneira, Fernando; Homuth, Georg; Petersmann, Astrid; Lorbeer, Roberto; Prokisch, Holger; Meitinger, Thomas; Herder, Christian; Roden, Michael; Grallert, Harald; Ripatti, Samuli; Perola, Markus; Wood, Andrew R.; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Knight, Julian C.; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Wang, De Yun; van den Berg, Leonard H.; Veldink, Jan H.; Rotzschke, Olaf; Makino, Seiko; Salomaa, Veikko; Strauch, Konstantin; Völker, Uwe; van Meurs, Joyce B. J.; Metspalu, Andres; Wijmenga, Cisca; Jansen, Ritsert C.; Franke, Lude

    2015-01-01

    The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus. PMID:25955312

  13. E-Government Goes Semantic Web: How Administrations Can Transform Their Information Processes

    NASA Astrophysics Data System (ADS)

    Klischewski, Ralf; Ukena, Stefan

    E-government applications and services are built mainly on access to, retrieval of, integration of, and delivery of relevant information to citizens, businesses, and administrative users. In order to perform such information processing automatically through the Semantic Web,1 machine-readable2 enhancements of web resources are needed, based on the understanding of the content and context of the information in focus. While these enhancements are far from trivial to produce, administrations in their role of information and service providers so far find little guidance on how to migrate their web resources and enable a new quality of information processing; even research is still seeking best practices. Therefore, the underlying research question of this chapter is: what are the appropriate approaches which guide administrations in transforming their information processes toward the Semantic Web? In search for answers, this chapter analyzes the challenges and possible solutions from the perspective of administrations: (a) the reconstruction of the information processing in the e-government in terms of how semantic technologies must be employed to support information provision and consumption through the Semantic Web; (b) the required contribution to the transformation is compared to the capabilities and expectations of administrations; and (c) available experience with the steps of transformation are reviewed and discussed as to what extent they can be expected to successfully drive the e-government to the Semantic Web. This research builds on studying the case of Schleswig-Holstein, Germany, where semantic technologies have been used within the frame of the Access-eGov3 project in order to semantically enhance electronic service interfaces with the aim of providing a new way of accessing and combining e-government services.

  14. Human papillomavirus 16 (HPV16) and HPV52 E6-specific immunity in HIV-infected adults on combination antiretroviral therapy.

    PubMed

    Leng, C Y; Low, H C; Chua, L L; Chong, M L; Sulaiman, H; Azwa, I; Roberts, J M; Kamarulzaman, A; Rajasuriar, R; Woo, Y L

    2017-05-01

    Human papillomavirus (HPV)-associated cancers disproportionately affect those infected with HIV despite effective combination antiretroviral therapy (cART). The primary aim of this study was to quantify HPV16 and HPV52 E6-specific interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) T-cell responses, a correlate of protective immunity, in the first year following cART initiation and subsequently in those patients with suboptimal (sIR) and optimal (oIR) immune reconstitution. Ninety-four HIV-infected patients were recruited to the study; a longitudinal cohort of patients recruited just prior to commencing cART and followed up for 48 weeks (n = 27), and a cross-sectional cohort (n = 67) consisting of patients with sIR (CD4 T-cell count < 350 cells/μL) and oIR (CD4 T-cell count > 500 cells/μL) after a minimum of 2 years on cART. Controls (n = 29) consisted of HIV-negative individuals. IFN-γ ELISPOT responses against HPV16 and HPV52 E6 were correlated to clinical characteristics, anal and oral HPV carriage, T-cell maturational subsets, markers of activation, senescence and T-regulatory cells. HPV16 and HPV52 E6-specific T-cell responses were detected in only one of 27 patients (3.7%) during the initial phase of immune recovery. After at least 2 years of cART, those who achieved oIR had significantly higher E6-specific responses (9 of 34; 26.5%) compared with those with sIR (2 of 32; 6.3%) (P = 0.029). Apart from higher CD4 T-cell counts and lower CD4 T-cell activation, no other immunological correlates were associated with the detection of HPV16 and HPV52 E6-specific responses. HPV16 and HPV52 E6-specific IFN-γ T-cell responses, a correlate of protective immunity, were detected more frequently among HIV-infected patients who achieved optimal immune recovery on cART (26.5%) compared with those with suboptimal recovery (6.3%). © 2016 British HIV Association.

  15. Evaluation of anti-melanoma activities of (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol from the Red Sea soft coral Sarcophyton glaucum.

    PubMed

    Szymanski, Pawel T; Ahmed, Safwat A; Radwan, Mohamed M; Khalifa, Sherief I; Fahmy, Hesham

    2014-08-01

    Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were evaluated for their inhibitory effects on mouse melanoma B16F10 cell growth. Results show that all the cembranoids strongly inhibit viability of melanoma cells particularly during 48 -72 hrs treatment and also inhibit de novo DNA synthesis and PARP activity and stimulate fragmentation of DNA. (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol was not cytotoxic to monkey kidney CV-1 cells at the concentration that produces the anti-melanoma effects which indicates that this compound may be a good candidate for further development. (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were found to be cytotoxic to healthy cells.

  16. Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer.

    PubMed

    Kleiter, M; Hirt, R; Kirtz, G; Day, M J

    2001-05-01

    A 7-year-old male Giant Schnauzer was referred with a history of severe vomiting, lethargy, weight loss, polydipsia and polyuria. Detailed investigations revealed leucocytosis with a marked lymphocytosis, mild non-regenerative anaemia, thrombocytopenia, hypercalcaemia and azotaemia. Circulating lymphocytes were small and well-differentiated, and the same lymphoid population was present in bone marrow. Chronic lymphocyctic leukaemia with associated paraneoplastic hypercalcaemia was diagnosed. Immunohistochemical staining of a bone marrow biopsy revealed a neoplastic B-cell line expressing CD79. The dog responded to therapy with prednisolone and chlorambucil for a period of 8 months.

  17. Tumour genesis syndrome: severe hypophosphatemia and hypokalemia may be ominous presenting findings in childhood acute myeloid leukaemia.

    PubMed

    Chan, Winnie Ky; Chang, Kai On; Lau, Wing Hung

    2017-08-01

    We report a 16-year-old girl who was diagnosed with acute leukaemia and a marked leucocytosis >200 × 10 9 /L. She presented with marked hypophosphatemia, hypokalemia, acute renal failure and acute respiratory failure. These electrolytes disturbances may indicate rapid tumour genesis. These ominous findings required urgent treatment to halt the crises of rapid leukemic cell proliferation. Mark hypophosphatemia and hypokalemia may be presenting electrolyte abnormalities in a patient with acute leukaemia, and these may be indicators of aggressive tumour genesis. What is known: • Mild electrolyte disturbances are common in oncology patients • Tumour lysis syndrome is well recognized by paediatriaticians What is new: • Life-threatening hypophosphatemia is an uncommon presentation • These electrolytes disorders may indicate an aggressive tumour genesis process even at presentation and require urgent treatment.

  18. Haematological profile of patients with mixed-phenotype acute leukaemia from a tertiary care centre of north India

    PubMed Central

    Sharma, Manupriya; Sachdeva, Man Updesh Singh; Bose, Parveen; Varma, Neelam; Varma, Subhash; Marwaha, R.K.; Malhotra, Pankaj

    2017-01-01

    Background & objectives: Mixed-phenotype acute leukaemia (MPAL) is a rare neoplasm with no definite treatment protocols and a distinctly poor outcome. Advancement in polychromatic flow cytometry has made its identification easier. This prospective study was designed to identify cases of MPAL and study their clinical presentation and haematological profile in a tertiary care hospital in north India. Methods: Ethylenediaminetetraacetic acid (EDTA)-anticoagulated bone marrow aspirate samples of patients diagnosed as acute leukaemia (AL) on the basis of morphology were utilized for immunophenotyping. A comprehensive panel of fluorochrome-labelled monoclonal antibodies targeting myeloid, B-cell, T-cell and immaturity markers was utilized. The patients diagnosed to have MPAL, on the basis of the World Health Organization 2008 classification, were selected for further analyses. Results: There were 15 (2.99%) patients with MPAL of the total 501 cases of AL. Seven were children, all males and mean age of 5.08±3.88 yr. Eight were adults, male:female=6:2 and mean age of 21.43±5.74 yr. Eight were diagnosed as B/myeloid and seven were T/myeloid. No association was observed between age and immunophenotype of MPAL. On morphology, 11 were diagnosed as AML and four as ALL, and no specific morphology of blasts was predictive of a MPAL. Interpretation & conclusions: MPAL appeared to be a rare neoplasm (2.99% of AL cases). A comprehensive primary panel of monoclonal antibodies should be used to identify this neoplasm known to have a poor outcome. PMID:28639598

  19. Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy

    PubMed Central

    Levin, Mattias; King, Jasmine J.; Glanville, Jacob; Jackson, Katherine J. L.; Looney, Timothy J.; Hoh, Ramona A.; Mari, Adriano; Andersson, Morgan; Greiff, Lennart; Fire, Andrew Z.; Boyd, Scott D.; Ohlin, Mats

    2016-01-01

    Background Specific immunotherapy (SIT) is the only treatment with proven long-term curative potential in allergic disease. Allergen-specific IgE is the causative agent of allergic disease, and antibodies contribute to SIT, but the effects of SIT on aeroallergen-specific B cell repertoires are not well understood. Objective To characterize the IgE sequences expressed by allergen-specific B cells, and track the fate of these B cell clones during SIT. Methods We have used high-throughput antibody gene sequencing and identification of allergen-specific IgE using combinatorial antibody fragment library technology to analyze immunoglobulin repertoires of blood and nasal mucosa of aeroallergen-sensitized individuals before and during the first year of subcutaneous SIT. Results Of 52 distinct allergen-specific IgE heavy chains from eight allergic donors, 37 were also detected by high-throughput antibody gene sequencing of blood, nasal mucosa, or both sample types. The allergen-specific clones had increased persistence, higher likelihood of belonging to clones expressing other switched isotypes, and possibly larger clone size than the rest of the IgE repertoire. Clone members in nasal tissue showed close mutational relationships. Conclusion Combining functional binding studies, deep antibody repertoire sequencing, and information on clinical outcomes in larger studies may in the future aid assessment of SIT mechanisms and efficacy. PMID:26559321

  20. Indoor residential radon exposure and risk of childhood acute myeloid leukaemia.

    PubMed

    Steinbuch, M; Weinberg, C R; Buckley, J D; Robison, L L; Sandler, D P

    1999-11-01

    Exposure to radon has been identified as a risk factor for lung cancer in uranium miners, but evidence of adverse health effects due to indoor radon exposure is inconsistent. Ecological studies have suggested a correlation between indoor radon levels and leukaemia incidence. We evaluated the risk associated with indoor residential radon exposure within a larger interview-based case-control study of risk factors for childhood acute myeloid leukaemia (AML). A total of 173 cases and 254 controls met the eligibility criteria, and information was collected through telephone interviews with parents and analysis of alpha-track radon detectors placed in the home for a period of 1 year. No association was observed between radon exposure and risk of AML, with adjusted odds ratios of 1.2 (95% confidence interval (CI) 0.7-1.8) for 37-100 Bq m(-3) and 1.1 (95% CI 0.6-2.0) for > 100 Bq m(-3) compared with < 37 Bq m(-3). Although there was an inverse association between radon level and AML risk among children < 2 years at diagnosis, among children > or = 2 years, AML risk was increased among those with higher radon exposure. The observed association after age 2 is most likely due to chance. Overall, there was no association between residential radon and risk of childhood AML.