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Sample records for e26 transforming-specific leukaemia

  1. Association of E26 Transformation Specific Sequence 1 Variants with Rheumatoid Arthritis in Chinese Han Population.

    Directory of Open Access Journals (Sweden)

    Lin Chen

    Full Text Available E26 transformation specific sequence 1 (ETS-1 belongs to the ETS family of transcription factors that regulate the expression of various immune-related genes. Increasing evidence indicates that ETS-1 could contribute to the pathogenesis of autoimmune disease. Recent research has provided evidence that ETS-1 might correlate with rheumatoid arthritis (RA, but it's not clearly defined. In this study, we aimed to identify whether polymorphisms of ETS-1 play a role in Rheumatoid arthritis (RA susceptibility and development in Chinese Han population.Four single nucleotide polymorphisms (SNPs within ETS-1 were selected based on HapMap data and previous associated studies. Whole blood and serum samples were obtained from 158 patients with RA and 192 healthy subjects. Genotyping was performed with polymerase chain reaction-high resolution melting (PCR-HRM assay and the data was analyzed using SPSS17.0.A significantly positive correlation was observed between the SNP rs73013527 of ETS-1 and RA susceptibility, DAS28 and CRP (P<0.001, P = 0.001, and P = 0.028, respectively. Carriers of the haplotype CCT or TCT for rs4937333, rs11221332 and rs73013527 were associated with decreased risk of RA as compared to controls. No statistical significant difference was observed in the distribution of rs10893872, rs4937333 and rs11221332 genotypes between RA patients and controls.Our data further supports that ETS-1 has a relevant role in the pathogenesis and development of RA. Allele T of rs73013527 plays a protective role in occurrence of RA but a risk factor in the high disease activity. Rs10893872, rs11221332 and rs4937333 are not associated with RA susceptibility and clinical features.

  2. Nuclear power and leukaemia

    International Nuclear Information System (INIS)

    Grimston, M.

    1991-03-01

    This booklet describes the nature of leukaemia, disease incidence in the UK and the possible causes. Epidemiological studies observing rates of leukaemia near nuclear power stations in the UK and other parts of the world are discussed. Possible causes of leukaemia excesses near nuclear establishments include radioactive discharges into the environment, paternal radiation exposure and viral causes. (UK)

  3. Cytochemical studies in leukaemias

    Directory of Open Access Journals (Sweden)

    Batra Neelam

    1978-01-01

    Full Text Available One hundred cases of acute leukaemia were studied, by Romanowsky stains and by cytochemical stains such as Sudan Black B, Periodic Acid Schiff, Alkaline phosphatase and Peroxidase stains. Cases difficult to diagnose by Romanowsky stained smears were easily classified by these supplementary stains. Their importance as supplements to the routine Romanowsky staining in the diagnosis of leukaemia is emphasized and the division of acute lymphoblastic leukaemia based on these patterns is suggested.

  4. Morphology of leukaemias

    Directory of Open Access Journals (Sweden)

    W. Ladines-Castro

    2016-04-01

    Full Text Available Acute leukaemias are characterised by uncontrolled proliferation of immature blood cells with lymphoid or myeloid lineage. Morphological classification is based on the identification of the leukaemia cell line and its stage of differentiation. The first microscopic descriptions dating from the 1930s pointed to 2 different types of leukaemia cells: lymphoid and myeloid. In 1976, the consensus that led to the French-American-British (FAB classification was achieved. This includes criteria for identifying myeloid and lymphoid leukaemias, and gives a list of morphological subtypes, describing how these affect the patient's prognosis. Today, despite new classifications based on sophisticated studies, FAB classification is widely used by experts due to its technical simplicity, good diagnostic reliability and cost-effectiveness.

  5. Leukaemia in East Suffolk

    International Nuclear Information System (INIS)

    Bush, M.F.H.

    1983-09-01

    An investigation was conducted by the East Suffolk Health Authority to determine whether there were any geographical variations in the incidence of leukaemia over the last fifteen years in East Suffolk suggesting an environmental hazard, e.g. Sizewell Power Station. No areas were found to have a statistically significant increased incidence of leukaemia cases although there did appear to be a cluster of cases in the Leiston area. (U.K.)

  6. New leukaemia link

    International Nuclear Information System (INIS)

    Roche, P.

    1993-01-01

    A new study around the Aldermaston and Burghfield nuclear weapons establishments published in the British Medical Journal has found a similar association between the risk of childhood leukaemia and employment in the nuclear industry to that found by Professor Gardner in 1990 at Sellafield. It suggests that occupational exposure to radiation prior to conception increases the risk of a subsequent child developing leukaemia by 9 times. It is clear that working at Aldermaston or Burghfield does not explain the entire excess of cancers -there must be another factor at work. The one factor that Aldermaston, Burghfield, Sellafield and Dounreay where a similar pattern is found, have in common is plutonium. Whilst further studies are important to determine the role played by plutonium, it should be declared 'guilty until proven innocent'. The production and use of plutonium should cease immediately. (author)

  7. Leukaemia near british nuclear installations

    International Nuclear Information System (INIS)

    Hubert, D.

    1991-01-01

    An excess of childhood leukaemia has been seen near some British nuclear installations, especially near the Sellafield reprocessing plant. The same result was found in a more general study including a large number of nuclear sites. Similar studies made in USA, Canada and France have been negative. Moreover, epidemiological studies made in England have discovered other childhood leukaemia clusters in areas far from nuclear facilities, and especially near potential sites of nuclear installations. Several explanations are suggested but no definite conclusion is yet possible. Doses from radioactive releases seem to be too low to account for the additional deaths from leukaemia by environmental contamination. A virus activation, which might be associated with population influx into rural isolated areas, has been considered. The hypothesis of genetic mutation induced by ionising radiation in the fathers of children with leukaemia has been made because a higher risk of leukaemia was observed for children of fathers employed at Sellafield. No firm conclusion is possible considering the small number of observed cases and the lack of excess leukaemias in the offspring of Hiroshima and Nagasaki survivors. The possibility of internal contamination, chemicals or even radon is discussed as other causes. Studies in progress might allow to find an answer to the problem of leukaemia in the vicinity of British nuclear installations [fr

  8. Oral manifestations of acute leukaemia

    Directory of Open Access Journals (Sweden)

    Ivanović Mirjana

    2011-01-01

    Full Text Available Acute leukaemia is the most common form of chilhood cancer. The aim of this paper was to underline the importance of oral manifestations in children with acute leukaemia. The disease and its treatment can directly or indirectly affect oral health. Oral manifestations are gingival inflammation and enlargement. Leukaemic cells are capable of infiltrating the gingiva and the deeper periodontal tissues which leads to ulceration and infection of oral tissues. Gingival bleeding is a common sign in patients with leukaemia. Symptoms include local lymphadenopathy, mucous membrane Petechiae and ecchymoses. Cytotoxic drugs have direct effects like mucositis, involving atrophy, desquamation and ulceration of the mucosa, with increasing the risk for local and systemic infections. Leukaemia can directly influence dental care and dental treatment, while oral lesions may have life-threatening consequences. Knowledge and skills among dentists may also not be adequate to treat children with acute leukaemia. It is therefore imperative that all stomatologists be aware of dental problems that occur in leukaemia in order to be able to effectively carry out appropriate measures to mitigate these problems.

  9. Leukaemia risks and radon

    International Nuclear Information System (INIS)

    Wolff, S.P.

    1991-01-01

    A correlation has been established between domestic radon exposure and mutation in peripheral T lymphocytes. Some caution must be exercised, however, in interpreting this result as evidence that levels of domestically encountered radon are sufficient to cause leukaemogenic chromosomal alterations. Radon may simply be acting as a surrogate for some other mutagenic factor. Correlations with Local Authority statistics collected in the United Kingdom 1981 Census appear to show that lower domestic radon levels reflect relatively greater socioeconomic deprivation whereas higher levels reflect greater prosperity. The relative risk of lymphoproliferative disease correlates with the same factors that determine domestic radon levels at the county level. Putative relationships between domestic radon exposure and cancer thus need to be controlled for socioeconomic status and associated factors, at least at the county level. (The correlations may not apply to smaller areas.) Similarly, the causative factors underlying the relationships between higher regional socioeconomic status and leukaemia require closer examination. (author)

  10. Pneumocystis carinii Pneumonia in Acute Lymphatic Leukaemia ...

    African Journals Online (AJOL)

    A case report of a patient who developed fatal pneumocystis pneumonia while in remission from acute lymphatic leukaemia is presented. Clinical and aetiological aspects of this rare infection are discussed. Attention is drawn to diagnostic pitfalls encountered in leukaemia.

  11. Leukaemia in childhood | Kruger | Continuing Medical Education

    African Journals Online (AJOL)

    Leukaemia means white blood. It is a disease of the white blood cells and was first described by Virchow in 1845.1 Leukaemia can present as an acute disease, occurring more often in the younger age groups, or as a chronic disease, usually in the older age group. Acute leukaemia is rare, but about 1 in 2 000 people will ...

  12. Acute myeloid leukaemia presenting as faecal incontinence

    Science.gov (United States)

    Lim, Hoon; Cho, Young Soon; Jang, Pyung Moon; Kim, Ho Jung; Jang, Hye Young

    2007-01-01

    Epidural sacral nerve compression as an initial feature of leukaemia is a rare complication. The findings in a 16‐year‐old boy who presented to an emergency department with symptoms of faecal incontinence are reported herein. Radiological imaging demonstrated soft‐tissue masses in the sacral epidural space. The diagnosis of acute myeloid leukaemia was confirmed on bone marrow aspirate. The characteristics and management of extramedullary leukaemia are discussed. PMID:17452690

  13. Childhood leukaemia around nuclear facilities

    International Nuclear Information System (INIS)

    Wojcik, Andrzej; Feychting, Maria

    2010-06-01

    In December 2007 the German Federal Office for Radiation Protection (BfS) published a report on the incidence of childhood cancers among children living in the vicinity of 16 German nuclear power plants. The results show a significantly enhanced risk of leukaemia in children aged below 5 years, who live within 5 km from a nuclear power plant. The study is known as KiKK (Epidemiologische Studie zu Kinderkrebs in der Umgebung von Kernkraftwerken) and stirred considerable concern about the safety of nuclear installations. In this review we summarise the present state-of-the art regarding childhood leukaemia in the vicinity of nuclear installations and present the main results of the KiKK study with a critical evaluation

  14. Summary curves for patients transplanted for chronic myeloid leukaemia salvaged by a donor lymphocyte infusion: the current leukaemia-free survival curve

    DEFF Research Database (Denmark)

    Klein, John P.; Keiding, Niels; Shu, Youyi

    2000-01-01

    CML, donor lymphocyte infusion, leukaemia-free survival, current leukaemia-free survival, statistical methods......CML, donor lymphocyte infusion, leukaemia-free survival, current leukaemia-free survival, statistical methods...

  15. immunophenotyping of acute leukaemias by flow cytometry

    African Journals Online (AJOL)

    2009-12-01

    Dec 1, 2009 ... ... of acute leukaemias within our resource constrained setting. ACKNOWLEDGEMENTS. To the University of Nairobi, and the American. Society of Hematology (ASH), which enabled me to undertake training in flow cytometry of leukaemias and lymphomas at the M.D. Anderson Cancer Center,. Houston ...

  16. Child leukaemia and low frequency electromagnetic fields

    International Nuclear Information System (INIS)

    Clavel, J.

    2009-01-01

    The author discusses the possible causes of child leukaemia: exposure to natural ionizing radiation (notably radon), to pesticides, and to hydrocarbons emitted by road traffic. Some studies suggested that an inadequate reaction of the immune system to an ordinary infection could result in leukaemia. Other factors are suspected, notably extremely low frequency electromagnetic fields, the influence of which is then discussed by the author. She evokes and discusses results of different investigations on this topic which have been published since the end of the 1970's. It appears that a distance less than 50 meters from high voltage lines or the vicinity of transformation stations may double the risk of child leukaemia

  17. Childhood leukaemia and nuclear power

    International Nuclear Information System (INIS)

    Berry, R.J.; Wakeford, R.

    1992-01-01

    There has been considerable scientific and media interest in the question of whether the risk of childhood leukemia is raised near nuclear facilities, and, if so, the reasons why. Serious consideration of this issue was initiated by a media report of an unusually large number of cases around the Sellafield installation in England, and reports of excess cases in the vicinity of other facilities in Britain have followed. Detailed radiological assessments have demonstrated that radioactive discharges are most unlikely to have been the cause of these reported excess cases, seemingly contradicting the epidemiological evidence. However, epidemiology is an observational (non-experimental) science, and the results of such studies must be interpreted with considerable care. The influence of prior knowledge of data upon the structure of a study has been a particular inferential problem. Furthermore, there are indications that non-radiological factors may be important in communities near nuclear facilities. Recently, a study has shown an association between childhood leukaemia cases near Sellafield and the recorded occupational radiation doses received by fathers before the conception of these children; but this novel finding has received little independent scientific support. At present, the British childhood leukaemia findings have not been replicated in studies based in other countries, and the reasons for the reported case excesses around British nuclear facilities remain unclear

  18. Gene expression profiling in acute myeloid leukaemia

    NARCIS (Netherlands)

    de Jonge, H. J. M.; Huls, G.; de Bont, E. S. J. M.

    Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by clonal malignant haematopoiesis with a differentiation arrest and excessive proliferation of leukaemic blasts. Over the past decades, the heterogeneity of AML has been illustrated by evolving classifications based on

  19. An investigation into childhood leukaemia in Northamptonshire

    International Nuclear Information System (INIS)

    1996-01-01

    This report has been written specifically for the families of children who have had leukaemia in Northamptonshire. It gives the Health Authority's answers to the questions and worries that they raised at a meeting we had on 22nd September 1995. The report will also be circulated to other people who have been concerned by this problem and will, therefore, include some background information as well. The report thus has several different purposes: to give a brief summary of what is known about leukaemia and its causes; to explain the implications of having five cases of childhood leukaemia in a small area over a number of years; to let people know what Northamptonshire Health Authority has done in response to their concerns; to explain why a local epidemiological study of these cases could not tell us what caused leukaemia in the affected children; to reassure residents in the Pembroke Road area that we have found no reason to be concerned that their children are at an increased risk of developing leukaemia; to give information to the families about the current scientific evidence on the relationship between several potential environmental hazards they have identified and childhood leukaemia; to let people know that the important questions about what causes leukaemia in children are being addressed in several important and well-designed scientific studies. We hope that this report can be understood by people who are not familiar with medical jargon. Sometimes it has been necessary to use medical and technical terms, so at the back of this report there is a glossary which gives the meaning of any medical terms used

  20. Recent trends and concepts in the management of leukaemia ...

    African Journals Online (AJOL)

    Currently the treatment for Acute Leukaemia, which consists of Acute Myeloblastic Leukaemia (AML) and Acute Lymphoblastic Leukaemia (ALL), consists of the preventive and the definitive aspects of therapy. Recent trends that have been elucidated involve aspects of chemotherapy, radiotherapy, stem cell transplant, and ...

  1. Acute leukaemia: making sense of a complex blood cancer.

    LENUS (Irish Health Repository)

    Meenaghan, Teresa

    2012-01-01

    Acute leukaemia represents a diverse group of blood cancers that affect both children and adults. Treatment schedules for these haematology cancers are often prolonged, with many associated side effects and complications. Nurses caring for patients with acute leukaemia require an anticipatory approach, where care is aimed at minimizing the side effects of treatment and being constantly vigilant for any impending adverse effects. Moreover, patients require support for the psychosocial issues that can arise for patients during their illness. This article provides an overview of acute lymphoblastic leukaemia and acute myeloid leukaemia. Nursing considerations in the care of patients being treated for acute leukaemia are also explored.

  2. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-04-28

    Apr 28, 2013 ... malignancies that occur in children <15year of age and. Acute lymphoblastic leukaemia (ALL) accounts for about 77% of cases of childhood leukemias.1 Bone pain, particularly of the lower extremities is a common manifestation of childhood ALL. Although the initial presentation of childhood ALL is usually ...

  3. Unusual presentations of childhood acute lymphoblastic leukaemia ...

    African Journals Online (AJOL)

    Childhood acute lymphoblastic leukaemia, (ALL) is increasingly reported to present in an atypical fashion which may have significant implications for treatment outcomes and survival. This case report presents a Nigerian child who's clinical and radiological features together with effusion cytological findings were suggestive ...

  4. Neurological Complications Of Chronic Myeloid Leukaemia: Any ...

    African Journals Online (AJOL)

    Of the five, two (40%) patients presented with bilateral hearing impairment, each beginning with the left ear; one (20%) presented with left ear hearing loss; one ... pathogenetic mechanisms underlying these complications with a view to finding specific treatment measures for worrisome chronic myeloid leukaemia-related ...

  5. ABSTRACT CHRONIC MYELOID LEUKAEMIA IN CENTRAL ...

    African Journals Online (AJOL)

    hi-tech

    2003-09-09

    , USA. .... anaemia (Hb ≤ 9.4g/dl recorded in 86 (57.3%) patients and ..... J.M. Chronic myeloid leukaemia. In. Haematology, Basic Principles and Practice 2nd edn., (ed.), R. Hoffman. Churchill Livingstone, New York, USA.

  6. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic ...

    African Journals Online (AJOL)

    Background: Acute Lymphoblastic Leukaemia in children commonly presents with osteo articular manifestations that may mimic Juvenile Idiopathic Arthritis. This may create considerable diagnostic difficulty and lead to delay in commencing appropriate treatment. Case: An eight year old boy who presented with multiple ...

  7. Splenic irradiation for hairy cell leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Al-Moundhri, A.; Graham, P.H. [St George Hospital, Kogarah, NSW, (Australia). Department of Radiation Oncology

    1997-11-01

    Splenic irradiation in the management of hairy cell leukaemia is previously unreported. A case is presented here to illustrate that splenic irradiation may be a useful addition to systemic therapies. It achieved local splenic and blood picture response and remission similar to splenectomy without any significant toxicity. (authors). 7 refs., 2 figs.

  8. Analysis of images of acute human and animal leukaemia

    International Nuclear Information System (INIS)

    Feinermann, Emmanuel

    1981-01-01

    This research thesis first proposes a review of the development of stereology: historical backgrounds, basic principles. It discusses the choices regarding instrumentation: Coulter counter (principle and theory), quantitative analysis of particles, image analyser (optical microscope, epidiascope, scanners, detection, electronic pencil, computers, programming and data processing system), and stereo-logical parameters. The author then reports the stereo-logical study of acute human leukaemia: definition, classification, determination of spherical particle size distribution, lympho-blast size distributions. He reports the comparative study of rat L 5222 leukaemia and Brown Norway rat acute myelocytic leukaemia, and discusses their relationship with acute human leukaemia

  9. Feverfew: weeding out the root of leukaemia.

    Science.gov (United States)

    Guzman, Monica L; Jordan, Craig T

    2005-09-01

    Malignant stem cells are central to the pathogenesis and perpetuation of acute myelogenous leukaemia (AML). Despite their crucial role, standard chemotherapy often does not target these critical cells and, thus, the 'root' of leukaemic disease is not eradicated. To derive better therapies, unique molecular features of malignant stem cells have been characterised for AML and evaluated with regard to ablation of disease. In the course of such studies, the compound parthenolide, which is derived from the medicinal plant feverfew, has recently been shown to preferentially induce AML stem cells to undergo apoptosis. Importantly, parthenolide had no discernable effect on normal blood cells. Thus, this naturally occurring agent may provide new avenues of investigation for the treatment of leukaemia. In this article, characteristics of parthenolide are reviewed.

  10. Ocular manifestations of leukaemia in Ethiopians.

    Science.gov (United States)

    Alemayehu, W; Shamebo, M; Bedri, A; Mengistu, Z

    1996-10-01

    A prospective ophthalmic evaluation of 74 newly diagnosed and 34 old (on follow-up) leukaemic patients, carried out from March 1990 to December 1995 is described. Primary ocular involvement, that is leukaemic retinal infiltrates, were detected in 32% of the newly diagnosed. In contrast, none of the old leukaemic patients had this lesion. In 69% of the new and 21% of the old cases, secondary ocular manifestations of leukaemia were observed. The major secondary ocular manifestation of leukaemia in both groups was intra-retinal haemorrhage. A variety of miscellaneous ocular findings, such as cataract, pterygium, pingeculae, etc. were detected in 36% of all leukemics. These findings indicate the importance of a complete ophthalmologic evaluation in the diagnosis, follow-up and management of leukaemic patients.

  11. Residential exposures to pesticides and childhood leukaemia

    International Nuclear Information System (INIS)

    Metayer, C.; Buffler, P. 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 geno-typing 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. (authors)

  12. Proteomic profile of acute myeloid leukaemia: A review update

    African Journals Online (AJOL)

    pathophysiology of acute myeloid leukaemia (AML) through proteome expressions, thus confirming the viability of ..... affected by acute lymphoid leukaemia) were .... these cells resistant to FTY-720 increase the expression of miR-191-5p and a suppression of. miR-142-3pcan be attributable to reduction of the. B subunit.

  13. The pathogenesis of radiation leukaemia and its significance for the pathogenesis of spontaneous leukaemias

    International Nuclear Information System (INIS)

    Ludwig, F.C.

    1985-01-01

    There is no radiation leukaemia per se, there is just a spontaneous disposition to this disease owing to irradiation. Weakened immunity is one component of the preleukaemic condition. Changes in organs with tumour-virus-sensitive cells should not be disregarded. Preleukaemic condition involves the release of tumour viruses and the increased occurrence of cells which can react with tumour viruses. (DG) [de

  14. Estimation of current cumulative incidence of leukaemia-free patients and current leukaemia-free survival in chronic myeloid leukaemia in the era of modern pharmacotherapy.

    Science.gov (United States)

    Pavlík, Tomáš; Janoušová, Eva; Pospíšil, Zdeněk; Mužík, Jan; Záčková, Daniela; Ráčil, Zdeněk; Klamová, Hana; Cetkovský, Petr; Trněný, Marek; Mayer, Jiří; Dušek, Ladislav

    2011-10-11

    The current situation in the treatment of chronic myeloid leukaemia (CML) presents a new challenge for attempts to measure the therapeutic results, as the CML patients can experience multiple leukaemia-free periods during the course of their treatment. Traditional measures of treatment efficacy such as leukaemia-free survival and cumulative incidence are unable to cope with multiple events in time, e.g. disease remissions or progressions, and as such are inappropriate for the efficacy assessment of the recent CML treatment. Standard nonparametric statistical methods are used for estimating two principal characteristics of the current CML treatment: the probability of being alive and leukaemia-free in time after CML therapy initiation, denoted as the current cumulative incidence of leukaemia-free patients; and the probability that a patient is alive and in any leukaemia-free period in time after achieving the first leukaemia-free period on the CML treatment, denoted as the current leukaemia-free survival. The validity of the proposed methods is further documented in the data of the Czech CML patients consecutively recorded between July 2003 and July 2009 as well as in simulated data. The results have shown a difference between the estimates of the current cumulative incidence function and the common cumulative incidence of leukaemia-free patients, as well as between the estimates of the current leukaemia-free survival and the common leukaemia-free survival. Regarding the currently available follow-up period, both differences have reached the maximum (12.8% and 20.8%, respectively) at 3 years after the start of follow-up, i.e. after the CML therapy initiation in the former case and after the first achievement of the disease remission in the latter. Two quantities for the evaluation of the efficacy of current CML therapy that may be estimated with standard nonparametric methods have been proposed in this paper. Both quantities reliably illustrate a patient's disease

  15. Leukaemia risks and exposure to ionizing radiations. ASN seminar, Tuesday, June 9, 2015, report

    International Nuclear Information System (INIS)

    Niel, Jean-Christophe; Samain, Jean-Paul; Colonna, Marc; Maynadie, Marc; Richardson, David; Bey, Pierre; Leuraud, Klervi; Laurier, Dominique; Hemon, Denis; Spycher, Ben; Kosti, Ourania; Bouville, Andre; Grosche, Bernd; Ziegelberger, Gunde; Kesminiene, Ausrele; Clavel, Jacqueline; Smeesters, Patrick; Murith, Christophe

    2015-08-01

    This seminar aims at proposing a review of present knowledge on leukaemia risks for children and adults associated with ionizing radiations, and at sharing knowledge between experts. After an introduction which outlined the interest of the ASN in research issues, and the importance awarded by the ASN to the variety of points of view, a first session addressed leukaemia and exposures to ionizing radiations. The contributions addressed some general aspects (an overview of leukaemia in France, the different types of adult and child leukaemia), leukaemia and acute exposures to ionizing radiations (ionizing radiation and leukaemia among Japanese bomb survivors, risks of leukaemia after radiotherapy), leukaemia and chronic exposures to ionizing radiations (assessment of epidemiological studies for adult chronic exposures). The second session addressed childhood leukaemia and ionizing radiations. The contributions of this second session more particularly addressed the following topics: childhood leukaemia and natural radioactivity (French studies, synthesis of international studies and a new Swiss study), childhood leukaemia and proximity of nuclear base installations (assessment of national and international studies, analysis of cancer risks in populations near nuclear facilities in the US, calculation of dose at the medulla as example of dosimetry of ionizing radiations and leukaemia, conclusions of the 2012 MELODI workshop), childhood leukaemia and scanner (recent results and perspectives), childhood leukaemia and other risk factors (etiology of childhood leukaemia - presentation of French studies initiated by the INSERM, and presentation of studies initiated by BfS)

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

    Science.gov (United States)

    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.

  17. Nuclear power and leukaemia in children

    International Nuclear Information System (INIS)

    Charles, M.W.; Harte, G.A.

    1985-01-01

    A summary is given of a session entitled ''Nuclear Power and Leukaemia in children'' held at a meeting of the Royal Statistical Society and the Society for Social Medicine in June 1985. The first part of the session was devoted to summarising the principal findings of the Black Report on the Investigation of the Possible Increased Incidence of Cancer in West Cumbria'', and to a description and critical review of the main evidence presented to the Committee. Later, further epidemiological studies arising out of and related to the Report were described. The meeting was useful in identifying areas of uncertainty in environmental modelling, radiobiology and epidemiology. (U.K.)

  18. Acute lymphocytic leukaemia in children in the Netherlands

    International Nuclear Information System (INIS)

    Does-van den Berg, A. van der.

    1980-01-01

    Some features, present at diagnosis in children with acute lymphocytic leukaemia, investigated during the period 1973-1975, and the results of treatment according to protocol AL II of the Dutch Childhood Leukaemia Study Group (SNWLK), are described. This report concerns the results of induction treatment, elective treatment of the central nervous system, and also of the prospective comparative study on the influence of the addition of cyclophosphamide to maintenance treatment with 6-mercaptopurine and methotrextate. In the context of the investigation of long-term side effects of disease and treatment, the immunocompetence of children with acute lymphocytic leukaemia in continuous remission after cessation of therapy was studied. (Auth.)

  19. Serum & cerebrospinal fluid ferritin levels in children with acute leukaemia.

    Science.gov (United States)

    Srinivasan, A; Rusia, U; Anand, N K; Sood, S K

    1989-06-01

    Serum and CSF ferritin were estimated in 35 consecutive patients of acute leukaemia at the time of admission and on induction of remission. Serum ferritin levels were significantly raised in 94 per cent patients of acute leukaemia. The mean (+/- SD) serum ferritin (314.36 +/- 158.4 micrograms/1) was significantly higher when compared with control values (P less than 0.001). Remission induction resulted in significant fall in serum ferritin values to a mean of 149 (+/- 98.7) micrograms/l (P less than 0.05). Serum ferritin is thus of value in assessing the state of remission and is a sensitive indicator of the leukaemic cell mass and the state of activity of the disease. CSF ferritin levels in acute leukaemia were comparable to normal control values. CSF ferritin did not reflect CNS involvement in acute leukaemia and therefore its value as a tumour marker of CNS infiltration is doubtful.

  20. Childhood leukaemia around Canadian nuclear facilities. Phase 1

    International Nuclear Information System (INIS)

    Clarke, E.A.; McLaughlin, J.; Anderson, T.W.

    1989-05-01

    A ninefold excess risk of leukaemia, as observed in vicinity of the Sellafield facility, was not observed amongst children born to mothers residing in the areas around nuclear research facilities and uranium mining, milling and refining facilities in Ontario. In the vicinity of nuclear research facilities, the rate of leukaemia was, in fact, less than expected. In the areas around the uranium mining, milling and refining facilities; leukaemia occurred slightly more frequently than expected; however, due to small frequencies these results may have risen by chance. A slightly greater than expected occurrence of leukaemia was also detected, which may well have been due to chance, in an exploratory study of the areas around nuclear power generating stations in Ontario

  1. Clinicopathological features of transient myeloproliferative syndrome and congenital leukaemia

    International Nuclear Information System (INIS)

    Sajid, N.; Ahmed, N.; Mahmood, S.

    2010-01-01

    The objectives of the study were to determine the spectrum of the clinical and pathological findings, the management and prognosis of patients of transient myeloproliferative syndrome (TMS) and congenital leukaemia. Study Design: Case series. Place and Duration of Study: The study was conducted over a period of 8 years, from January 2000 to December 2007, at the Children's Hospital and the Institute of Child Health, Lahore. Methodology: Suspected patients presenting with fever, pallor, bruises and hepatosplenomegaly and diagnosed as either transient myeloproliferative disorder or congenital leukaemia were studied. The complete blood count, reticulocyte count, leukocyte alkaline phosphatase score, liver function tests, karyotyping studies and bone marrow aspiration biopsy were performed in all of those patients. Management and out come was noted. Results were described as frequency percentages. Results: Out of 10,000 patients presenting during this period, 24 patients were diagnosed as either of transient myeloproliferative syndrome or congenital leukaemia. Fifteen of these were diagnosed as patients of TMS and 9 as patients of congenital leukaemia. Down syndrome (DS) was diagnosed in 75% of these patients. TMS patients were put on supportive treatment and recovered spontaneously. One DS patient with congenital leukaemia went into spontaneous remission and 2 of DS patients with congenital leukaemia responded to chemotherapy while rest of them either died or lost to follow-up. Conclusion: TMS and congenital leukaemia were not very uncommon in the studied population. Majority had Down syndrome. It is important to differentiate their clinical and pathological presentations for proper management. TMS may resolve with supportive treatment while congenital leukaemia is a fatal condition requiring chemotherapy. (author)

  2. Pattern of Leukaemia Patients Admitted in Ayub Teaching Hospital Abbottabad

    International Nuclear Information System (INIS)

    Khan, T. M.

    2016-01-01

    Background: 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. Methods: 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. Results: In our analysis about 16 percent patients had acute myelocytic leukaemia and 32 percent patients had acute lymphocytic leukaemia; while chronic myeloid leukaemia outnumbered chronic lymphocytic leukaemia (11 percent and 3 percent); Hodgkin lymphoma was seen in 18 percent cases while Non Hodgkin lymphoma (NHL) was present in 20 percent cases. Out of the total, 150 cases (75 percent) 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 percent) cases were from the plain areas of Abbottabad and Haripur districts, i.e., 20 and 30 cases respectively. Conclusion: 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. (author)

  3. Childhood leukaemia and socioeconomic status: What is the evidence?

    International Nuclear Information System (INIS)

    Adam, M.; Rebholz, C. E.; Egger, M.; Zwahlen, M.; Kuehni, C. E.

    2008-01-01

    The objectives of this systematic review are to summarise the current literature on socioeconomic status (SES) and the risk of childhood leukaemia, to highlight methodological problems and formulate recommendations for future research. Starting from the systematic review of Poole et al. (Socioeconomic status and childhood leukaemia: a review. Int. J. Epidemiol. 2006;35(2):370-384.), an electronic literature search was performed covering August 2002-April 2008. It showed that (1) the results are heterogeneous, with no clear evidence to support a relation between SES and childhood leukaemia; (2) a number of factors, most importantly selection bias, might explain inconsistencies between studies; (3) there is some support for an association between SES at birth (rather than later in childhood) and childhood leukaemia and (4) if there are any associations, these are weak, limited to the most extreme SES groups (the 10-20% most or least deprived). This makes it unlikely that they would act as strong confounders in research addressing associations between other exposures and childhood leukaemia. Future research should minimise case and control selection bias, distinguish between different SES measures and leukaemia subtypes and consider timing of exposures and cancer outcomes. (authors)

  4. Leukaemia clusters around Sellafield and Dounreay. Dosimetry and epidemiology

    International Nuclear Information System (INIS)

    Wakeford, R.

    2003-01-01

    In 1983, a television programme identified a striking cluster of childhood leukaemia in the coastal village of Seascale, adjacent to the Sellafield nuclear complex in England. Excesses of childhood leukaemia near certain other nuclear installation in Britain were later reported during the 1980s. Detailed radiological investigations demonstrated that radiation exposures from discharged radioactive material were most unlikely to be the cause of these excesses and no serious deficiencies in these assessments have been discovered despite exhaustive searches. In 1990, a report was published suggesting that occupational radiation exposure of men before the conception of their children could be responsible for the Seascale cluster. Extensive research has not supported a causal link between paternal preconceptional radiation dose and childhood leukaemia, and the idea that radiation exposure of fathers materially increases the risk of leukaemia in offspring and could account for the clusters has now effectively been abandoned. In contrast, evidence has mounted that childhood leukaemia has an infectious basis and that unusual population mixing increases the risk of the disease. It now seems that population mixing is the explanation for the excesses of childhood leukaemia near nuclear sites and at other locations with no enhanced exposure to radiation. (orig.) [de

  5. Aberrant Gene Expression in Acute Myeloid Leukaemia

    DEFF Research Database (Denmark)

    Bagger, Frederik Otzen

    genes and genetic signatures and for reducing dimensionally of gene expression data. Next, we have used machine-learning methods to predict survival and to assess important predictors based on these results. General application of a number of these methods has been implemented into two public query......Summary Acute Myeloid Leukaemia (AML) is an aggressive cancer of the bone marrow, affecting formation of blood cells during haematopoiesis. This thesis presents investigation of AML using mRNA gene expression profiles (GEP) of samples extracted from the bone marrow of healthy and diseased subjects....... Here GEPs from purified healthy haematopoietic populations, with different levels of differentiation, form the basis for comparison with diseased samples. We present a mathematical transformation of mRNA microarray data to make it possible to compare AML samples, carrying expanded aberrant...

  6. Minimal residual disease in chronic lymphocytic leukaemia.

    Science.gov (United States)

    García Vela, José Antonio; García Marco, José Antonio

    2018-02-23

    Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  7. Childhood leukaemia around Canadian nuclear facilities. Phase 2

    International Nuclear Information System (INIS)

    Clarke, E.A.; McLaughlin, J.; Anderson, T.W.

    1991-06-01

    Prompted by findings of increased occurrence of childhood leukaemia in the vicinity of some nuclear facilities in the United Kingdom, this study aimed to investigate whether the frequency of leukaemia among children born to mothers living near nuclear facilities in Ontario differed from the provincial average. The Ontario Cancer Registry was used to identify 1894 children aged 0 to 14 years who died from leukaemia between 1950 and 1987, and 1814 children who were diagnosed with leukaemia between 1964 and 1986. Residence at birth and death was obtained from birth and death certificates. Analyses were performed separately for nuclear research and development facilities; uranium mining, milling and refining facilities; and, nuclear generating stations; and for areas within the same county as the facility and 'nearby' - within a 25-km radius of the facility. Risk estimates were calculated as the ratio of the observed (O) number of events over the expected (E) number. In the vicinity of nuclear research and development facilities the rate of leukaemia was less than expected and within the bound of chance variation. In the areas around the uranium mining, milling and refining facilities and nuclear power plants leukaemia occurred slightly more frequently than expected, but due to small frequencies these differences may have arisen due to chance. Large differences between observed and expected rates were not detected around any of the Ontario facilities. This study was large enough to detect excess risks of the magnitude reported in the United Kingdom, but it was not large enough to discriminate between the observed relative risks and a chance finding. Levels of leukaemia detected near nuclear generating stations indicate the need for further investigation. (20 tabs., 15 figs., 32 refs.)

  8. Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Hjalgrim, L L; Madsen, H O; Melbye, M; Jørgensen, P; Christiansen, M; Andersen, M T; Pallisgaard, N; Hokland, P; Clausen, N; Ryder, L P; Schmiegelow, K; Hjalgrim, H

    2002-10-21

    Recent studies have suggested that development of childhood acute lymphoblastic leukaemia may often be initiated in utero. To provide further evidence of an prenatal origin of childhood leukaemia, we conducted a molecular biological investigation of nine children with B-precursor acute lymphoblastic leukaemia carrying the chromosomal translocation t(12;21), the most common subtype of all childhood acute lymphoblastic leukaemia. Specifically, for each child we identified the non-constitutive chromosomal sequences made up by the t(12;21) fusion gene. From these, leukaemia clone-specific DNA primers were constructed and applied in nested polymerase chain reaction analyses of DNA extracted from the patients' Guthrie cards obtained at birth. Leukaemia clone-specific fusion gene regions were demonstrated in Guthrie card DNA of three patients, age 2 years 11 months, 3 years 4 months, and 5 years 8 months at leukaemia diagnosis. Our findings are consistent with previous observations, and thus provide further evidence that the development of t(12;21) B-precursor acute lymphoblastic leukaemia may be initiated in utero. Review of the current literature moreover indicates that age at leukaemia may be inversely correlated with the burden of cells with leukaemia clonal markers, i.e. leukaemia predisposed cells at birth, and that certain types of childhood acute lymphoblastic leukaemia develop as a multiple step process involving both pre- and postnatal genetic events.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  11. The risk of childhood leukaemia near nuclear establishments

    International Nuclear Information System (INIS)

    Stather, J.W.; Clarke, R.H.; Duncan, K.P.

    1988-01-01

    Childhood leukaemia has been reported to be increased in communities living near a number of nuclear sites in the United Kingdom. The National Radiological Protection Board has, over the last three and a half years, published the results of a series of studies giving radiation doses and risks calculated for some of these populations. The studies have all indicated that it is most unlikely that radiation doses arising from releases of radioactive materials into the environment could have contributed to any increase in the leukaemia incidence in local communities. In the absence of any other obvious causative agent, however, there remains some concern that the radiation doses and risks of leukaemia have been underestimated. This report, therefore, summarises the methods used in the analyses by the Board, examines possible sources of uncertainty in the calculations, and considers the extent to which more information is required. (author)

  12. Molecular genetics, natural history and the demise of childhood leukaemia.

    Science.gov (United States)

    Greaves, M

    1999-12-01

    The patterns of genetic change, clonal evolution, natural history and latency are very different in the paediatric leukaemias compared with adult epithelial cancers but are similar to those in other childhood cancers of mesenchymal stem cell origin. This distinction has a biological logic in the context of the selective pressures for clonal emergence in different developmental and cellular contexts and has a major impact on curability. Most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasize without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the 'bad news' genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option.

  13. Antibiotic use from conception to diagnosis of child leukaemia as compared to the background population

    DEFF Research Database (Denmark)

    Gradel, Kim Oren; Kaerlev, Linda

    2015-01-01

    BACKGROUND: 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. PROCEDURE: 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. RESULTS: A total of 120/360 (33.3%) leukaemia mothers and 1...

  14. Imaging findings of upper abdominal involvement by acute megakaryoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Amemiya, Shiori; Akahane, Masaaki; Ohtomo, Kuni [University of Tokyo, Department of Radiology, Graduate School of Medicine, Tokyo (Japan); Takita, Junko; Igarashi, Takashi [University of Tokyo, Department of Paediatrics, Graduate School of Medicine, Tokyo (Japan)

    2008-04-15

    Acute megakaryoblastic leukaemia (AMKL), a relatively rare type of acute myeloid leukaemia, is characterized by frequent involvement of the liver, spleen and lymph nodes in addition to myelofibrosis in children. Diagnosis is difficult both clinically and pathologically, and the hepatic or lymph node involvement is not uncommonly misinterpreted as solid tumour. We report the imaging findings of upper abdominal involvement by AMKL in an infant. The hepatic lesion, initially suspected to be hepatoblastoma, showed a distinctive appearance on MRI suggesting its infiltrative nature. With the association of splenic lesion and lymphadenopathy, the imaging findings were considered indicative of a haematological disorder. (orig.)

  15. The risk of childhood leukaemia near nuclear establishments

    International Nuclear Information System (INIS)

    Fry, F.A.

    1997-01-01

    The author concentrates on an epidemiological investigation on the increased incidence of leukaemia in young people of age 0∼24 years old in the years of 1963∼1992 in Seascale, a Village near the BNFL reprocessing plant at Sellafield on the north-west coast of England. A comparison of this incidence is made with that revealed in regions of other similar nuclear establishments. It has been concluded that the increased incidence of leukaemia in young people in Seascale can not be imputed to any single factor, but interaction between different factor cannot be ruled out

  16. TREATMENT OF PRIMARY PLASMA CELL LEUKAEMIA

    Directory of Open Access Journals (Sweden)

    Peter Černelč

    2003-04-01

    Full Text Available Background. The author describes long-term survival in 3 patients with primary plasma cell leukaemia (PL after different therapeutic regimen and maintenance treatment with interferon alpha (INF.Patients and treatment. In a 52-year-old male patient, a partial remission of PL was achieved after 6 months of treatment with melphalan and prednisone. The patient did not consent to stem cell transplantation (SCT. An 86-year-old female patient with PL achieved a complete remission after 6 months of treatment with vincristine, doxorubicin and dexamethasone. A 31-year-old male patient experienced a complete remission of PL after 6 months of treatment with cyclophosphamide, vincristine, doxorubicin, methilprednisone, followed by autologous SCT. All three patients were placed on maintenance therapy with INF-2b (Intron A 3 × 106 IU given subcutaneously on two days per week. In the 52-year-old man, the remission lasted 9 months and in the woman 23 months, whereupon they developed a relapse with signs of disseminated plasmacytoma. In both patients the former chemotherapy was applied again, resulting in a slight improvement. The man died 37 months and the woman 43 months after the diagnosis of PL, while the youngest patient has been in complete remission for 82 months.Conclusions. Long remission achieved in our patients confirmed the favourable effect of INF in terms of prolongation of the remission duration in this patients. The effect of maintenance treatment with INF is usually directly dependent on the degree of remission induced by different therapeutic regimen.

  17. Environmental factors and leukaemia risks of children: an overview

    International Nuclear Information System (INIS)

    Schuez, Joachim

    2008-01-01

    Leukaemia is the most common malignancy in childhood, with an incidence rate in Germany of 5.5 per 100,000 children aged 0 to 14 years per year. Overall, epidemiological studies suggest a rather minor role of environmental factors in the development of childhood leukaemia. Ionising radiation is the only established risk factor; however, it is currently unclear at which doses effects occur. Low doses from terrestrial exposures or related to living close to a nuclear power plant show weak associations in recent epidemiological studies, but the findings can at present not be explained with mechanistic models from radiation biology. The consistent association observed in epidemiological studies between extremely low-frequency magnetic fields and childhood leukaemia risk also lacks a good explanation and it is still not known whether this observation displays an artefact or a causal link. Some pesticides appear to be carcinogenic in experiments, but the results from epidemiological studies are inconsistent. No substantial risk appears to be related to air pollution from road traffic. Recent research focused on working hypotheses related to patterns of infections, in particular that an isolation from infectious stimulation in infancy leads to an immature immune system reacting inappropriately to later common infections. While children being at day care at an early age appear to have a reduced risk of childhood leukaemia, more work needs to be done to clearly identify the agents involved in a putative mechanism. (orig.)

  18. Cryptic Chromosome Abormalities in Acute Leukaemia: Identification and Detection

    NARCIS (Netherlands)

    L.J.C.M. van Zutven

    2005-01-01

    textabstractSpecific chromosome aberrations are observed in 50% of all new acute leukaemia patients. As a result of chromosome aberrations, genes located at the breakpoints can be disrupted and fusion genes can be formed. In addition, genes can be lost or amplified. An increasing number of these

  19. Therapy related Acute Myeloid Leukaemia 8 Years after Treatment ...

    African Journals Online (AJOL)

    Hodgkin's Disease (HD) is a curable malignancy even in Nigeria, our limitations in health care delivery notwithstanding. However, secondary malignancies especially Acute Myeloid Leukaemia (AML) may occur as late complications following alkylating cytotoxic drugs therapy, with or without radiotherapy. This is a case ...

  20. Complications of lumbar puncture in a child treated for leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Staebler, Melanie; Delpierre, Isabelle; Damry, Nash; Christophe, Catherine [Children' s University Hospital Queen Fabiola, Department of Medical Imaging, Brussels (Belgium); Azzi, Nadira [Children' s University Hospital Queen Fabiola, Haematology-Oncology Unit, Brussels (Belgium); Sekhara, Tayeb [Children' s University Hospital Queen Fabiola, Department of Neurology, Brussels (Belgium)

    2005-11-01

    Lumbar puncture may lead to neurological complications. These include intracranial hypotension, cervical epidural haematomas, and cranial and lumbar subdural haematomas. MRI is the modality of choice to diagnose these complications. This report documents MRI findings of such complications in a child treated for leukaemia. (orig.)

  1. Priapism as an initial presentation of chronic myeloid leukaemia ...

    African Journals Online (AJOL)

    ... the idiopathic types are believed to be associated with an initial prolonged sexual stimulation. Two case reports illustrating the possibility of such cases being the first presentation of myeloproliferative disorder are thus presented. Keywords: Chronic myeloid leukaemia, Priapism, Presentation Sahel Medical Journal Vol.

  2. Incidence of acute lymphoblastic leukaemia in white and coloured ...

    African Journals Online (AJOL)

    Objectives. To record the age-specific incidence rate (ASIR) for diagnosed acute lymphoblastic leukaemia (ALL) in coloured and white children aged 0 - 12 years in the Western Cape (WC). Design. A retrospective population-based study using the 1991 population census to calculate the mean annual childhood population ...

  3. Academic career after treatment for acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Kingma, A; Rammeloo, LAJ; van der Does-van den Berg, A; Rekers-Mombarg, L; Postma, A

    Aim-To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings. Patients-Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at

  4. Oxidative Stress Responses and NRF2 in Human Leukaemia

    Directory of Open Access Journals (Sweden)

    Amina Abdul-Aziz

    2015-01-01

    Full Text Available Oxidative stress as a result of elevated levels of reactive oxygen species (ROS has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2-like 2 (NRF2 transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.

  5. Defective monocyte function in Legionnaires' disease complicating hairy cell leukaemia

    DEFF Research Database (Denmark)

    Nielsen, H; Bangsborg, Jette Marie; Rechnitzer, C

    1986-01-01

    We describe a case of Legionnaires' disease in a 64-year-old man, in which hairy cell leukaemia was diagnosed after the onset of the infection. Immunological studies revealed a complete suppression of blood monocyte chemotactic and oxidative burst activities. We suggest that in hairy cell leukaem...

  6. Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia

    NARCIS (Netherlands)

    Daniels, J. M. A.; Vonk-Noordegraaf, A.; Janssen, J. J. W. M.; Postmus, P. E.; van Altena, R.

    Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are

  7. Complications of lumbar puncture in a child treated for leukaemia

    International Nuclear Information System (INIS)

    Staebler, Melanie; Delpierre, Isabelle; Damry, Nash; Christophe, Catherine; Azzi, Nadira; Sekhara, Tayeb

    2005-01-01

    Lumbar puncture may lead to neurological complications. These include intracranial hypotension, cervical epidural haematomas, and cranial and lumbar subdural haematomas. MRI is the modality of choice to diagnose these complications. This report documents MRI findings of such complications in a child treated for leukaemia. (orig.)

  8. Childhood leukaemia incidence below the age of 5 years near French nuclear power plants

    International Nuclear Information System (INIS)

    Laurier, D; Hemon, D; Clavel, J

    2008-01-01

    A recent study indicated an excess risk of leukaemia among children under the age of 5 years living in the vicinity of nuclear power plants in Germany. We present results relating to the incidence of childhood leukaemia in the vicinity of nuclear power plants in France for the same age range. These results do not indicate an excess risk of leukaemia in young children living near French nuclear power plants. (note)

  9. Dissecting the role of aberrant DNA methylation in human leukaemia.

    Science.gov (United States)

    Amabile, Giovanni; Di Ruscio, Annalisa; Müller, Fabian; Welner, Robert S; Yang, Henry; Ebralidze, Alexander K; Zhang, Hong; Levantini, Elena; Qi, Lihua; Martinelli, Giovanni; Brummelkamp, Thijn; Le Beau, Michelle M; Figueroa, Maria E; Bock, Christoph; Tenen, Daniel G

    2015-05-22

    Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22)(q34;q11.2) encoding for the BCR-ABL fusion oncogene. However, many molecular mechanisms of the disease progression still remain poorly understood. A growing body of evidence suggests that the epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukaemic clone escape and disease propagation. Here we show that, by applying cellular reprogramming to primary CML cells, aberrant DNA methylation contributes to the disease evolution. Importantly, using a BCR-ABL inducible murine model, we demonstrate that a single oncogenic lesion triggers DNA methylation changes, which in turn act as a precipitating event in leukaemia progression.

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

    Science.gov (United States)

    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

  11. Granular acute lymphoblastic leukaemia of childhood: a morphological phenomenon.

    Science.gov (United States)

    Darbyshire, P J; Lilleyman, J S

    1987-01-01

    Three hundred and twenty consecutive children with lymphoblastic leukaemia (ALL), treated on the Medical Research Council UKALL VIII schedule, had their Romanowsky stained diagnostic marrows reviewed for the presence of azurophil granules in blast cell cytoplasm. Twenty patients (7%) had greater than 5% blasts showing this feature; 19 had the cell phenotype of "common ALL." Male children and those with French-American-British (FAB) L2 morphology predominantly showed this feature. There was also a strong correlation between granularity and non-diffuse acid phosphate positivity, but no obvious difference between the 20 patients in their response to treatment emerged during a minimum follow up of 15 months. The "granular" variant occurs in around 7% of children with ALL, but has no clear prognostic importance. Morphologists should be aware of its existence and incidence to avoid confusion with acute myeloid leukaemia. Images p252-a PMID:3470317

  12. High-flow priapism in acute lymphatic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Mentzel, Hans-Joachim; Vogt, Susanna; Kaiser, Werner A. [Institute of Diagnostic and Interventional Radiology, Department of Pediatric Radiology, Friedrich-Schiller-Universitaet Jena, Bachstrasse 18, 07740, Jena (Germany); Kentouche, Karim; Doerfel, Claus; Zintl, Felix [Department of Paediatrics, University of Jena (Germany)

    2004-07-01

    Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. It is associated with excessive hyperleukocytosis (e.g. in acute or chronic leukaemia); however, this complication is rarely seen in the pediatric population. We report a 12-year-old boy suffering from acute leukaemia presenting with, at first intermittent, but increasingly persistent erection. Doppler US revealed signs of high-flow priapism. MRI excluded intrapelvic tumour masses, and three-dimensional contrast-enhanced MR angiography could not demonstrate an arteriovenous fistula or thrombosis. Cavernosal blood-gas measurement was in agreement with high-flow priapism. On the basis of the imaging findings, invasive therapeutic management was avoided in our patient with a successful outcome. (orig.)

  13. Extramedullary Myeloid Cell Tumour Presenting As Leukaemia Cutis

    Directory of Open Access Journals (Sweden)

    Thappa Devinder Mohan

    2002-01-01

    Full Text Available We herewith report a case of extramedullary myeloid cell tumour presenting as leukaemia cutis for its rarity. It occurred in a 50 year old male patient who presented to us with a 40 days history of painless raised solid skin swellings over the trunk. Histopathological examination of the skin biopsy and bone marrow biopsy showed features suggestive of non-Hodgkin’s lymphoma. Immunophenotyping on skin biopsy specimens and bone marrow biopsy found tumour cells expressing CD43 and Tdt but were negative for CD3 and CD20. These features were consistent with extramedullary myeloid cell tumour involving skin and subcutis (cutaneous manifestation of acute myeloid leukaemia.

  14. Molecular processes involved in B cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Malouf, Camille; Ottersbach, Katrin

    2018-02-01

    B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.

  15. Screening microarrays of novel monoclonal antibodies for binding to T-, B- and myeloid leukaemia cells.

    Science.gov (United States)

    Belov, Larissa; Huang, Pauline; Chrisp, Jeremy S; Mulligan, Stephen P; Christopherson, Richard I

    2005-10-20

    We have developed a microarray (DotScan) that enables rapid immunophenotyping and classification of leukaemias and lymphomas by measuring the capture of cells by immobilized dots of 82 CD antibodies [Belov, L., de la Vega, O., dos Remedios, C.G., Mulligan, S.P., 2001. Immunophenotyping of leukemia using a cluster of differentiation antibody microarray. Cancer Res. 61, 4483; Belov, L., Huang, P., Barber, N., Mulligan, S.P., Christopherson, R.I., 2003. Identification of repertoires of surface antigens on leukemias using an antibody microarray. Proteomics 3, 2147]. The DotScan technology has been used to investigate the properties of 498 new antibodies submitted to the HLDA8 Workshop. These antibodies have been applied as 10 nl dots to a film of nitrocellulose on a microscope slide to make an HLDA8 microarray. After blocking the remaining nitrocellulose surface, individual arrays were incubated with each of 7 cell types from a human leukaemia cell panel consisting of three cell lines, CCRF-CEM (a T-cell acute lymphocytic leukaemia), MEC-1 (derived from B-cell chronic lymphocytic leukaemia) and HL-60 (a promyelocytic leukaemia), and four leukaemias from patients: a T-cell prolymphocytic leukaemia, a B-cell chronic lymphocytic leukaemia, and two acute myeloid leukaemias. Leukaemia cells were captured by those immobilized antibodies for which they expressed the corresponding surface molecule. Unbound cells were gently washed off, bound cells were fixed to the arrays and dot patterns were recorded using a DotScan array reader and quantified using DotScan data analysis software. The data obtained show the unique expression profiles of the 7 cell types in the leukaemia cell panel obtained with the DotScan microarray, and the differential capture patterns for these 7 cell types screened against the 498 antibodies in the HLDA8 microarray constructed for this study.

  16. CD19-Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia

    DEFF Research Database (Denmark)

    Lorentzen, C L; thor Straten, Per

    2015-01-01

    Adoptive cell therapy (ACT) for cancer represents a promising new treatment modality. ACT based on the administration of cytotoxic T cells genetically engineered to express a chimeric antigen receptor (CAR) recognizing CD19 expressed by B cell malignancies has been shown to induce complete lasting...... responses in patients with chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL). So far, eleven clinical trials including 99 CLL and ALL patients treated with CAR T cells targeting CD19 have been published, and the results from these trials are promising with impressive clinical...... responses in heavily pretreated patients. Thus, CAR T cell therapy has induced complete responses in both CLL and ALL, and surprisingly, current results indicate that patients with ALL are more prone to respond than are CLL patients. Importantly, the majority of CAR cell studies have observed severe therapy...

  17. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Henriksen, Louise Tram; Nersting, Jacob; Raja, Raheel A

    2014-01-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy...

  18. Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia

    NARCIS (Netherlands)

    Lim, K. H.; Thomas, G.; van Beers, E. J.; Hosman, A. E.; Mourits, M. P.; van Noesel, C. J. M.; Kater, A. P.; Reinartz, S. M.

    2014-01-01

    Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of

  19. Birth weight in offspring and leukaemia risk in parents-A nation-wide register-based cohort study from Denmark

    DEFF Research Database (Denmark)

    Marklund, Maria; Rostgaard, Klaus; Hjalgrim, Lisa

    2013-01-01

    with parental risk of leukaemia overall or of leukaemia subtypes except for a twofold increased acute lymphatic leukaemia risk in fathers of high birth weight offspring and an increasing paternal risk of chronic myeloid leukaemia with increasing offspring birth weight. These may both be chance findings. Our...

  20. Congenital Acute Myeloid Leukaemia with Pseudo-Chediak-Higashi Like Granules: A Case Report.

    Science.gov (United States)

    Puri, Vandana; Barman, Sandip; Sharma, Pooja; Sikka, Meera

    2016-11-01

    Congenital leukaemia is a very rare entity comprising 0.8% of all childhood leukaemias. Pseudo-Chediak-Higashi Anomaly (PCHA) in acute leukaemia is a rarely described entity. However, co-existence of congenital myeloid leukaemia with PCHA is a very rare entity and to the best of our knowledge has not been described in literature till date. A full term new-born presented on the 27 th day of life with severe gastroenteritis. Complete blood counts and peripheral smear examination revealed leucocytosis with presence of 76% blast cells. Approximately 15% of these blast cells showed presence of pseudo-Chediak-Higashi like granules. The diagnosis of acute myeloid leukaemia was confirmed by flow cytometry. The case report is presented due to its rarity and to highlight the differential diagnosis and clinical implications of this entity.

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

    Science.gov (United States)

    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.

  2. Low dose irradiation and risk of leukaemia: A case-control study

    International Nuclear Information System (INIS)

    Chobanova, N.; Bayrakova, A.

    1997-01-01

    The effect of low dose irradiation (medical X-ray diagnostic) on the developing of leukaemias in adults is investigated. The influence of non-radiation agents (occupational exposure to chemical carcinogens, past viral infections, family aggregations) to leukaemias are considered also. During this retrospective study 228 patients have been examined with the following diagnosis: acute myeloid leukaemia, chronic myelogenous leukaemias, myelodisplastic syndrome and non-Hodgkin lymphoma (diagnosed between 1991-1993). Each case has been matched with two controls. Statistically significant increase has been found in the risk of developing leukaemias after X-ray diagnostic irradiation (OR = 1.98, 95% CI = 1.14 ./. 3.46). Exposure to chemical agents is also associated with significant increase in the risk (OR = 1.98, 95% CI = 1.25 ./. 2.86). (author)

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

    Science.gov (United States)

    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.

  4. [Disseminated fusariosis in a patient with acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Hermansen, N.E.; Ralfkiaer, E.M.; Kjeldsen, L.

    2008-01-01

    Invasive mould infections are a major cause of infectious mortality in highly immunosuppressed patients. Incidence in this high risk group is 10-20% with a death rate in excess of 50%. Most invasive moulds are Aspergillus spp. We present a case of a 74-year-old woman with acute lymphoblastic...... leukaemia who developed a rare disseminated mould infection with Fusarium solani during induction chemotherapy. We present the case story and discuss the pathogenesis, clinical characteristics and treatment of invasive fusariosis Udgivelsesdato: 2008/9/8...

  5. Risk factors of childhood leukaemia with a focus on environmental hazards

    International Nuclear Information System (INIS)

    Schuez, J.

    2002-01-01

    Leukaemia is the most common malignancy in childhood. In Germany, there are annually about 620 new cases of childhood leukaemia among 13.2 million children. The causes of most leukaemias are still not known. Previous studies suggested a major role of environmental factors like low doses of ionizing radiation as well as electric and magnetic fields or pesticides. But recent studies contradict these assumptions. While weak associations between such factors and childhood leukaemia can not be ruled out, it can be estimated that they contribute at most to a minor fraction of leukaemias. Since leukaemia incidence is much higher in developed countries and since space-time clustering seems to be established for this disease, hypotheses involving a role of infectious agents have been put forward. Recent studies are suggestive that children with an appropriately modulated immune system have a lower risk of developing a leukaemia during childhood. As international collaborations emerge, it must be an aim that preventive actions are not only wishful thinking. (orig.) [de

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

    Science.gov (United States)

    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.

  7. Late effects of treatment in survivors of childhood acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Roux, P.

    1987-01-01

    The overall aim of this study was a comprehensive assessment of the nature and severity of the late effects of treatment in a group of children surviving acute lymphoblastic leukaemia. In the absence of damage preceding treatment, late effects could be ascribed to treatment. Cranial irradiation, methotrexate, L-asparaginase and cytosine arabinoside are therapeutic modalities most likely to cause injury to the central nervous system. Survivors of childhood leukaemia also showed an increase in weight-for-height during and after therapy which appeared to be the consequence of a loss in statural growth as well as increasing weight-for-age. Assessment of endocrine function in leukaemia survivors indicated abnormalities in the regulation of growth hormone and thyroid stimulating hormone in some patients. Survivors of childhood leukaemia were shown to have an intellectual deficit compared with their siblings and a high incidence of visual-perceptual defects. The intellectual effects of lower doses of cranial irradiation are as yet unknown. A variety of minor neurological abnormalities were detected among leukaemia survivors and thought to be related to preceding central nervous system 'prophylactic' chemotherapy and irradiation. A new instrument, the functional deficit score, was derived to reflect overall outcome in survivors of childhood leukaemia. With few exceptions, leukaemia survivors in this study had received 2400 rads of deep x-ray therapy as cranial irradiation. This dosage has since been reduced world-wide. Current cranial irradiation 'prophylaxis' consists of 1800 rad of megavoltage radiotherapy

  8. Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia.

    Science.gov (United States)

    Tan, Li; Xu, Hongfa; Chen, Guoshu; Wei, Xiaoping; Yu, Baodan; Ye, Jingmei; Xu, Lihua; Tan, Huo

    2018-02-06

    High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown. To reveal the role and mechanism of HMGA2 in differentiation arrest of myeloid leukaemia cells, the quantitative expression of HMGA2 and homeobox A9 (HOXA9) was analysed by real-time PCR (qRT-PCR). The regulatory function of HMGA2 in blockage of differentiation in human myeloid leukaemia was investigated through in vitro assays (XTT assay, May-Grünwald-Giemsa, flow cytometry analysis and western blot). We found that the expression of HMGA2 and HOXA9 was reduced during the process of granulo-monocytic maturation of acute myeloid leukaemia (AML) cells, knockdown of HMGA2 promotes terminal (granulocytic and monocytic) differentiation of myeloid leukaemia primary blasts and cell lines, and HOXA9 was significantly downregulated in leukaemic cells with knockdown of HMGA2. Downregulation of HOXA9 in myeloid leukaemia cells led to increased differentiation capacity in vitro. Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia.

  9. The incidence of and mortality from leukaemias in the UK: a general population-based study

    OpenAIRE

    Bhayat, Fatima; Das-Gupta, Emma; Smith, Chris; McKeever, Tricia; Hubbard, Richard

    2009-01-01

    Abstract Background The acute and chronic leukaemias constitute about 2.5% of all newly diagnosed malignancies and kill over 4000 people/year in the UK, yet there is little accurate up-to-date data on how the incidence of and mortality from leukaemias vary with socio-economic status in the UK. We aimed to quantify the incidence of and mortality from leukaemias in the UK and their variation with gender, age, year of diagnosis as well as socio-economic status. Methods All incident cases of leuk...

  10. IRSN-ANCCLI partnership. Information day: Childhood leukaemia around French nuclear power plants - April 2012

    International Nuclear Information System (INIS)

    Clavel, Jacqueline; Laurier, Dominique; Sommelet, Daniele; Chantal Bardelay

    2012-04-01

    As an epidemiological study performed by the INSERM highlighted an excess of childhood leukaemia within 5 km around nuclear power plants during the 2002-2007 period, this meeting has been organised to discuss this issue. After a presentation of these results, a contribution discusses the context and research perspectives on the relationship between childhood leukaemia and nuclear sites. After the reported debate, a contribution presents the conclusion of a work-group on childhood leukaemia and ASN works, and a last one presents the activities of a work-group gathering the ANCCLI, IRSN and InVS on the health impact of nuclear installations. A debate on these issues is reported

  11. MicroRNAs as Potential Biomarkers in Acute Promyelocytic Leukaemia

    Directory of Open Access Journals (Sweden)

    Imilia Ismail

    2014-01-01

    Full Text Available Acute promyelocytic leukaemia (APL is an M3 subtype of acute myeloid leukaemia (AML. This classification is based on the morphology of promyelocytic cell. The clinical characteristics of APL can be recognized by haemorrhagic episodes, a differentiation block at the promyelocytic stage, and sensitivity to the differentiation response to all-trans-retinoic acid (ATRA. Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the production of PML/RARα fusion protein. Recent studies reported that microRNAs (miRNAs have also been proposed to contribute to the pathogenesis of APL. miRNAs have been associated with the pathogenesis of cancer and their involvement as oncogenic and tumour suppressor activities have been identified. They are involved in various biological processes including the cell proliferation, differentiation, growth and development, metabolism, apoptosis, and haematopoiesis. The new discovery of miRNAs as possible therapeutic markers will provide new insight for the diagnosis and therapeutic entries for the treatment of APL. This review highlights the potential of miRNAs as biomarkers in APL.

  12. Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview.

    Science.gov (United States)

    Manola, Kalliopi N

    2013-10-01

    Acute leukaemia of ambiguous lineage (ALAL) is a rare complex entity with heterogeneous clinical, immunophenotypic, cytogenetic and molecular genetic features and adverse outcome. According to World Health Organization 2008 classification, ALAL encompasses those leukaemias that show no clear evidence of differentiation along a single lineage. The rarity of ALAL and the lack of uniform diagnostic criteria have made it difficult to establish its cytogenetic features, although cytogenetic analysis reveals clonal chromosomal abnormalities in 59-91% of patients. This article focuses on the significance of cytogenetic analysis in ALAL supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow up and treatment selection of ALAL. It reviews in detail the types of chromosomal aberrations, their molecular background, their correlation with immunophenotype and age distribution and their prognostic relevance. It also summarizes some novel chromosome aberrations that have been observed only once. Furthermore, it highlights the ongoing and future research on ALAL in the field of cytogenetics. © 2013 John Wiley & Sons Ltd.

  13. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Wolthers, Benjamin O.; Frandsen, Thomas L.; Baruchel, André

    2017-01-01

    BACKGROUND: 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 pa......BACKGROUND: 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...... of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need...... for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING: The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181)....

  14. Using multistage models to describe radiation-induced leukaemia

    International Nuclear Information System (INIS)

    Little, M.P.; Muirhead, C.R.; Boice, J.D. Jr.; Kleinerman, R.A.

    1995-01-01

    The Armitage-Doll model of carcinogenesis is fitted to data on leukaemia mortality among the Japanese atomic bomb survivors with the DS86 dosimetry and on leukaemia incidence in the International Radiation Study of Cervical Cancer patients. Two different forms of model are fitted: the first postulates up to two radiation-affected stages and the second additionally allows for the presence at birth of a non-trivial population of cells which have already accumulated the first of the mutations leading to malignancy. Among models of the first form, a model with two adjacent radiation-affected stages appears to fit the data better than other models of the first form, including both models with two affected stages in any order and models with only one affected stage. The best fitting model predicts a linear-quadratic dose-response and reductions of relative risk with increasing time after exposure and age at exposure, in agreement with what has previously been observed in the Japanese and cervical cancer data. However, on the whole it does not provide an adequate fit to either dataset. The second form of model appears to provide a rather better fit, but the optimal models have biologically implausible parameters (the number of initiated cells at birth is negative) so that this model must also be regarded as providing an unsatisfactory description of the data. (author)

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

    Science.gov (United States)

    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.

  16. Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis

    Science.gov (United States)

    Williams, Christopher KO; Foroni, Letizia; Luzzatto, Lucio; Saliu, Idris; Levine, Arthur; Greaves, Mel F

    2014-01-01

    Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under-five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt’s lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross’s experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology. PMID:25435906

  17. Host genome variations and risk of infections during induction treatment for childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Wesolowska-Andersen, Agata; Lausen, Birgitte

    2014-01-01

    Objectives: To investigate association of host genomic variation and risk of infections during treatment for childhood acute lymphoblastic leukaemia (ALL). Methods: We explored association of 34 000 singlenucleotide polymorphisms (SNPs) related primarily to pharmacogenomics and immune function...

  18. Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis.

    Science.gov (United States)

    Williams, Christopher Ko; Foroni, Letizia; Luzzatto, Lucio; Saliu, Idris; Levine, Arthur; Greaves, Mel F

    2014-01-01

    Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under-five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt's lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross's experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology.

  19. The incidence of and mortality from leukaemias in the UK: a general population-based study

    Directory of Open Access Journals (Sweden)

    McKeever Tricia

    2009-07-01

    Full Text Available Abstract Background The acute and chronic leukaemias constitute about 2.5% of all newly diagnosed malignancies and kill over 4000 people/year in the UK, yet there is little accurate up-to-date data on how the incidence of and mortality from leukaemias vary with socio-economic status in the UK. We aimed to quantify the incidence of and mortality from leukaemias in the UK and their variation with gender, age, year of diagnosis as well as socio-economic status. Methods All incident cases of leukaemia were identified in 'The Health Improvement Network' (THIN General Practice dataset. Crude incidence rates and incidence rate ratios (using Poisson Regression stratified by age, gender, year of diagnosis and socio-economic status were calculated. Median survival and hazard ratios for risk of death (using Cox regression were then calculated, and stratified in a similar manner. Results A total of 4162 cases of leukaemia were identified, 2314 (56% of whom were male. The overall incidence of leukaemia was 11.25 per 100 000 person-years. The age and gender distributions of ALL, AML, CLL and CML were similar to UK cancer registry data. The incidence of leukaemias was independent of socio-economic class. Median survival from leukaemia was 6.58 years and mortality increased with increasing age at diagnosis. The prognosis in AML was dismal and worsened with increasing socio-economic deprivation. For other leukaemias mortality was independent of socio-economic status. Conclusion This is the first general population study to describe the incidence of and mortality from leukaemias in the UK by socio-economic status. Similar mortality across socio-economic gradients in the leukaemias studied suggests equal access to and uptake of services. The exception to this was in AML, where poorer survival in AML patients from lower socio-economic classes may represent a class bias in treatment offered and/or greater co-morbidity in these patients, and warrants further

  20. Chicken pox and acute monocytic leukaemia skin lesions in an HIV-seropositive man.

    Science.gov (United States)

    De la Salmonière, P; Janier, M; Gilquin, J; Carlotti, A; Sutton, L; Leblond, V; Daniel, F

    1994-11-01

    Lymphoid neoplasia is now well known to occur in patients with human immunodeficiency virus (HIV) infection but the first case of acute monocytic leukaemia in an HIV-seropositive man has been only recently described. We report the case of an HIV-infected patient who simultaneously developed skin lesions of acute monocytic leukaemia and chicken pox. We suggest that HIV may produce a malignant transformation of monocytic cells.

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

    Science.gov (United States)

    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.

  2. A case-control study of risk of leukaemia in relation to mobile phone use.

    Science.gov (United States)

    Cooke, R; Laing, S; Swerdlow, A J

    2010-11-23

    Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted. In a case-control study in South East England to investigate the relation of acute and non-lymphocytic leukaemia risk to mobile phone use, 806 cases with leukaemia incident 2003-2009 at ages 18-59 years (50% of those identified as eligible) and 585 non-blood relatives as controls (provided by 392 cases) were interviewed about mobile phone use and other potentially aetiological variables. No association was found between regular mobile phone use and risk of leukaemia (odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76, 1.46). Analyses of risk in relation to years since first use, lifetime years of use, cumulative number of calls and cumulative hours of use produced no significantly raised risks, and there was no evidence of any trends. A non-significantly raised risk was found in people who first used a phone 15 or more years ago (OR=1.87, 95% CI=0.96, 3.63). Separate analyses of analogue and digital phone use and leukaemia subtype produced similar results to those overall. This study suggests that use of mobile phones does not increase leukaemia risk, although the possibility of an effect after long-term use, while biologically unlikely, remains open.

  3. Leukaemia inhibitory factor--an exercise-induced myokine

    DEFF Research Database (Denmark)

    Broholm, Christa; Pedersen, Bente Klarlund

    2010-01-01

    During and following exercise skeletal muscle synthesises and releases a number of myokines that exert their effects either systemically or locally within the muscle. Several of these myokines influence metabolism, regeneration and/or hypertrophy and are therefore considered to be important...... to oscillations in intracellular Ca2+ concentrations. However, circulating levels of LIF are not increased with exercise suggesting that LIF exerts its effect locally. LIF stimulates muscle satellite cell proliferation and is involved in muscle hypertrophy and regeneration. Thus, LIF may be produced by skeletal...... contributing factors in muscle homeostasis and muscle adaptation to exercise training. Leukaemia inhibitory factor (LIF) is produced and released from muscle cells in vitro and from intact skeletal muscle in vivo. During exercise, skeletal muscle potently up-regulates LIF mRNA expression, likely due...

  4. Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing.

    Science.gov (United States)

    Wakeford, Richard; Darby, Sarah C; Murphy, Michael F G

    2010-05-01

    Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that

  5. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme

    NARCIS (Netherlands)

    van der Helm, Lieke H.; Alhan, Canan; Wijermans, Pierre W.; van Marwijk Kooy, Marinus; Schaafsma, Ron; Biemond, Bart J.; Beeker, Aart; Hoogendoorn, Mels; van Rees, Bastiaan P.; de Weerdt, Okke; Wegman, Jurgen; Libourel, Ward J.; Luykx-de Bakker, Sylvia A.; Minnema, Monique C.; Brouwer, Rolf E.; Croon-de Boer, Fransien; Eefting, Matthijs; Jie, Kon-Siong G.; van de Loosdrecht, Arjan A.; Koedam, Jan; Veeger, Nic J. G. M.; Vellenga, Edo; Huls, Gerwin

    2011-01-01

    The efficacy of azacitidine in the treatment of high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20-30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors

  6. Leukaemia incidence among workers in the shoe and boot manufacturing industry: a case-control study

    Directory of Open Access Journals (Sweden)

    Forand Steven P

    2004-08-01

    Full Text Available Abstract Background Previous reports have indicated an excess of leukaemia in Broome County, New York, particularly in the Town of Union. Surveillance of cancer incidence data indicates that a large proportion of these cases occurred among males ages 65 and older. Shoe and boot manufacturing has been the largest single industry in this area throughout much of the past century. Occupational studies from Europe suggest a link between leukaemia and employment in the shoe and boot manufacturing industry. However, researchers have not found a positive association between leukaemia and employment in the shoe industry among workers in the United States. Methods A matched case-control study was conducted to investigate the association between leukaemia incidence among males 65 and older and employment in the shoe and boot manufacturing industry. Thirty-six cases of leukaemia occurring between 1981–1990; among males age 65 and older; residing in the town of Union met the study case criteria. Death certificates were obtained for each of the cases. These were matched to death certificates of 144 controls on date of death and date of birth +/- 1 year. Death certificates were then examined to determine the employer and occupation of each study subject. Conditional logistic regression was used to determine the risk of leukaemia among those working in the industry. Results The risk of both leukaemia (OR = 1.47; 95% CI 0.70, 3.09 and acute myeloid leukaemia (OR = 1.19; 95% CI 0.33, 4.28 were elevated among those employed in the shoe and boot manufacturing industry, however neither was statistically significant. Conclusion The results, though suggestive of an association between leukaemia and employment in the shoe and boot manufacturing industry, were not statistically conclusive due mainly to limited study power. Several additional limitations may also have prevented the observance of more conclusive findings. Better exposure assessment, information on

  7. Epidemiological studies of leukaemia in children and young adults around nuclear facilities: a critical review

    International Nuclear Information System (INIS)

    2008-01-01

    An epidemiological study published in late 2007 described an increased risk of leukaemia in children under 5 living within 5 kilometres of German nuclear power plants. A great deal of research has been carried out on this subject since the early 1980's. The aim of this report was to provide a synthesis and critical analysis of results related to the risk of leukaemia in children and young adults aged under 25 living close to nuclear facilities. The report is structured in three sections: - a reminder of the main characteristics of childhood leukaemia and a description of the methods used to conduct epidemiological studies; - the most exhaustive review possible of epidemiological studies published in the international literature describing the frequency of leukaemia close to nuclear facilities in different countries around the world. A critical analysis is made of the published results. Some results from studies not focused on nuclear facilities are also presented. The methodological limitations associated with descriptive studies are explained and discussed; - the last section discusses the possible causes of childhood leukaemia and the main hypotheses explored to explain certain clusters of cases observed locally close to some nuclear sites. Appendices at the end of the document provide additional explanations of the concepts and methods used in epidemiology and statistics, and of the classification of malignant hemopathies. (authors)

  8. Risk of childhood leukaemia in the vicinity of nuclear installations: Findings and recent controversies

    International Nuclear Information System (INIS)

    Dominique Laurier; Bernd Grosche; Hall, Per

    2002-01-01

    The identification of a local excess of cancer cases, possibly associated with ionizing radiation, always receives substantial media coverage and communication about clusters is difficult. We reviewed studies that examined the risk of leukaemia among young people near nuclear installations. An excess of leukaemia exists near some nuclear installations, at least for the reprocessing plants at Sellafield and Dounreay and the nuclear power plant Kruemmel. Nonetheless, the results of multi-site studies invalidate the hypothesis of an increased risk of leukaemia related to nuclear discharge. Up until now, analytic studies have not found an explanation for the leukaemia clusters observed near certain nuclear installations. The hypothesis of an infectious aetiology associated with population mixing has been proposed, but needs to be investigated further. The review illustrates two recent examples in France (La Hague reprocessing plant) and in Germany (Kruemmel power plant), where controversies developed after reports of increased leukaemia risks. These examples show the importance of recalling the current epidemiological knowledge and of using systematic recording of cases to replace the alleged excesses in a more general framework. Some elements should also be suggested from the recent French and German experiences to reinforce credibility in the results

  9. Leucocyte classification for leukaemia detection using image processing techniques.

    Science.gov (United States)

    Putzu, Lorenzo; Caocci, Giovanni; Di Ruberto, Cecilia

    2014-11-01

    The counting and classification of blood cells allow for the evaluation and diagnosis of a vast number of diseases. The analysis of white blood cells (WBCs) allows for the detection of acute lymphoblastic leukaemia (ALL), a blood cancer that can be fatal if left untreated. Currently, the morphological analysis of blood cells is performed manually by skilled operators. However, this method has numerous drawbacks, such as slow analysis, non-standard accuracy, and dependences on the operator's skill. Few examples of automated systems that can analyse and classify blood cells have been reported in the literature, and most of these systems are only partially developed. This paper presents a complete and fully automated method for WBC identification and classification using microscopic images. In contrast to other approaches that identify the nuclei first, which are more prominent than other components, the proposed approach isolates the whole leucocyte and then separates the nucleus and cytoplasm. This approach is necessary to analyse each cell component in detail. From each cell component, different features, such as shape, colour and texture, are extracted using a new approach for background pixel removal. This feature set was used to train different classification models in order to determine which one is most suitable for the detection of leukaemia. Using our method, 245 of 267 total leucocytes were properly identified (92% accuracy) from 33 images taken with the same camera and under the same lighting conditions. Performing this evaluation using different classification models allowed us to establish that the support vector machine with a Gaussian radial basis kernel is the most suitable model for the identification of ALL, with an accuracy of 93% and a sensitivity of 98%. Furthermore, we evaluated the goodness of our new feature set, which displayed better performance with each evaluated classification model. The proposed method permits the analysis of blood cells

  10. Metabolic syndrome in the survivors of childhood acute lymphoblastic leukaemia.

    Science.gov (United States)

    Abu-Ouf, Noran M; Jan, Mohammed M

    2015-01-01

    Metabolic syndrome is a common complication encountered in children surviving acute lymphoblastic leukaemia (ALL). Affected patients develop obesity, insulin resistance, hypertension, and hyperlipidemia. Metabolic syndrome is a consequence of multiple factors, particularly hormonal imbalance induced by various ALL treatments. This review aims to evaluate the risk factors and mechanisms leading to the development of metabolic syndrome. Further research is needed to improve our understanding of the mechanisms leading to insulin resistance and the associated endothelial and adipose tissue dysfunction. Future studies should also examine other possible contributing factors, such as environmental and genetic factors. Understanding these factors will help in guiding modifications of the current ALL treatment protocols in order to prevent the development of this syndrome and hence improve the quality of life of ALL survivors. Until this is achieved, clinicians should continue to identify patients at risk early and use a therapeutic approach that combines dietary restrictions and enhanced physical activity. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  11. L-asparaginase induced hyperlipidaemia in acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Nesheli, H. M.; Tamaddoni, A.; Hosseinzadeh, F.; Moghaddam, T. G.

    2013-01-01

    Objective: To evaluate hyperlipidaemia in patients with acute lymphoblastic leukaemia (ALL) receiving L-asparaginase. Methods: A case-control study carried out between October 2007 and October 2010 with 77 patients undergoing chemotherapy at a teaching children hospital in Babol, Iran. Patients were treated with anti-leukaemic agents according to the protocols for standard-risk and high-risk ALL. Those patients who received asparaginase represented the cases and those who did not receive it were the controls. Biochemical markers were checked during the induction phase chemotherapy. Lipid profile of patients was recorded. Data was analysed using SPSS 16. Results: Of the 77 patients, 37 (48.05%) received asparaginase therapy and 40 (51.94%) patients did not. The mean peak triglyceride and cholesterol levels during asparaginase therapy in the first group were significantly higher than the levels in the second group. Conclusion: Severe hyperlipidaemia may be the cause of some morbidity in children receiving asparaginase. Asparaginase-induced hyperlipidaemia should be monitored in ALL patients during the induction phase of treatment. (author)

  12. Current approach to the treatment of chronic myeloid leukaemia.

    Science.gov (United States)

    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.

  13. Clofarabine in the treatment of poor risk acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Krawczyk, Janusz

    2010-09-01

    Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara-C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24-76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17-120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients.

  14. The cribriform plate: a sanctuary site for meningeal leukaemia

    International Nuclear Information System (INIS)

    Williams, M.V.

    1987-01-01

    Cranial irradiation is an effective prophylactic treatment for subclinical meningeal infiltration in lymphoblastic leukaemia, but, central nervous system (CNS) relapse still occurs in 6-10% of cases overall and as many as 30% of cases with a poor prognosis in some series. These recurrences may be due in part to inadvertent underdosage of the cribriform plate, centrally situated between the orbits and projected over their upper third in a lateral view. The dose to the adjacent meninges may thus be reduced by shielding of the radiosensitive lenses. This problem is exacerbated if conventional lateral fields centred on the mid-skull are used, because the eyes will not then project over one another. If the field centre is moved to the edge of the orbit, this problem of beam divergence can be overcome. Central axis beam blocking of both lenses is possible, in some patients the cribriform plate can be adequately irradiated. In most children the geometry of the orbit is such that it is necessary to add an anterior electron beam to ensure homogeneous dosage. These refinements in technique might prevent meningeal relapse with a lower whole-brain dose and, hence, fewer neurophyschological sequelae. (author)

  15. Sudden sensorineural hearing loss as the first manifestation of chronic myeloid leukaemia: case report.

    Science.gov (United States)

    Diao, M; Tian, F; Sun, J

    2014-11-01

    Sudden sensorineural hearing loss rarely occurs in patients with chronic myeloid leukaemia. We present a case report of a patient who presented with sudden sensorineural hearing loss as the first manifestation of chronic myeloid leukaemia, and review the mechanisms responsible for sudden sensorineural hearing loss in leukaemic patients. A 31-year-old female presented to our clinic with unilateral sudden sensorineural hearing loss and tinnitus. Pure tone audiometry revealed profound sensorineural hearing loss in the left ear at all frequencies. During an investigation into her hearing loss, the patient was found to have chronic myeloid leukaemia. Every case of sudden sensorineural hearing loss must be carefully evaluated, and haematological disorders must be considered in the differential diagnosis of sudden hearing loss.

  16. The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia.

    Science.gov (United States)

    Maung, Z T; MacLean, F R; Reid, M M; Pearson, A D; Proctor, S J; Hamilton, P J; Hall, A G

    1994-09-01

    Immunocytochemistry was used to assess bcl-2 expression in blasts obtained from the bone marrow of 28 patients with acute lymphoblastic leukaemia (ALL) (16 children and six adults at presentation and three children and three adults on relapse) and 20 with acute myeloid leukaemia (AML) (19 adults and one child, 13 with de novo AML, 11 at presentation and two on relapse, and seven secondary to myelodysplasia or chronic myeloid leukaemia). Slides were examined both for the percentage of positive cells and for the intensity of staining using a five-point scale. There was a statistically significant increase in both the percentage of positive cells seen (P presentation in ALL. There was a significantly greater intensity of staining in cells from patients with ALL (P important prognostic feature in both de novo AML and in ALL, but not in secondary AML.

  17. Gemtuzumab ozogamicin: an anti-CD33 immunoconjugate for the treatment of acute myeloid leukaemia.

    Science.gov (United States)

    Stasi, Roberto

    2008-04-01

    Gemtuzumab ozogamicin consists of a semisynthetic derivative of calicheamicin, a potent cytotoxic antibiotic, linked to a humanized anti-CD33 monoclonal antibody. To describe the pharmacology of gemtuzumab ozogamicin and to provide an overview of clinical trials in acute myeloid leukaemia. Review and summary of publications on gemtuzumab ozogamicin indexed in the PubMed electronic database. Gemtuzumab ozogamicin has shown moderate activity as a single agent in patients with CD33-positive refractory or relapsed acute myeloid leukaemia, with more promising results in acute promyelocytic leukaemia. The side effect profile may be an improvement on conventional chemotherapy, except for a higher frequency of veno-occlusive disease or sinusoidal obstructive syndrome, especially after a subsequent haematopoietic stem cell transplantation. Because of the different mechanisms of action and non-overlapping toxicities, the integration of this immunoconjugate with standard chemotherapy is a rational approach, and Phase III trials are ongoing both in the induction and in the post-remission settings.

  18. Detection and analysis of tumour biomarkers to strengthen the diagnosis of acute and chronic leukaemias

    Directory of Open Access Journals (Sweden)

    R. Cerón-Maldonado

    2015-04-01

    A panel of molecular markers that included 11 genes derived from chromosomal translocations BCR-ABL major and minor breakpoints, E2A-PBX1, MLL-AF4, TEL-AML1, PML-RARα, AML1-ETO was standardised; cancer testis antigens (CTA derived from NY-ESO1 and MAGE-A3 epigenetic alterations and multi-drug-resistant genes ABCB1 and ABCG2. 30 patients diagnosed with leukaemia from Mexico's General Hospital (Hospital General de Mexico were included. They suffered from acute lymphoblastic leukaemia (ALL and acute myeloblastic leukaemia (AML; bone marrow mononuclear cells were used, from which RNA was extracted for the synthesis of cDNA and RT-PCR for each of the markers. In acute lymphoblastic leukaemia (ALL, BCR-ABL biomarkers expressed under 30% (3/10, E2A-PBX1 10% (1/10, ABC-B1 80% (8/10, and ABC-G2 60% (6/10. Patients with acute myeloblastic leukaemia (AML expressed 30% PML-RARα (3/10, 40% ABC-B1 (4/10, and 10% ABC-G2 (1/10. Lastly, in patients with chronic myeloid leukaemia (CML, BCR-ABL was over 100% (10/10, ABC-B1 20% (2/10, and ABC-G2 50% (5/10. The presence of transcripts from chimeric genes minor BCR-ABL and E2A-PBX1 in ALL; PML-RARα in AML; and major BCR-ABL in CML, confirms the importance that the panel of molecular markers has in strengthening the diagnosis and prognosis of these conditions.

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

    Science.gov (United States)

    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

  20. Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

    International Nuclear Information System (INIS)

    Wakeford, R.

    2008-01-01

    A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant ∼50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy -1 (equivalent to an excess absolute risk coefficient of about 3% Gy -1 ), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia. (authors)

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

    Directory of Open Access Journals (Sweden)

    Morgulis Yuri

    2012-05-01

    Full Text Available Abstract 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.

  2. MR features of isolated uterine relapse in an adolescent with acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Novellas, Sebastien; Fournol, Maude; Geoffray, Anne; Chevallier, Patrick [Regional Hospital Centre and University of Nice, Medical Imaging Service, Archet 2 Hospital, 151 route de Saint Antoine de Ginestiere, B.P. 3079, Nice Cedex 3 (France); Deville, Anne [Regional Hospital Centre and University of Nice, Paediatric Service, Archet 2 Hospital, Nice (France); Kurzenne, Jean-Yves [Regional Hospital Centre and University of Nice, Paediatric Surgery Service, Archet 2 Hospital, Nice (France)

    2008-03-15

    Relapses of lymphoblastic leukaemia traditionally involve the central nervous system and testes in boys. Involvement of the female pelvic organs is frequently found at autopsy; however, involvement of the cervical uterus is rare and even less commonly symptomatic. A 13-cm uterine mass was discovered in a 15-year-old adolescent with a history of lymphoblastic leukaemia during childhood. Pelvic MRI was the best tool to assess the size, characteristics and invasive nature of this lesion of the uterine cervix. To our knowledge, this is a unique case in that we describe the MRI appearance of a relapsing lymphoblastic leukaemic mass both before and after treatment. (orig.)

  3. Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q.

    LENUS (Irish Health Repository)

    Kelly, Kevin

    2008-12-01

    Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.

  4. Florid radiological appearance of megakaryoblastic leukaemia - an aid to earlier diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Moody, A.; Shaw, D.; Simpson, E.

    1989-07-01

    Accurate diagnosis of leukaemia is essential to enable appropriate treatment. The diagnosis is made by cytological and cytochemical techniques but radiology may, however, serve a very useful role in first suggesting a diagnosis. We present here four cases of megakaryoblastic leukaemia (AML FAB classification M7), three of which have strikingly similar unusual radiological changes. A review of the literature suggests this condition has previously been diagnosed as acute or malignant myelofibrosis, and the megakaryoblastic nature of the disease was not recognised. The presence of these radiological features may therefore prompt specific immunocytochemical testing, in a disease that is otherwise difficult to diagnose early. (orig.).

  5. Epidemiological patterns of leukaemia in 184 countries: a population-based study.

    Science.gov (United States)

    Miranda-Filho, Adalberto; Piñeros, Marion; Ferlay, Jacques; Soerjomataram, Isabelle; Monnereau, Alain; Bray, Freddie

    2018-01-01

    Leukaemia is a heterogeneous group of haemopoietic cancers that comprises a number of diverse and biologically distinct subgroups. We examine the leukaemia burden worldwide and highlight the distinct incidence patterns in order to elucidate explanatory factors that may support preventive measures and health resource planning. We aimed to estimate the global burden of leukaemia incidence according to the four major subtypes stratified by age and sex. In this population-based study, we assessed leukaemia incidence for the major subtypes using the Cancer Incidence in Five Continents Volume X (CI5-X), which includes data from 290 cancer registries in 68 countries covering the diagnostic period 2003-07, for all ages and both sexes. We then extracted counts and incidence rates in 184 countries for the year 2012 from IARC's GLOBOCAN database of national estimates. We calculated age-specific incidence rates per 100 000 person-years and age-standardised rates (ASRs) using the world standard population by country, sex, age group, and where applicable, by major subtypes. We excluded from all analyses registries for which the total number of leukaemia cases was less than 100 or the proportion of microscopically verified (MV%) cases was less than 80% (2572 cases). 717 863 cases between 2003-07 were included in this analysis. More than 350 000 new leukaemia cases were estimated in 2012. We observed substantial variation in incidence between and within world regions. The highest leukaemia incidence rates for both sexes were estimated in Australia and New Zealand (ASR per 100 000 11·3 in males and 7·2 in females), Northern America (10·5 in males and 7·2 in females), and western Europe (9·6 in males and 6·0 in females), and the lowest was in in western Africa (1·4 in males and 1·2 in females). Rates were generally higher in males than females with an overall male to female ratio of 1·4. In children, acute lymphoblastic leukaemia was the main subtype in all studied

  6. Splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia

    International Nuclear Information System (INIS)

    Gratwohl, A.; Hermans, J.; Biezen, A.V.

    1996-01-01

    A total of 229 patients with chronic myeloid leukaemia (CML) in chronic phase were randomized between 1986 and 1990 to receive or not receive additional splenic irradiation as part of their conditioning prior to bone marrow transplantation (BMT). Both groups, 115 patients with and 114 patients without splenic irradiation, were very similar regarding distribution of age, sex, donor/recipient sex combination, conditioning, graft-versus-host disease (GvHD) prevention method and blood counts at diagnosis or prior to transplant. 135 patients (59%) are alive as of October 1995 with a minimum follow-up of 5 years. 52 patients have relapsed (23%), 26 patients in the irradiated, 26 patients in the non-irradiated group (n.s.) with a relapse incident at 6 years of 28%. The main risk factor for relapse was T-cell depletion as the method for GvHD prevention, and an elevated basophil count in the peripheral blood prior to transplant. Relapse incidence between patients with or without splenic irradiation was no different in patients at high risk for relapse, e.g. patients transplanted with T-cell-depleted marrows (P = n.s.) and in patients with low risk for relapse, e.g. patients transplanted with non-T-cell-depleted transplants and basophil counts 3% basophils in peripheral blood). In this patient group, relapse incidence was 11% at 6 years with splenic irradiation but 32% in the non-irradiated group (P = 0.05). Transplant-related mortality was similar whether patients received splenic irradiation or not. This study suggests an advantage in splenic irradiation prior to transplantation for CML in this subgroup of patients and illustrates the need for tailored therapy. (Author)

  7. Radiation-induced acute myeloid leukaemia in mice

    Energy Technology Data Exchange (ETDEWEB)

    Bouffler, S.D.; Silver, A.R.J.; Cox, R. [National Radiological Protection Board, Chilton (United Kingdom)

    2000-07-01

    Ample epidemiological studies of human populations implicate ionizing radiation as a carcinogen and these quantitative studies provide the foundation for the core estimates of radiation cancer risk. The majority of the epidemiological data originate from situations of radiation exposure at high dose and high dose rate. The relevance of risk estimates based on such exposures to the more commonly encountered low dose and dose rate situation has been questioned frequently. Thus, there is a need to investigate and quantitate low dose and dose rate effects. A number of approaches may be considered, for example, very large scale epidemiology, very large scale animal experimentation; however, both of these present problems of a practical and/or ethical nature. A further possible approach is that of mechanistic modelling. This requires a fairly detailed understanding of neoplastic disease and how it develops post-irradiation. Many factors and variables have to be taken into consideration in mechanistic modelling approaches. Testing of mechanistic modelling schemes is best carried out using animal model systems. Acute myeloid leukaemia (AML) is a radiogenic cancer of significance in man and several good mouse models of the disease are available. Here, recent studies conducted at NRPB with the aim of elucidating the post-irradiation development of AML will be discussed. In particular three areas critical for developing a sound mechanistic model will be covered, definition of the initiating event; study of disease progression, this addresses the question of the frequency of conversion of initiated cells into the neoplastic state and the influence of genetic background on leukaemogenesis. (author)

  8. Translating microarray data for diagnostic testing in childhood leukaemia

    International Nuclear Information System (INIS)

    Hoffmann, Katrin; Firth, Martin J; Beesley, Alex H; Klerk, Nicholas H de; Kees, Ursula R

    2006-01-01

    Recent findings from microarray studies have raised the prospect of a standardized diagnostic gene expression platform to enhance accurate diagnosis and risk stratification in paediatric acute lymphoblastic leukaemia (ALL). However, the robustness as well as the format for such a diagnostic test remains to be determined. As a step towards clinical application of these findings, we have systematically analyzed a published ALL microarray data set using Robust Multi-array Analysis (RMA) and Random Forest (RF). We examined published microarray data from 104 ALL patients specimens, that represent six different subgroups defined by cytogenetic features and immunophenotypes. Using the decision-tree based supervised learning algorithm Random Forest (RF), we determined a small set of genes for optimal subgroup distinction and subsequently validated their predictive power in an independent patient cohort. We achieved very high overall ALL subgroup prediction accuracies of about 98%, and were able to verify the robustness of these genes in an independent panel of 68 specimens obtained from a different institution and processed in a different laboratory. Our study established that the selection of discriminating genes is strongly dependent on the analysis method. This may have profound implications for clinical use, particularly when the classifier is reduced to a small set of genes. We have demonstrated that as few as 26 genes yield accurate class prediction and importantly, almost 70% of these genes have not been previously identified as essential for class distinction of the six ALL subgroups. Our finding supports the feasibility of qRT-PCR technology for standardized diagnostic testing in paediatric ALL and should, in conjunction with conventional cytogenetics lead to a more accurate classification of the disease. In addition, we have demonstrated that microarray findings from one study can be confirmed in an independent study, using an entirely independent patient cohort

  9. Childhood vaccinations and risk of acute lymphoblastic leukaemia in children.

    Science.gov (United States)

    Søegaard, Signe Holst; Rostgaard, Klaus; Schmiegelow, Kjeld; Kamper-Jørgensen, Mads; Hargreave, Marie; Hjalgrim, Henrik; Hviid, Anders

    2017-06-01

    It has been proposed that childhood vaccinations protect against acute lymphoblastic leukaemia (ALL) in children by modulation of future responses to common infections in childhood. However, the available studies provide inconsistent findings, and population-based cohort studies with longitudinal information on vaccinations are lacking. In a register-based cohort of all children born in Denmark from 1 January 1990 to 31 December 2008, followed up until age 15 years or 31 December 2009 ( n  = 1 225 404), we evaluated exposure to childhood vaccination and risk of childhood ALL, including information on ALL subtypes. Using Cox regression, we estimated hazard ratios (HRs) comparing vaccinated with unvaccinated children. Childhood ALL was diagnosed in 490 children during 10 829 194 person-years of follow-up. Neither the total number of vaccine doses received nor exposure to each vaccination given in childhood was associated with altered risk of ALL, including the following: (i) Haemophilus influenzae type b [HR, 1.04; 95% confidence interval (CI), 0.68-1.61]; ii) measles, mumps and rubella (HR, 1.01; 95% CI, 0.76-1.34); iii) whole-cell pertussis (HR, 1.10; 95% CI, 0.51-2.39); and iv) diphtheria, tetanus and inactivated polio (HR, 1.14; 95% CI, 0.42-3.13). Analyses conducted according to ALL subtypes defined by immunopheno- and karyotypes showed no association with childhood vaccination. This nationwide cohort study provides no support of the proposed protective effect of childhood vaccination against childhood ALL. © The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

  10. Mutational analysis of Bax and Bcl-2 in childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Salomons, G. S.; Buitenhuis, C. K.; Martínez Muñoz, C.; Verwijs-Jassen, M.; Behrendt, H.; Zsiros, J.; Smets, L. A.

    1998-01-01

    In childhood acute lymphoblastic leukaemia there are large interpatient variations in levels of the apoptosis-regulating proteins Bax and Bcl-2, but the molecular basis for this variation is unknown. Point-mutations in bax have been reported in cell lines derived from haematological malignancies.

  11. Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Mortensen, B T; Jensen, P O; Helledie, N

    1998-01-01

    The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....

  12. Studies on the role of RNA tumour viruses in human leukaemia

    International Nuclear Information System (INIS)

    Nooter, K.

    1979-01-01

    A search has been made for an etiological role of retroviruses in human leukemia and cocultivation studies have led to the isolation of a presumed human type C virus which appeared to be oncogenic for experimental animals. The experimental procedures and results are fully discussed. The parallels between irradiation induced lymphomas in mice and leukaemias in man are explored. (C.F.)

  13. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

    NARCIS (Netherlands)

    Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana; Blume, Carolin; Sellner, Leopold; Jauch, Anna; Sill, Martin; Kater, Arnon P.; te Raa, G. Doreen; Geisler, Christian; van Oers, Marinus; Dietrich, Sascha; Dreger, Peter; Ho, Anthony D.; Paruzynski, Anna; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno; Zenz, Thorsten

    2013-01-01

    Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were

  14. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana

    2013-01-01

    Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were...

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

    Science.gov (United States)

    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.

  16. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Åsberg, Ann; Heyman, Mats

    2011-01-01

    BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92...... towards patients at risk. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc....

  17. Feasibility of neuropsychological assessment in leukaemia patients shortly after diagnosis: directions for future prospective research

    NARCIS (Netherlands)

    Jansen, NC; Kingma, A; Tellegen, P; van Dommelen, RI; Bouma, A; Veerman, A; Kamps, WA

    Aims: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. Methods: Fifty consecutive patients (median age at testing 6.6

  18. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood

    NARCIS (Netherlands)

    van Dongen, JJM; Seriu, T; Panzer-Grumayer, ER; Biondi, A; Pongers-Willemse, MJ; Corral, L; Stolz, F; Schrappe, M; Masera, G; Kamps, WA; Gadner, H; van Wering, ER; Ludwig, WD; Basso, G; de Bruijn, MAC; Cazzaniga, G; Hettinger, A; van der Does-van den Berg, A; Hop, WCJ; Riehm, H; Bartram, CR

    1998-01-01

    Background Sensitive techniques for detection of minimal residual disease (MRD) at degrees of one leukaemic cell per 10(3)-10(6) cells (10(-3)-10(-6)) during follow-up of children with acute lymphoblastic leukaemia (ALL) can provide insight into the effectiveness of cytotoxic treatment. However, it

  19. Cases of leukaemia in the Sellafield area: the ''Sir Douglas Black'' report

    International Nuclear Information System (INIS)

    Dousset, M.; Jammet, H.

    1984-01-01

    The report of this Advisory Group was published in the summer of 1984. Its conclusions can be summarised as follows: 1. Epidemiological surveys, although still incomplete, show that the incidence of cases of leukaemia and deaths caused by leukaemia in persons under 25 years of age is ''unusual'' in the village of Seascale and the Millom rural district. However, they are not unique and the same phenomenon can be found in comparable population groups located far away from any nuclear plants. 2. Taking all children born Seascale since 1950 who lived in the village up until 1980, their equivalent dose in the red marrow of the bone caused by Sellafield nuclear waste and the Windscale reactor fire of 1957 is only 13% of the equivalent dose due to background radiation. 3. The excessive leukaemia mortality rate at Seascale cannot be explained by radioactive waste. For this, a factor of 40 to 400 would be necessary. However, since doubts remain with respect to Sellafield nuclear waste, it must be temporarily concluded that the hypothesis of a connexion between the proximity of the nuclear plant and the excessive leukaemia rate cannot be fully eliminated. But neither can it be easily proven. The advisory Group recommendations are relating to: the surveys to be carried on; the inspection to be improved around the Sellafield plant; the incumbent regulations to be taken into consideration [fr

  20. Triple immunofluorescence staining for prediction of relapse in childhood precursor B acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Vervoordeldonk, S. F.; Merle, P. A.; Behrendt, H.; Steenbergen, E. J.; van Leeuwen, E. F.; van den Berg, H.; von dem Borne, A. E.; van der Schoot, C. E.; Slaper-Cortenbach, I. C.

    1996-01-01

    In this study we describe a fast and sensitive method using three-colour immunofluorescence for the detection of cells with phenotypes that are rare in normal bone marrow (BM) but occur frequently in children with precursor B acute lymphoblastic leukaemia. We show that, in the first year after

  1. Autoimmune diseases, infections, use of antibiotics and the risk of acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Østgård, Lene S G; Nørgaard, Mette; Pedersen, Lars

    2018-01-01

    Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case-control study that included...

  2. Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture.

    Science.gov (United States)

    Conte, N; Varela, I; Grove, C; Manes, N; Yusa, K; Moreno, T; Segonds-Pichon, A; Bench, A; Gudgin, E; Herman, B; Bolli, N; Ellis, P; Haddad, D; Costeas, P; Rad, R; Scott, M; Huntly, B; Bradley, A; Vassiliou, G S

    2013-09-01

    Advances in sequencing technologies are giving unprecedented insights into the spectrum of somatic mutations underlying acute myeloid leukaemia with a normal karyotype (AML-NK). It is clear that the prognosis of individual patients is strongly influenced by the combination of mutations in their leukaemia and that many leukaemias are composed of multiple subclones, with differential susceptibilities to treatment. Here, we describe a method, employing targeted capture coupled with next-generation sequencing and tailored bioinformatic analysis, for the simultaneous study of 24 genes recurrently mutated in AML-NK. Mutational analysis was performed using open source software and an in-house script (Mutation Identification and Analysis Software), which identified dominant clone mutations with 100% specificity. In each of seven cases of AML-NK studied, we identified and verified mutations in 2-4 genes in the main leukaemic clone. Additionally, high sequencing depth enabled us to identify putative subclonal mutations and detect leukaemia-specific mutations in DNA from remission marrow. Finally, we used normalised read depths to detect copy number changes and identified and subsequently verified a tandem duplication of exons 2-9 of MLL and at least one deletion involving PTEN. This methodology reliably detects sequence and copy number mutations, and can thus greatly facilitate the classification, clinical research, diagnosis and management of AML-NK.

  3. An analysis of prognostic variables in acute lymphocytic leukaemia in a heterogenous South African population

    NARCIS (Netherlands)

    Hesseling, PB; Buurman, M; Oud, C; Nel, ED

    The records of all 96 children below the age of 15 years diagnosed with acute lymphoblastic leukaemia at Tygerberg Hospital in the Republic of South African between 1983 and 1995 were reviewed to determine risk factors which may predict poor outcome. Age <2 and > 8 years, and white cell count >20 x

  4. Childhood leukaemia in Europe after Chernobyl: Five year follow-up of cancer registry populations

    International Nuclear Information System (INIS)

    Parkin, D.M.; Black, R.J.; Kramarova, E.; Clayton, D.

    1997-01-01

    The European Childhood Leukaemia-Lymphoma Incidence Study (ECLIS) aims to monitor trends in the incidence of these diseases in European populations in relation to estimated exposures to radioactive material released at the time of the Chernobyl accident. Thirty-six cancer registries in 23 countries are collaborating in ECLIS, coordinated by the International Agency for Research on Cancer (IARC). 3 figs, 3 tabs

  5. Experience with alemtuzumab in treatment of chronic lymphocytic leukaemia in the Netherlands.

    NARCIS (Netherlands)

    Laros, B.A.P. van; Huisman, C.A.; Wijermans, P.W.; Schipperus, M.R.

    2007-01-01

    BACKGROUND: Alemtuzumab (MabCampath) is a monoclonal antibody against CD52, indicated as third-line treatment of chronic lymphocytic leukaemia (CLL). As most important side effect opportunistic infections are mentioned. It is, however, unknown whether these complications often lead to problems in

  6. Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.

    Science.gov (United States)

    Crowell, Helena L; MacLean, Adam L; Stumpf, Michael P H

    2016-07-21

    Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that - somewhat paradoxically - within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    NARCIS (Netherlands)

    Law, Philip J; Berndt, Sonja I.; Speedy, Helen E; Camp, Nicola J; Sava, Georgina P; Skibola, Christine F.; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R; Clot, Guillem; Teras, Lauren R.; Quintela, Inés; Birmann, Brenda M.; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R.; Hall, Andrew G; Purdue, Mark P.; Mainou-Fowler, Tryfonia; Vajdic, Claire M.; Jackson, Graham H; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G.; Lawrence, Charles; Call, Timothy G.; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W. Ryan; Link, Brian K.; Conde, Lucia; Bracci, Paige M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C H; Southey, Melissa C.; Milne, Roger L; Clavel, Jacqueline; Topka, Sabine; Spinelli, John; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M; Harris, Robert J; Miligi, Lucia; Pettitt, Andrew R; North, Kari E.; Allsup, David J; Fraumeni, Joseph F.; Bailey, James R; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J.; Fegan, Chris; Rosenquist, Richard; De Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J S; Catovsky, Daniel; Campo, Elias; Cerhan, James R.; Allan, James M; Rothman, Nathanial; Houlston, Richard S; Slager, Susan L.

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling

  8. Periodic acid Schiff reaction in childhood lymphoblastic leukaemia. The Medical Research Council Working Party on Childhood Leukaemia.

    Science.gov (United States)

    Lilleyman, J S; Britton, J A; Anderson, L M; Richards, S M; Bailey, C C; Chessells, J M

    1994-01-01

    AIMS--To assess the prevalence and degree of periodic acid Schiff (PAS) positivity in blast cells from children with lymphoblastic leukaemia (ALL); its association with other disease characteristics; and its clinical importance in predicting the outcome of treatment. METHODS--Marrow slides from entrants to a large United Kingdom multicentre ALL trial (UKALL X) were batch processed and assessed blind for PAS positivity by one morphologist. Patients were classified into groups A, B, and C, corresponding to less than 1% PAS positive cells, 1-10%, and over 10%, respectively. Their PAS pattern was then compared with other clinical and pathological features of ALL and with treatment outcome. RESULTS--Slides from 921 children were examined of which 371 (40%) were categorised as group A, 324 (35%) as group B, and 226 (25%) as group C. There was a clear association between the presence of blast cell vacuoles on Romanowsky staining and PAS positivity. Group A (PAS negative) patients included a disproportionate excess of those with L2 morphology, those under 2 or over 6 years of age, those with an initial white cell count over 50 x 10(9)/l, those with a T or null cell immunophenotype, and those with chromosomal abnormalities other than "high hyperdiploidy". Four years from diagnosis, group C patients had an 8% disease free survival advantage over those in group A (2p = 0.01). This was irrespective of initial white cell count, but not of immunophenotype or the presence of vacuoles. CONCLUSIONS--Strong PAS positivity is a feature of "common" ALL and is particularly associated with blast cell vacuoles. It does occasionally occur in other disease subtypes with or without vacuoles. It predicts a better response to current treatment, but not independently of other cell characteristics. Images PMID:7962616

  9. Occupational exposure of fathers to ionizing radiation and the risk of leukaemia in offspring

    International Nuclear Information System (INIS)

    McLaughlin, J.R.; Clarke, E.A.; Anderson, T.W.; King, W.

    1992-08-01

    An epidemiologic study was performed to determine whether there was an association between childhood leukaemia and the occupational exposure of fathers in the nuclear industry to ionizing radiation prior to the child's conception. The study employed a case-control design. Children with cancer ('cases') and children who did not develop cancer ('controls') were compared with respect to their exposure history. The cases, which occurred from 1950 to 1988, consisted of children aged 0 to 14 years who died from or were diagnosed with leukaemia and were born to mothers who lived near an operating nuclear facility in Ontario. Eight controls were matched to each case according to date of birth and mother's residence. There were 112 cases and 890 controls (six controls died before the development of the associated case's leukaemia). Data on the occupational exposure of the 1002 fathers were obtained from the Canadian National Dose Registry (NDR) and examination of employer records. Links to the NDR were found for 95 fathers. For each father doses were obtained regarding whole body external dose, tritium dose, and (for uranium miners) internal exposures to the lungs due to radon and radon daughters. Radiation exposures were estimated (a) over the father's lifetime before the child's conception; (b) during the six months prior to the child's conception; (c) during the three months prior to the child's conception; and (d) over the father's lifetime, ending in the month of the child's diagnosis. There was no evidence of an elevated leukaemia risk in relation to any exposure period or exposure type, and there was no apparent gradient of effect with increasing radiation dose. It is concluded that there was no association between childhood leukaemia and the occupational exposure of fathers to ionizing radiation prior to conception or diagnosis. Odds ratios were close to 1.0 for all radiation dose categories and occupations except for uranium mining, which had a larger but not

  10. 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

    OpenAIRE

    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

    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. O...

  11. Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

    OpenAIRE

    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...

  12. Molecular evidence for a common leukaemic progenitor in acute mixed lymphoid and myeloid leukaemia.

    Science.gov (United States)

    Lim, S H; Culligan, D; Couzens, S; Fisher, J; John, S; Pollard, P; Burnett, A; Whittaker, J

    1996-01-01

    De novo acute leukaemia presenting with a mixed lymphoid and myeloid leukaemic population has rarely been described. We have used the consensus Ig heavy chain primers and DNA isolated from these two distinct populations of cells in polymerase chain reactions. We demonstrated that both populations of cells exhibited Ig heavy chain gene rearrangements. Cloning and subsequent DNA sequencing of the amplified products showed a common V-D-J junctional nucleotide sequence. This work therefore provides the first evidence that the leukaemic cells in de novo acute leukaemia with a mixed lymphoid and myeloid population are derived from a common progenitor clone and may offer an explanation for the poor prognosis in these patients.

  13. Chronic myelogenous leukaemia with persistent neutrophilia, eosinophilia and basophilia in a cat.

    Science.gov (United States)

    Mochizuki, Hiroyuki; Seki, Takahiro; Nakahara, Yoshitaka; Tomita, Akitada; Takahashi, Masashi; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2014-06-01

    Chronic myelogenous leukaemia was diagnosed in a 7-year-old male neutered domestic shorthair cat. Leukocytosis (74,900/µl)--mature neutrophilia, eosinophilia and basophilia--was observed. Bone marrow aspiration revealed hypercellularity with proliferation of cells of myeloid lineage. An underlying condition leading to leukocytosis was not identified. The severe leukocytosis did not respond to antibiotic therapy. Based on these findings, chronic myelogenous leukaemia was diagnosed. Because of the absence of clinical signs, the cat was monitored without treatment until 7 months after diagnosis, when it developed pruritic skin lesions. Pruritus was controlled with oral prednisolone. Forty-two months after diagnosis, the cat developed nasal lymphoma, which was treated with radiation therapy, resulting in complete remission. The cat was still in good physical condition 63 months after diagnosis, despite the persistence of marked neutrophilia, eosinophilia and basophilia. © ISFM and AAFP 2013.

  14. Epidemiological studies of leukaemia in children and young adults around nuclear facilities: A critical review

    International Nuclear Information System (INIS)

    Laurier, D.; Jacob, S.; Bernier, M. O.; Leuraud, K.; Metz, C.; Samson, E.; Laloi, P.

    2008-01-01

    The existence of an increased risk of childhood leukaemia near nuclear installations is a recurrent issue. A review of the related epidemiological literature is presented here. Results for 198 nuclear sites throughout 10 countries were included in the review. In addition to local studies, 25 multi-site studies have been published for eight countries. A large variability was noticed in the quality of the data as well as in the definition of the study population and in the methods of analysis. Many studies present important limits that make the results difficult to interpret. The review confirms that some clusters of childhood leukaemia cases exist locally. However, results based on multi-site studies around nuclear installations do not indicate an increased risk globally. Many studies were launched to investigate possible origins of the observed clusters around specific sites, but up to now, none of the proposed hypotheses have explained them. (authors)

  15. Successful treatment of acute promyelocytic leukaemia without chemotherapy and blood transfusion

    DEFF Research Database (Denmark)

    Tøstesen, Michael; Østgård, Lene S G; Kjeldsen, Eigil

    2018-01-01

    Untreated acute promyelocytic leukaemia (APL) is a rapidly lethal blood cancer. Conventional treatment consists of all-trans retinoic acid and chemotherapy. Standard chemo-therapy-containing treatments necessitate the use of blood products. This is a case report of typical APL in a 32-year-old fe......-old female patient, who due to religious conviction refused supportive therapy with blood products. A treatment regimen consisting of all-trans retinoic acid and arsenic trioxide was successful without the use of blood transfusions.......Untreated acute promyelocytic leukaemia (APL) is a rapidly lethal blood cancer. Conventional treatment consists of all-trans retinoic acid and chemotherapy. Standard chemo-therapy-containing treatments necessitate the use of blood products. This is a case report of typical APL in a 32-year...

  16. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes

    DEFF Research Database (Denmark)

    Schmiegelow, K.

    2016-01-01

    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...

  17. The relevance of population mixing to the aetiology of childhood leukaemia

    International Nuclear Information System (INIS)

    Kinlen, L.J.

    1989-01-01

    It is postulated that childhood leukaemia represents a rare response to some unidentified common infection(s), epidemics of which would be encouraged by mixing of populations with plausibly different previous experiences of infective agents. This has been tested in two studies, the first in the only rural local authority district of Scotland moderately separated from a conurbation that received a large influx of people in the 1950s; the second concerned those new towns in Britain designated by 1950 situated away from the major conurbations of London and Glasgow. In both, highly significant excesses of leukaemia at ages 0-4 were observed, suggesting that it originates in some form of infective process and in one that is favoured by certain types of population mixing. Strong reasons would be required for supposing that this effect did not operate near nuclear reprocessing sites, so unusual is the population mixing associated with them. (author)

  18. Isochromosome 9q as a sole anomaly in an Omani boy with acute lymphoblastic leukaemia

    Science.gov (United States)

    Achandira, Udayakumar Muthappa; Pathare, Anil V; Kindi, Salam Al; Dennison, David; Yahyaee, Said Al

    2009-01-01

    This report describes a case of acute lymphoblastic leukaemia in which isochromosome 9q (i(9q)) was the sole acquired cytogenetic abnormality. The Immunophenotype showed positivity for CD3, CD4, CD5, CD7, CD8, CD10, CD71, CD117 and TdT, consistent with T cell acute lymphoblastic leukaemia (ALL). The chromosomal analysis of bone marrow showed 46,XY,i(9)(q10) in all the metaphases analysed. The bone marrow morphology was ALL-L2 as per the French–American–British criteria. Isochromosomes are rare chromosomal abnormalities in childhood ALL and the effect of i(9q) is not well established. The patient’s good response to therapy with normal cytogenetics within a month of induction, and disease-free survival after bone marrow transplant are indicative of a good prognosis in such cases. PMID:21686579

  19. Conditions for gene transfection into the HL-60 human leukaemia cell line by electroporation

    Czech Academy of Sciences Publication Activity Database

    Pacherník, Jiří; Janík, Robert; Hofmanová, Jiřina; Bryja, Vítězslav; Kozubík, Alois

    2002-01-01

    Roč. 48, č. 4 (2002), s. 154-156 ISSN 0015-5500 R&D Projects: GA ČR GA524/99/0694; GA AV ČR IBS5004009; GA AV ČR KSK5011112 Institutional research plan: CEZ:AV0Z5004920 Keywords : leukaemia cell line HL-60 * electroporation * gene transfection Subject RIV: BO - Biophysics Impact factor: 0.615, year: 2002

  20. Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells

    Czech Academy of Sciences Publication Activity Database

    Kaplánek, R.; Jakubek, M.; Rak, J.; Kejik, Z.; Havlík, M.; Dolenský, B.; Frydrych, I.; Hajduch, M.; Kolář, M.; Bogdanová, K.; Králová, Jarmila; Dzubak, P.; Král, V.

    2015-01-01

    Roč. 60, Jun (2015), s. 19-29 ISSN 0045-2068 Grant - others:GA MŠk(CZ) EE2.3.30.0060; GA MŠk CZ.1.07/2.3.00/30.0041; GA MŠk(CZ) LO1304 Program:EE; LD Institutional support: RVO:68378050 Keywords : Anticancer agents * Cancer treatment * Caffeine -hydrazones * Leukaemia * Selectivity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.252, year: 2015

  1. Effect of Anacardium occidentale leaf extract on human acute lymphoblastic leukaemia cell lines.

    Science.gov (United States)

    Santos, Janaína M; Cury, Nathalia M; Yunes, José A; López, Jorge A; Hernández-Macedo, Maria L

    2018-01-16

    Anacardium occidentale leaves are used in folk medicine due its therapeutic properties attributed to phenolic compounds. Therefore, this study was undertaken on its hydroethanolic leaf extract (AoHE) to evaluate cytotoxicity and apoptosis induction on acute lymphoblastic leukaemia cells. Results indicated that AoHE interfered in the cell cycle progression, inducing apoptosis by activation of casp3 at lower concentrations, thence, a promising candidate for the development of new cancer drugs.

  2. Leukaemia following childhood radiation exposure in the Japanese atomic bomb survivors and in medically exposed groups

    International Nuclear Information System (INIS)

    Little, M. P.

    2008-01-01

    Incidence and mortality risks of radiation-associated leukaemia are surveyed in the Japanese atomic bomb (A-bomb) survivors exposed in early childhood and in utero. Leukaemia incidence and mortality risks are also surveyed in 16 other studies of persons who received appreciable doses of ionizing radiation in the course of treatment in childhood and for whom there is adequate dosimetry and cancer incidence or mortality follow-up. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The relative risks in the medical studies tend to diminish with increasing average therapy dose. After taking account of cell sterilisation and dose fractionation, the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilisation largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Excess absolute risk has also been assessed in four studies, and there is found to be more variability in this measure than in excess relative risk. In particular, there is a substantial difference between the absolute risk in the Japanese atomic bomb survivor data and those in three other (European) populations. In summary, the relative risks of leukaemia in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions in childhood are generally less than those in the Japanese A-bomb survivor data. The effects of cell sterilisation can largely explain the discrepancy between the Japanese and the medical series. (authors)

  3. Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Karlsson, Lene; Forestier, Erik; Hasle, Henrik

    2017-01-01

    Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children rel...... receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML....

  4. Effects of epigenetic-based anti-cancer drugs in leukaemia and multiple myeloma cells

    Czech Academy of Sciences Publication Activity Database

    Jugová, Alžbeta; Galiová-Šustáčková, Gabriela; Legartová, Soňa; Stixová, Lenka; Kozubek, Stanislav; Bártová, Eva

    2011-01-01

    Roč. 35, č. 12 (2011), 1195-1203 ISSN 1065-6995 R&D Projects: GA MŠk(CZ) LC06027; GA MŠk(CZ) ME 919; GA ČR(CZ) GAP302/10/1022; GA MŠk(CZ) LD11020 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : epigenetics * histone code * leukaemia cells Subject RIV: BO - Biophysics Impact factor: 1.482, year: 2011

  5. Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

    OpenAIRE

    Flores-Lujano, J; Perez-Saldivar, M L; Fuentes-Panan?, E M; Gorodezky, C; Bernaldez-Rios, R; Del Campo-Martinez, M A; Martinez-Avalos, A; Medina-Sanson, A; Paredes-Aguilera, R; De Diego-Flores Chapa, J; Bolea-Murga, V; Rodriguez-Zepeda, M C; Rivera-Luna, R; Palomo-Colli, M A; Romero-Guzman, L

    2009-01-01

    Background: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. Methods: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in childre...

  6. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia.

    Science.gov (United States)

    Loh, Mignon L

    2011-03-01

    Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Expansion of myeloid blasts with suppression of normal haematopoiesis is the hallmark of AML, whereas MPN is associated with over-proliferation of one or more lineages that retain the capacity to differentiate, and MDS is characterized by cytopenias and aberrant differentiation. MPD and MDS can progress to AML, which is likely due to the acquisition of cooperative mutations. Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap MPN/MDS by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukaemia, a similar disease in adults. While the current standard of care for patients with JMML relies on allogeneic haematopoietic stem cell transplant (HSCT), relapse is the most frequent cause of treatment failure. This review outlines our understanding of the genetic underpinnings of JMML with a recent update on the discovery of novel CBL mutations, as well as a brief review on current therapeutic approaches. © 2011 Blackwell Publishing Ltd.

  7. Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells.

    Science.gov (United States)

    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.

  8. Negative trends for in utero Chernobyl exposure and early childhood leukaemia in Western Germany

    International Nuclear Information System (INIS)

    Burkart, W.; Steiner, M.; Grosche, B.; Kaletsch, U.; Michaelis, J.

    1997-01-01

    A recent report in Nature linked increased incidence of early infant leukaemia in Greece with 137 Cs fallout density, attributing the effect to an increased in utero exposure to ionizing radiation from the Chernobyl accident. As a validation exercise in a similarly affected region, we performed an analysis based on the data of the Childhood Cancer Registry for Western Germany. Using the same definitions as Petridou et al. we also observed an increased incidence of infant leukaemia in a cohort of children who were born after the Chernobyl accident. More detailed analyses of embryonic/foetal doses regarding areas of different contamination levels and dose rate gradients with time since the accident showed non-significant negative trends with exposure. Therefore, we conclude that the observed effect was not caused by exposure to ionizing radiation due to the Chernobyl accident. Dosimetric considerations per se, based on careful assessment of in utero doses in three different exposure categories, show doses much too small relative to natural radiation exposures to account for a significant effect on leukaemia rates. (author)

  9. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia.

    Directory of Open Access Journals (Sweden)

    Amanda Dixon-McIver

    2008-05-01

    Full Text Available Acute myeloid leukaemia (AML is the most common acute leukaemia in adults; however, the genetic aetiology of the disease is not yet fully understood. A quantitative expression profile analysis of 157 mature miRNAs was performed on 100 AML patients representing the spectrum of known karyotypes common in AML. The principle observation reported here is that AMLs bearing a t(15;17 translocation had a distinctive signature throughout the whole set of genes, including the up regulation of a subset of miRNAs located in the human 14q32 imprinted domain. The set included miR-127, miR-154, miR-154*, miR-299, miR-323, miR-368, and miR-370. Furthermore, specific subsets of miRNAs were identified that provided molecular signatures characteristic of the major translocation-mediated gene fusion events in AML. Analysis of variance showed the significant deregulation of 33 miRNAs across the leukaemic set with respect to bone marrow from healthy donors. Fluorescent in situ hybridisation analysis using miRNA-specific locked nucleic acid (LNA probes on cryopreserved patient cells confirmed the results obtained by real-time PCR. This study, conducted on about a fifth of the miRNAs currently reported in the Sanger database (microrna.sanger.ac.uk, demonstrates the potential for using miRNA expression to sub-classify cancer and suggests a role in the aetiology of leukaemia.

  10. Spatial variation of natural radiation and childhood leukaemia incidence in Great Britain

    International Nuclear Information System (INIS)

    Richardson, Sylvia; Monfort, Christine; Green, Martyn; Muirhead, Colin; Draper, Gerald

    1995-01-01

    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. (author)

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

    LENUS (Irish Health Repository)

    Oshea, J

    2012-02-03

    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.

  12. Cytotoxicity of purified listeriolysin O on mouse and human leukocytes and leukaemia cells.

    Science.gov (United States)

    Stachowiak, Radosław; Łyżniak, Marcin; Grabowska, Maja; Roeske, Katarzyna; Jagielski, Tomasz; Bielecki, Jacek; Budziszewska, Bożena K; Hoser, Grażyna; Kawiak, Jerzy

    2014-08-18

    Listeriolysin O (LLO) is the main virulence factor of Listeria monocytogenes and facilitates the intracellular survival of the pathogen. Some of its characteristics endorse the growing popularity of LLO for use in biotechnology, particularly in the development of novel vaccines. Here, we evaluate the use of LLO to eradicate leukaemia cells. A purified LLO preparation was obtained by affinity chromatography. The LLO preparation procedure was optimized and purified LLO was tested for optimal conditions of storage including temperature, application of proteinase inhibitors and serum components. We demonstrated the possibility of regulating LLO activity by adjusting cell membrane cholesterol content. The LLO preparation had haemolytic activity and had a cytotoxic effect on the human T-leukaemia Jurkat cell line as well as mouse and human peripheral blood mononuclear cells. LLO has a very potent cytotoxic activity towards human leukocytes. Importantly, the cytotoxic activity was easily regulated in vitro and could be restricted to areas containing malignant cells, raising the possibility of future clinical application of LLO for leukaemia treatment.

  13. Childhood Leukaemia Incidence in Hungary, 1973-2002. Interpolation Model for Analysing the Possible Effects of the Chernobyl Accident

    International Nuclear Information System (INIS)

    Toeroek, Szabolcs; Borgulya, Gabor; Lobmayer, Peter; Jakab, Zsuzsanna; Schuler, Dezsoe; Fekete, Gyoergy

    2005-01-01

    The incidence of childhood leukaemia in Hungary has yet to be reported, although data are available since the early 70s. The Hungarian data therefore cover the time before and after the Chernobyl nuclear accident (1986). The aim of this study was to assess the effects of the Chernobyl accident on childhood leukaemia incidence in Hungary. A population-based study was carried out using data of the National Paediatric Cancer Registry of Hungary from 1973 to 2002. The total number of cases was 2204. To test the effect of the Chernobyl accident the authors applied a new approach called 'Hypothesized Impact Period Interpolation'-model, which takes into account the increasing trend of childhood leukaemia incidence and the hypothesized exposure and latency times. The incidence of leukaemia in the age group 0-14 varied between 33.2 and 39.4 per million person-years along the observed 30 year period, and the incidence of childhood leukaemia showed a moderate increase of 0.71% annually (p=0.0105). In the period of the hypothesized impact of the Chernobyl accident the incidence rate was elevated by 2.5% (95% CI: -8.1%; +14.3%), but this change was not statistically significant (p=0.663). The age standardised incidence, the age distribution, the gender ratio, and the magnitude of increasing trend of childhood leukaemia incidence in Hungary were similar to other European countries. Applying the presented interpolation method the authors did not find a statistically significant increase in the leukaemia incidence in the period of the hypothesized impact of the Chernobyl accident

  14. In vivo expansion of the endogenous B-cell compartment stimulated by radiation and serial bone marrow transplantation induces B-cell leukaemia in mice.

    Science.gov (United States)

    Holyoake, T L; Freshney, M G; Samuel, K; Ansell, J; Watson, G E; Wright, E G; Graham, G J; Pragnell, I B

    2001-07-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells. This B-cell lineage is established during ontogeny and replenished by the process of self-renewal. Spontaneous and induced leukaemias that frequently affect this lineage are thought to arise as a result of the frequent cell division required to maintain the population throughout adulthood and in response to repeated exposure to environmental antigens. In a series of bone marrow transplant (BMT) experiments performed in B6D2F1 mice, B-cell leukaemia occurred in recipients of serially transplanted syngeneic bone marrow. This study was therefore designed to determine the frequency and phenotype of the observed leukaemia. Male donor cells were initially transplanted into lethally irradiated female hosts and secondary (2 degrees ) BMT was performed at 3 months. At 1, 2, 3 and 16 months following primary (1 degrees ) BMT, and when 2 degrees BMT recipients developed leukaemia, animals were sacrificed and their tissues extensively examined. These analyses confirmed a host-derived CD5(+) transplantable B-cell leukaemia that was initiated in 50% of 1 degrees BMT recipients. With serial passage, the leukaemia became more aggressive and lost CD5 expression, suggesting transformation to a high-grade leukaemia/lymphoma. This previously unreported observation suggests that the combination of radiation and subsequent serial transplantation induces a proliferative stress to the host B-cell compartment that is causative in leukaemic transformation.

  15. Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.

    NARCIS (Netherlands)

    Rao, A.; Hills, R.K.; Stiller, C.; Gibson, B.E.; Graaf, S.S.N. de; Hann, I.M.; O'Marcaigh, A.; Wheatley, K.; Webb, D.K.

    2006-01-01

    Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience

  16. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

    DEFF Research Database (Denmark)

    Grövdal, Michael; Karimi, Mohsen; Khan, Rasheed

    2010-01-01

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction...

  17. Antibodies to HTLV-I in Nigerian blood-donors, their relatives and patients with leukaemias, lymphomas and other diseases.

    Science.gov (United States)

    Fleming, A F; Maharajan, R; Abraham, M; Kulkarni, A G; Bhusnurmath, S R; Okpara, R A; Williams, E; Akinsete, I; Schneider, J; Bayer, H

    1986-12-15

    Antibodies to HTLV-I have been detected in sera from 15 (2.0%) of 736 adult blood-donors in Nigeria, in 4 (20.0%) of 20 patients with chronic lymphatic leukaemia, 3 (10.0%) of 30 with non-Hodgkin's lymphoma, one of 12 with Burkitt's lymphoma and one of 7 with acute lymphoblastic leukaemia. The frequency of positivity was higher (3.6%) in the blood-donors from the guinea and wooded savanna of northern Nigeria than in those from the rain-forest and mangrove swamps of southern Nigeria (1.8% in Lagos and 0.7% in Calabar). Two of the 3 seropositive patients with lymphoma had clinical presentation and courses similar to those of Japanese and Caribbean patients with adult T-cell leukaemia/lymphoma.

  18. A review of epidemiological studies concerning leukaemia and lymphoma among young people and the genetic effects of ionizing radiation

    International Nuclear Information System (INIS)

    Rose, K.S.B.

    1994-01-01

    The review seeks to identify consistent patterns of results between 30 epidemiological studies of low dose parental exposure to radiation and leukaemia etc. in their offspring. Eight of the studies show significant increases in leukaemia but most are unreliable because they have flawed methodologies and several analyse the same basic data. Two studies free from major criticism do show an association with parental irradiation but both contain data from Seascale and are not independent. Two well conducted studies based on other areas (Canada and Scotland) are claimed by their authors to have sufficient statistical power to test the Seascale findings and do not confirm an association with paternal irradiation. It is concluded that there is little reliable evidence from epidemiological studies for a causal association between pre-conception, paternal or maternal, irradiation and an increase in the frequency of leukaemia or malignancies among offspring. (author)

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

    Science.gov (United States)

    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.

  20. Report of the Social Minister of Lower Saxony on the mortality rate due to leukaemia in Lower Saxony

    International Nuclear Information System (INIS)

    Anon.

    1980-01-01

    The mortality rate due to malignant neoplasms as well as due to leukaemia in children under the age of 15 in the various administrative districts of Lower Saxony is independent of the existence of nuclear facilities there or in the direct vicinity. In the population as a whole, the well-known age dependence was observed. In the administrative district of Emsland, where the Lingen nuclear power plant was operated until January 1977, the number of children is markedly higher than the Lower Saxony average, mortality due to leukaemia and malignant growths was significantly lower than average. For this reason, a higher incidence of leukaemia and malignant growths due to the operation of Lingen nuclear power plant and other nuclear facilities can be excluded. (orig./HP) [de

  1. Rapidly progressing, fatal and acute promyelocytic leukaemia that initially manifested as a painful third molar: a case report

    Directory of Open Access Journals (Sweden)

    Suárez-Cuenca Juan A

    2009-11-01

    Full Text Available Abstract Introduction Acute promyelocytic leukaemia, an uncommon and devastating subtype of leukaemia, is highly prevalent in Latin American populations. The disease may be detected by a dentist since oral signs are often the initial manifestation. However, despite several cases describing oral manifestations of acute promyelocytic leukaemia and genetic analysis, reports of acute promyelocytic leukaemia in Hispanic populations are scarce. The identification of third molar pain as an initial clinical manifestation is also uncommon. This is the first known case involving these particular features. Case presentation A 24-year-old Latin American man without relevant antecedents consulted a dentist for pain in his third molar. After two dental extractions, the patient experienced increased pain, poor healing, jaw enlargement and bleeding. A physical examination later revealed that the patient had pallor, jaw enlargement, ecchymoses and gingival haemorrhage. Laboratory findings showed pancytopaenia, delayed coagulation times, hypoalbuminaemia and elevated lactate dehydrogenase. Splenomegaly was detected on ultrasonography. Peripheral blood and bone marrow analyses revealed a hypercellular infiltrate of atypical promyelocytic cells. Cytogenetic analysis showing genetic translocation t(15;17 further confirmed acute promyelocytic leukaemia. Despite early chemotherapy, the patient died within one week due to intracranial bleeding secondary to disseminated intravascular coagulation. Conclusion The description of this unusual presentation of acute promyelocytic leukaemia, the diagnostic difficulties and the fatal outcome are particularly directed toward dental surgery practitioners to emphasise the importance of clinical assessment and preoperative evaluation as a minimal clinically-oriented routine. This case may also be of particular interest to haematologists, since the patient's cytogenetic analysis, clinical course and therapeutic response are well

  2. Functional exhaustion of CD4+T cells induced by co-stimulatory signals from myeloid leukaemia cells.

    Science.gov (United States)

    Ozkazanc, Didem; Yoyen-Ermis, Digdem; Tavukcuoglu, Ece; Buyukasik, Yahya; Esendagli, Gunes

    2016-12-01

    To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T-cell exhaustion. T-cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co-stimulatory molecules to T-cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia-derived co-stimulatory signals on CD4 + T helper (Th) cell exhaustion, which may limit anti-tumour immunity. Here, CD86 and inducible T-cell co-stimulator ligand (ICOS-LG) co-stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co-cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro-generated exhausted Th cells were defined by up-regulation of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitory receptors. They were reluctant to proliferate upon re-stimulation and produced reduced amounts of interleukin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Nonetheless, IL-2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co-stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD-1, TIM-3 and/or LAG3 was identified together with CD86 + and/or ICOS-LG + myeloid blasts. Collectively, co-stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells. © 2016 John Wiley & Sons Ltd.

  3. Forced recombination of psi-modified murine leukaemia virus-based vectors with murine leukaemia-like and VL30 murine endogenous retroviruses

    DEFF Research Database (Denmark)

    Mikkelsen, J G; Lund, Anders Henrik; Duch, M

    1999-01-01

    -impaired Akv-MLV-derived vectors, we here examine putative genetic interactions between vector RNAs and copackaged endogenous retroviral RNAs of the murine leukaemia virus (MLV) and VL30 retroelement families. We show (i) that MLV recombination is not blocked by nonhomology within the 5' untranslated region....... We note that recombination-based rescue of primer binding site knock-out retroviral vectors may constitute a sensitive assay to register putative genetic interactions involving endogenous retroviral RNAs present in cells of various species.......Co-encapsidation of retroviral RNAs into virus particles allows for the generation of recombinant proviruses through events of template switching during reverse transcription. By use of a forced recombination system based on recombinational rescue of replication- defective primer binding site...

  4. Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells

    International Nuclear Information System (INIS)

    Friesen, Claudia; Lubatschofski, Annelie; Debatin, Klaus-Michael; Kotzerke, Joerg; Buchmann, Inga; Reske, Sven N.

    2003-01-01

    Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-x L , a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies. (orig.)

  5. Self-Esteem and Academic Difficulties in Preadolescents and Adolescents Healed from Paediatric Leukaemia.

    Science.gov (United States)

    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.

  6. Acute myeloid leukaemia presenting as bilateral proptosis in a young child

    Directory of Open Access Journals (Sweden)

    Charudutt Kalamkar

    2016-06-01

    Full Text Available Myeloid sarcoma is an extramedullary manifestation of acute myeloid leukaemia (AML. Aims We are reporting a paediatric case presenting with bilateral proptosis, which we were able to diagnose with peripheral blood smear (PBS examination. Methods Case Report Results This case highlights the utility of simple routinely available PBS test in diagnosing this rare disease. Conclusion Our case highlights the importance of haemogram and peripheral blood smear in the initial evaluation of proptosis. Correct diagnosis of this rare entity is vital especially in cases where (myeloid sarcoma MS is the presenting feature of AML.

  7. Competitive PCR for quantification of minimal residual disease in acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Nyvold, C; Madsen, H O; Ryder, L P

    2000-01-01

    A very precise and reproducible polymerase chain reaction (PCR) method was developed in order to quantify minimal residual disease (MRD) in children with acute lymphoblastic leukaemia (ALL). A clone-specific competitor was constructed by introducing a restriction site in a PCR product identical...... under identical conditions. After restriction enzyme cleavage, the PCR products originating from the competitor and the malignant clone can be distinguished by size in a gel electrophoresis step and the amount of residual disease can be determined. The method is very sensitive with a detection limit...

  8. Thapsigargin-induced nuclear calcium signals in rat basophilic leukaemia cells.

    OpenAIRE

    Horikoshi, Y; Furuno, T; Teshima, R; Sawada, J; Nakanishi, M

    1994-01-01

    By a confocal fluorescence microscope with an argon-ion laser (488 nm) and a He-Cd laser (325 nm) we have studied thapsigargin-induced calcium signals in individual rat basophilic leukaemia (RBL-2H3) cells. In the presence or absence of external calcium ions, thapsigargin-induced calcium signals were transferred to the nucleus as well as to the cytoplasm of RBL-2H3 cells. The calcium signals were generally much stronger in the nucleus than in the cytoplasm. However, some of the RBL-2H3 cells ...

  9. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma

    DEFF Research Database (Denmark)

    Nysom, K; Holm, K; Hesse, B

    1996-01-01

    Longitudinal data were analysed on the lung function of 25 of 29 survivors of childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide and total body irradiation before allogeneic bone marrow transplantation, to test whether children are particularly vulnerable to pulmonary...... significantly reduced transfer factor, total lung capacity, and forced vital capacity (-1.0, -1.2, and -0.8 SD score, respectively), and increased ratio of forced expiratory volume in one second to forced vital capacity (+0.9 SD score). None of the patients had pulmonary symptoms, and changes were unrelated...

  10. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    OpenAIRE

    Law, P. J.; Berndt, S. I.; Speedy, H. E.; Camp, N. J.; Sava, G. P.; Skibola, C. F.; Holroyd, A.; Joseph, V.; Sunter, N. J.; Nieters, A.; Bea, S.; Monnereau, A.; Martin-Garcia, D.; Goldin, L. R.; Clot, G.

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10(-13)), 1q42.13 (rs41271473, P=1.06 × 10(-10)), 4q24 (rs71597109, P=1.37 × 10(-10)), 4q3...

  11. Immunological and molecular biological identification of a true case of T-hairy cell leukaemia

    DEFF Research Database (Denmark)

    Demeter, J; Pálóczi, K; Földi, J

    1990-01-01

    A hairy cell leukaemia (HCL) patient is presented in whom the peripheral blood mononuclear cells (PBMCs) carried suppressor T-cell markers (CD3+, CD2+, CD8+/CD4-, CD38+). Analysis of genomic DNA of PBMNC showed the presence of a monoclonal population of T cells, the T-cell receptor (TCR) beta......-chain gene being rearranged on both alleles (DR/DR), while the immunoglobulin (Ig) heavy chain-genes were in germline configuration. The neoplastic cells were found to react with the monoclonal antibody RAB-1 - originally described as belonging to the B lineage-restricted monoclonal antibodies - and to carry...

  12. Antiglycine receptor-related stiff limb syndrome in a patient with chronic lymphocytic leukaemia.

    Science.gov (United States)

    Derksen, Angelika; Stettner, Mark; Stöcker, Winfried; Seitz, Rüdiger J

    2013-05-20

    We report a 61-year-old man presenting with rapidly progressive stiffness and painful muscle spasms in the lower extremity muscles. The patient was diagnosed with chronic lymphocytic leukaemia (CLL) approximately a year before symptom onset. Electromyography displayed continuous motor unit activity and immunocytochemistry showed a positive staining for antiglycine receptor (anti-GlyR) antibodies. The clinical course was complicated by autonomic instability and cardiac arrest, but stabilised under continuous therapy with plasma exchange and symptomatic treatment with baclofen and clonazepam. Anti-GlyR antibodies induce rare, but severe, variants of stiff person syndrome that can be of paraneoplastic origin and life threatening due to autonomic dysfunction.

  13. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Åsberg, Ann; Heyman, Mats

    2011-01-01

    BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92.......2%), and the overall subsequent risk of induction death and death in first complete remission (CR1) was 1.2% and 1.8%, respectively. Infections were the major cause of death comprising 72% of all cases including 9 deaths from Pseudomonas aeruginosa and 11 deaths from fungal infections. Other causes of death included...

  14. The effect of gamma radiation and neocarzinostatin on NAD and ATP levels in mouse leukaemia cells

    International Nuclear Information System (INIS)

    Goodwin, P.M.; Lewis, P.J.; Davies, M.I.; Skidmore, C.J.; Shall, S.

    1978-01-01

    When mouse leukaemia cells are treated with γ-radiation or neocarzinostatin the intracelluiar NAD and ATP levels fall rapidly. It is shown that the ATP response is a consequence of the decreased NAD level. It is suggested that this low NAD level results in decreased glycolytic activity and that there is a subsequent accumulation of phosphorylated sugars associated with the fall in ATP. Under these extreme conditions, therefore, the NAD level probably regulates the rate of glycolysis in cells which are utilising a rapidly metabolisable sugar as their energy source. (Auth.)

  15. [Dasatinib. A novel tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia

    DEFF Research Database (Denmark)

    Dufva, I.H.; Stentoft, J.; Hasselbalch, H.C.

    2008-01-01

    Chronic myeloid leukaemia is characterized by an abnormal tyrosin kinase in the cytoplasm of the clonal cells. The enzyme is derived from a fusion gene on the Philadelphia-chromosome, evolved by a translocation between chromosomes 9 and 22. Understanding the biology of the tyrosin kinase led to t...... to targeted therapy, inhibiting the ATP-binding site by a small molecule--imatinib (Glivec). A novel 2nd generation tyrosin kinase inhibitor--dasatinib (Sprycel)--is now available in cases of insufficient response or intolerance to imatinib Udgivelsesdato: 2008/1/28...

  16. Chronic Lymphocytic Leukaemia/ Small-Cell Lymphocytic Lymphoma of the Lacrimal Sac: A Case Series.

    Science.gov (United States)

    Krishna, Yamini; Irion, Luciane D; Karim, Sozan; Dharmsena, Aruna; McCormick, Austin; Coupland, Sarah E

    2017-09-01

    Lymphomas of the lacrimal sac are rare, accounting for less than 10% of lacrimal sac malignant tumours. They may present with symptoms typical of secondary acquired nasolacrimal duct obstruction and are thus often misdiagnosed. Case series and literature review. Herein we describe 3 cases of chronic lymphocytic leukaemia (CLL)/small-cell lymphocytic lymphoma (SLL) of the lacrimal sac with immunohistochemical and in 1 case molecular confirmation. Lymphomas of the lacrimal sac should be suspected in patients with known CLL presenting with epiphora and dacryocystitis. During dacryocystorhinostomy, an incisional biopsy of the lacrimal sac is essential for confirming CLL/SLL involvement and may guide treatment.

  17. Research on potential radiation risks in areas with nuclear power plants in Japan: leukaemia and malignant lymphoma mortality between 1972 and 1997 in 100 selected municipalities

    International Nuclear Information System (INIS)

    Yoshimoto, Yasuhiko; Yoshinaga, Shinji; Yamamoto, Kazuhide; Fijimoto, Kenzo; Nishizawa, Kanae; Sasaki, Yasuhito

    2004-01-01

    The results of a geographical correlation study using Poisson regression analysis are reported for leukaemia and malignant lymphoma mortality between 1972 and 1997 in 100 selected Japanese municipalities with or without a nuclear power plant (NPP). The data did not support social concerns of an increased risk of malignant lymphoma in the vicinity of Japanese NPPs. However, some estimates of overall excess relative risk (ERR; relative risk minus one) were statistically significantly positive for leukaemia mortality in 20 NPP municipalities compared with mortality in the remaining 80 control areas, taking into account a minimum two-year latency following the start of commercial operation. One estimate was 0.228 (95% CI: 0.074-0.404) from a simple area adjustment using the mortality in all Japan as the external baseline rate. This superficial increase is not due to leukaemia among young people, aged less than 25 years at death. The ERR estimate for ages at death of 50-74 years was confounded to be positive for leukaemia and distorted to be negative for malignant lymphoma. For leukaemia, a positive ERR estimate was seen, especially for females and during specific periods. Confounding of the ERR estimate for two causes was also seen in some NPP areas including a high adult T-cell leukaemia (ATL) area. Temporal area variations associated with ATL misclassification and a temporal increasing trend of leukaemia mortality in the elderly caused the confounding effects. Our findings do not support the hypothesis of a leukaemogenic impact of NPPs in Japan

  18. Updated estimates of the proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionising radiation

    International Nuclear Information System (INIS)

    Little, Mark P; Wakeford, Richard; Kendall, Gerald M

    2009-01-01

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionising radiation, such as was experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily upon studies of the Japanese A-bomb survivors imply that low-level exposure to ionising radiation, including to ubiquitous natural background radiation, also raises the risk of childhood leukaemia. In a recent paper (Wakeford et al 2009 Leukaemia 23 770-6) we estimated the proportion of childhood leukaemia incidence in Great Britain attributable to natural background radiation to be about 20%. In this paper we employ the two sets of published leukaemia risk models used previously, but use recently published revised estimates of natural background radiation doses received by the red bone marrow of British children to update the previous results. Using the newer dosimetry we calculate that the best estimate of the proportion of cases of childhood leukaemia in Great Britain predicted to be attributable to this source of exposure is 15-20%, although the uncertainty associated with certain stages in the calculation (e.g. the nature of the transfer of risk between populations and the pertinent dose received from naturally occurring alpha-particle-emitting radionuclides) is significant. The slightly lower attributable proportions compared with those previously derived by Wakeford et al (Leukaemia 2009 23 770-6) are largely due to the lower doses (and in particular lower high LET doses) for the first year of life.

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

    Science.gov (United States)

    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.

  20. Childhood leukaemia in the West Berkshire and Basingstoke and North Hampshire District Health Authorities in relation to nuclear establishments in the vicinity

    International Nuclear Information System (INIS)

    Roman, Eve; Beral, Valerie; Carpenter, Lucy; Watson, Ann; Barton, Carol; Ryder, Hilary; Aston, D.L.

    1987-01-01

    These data indicate that in the two district health authorities studied there was an excess incidence of childhood leukaemia during 1972-85 in the vicinity of the nuclear establishments. In the West Berkshire and Basingstoke and North Hampshire District Health Authorities an average of 60 000 children aged 0-14 lived within a 10 km radius of a nuclear establishment each year. The normal expectation of leukaemia in these children was two cases a year, whereas the recorded incidence was three cases per year, representing one extra case of leukaemia each year among these 60 000 children. (author)

  1. DNA apoptosis and stability in B-cell chronic lymphoid leukaemia: implication of the DNA double-strand breaks repair system by non homologous recombination

    International Nuclear Information System (INIS)

    Deriano, L.

    2005-01-01

    After an introduction presenting the diagnosis and treatment of chronic lymphoid leukaemia, its molecular and genetic characteristics, and its cellular origin and clonal evolution, this research thesis describes the apoptosis (definition and characteristics, cancer and chemotherapy, apoptotic ways induced by gamma irradiation), the genotoxic stresses, the different repair mechanisms for different damages, and the DNA repair processes. It reports how human chronic lymphocytic leukaemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway, and presents non-homologous end-joining DNA repair as a potent mutagenic process in human chronic lymphocytic leukaemia B cells

  2. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Åsberg, Ann; Heyman, Mats

    2011-01-01

    BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92 an...... towards patients at risk. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc.......BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92...... and ALL-2000 protocols. Fifty-five TRDs were identified among the 1,645 ALL-92 patients and 33 among the 1,090 ALL-2000 patients. RESULTS: There was no significant difference in the incidence of TRDs between the two protocols (3.4% vs. 3.2%). Five patients died before initiation of therapy (0...

  3. Exposure assessment and other challenges in non-ionizing radiation studies of childhood leukaemia.

    Science.gov (United States)

    Kheifets, L; Oksuzyan, S

    2008-01-01

    Studies of electromagnetic fields (EMF) and the development of childhood leukaemia face unique difficulties. EMF are imperceptible, ubiquitous, have multiple sources, and can vary greatly over time and distances. Childhood leukaemia and high average exposures to magnetic fields are both quite rare. Thus, a major challenge in EMF epidemiology is the small number of highly exposed cases and the necessity for retrospective assessment of exposure. Only studies designed to minimize bias while maximizing our ability to detect an association, should one exist, would have a potential to contribute to our understanding. New approaches are needed; the most promising in the extremely low-frequency range involves a study of a highly exposed cohort of children who have lived in apartments next to built-in transformers or electrical equipment rooms. Another promising avenue is an investigation of possible joint effects of environmental exposures and genetic co-factors. An exposure assessment methodology for residential radiofrequency fields is still in its infancy. Rapid changes in technology and exponential increases in its use make exposure assessment more difficult and urgent.

  4. Disturbed pubertal growth in girls after acute leukaemia: a relative growth hormone insufficiency with late presentation.

    Science.gov (United States)

    Moëll, C

    1988-01-01

    Long-term follow-up of growth and development after acute lymphoblastic leukaemia (ALL) in childhood has previously been limited to the prepubertal period. This study describes pubertal growth, final height and the spontaneous secretion of GH in girls treated for ALL, including CNS irradiation with 24 Gy. Ten girls, treated earlier for ALL, experienced the menarche at a mean age of 12.2 years. This is significantly earlier than the mean for Swedish girls. Prepubertal growth was near normal after the end of therapy for leukaemia. Mean final height was -1.7 SD, which is 1.5 SD less than at onset and 1.0 SD less than 1 year after the end of treatment. Thirteen other girls had a blunted spontaneous secretion of GH, several years after treatment for ALL; there was no increase in GH secretion during puberty. These results suggest that girls who have been treated for ALL, including CNS irradiation, have a relative GH insufficiency. This insufficiency becomes obvious only when the girls cannot respond to the increased need for GH during the pubertal spurt.

  5. Endoplasmic reticulum calcium transport ATPase expression during differentiation of colon cancer and leukaemia cells

    International Nuclear Information System (INIS)

    Papp, Bela; Brouland, Jean-Philippe; Gelebart, Pascal; Kovacs, Tuende; Chomienne, Christine

    2004-01-01

    The calcium homeostasis of the endoplasmic reticulum (ER) is connected to a multitude of cell functions involved in intracellular signal transduction, control of proliferation, programmed cell death, or the synthesis of mature proteins. Calcium is accumulated in the ER by various biochemically distinct sarco/endoplasmic reticulum calcium transport ATPase isoenzymes (SERCA isoforms). Experimental data indicate that the SERCA composition of some carcinoma and leukaemia cell types undergoes significant changes during differentiation, and that this is accompanied by modifications of SERCA-dependent calcium accumulation in the ER. Because ER calcium homeostasis can also influence cell differentiation, we propose that the modulation of the expression of various SERCA isoforms, and in particular, the induction of the expression of SERCA3-type proteins, is an integral part of the differentiation program of some cancer and leukaemia cell types. The SERCA content of the ER may constitute a new parameter by which the calcium homeostatic characteristics of the organelle are adjusted. The cross-talk between ER calcium homeostasis and cell differentiation may have some implications for the better understanding of the signalling defects involved in the acquisition and maintenance of the malignant phenotype

  6. The risks of leukaemia and other cancers in Seascale from radiation exposure

    International Nuclear Information System (INIS)

    Stather, J.W.; Dionian, J.; Brown, J.; Fell, T.P.; Muirhead, C.R.

    1986-04-01

    Including new data in the radiation dose calculations for the Seascale study population of 1225 children and young persons, followed to 20 years of age or 1980, has, with modifications to dosimetric models, increased the predicted number of radiation-induced leukaemia resulting from Sallafield discharges from 0.01 to 0.016. Risk to the average child in the study, from the discharges, is now calculated as about 1 in 75,000 with a maximum risk of about 1 in 30,000 for children born in the mid-1950s. For the four fatal leukemias to be attributed to the Sellafield operations, the calculated average risk for all the children would have to be increased about 250 times. Estimate of the overall risk of radiation-induced leukaemia in the study population, from combined sources, has increased by less than 10% of the previous estimate and the total number of cases is still rounded to 0.1, as in R171. Risk to the average child is now calculated as about 1 in 12,250, about two thirds from natural background, 16% from Sellafield discharges, and 9% each from weapons fallout and medical exposure. (U.K.)

  7. Central nervous system lesions in adult T-cell leukaemia: MRI and pathology

    International Nuclear Information System (INIS)

    Kitajima, M.; Korogi, Y.; Shigematsu, Y.; Liang, L.; Takahashi, M.; Matsuoka, M.; Yamamoto, T.; Jhono, M.; Eto, K.

    2002-01-01

    Adult T-cell leukaemia (ATL) is a T-cell lymphoid neoplasm caused by human T-cell leukaemia virus type I (HTLV-I). Radiological findings in central nervous system (CNS) involvement have not been well characterised. We reviewed the MRI of 18 patients with ATL who developed new neurological symptoms or signs, and pathology specimens from a 53-year-old woman who died of ATL. MRI findings were divided into three categories: definite, probable, and other abnormal. Definite and probable findings were defined as ATL-related. The characteristic findings were multiple parenchymal masses with or without contrast enhancement adjacent to cerebrospinal fluid (CSF) spaced and the deep grey matter of both cerebral hemispheres, plus leptomeningeal lesion. One patient had both cerebral and spinal cord lesions. Other abnormal findings in eight patients included one case of leukoencephalopathy caused by methotrexate. The histology findings consisted of clusters of tumour cells along perivascular spaces, and scattered infiltration of the parenchyma, with nests of tumour cells. Leptomeningeal infiltration by tumour spread into the parenchyma and secondary degeneration of the neuronal tracts was observed. MRI was useful for detecting CNS invasion by ATL and differentiating it from other abnormalities. The MRI findings seemed to correlate well with the histological changes. (orig.)

  8. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    Science.gov (United States)

    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

  9. The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    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.

  10. Childhood leukaemia near British nuclear installations: Methodological issues and recent results

    International Nuclear Information System (INIS)

    Bithell, J. F.; Keegan, T. J.; Kroll, M. E.; Murphy, M. F. G.; Vincent, T. J.

    2008-01-01

    In 2008, the German Childhood Cancer Registry published the results of the Kinderkrebs in der Umgebung von Kernkraftwerken (KiKK) study of childhood cancer and leukaemia around German nuclear power stations. The positive findings appeared to conflict with the results of a recent British analysis carried out by the Committee on Medical Aspects of Radiation in the Environment (COMARE), published in 2005. The present paper first describes the COMARE study, which was based on data from the National Registry of Children's Tumours (NRCT); in particular, the methodology used in this study is described. Although the results of the COMARE study were negative for childhood leukaemia, this apparent discrepancy could be accounted for by a number of differences in approach, especially those relating to the distances from the power stations and the ages of the children studied. The present study was designed to match the KiKK study as far as possible. The incidence observed (18 cases within 5 km against 14.58 expected, p = 0.21) was not significantly raised. The risk estimate for proximity in the regression fitted was actually negative, though the confidence intervals involved are so wide that the difference from that reported in the KiKK study is only marginally statistically significant (p = 0.063). (authors)

  11. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    Directory of Open Access Journals (Sweden)

    Philipp Koehler

    2012-01-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

  12. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Cowan-Jacob, Sandra W., E-mail: sandra.jacob@novartis.com; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W. [Novartis Institutes for Biomedical Research, Basel (Switzerland)

    2007-01-01

    A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

  13. Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Sutton, Rosemary; Shaw, Peter J; Venn, Nicola C; Law, Tamara; Dissanayake, Anuruddhika; Kilo, Tatjana; Haber, Michelle; Norris, Murray D; Fraser, Chris; Alvaro, Frank; Revesz, Tamas; Trahair, Toby N; Dalla-Pozza, Luciano; Marshall, Glenn M; O'Brien, Tracey A

    2015-02-01

    Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P 50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy. © 2014 John Wiley & Sons Ltd.

  14. Prolonged bone marrow T1-relaxation in acute leukaemia. In vivo tissue characterization by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Thomsen, C; Sørensen, P G; Karle, H

    1987-01-01

    osseous tissue. Nine patients with acute leukaemia, one patient with myelodysplastic syndrome, and ten normal volunteers were included in the study. The T1- and T2-relaxation processes were measured in the lumbar spine bone marrow using a wholebody superconductive MR-scanner operating at 1.5 Tesla...

  15. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia | Office of Cancer Genomics

    Science.gov (United States)

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden.

  16. Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells

    DEFF Research Database (Denmark)

    Klitgaard, Josephine L; Koefoed, Klaus; Geisler, Christian

    2013-01-01

    The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage...

  17. Granulocytic sarcoma presenting with necrotic cervical lymph nodes as an initial manifestation of childhood leukaemia: imaging features

    Energy Technology Data Exchange (ETDEWEB)

    An, Sang Bu; Cheon, Jung-Eun; Kim, In-One; Kim, Woo Sun [Seoul National University College of Medicine, Department of Radiology, Seoul (Korea); Seoul National University Medical Research Center, Institute of Radiation Medicine, Seoul (Korea); Ahn, Hyo Seop; Shin, Hee Young; Kang, Hyoung Jin; Yeon, Kyung Mo [Seoul National University College of Medicine, Department of Pediatrics, Cancer Research Institute, Seoul (Korea)

    2008-06-15

    We present two cases of granulocytic sarcoma of the cervical lymph nodes with central necrosis as an initial manifestation of childhood leukaemia, focusing on the imaging features. Recognition of the CT and MR imaging findings of granulocytic sarcoma involving the cervical lymph nodes assists the differential diagnosis of noninfective lymphadenopathy in children. (orig.)

  18. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region

    NARCIS (Netherlands)

    Pui, CH; Gaynon, PS; Boyett, JM; Chessells, JM; Baruchel, A; Kamps, W; Silverman, LB; Biondi, A; Harms, DO; Vilmer, E; Schrappe, M; Camitta, B

    2002-01-01

    Background The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic

  19. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?

    NARCIS (Netherlands)

    Groninger, E.; Boer, A.W. de; Graaf, S.S.N. de; Kamps, W.A.; Bont, E.S. de

    2002-01-01

    Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow

  20. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells : A mitochondrial controlled pathway regulated by reactive oxygen species?

    NARCIS (Netherlands)

    Groninger, E; Meeuwsen-De Boer, GJ; Kamps, WA; De Bont, ESJM

    2002-01-01

    Vincristine (VCR), a microtubule interfering anticancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow

  1. Resilience factors play an important role in the mental health of parents when children survive acute lymphoblastic leukaemia.

    Science.gov (United States)

    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.

  2. Childhood leukaemia and non-Hodgkin's lymphoma near large rural construction sites, with a comparison with Sellafield nuclear site

    International Nuclear Information System (INIS)

    Kinlen, L.J.; Dickson, M.; Stiller, C.A.

    1995-01-01

    The objective was to determine whether population mixing produced by large, non-nuclear construction projects in rural areas is associated with an increase in childhood leukaemia and non-Hodgkin's lymphoma. A study was undertaken of the incidence of leukaemia and non-Hodgkin's lymphoma among children living near large construction projects in Britain since 1945, situated more than 20 km from a population centre, involving a workforce of more than 1000, and built over three or more calendar years. A 37% excess of leukaemia and non-Hodgkin's lymphoma at 0-14 years of age was recorded during construction and the following calendar year. The excesses were greater at times when construction workers and operating staff overlapped (72%), particularly in areas of relatively high social class. For several sites the excesses were similar to or greater than that near the nuclear site of Sellafield (67%), which is distinctive in its large workforce with many construction workers. Seascale, near Sellafield, with a ninefold increase had an unusually high proportion of residents in social class I. The findings support the infection hypothesis and reinforce the view that the excess of childhood leukaemia and non-Hodgkin's lymphoma near Sellafield has a similar explanation. (author)

  3. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Gordijn, Maartje S.; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2012-01-01

    Background Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress

  4. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Gordijn, Maartje S.; Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2015-01-01

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate

  5. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.

    2017-01-01

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate

  6. Genome‐wide analysis of cytogenetic aberrations in ETV6/RUNX1‐positive childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Borst, Louise; Wesolowska, Agata; Joshi, Tejal

    2012-01-01

    The chromosomal translocation t(12;21) resulting in the ETV6/RUNX1 fusion gene is the most frequent structural cytogenetic abnormality among patients with childhood acute lymphoblastic leukaemia (ALL). We investigated 62 ETV6/RUNX1‐positive childhood ALL patients by single nucleotide polymorphism...

  7. DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Hedeland, Rikke L; Hvidt, Kristian; Nersting, Jacob

    2010-01-01

    To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN...

  8. Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells.

    Science.gov (United States)

    Zaini, Rana G; Brandt, Kirsten; Clench, Malcolm R; Le Maitre, Christine L

    2012-07-01

    New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.

  9. Recruitment of childhood leukaemia patients to clinical trials in Great Britain during 1980-2007: variation by birth weight, congenital malformation, socioeconomic status and ethnicity.

    Science.gov (United States)

    Shah, Anjali; Diggens, Nicole; Stiller, Charles; Richards, Sue; Stevens, Michael C G; Murphy, Michael F G

    2014-05-01

    To assess recruitment of children to national clinical trials for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in Great Britain during 1980-2007 and describe variation by some factors that might influence trial entry. Records of leukaemia patients aged 0-14 years at diagnosis were identified in the National Registry of Childhood Tumours and linked to birth registrations, Children's Cancer and Leukaemia Group records, Hospital Episode Statistics and Medical Research Council clinical trial registers. Trial entry rates were compared between categories of birth weight, congenital malformation, socioeconomic status and ethnicity. 9147 ALL and 1466 AML patients were eligible for national clinical trials during 1980-2007. Overall recruitment rates were 81% and 60% respectively. For ALL, rates varied significantly with congenital malformation (Down syndrome 61%, other malformations 80%, none 82%; p4000 g 67%; p=0.001) and congenital malformation (Down syndrome 28%, other malformations 56%, none 63%; pcongenital malformations.

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

    Science.gov (United States)

    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.

  11. Methods and basic data of case-control study of leukaemia and lymphona among young people near Sellafield nuclear plant in West Cumbria

    International Nuclear Information System (INIS)

    Gardner, M.J.; Hall, A.J.; Snee, M.P.; Downes, S.; Powell, C.A.

    1990-01-01

    The methods and basic data of a case-control study of leukaemia and lymphoma among young people near Sellafield are examined for reliability. Fifty-two cases of leukaemia, 22 of non-Hodgkin's lymphoma and 23 of Hodgkins disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25, and 1001 controls matched for sex and date of birth taken from the same birth registers were used in the study. (author)

  12. Effect of central nervous system radiotherapy in children with acute lymphoblastic leukaemia on lymphocyte subpopulations and indicators of leucocyte migration inhibition in the peripheral blood

    International Nuclear Information System (INIS)

    Cesarz-Kruz, E.; Lukas, A; Sroczynska, M.; Lukas, W; Sonta-Jakimczyk, D.

    1981-01-01

    The reported investigations of changes in lymphocyte subpopulations and indicators of leycocyte migration inhibition in the peripheral blood were carried out in 17 children with acute lymphoblastic leukaemia subjected to prophylactic irradiation of the central nervous system. It was found that the depressive effect of radioprophylaxis affected mostly lymphocytes B. The usefulness of immunomodulation application in children with this leukaemia immediately after completion of radiotherapy is considered. (author)

  13. Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia.

    Science.gov (United States)

    Oram, S H; Thoms, J; Sive, J I; Calero-Nieto, F J; Kinston, S J; Schütte, J; Knezevic, K; Lock, R B; Pimanda, J E; Göttgens, B

    2013-06-01

    LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.

  14. [Expression of promyelocytic leukaemia protein in Bowen's disease, skin squamous cell carcinoma and basal cell carcinoma].

    Science.gov (United States)

    Wang, Qiongyu; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

    2013-07-01

    To investigate the expression of promyelocytic leukaemia (PML) protein of PML protein in Bowen's disease (BD), skin squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and explore the role of PML in the pathogenesis of these diseases. PML protein in normal skin tissues and lesions of Bowen's disease, SCC and BCC were detected with immunohistochemistry. Normal skin tissues did not express PML protein. In BCC, PML showed rather low expressions in the skin lesions (8.69% in cell nuclei and 4.35% in cytoplasm). The lesions in BD and SCC (grade I and II) showed obvious overexpression of PML protein in the cell nuclei and cytoplasm, and its expression in the cell nuclei of these lesions was significantly higher than that in grade III-IV SCC. PML protein may play an important role in the early stage of SCC, and its overexpression may contribute to the carcinogenesis and metastasis of SCC.

  15. Parental reports of behavioural outcome among paediatric leukaemia survivors in Malaysia: a single institution experience.

    Science.gov (United States)

    Hamidah, Alias; Sham Marina, Mohd; Tamil, Azmi M; Loh, C-Khai; Zarina, Latiff A; Jamal, Rahman; Tuti Iryani, Mohd Daud; Ratnam, Vijayalakshmi C

    2014-10-01

    To determine the behavioural impact of chemotherapy in survivors of acute lymphoblastic leukaemia (ALL) treated with chemotherapy only and to identify treatment-related or sociodemography-related factors that might be associated with behavioural outcome. We examined 57 survivors of childhood ALL, who were off treatment for at least 2 years and were in remission, aged 4-18 years, and 221 unrelated healthy controls. The Child Behaviour Checklist (CBCL) parent report was used either in English or in Bahasa Malaysia (the national language of Malaysia) to assess the behavioural outcome. Childhood ALL survivors had significantly higher scores on externalising behaviour on the CBCL parent report than did controls. Higher problem scores were found in ALL survivors with single parents on 'total problems' (P = 0.03) and subscales 'withdrawn' (P = 0.03), 'social problems' (P design the most appropriate remedy for problem behaviours detected in this multi-ethnic population. © 2014 John Wiley & Sons Ltd.

  16. Nuclear power plant and childhood leukaemia - Report by the pluralist working group

    International Nuclear Information System (INIS)

    Sommelet, Daniele; Barbey, Pierre; Baruchel, Andre; Bey, Pierre; Catelinois, Olivier; Vacquier, Blandine; Chartier, Michel; Chenal, Christian; Clavel, Jacqueline; De Vathaire, Florent; Grosche, Bernd; Faure, Claire; Jacob, Sophie; Laurier, Dominique; Marignac, Yves; Unwin, Philippe; Vernez, David; Gagniere, Bertrand; Perel, Yves

    2011-04-01

    nuclear power plant and the risk of leukaemia in children? There is no official answer to this question, barring that exposure to high doses or to high dose rates increases the risk. Many other genetic and environmental causes must also be taken into consideration, in order to prevent any misunderstanding. The molecular heterogeneity of leukaemia must also be taken into account when interpreting the data. Despite this complexity, the general public needs objective, comprehensible information. Scientists are under the obligation to meet the legitimate expectations of a society that is not only fully aware of its 'right to know', but is also eager for greater humanity and trust. For the reasons listed above, an independent, pluralist, technical working group composed of French and foreign experts with complementary skills and interests was created with the following mandate: - Issue an opinion on the available epidemiological knowledge of the effects of nuclear power plant (NPP), focusing in particular on the risk of childhood leukaemia; - Define the research needed to improve the existing data; - Help to deliver clear, transparent and regular information to the general public.; - Draw up guidelines for improving the existing knowledge on the link between childhood leukaemia and nuclear power plant (especially the impact of very low doses of ionising radiations). These guidelines will be made public. - Present the progress of this work to a national committee tasked with planning and monitoring the measures needed to improve the available knowledge of the effects of discharge from the nuclear industry on the health of people living nearby

  17. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    Science.gov (United States)

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  18. Metastatic renal cell carcinoma mimicking diverticulitis in a patient with chronic lymphocytic leukaemia.

    Science.gov (United States)

    Hwang, S M; Kuyava, J M; Grande, J P; Swetz, K M

    2015-01-07

    We present an unusual case of metastatic renal cell carcinoma (RCC) mimicking diverticulitis in a 76-year-old man with a 16-year history of chronic lymphocytic leukaemia (CLL) and a 2 cm left renal mass. The patient presented with severe abdominal pain and lower gastrointestinal bleeding with anticoagulation from recent pulmonary embolism. His clinical course was troubled by recurrent hospitalisations and complications that delayed investigations and potential treatments. Radiographic findings revealed stable CLL, mild sigmoid diverticulitis and a small renal mass. Small renal masses (less than 4 cm) are considered low risk for metastasising and are, thus, often observed or ablated, rather than resected. Furthermore, gastrointestinal metastases from RCC are rare. This case adds new perspective to the unpredictable nature of RCC and how synchronous malignancies may be masked in patients with long-standing CLL. 2015 BMJ Publishing Group Ltd.

  19. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Attarbaschi, Andishe; Barzilai, Shlomit

    2016-01-01

    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......, 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...

  20. Maternal diabetes and risk of childhood acute lymphoblastic leukaemia in the offspring

    DEFF Research Database (Denmark)

    Søegaard, Signe Holst; Rostgaard, Klaus; Kamper-Jørgensen, Mads

    2018-01-01

    BACKGROUND: Maternal diabetes may be linked to childhood acute lymphoblastic leukaemia (ALL) in the offspring. METHODS: We assessed the association between maternal pregestational or gestational diabetes and offspring risk of childhood ALL in a register-based study, including all singletons born...... in Denmark during 1996-2015 (n=1 187 482). RESULTS: Adjusted hazard ratios of childhood ALL were 2.91 (95% confidence interval (CI): 1.30-6.51) for maternal pregestational diabetes and 1.75 (95% CI: 1.02-2.98) for maternal gestational diabetes. Paternal diabetes did not alter offspring ALL risk, and we found...... no association between offspring ALL and later maternal risk of diabetes. CONCLUSIONS: Regardless that absolute ALL risk among offspring of women with diabetes remains low, our findings suggest that characteristics of the diabetic intrauterine environment promote ALL development. This offers a setting for future...

  1. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Greenberg, Steven A; Pinkus, Jack L; Amato, Anthony A

    2016-01-01

    SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we...... on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects...... prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD...

  2. E2A-PBX1 fusion in adult acute lymphoblastic leukaemia: biological and clinical features.

    Science.gov (United States)

    Foa, Robin; Vitale, Antonella; Mancini, Marco; Cuneo, Antonio; Mecucci, Cristina; Elia, Loredana; Lombardo, Romina; Saglio, Giuseppe; Torelli, Giuseppe; Annino, Luciana; Specchia, Giorgina; Damasio, Eugenio; Recchia, Anna; Di Raimondo, Francesco; Morra, Enrica; Volpe, Ettore; Tafuri, Agostino; Fazi, Paola; Hunger, Stephen P; Mandelli, Franco

    2003-02-01

    Molecular and cytogenetic studies performed in 305 adult acute lymphoblastic leukaemia (ALL) patients enrolled in the gimema (Gruppo Italiano Malattie EMatologiche dell'Adulto) multicentric protocols identified an E2A-PBX1 fusion and/or t(1;19) in 10 patients (3.3%). All had common ALL, were mostly CyIg+ and were CD34/CD13/CD33-. Nine patients achieved a complete remission (CR); five patients showed a haematological relapse after 7 months (median). Four patients are alive in first CR with a median follow-up of 29 months; three patients are molecularly negative. This abnormality is frequently associated with early treatment failure. E2A-PBX1+ adult ALL should be considered for intensified treatment strategies and monitoring of minimal residual disease.

  3. Assessment of environmental exposures from agricultural pesticides in childhood leukaemia studies: Challenges and opportunities

    International Nuclear Information System (INIS)

    Ritz, B.; Rull, R. P.

    2008-01-01

    Pesticides are ubiquitous in environments of many rural communities due to drift from agricultural applications and home/garden use. Studies of childhood leukaemia predominantly relied on retrospective pesticide exposure assessment and parental recall of use or proximity to fields or pesticide applications. Sample size requirements mostly preclude the collection of individual-level exposure information, bio-markers or environmental measurements of pesticides prospectively in cohorts. Yet such measures can be used in nested case-control approaches or for validating exposure models that can be applied to large populations. Recently developed models incorporate geographic information system technology and environmental databases of pesticide and/or crop data to assess exposure. Models developed in California to estimate residential exposures are presented by linking addresses to agricultural pesticide application data and land-use maps. Results from exposure validation and simulation studies and exposure measurement error issues are discussed. (authors)

  4. Molecular techniques for the personalised management of patients with chronic myeloid leukaemia.

    Science.gov (United States)

    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.

  5. Growth hormone secretion in children after therapy for acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Pawlaczyk, B.; Krause, W.

    1990-01-01

    In eight children, after the termination of therapy for acute lymphoblastic leukaemia (ALL) the secretion of growth hormone (GH) was determined by the stimulation test with clonidine. The children were treated in the period from 1983 till 1988 and they were administered chemotherapy, intrathecal methotrexate therapy and cranial 60 Co irradiation in a dose of 1800 rads. In one case a complete GH deficiency was found, in three cases there was a partial deficiency and in the remaining cases the secretion was regular. No correlation was found between the biochemical values of GH and the clinical stature. There was also no interrelation between the duration of chemotherapy and the degree of pituitary gland failure. We have compared the results of GH output in children treated for ALL with those of 44 children in whom short stature was diagnosed. The age in both groups was similar. (author)

  6. Pneumonia diagnosis in childhood and incidence of leukaemia, lymphoma and brain cancer

    DEFF Research Database (Denmark)

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

    2017-01-01

    OBJECTIVES: 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. DESIGN: Population-based cohort study. SETTING: Denmark, hospital diagnoses, 1994-2013. METHODS: 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. RESULTS: The cancer SIRs were substantially increased during the first 6 months of follow-up; lymphoid...

  7. HSE investigation of leukaemia and other cancers in the children of male workers at Sellafield

    International Nuclear Information System (INIS)

    1994-01-01

    This report presents two findings of the U.K. Health and Safety Executive study group responsible for examining the conclusions of the Gardner Report that ''the raised incidence of leukaemia particularly, and non-Hodgkin's lymphoma, among children near Sellafield was associated with paternal employment and recorded external dose of whole body penetrating radiation during work at the plant before conception''. The HSE report is divided into three:- the Case-only study and the Radiation Dose study, concerned with the 11 case fathers who had worked at Sellafield. The third part, the Case-control study, is an epidemiological study which seeks to identify all cancer cases diagnosed before the age of 25, where the children concerned had been born in West Cumbria to fathers who were Sellafield employees. The search included the whole country from January 1980 to September 1989. (UK)

  8. Co-trimoxazole alone for prevention of bacterial infection in patients with acute leukaemia.

    Science.gov (United States)

    Starke, I D; Donnelly, P; Catovsky, D; Darrell, J; Johnson, S A; Goldman, J M; Galton, D A

    1982-01-02

    43 patients undergoing treatment for acute leukaemia were randomised to receive either co-trimoxazole alone or co-trimoxazole with framycetin and colistin as antibacterial prophylaxis during periods of neutropenia. There were no significant differences between the two treatment groups in the time before the onset of the first fever, the number of episodes of fever or of septicaemia per patient, the number of neutropenic days during which patients remained afebrile or did not require systemic antibiotics, or the number of resistant organisms acquired. Co-trimoxazole alone is cheaper and easier to take than co-trimoxazole with framycetin and colistin, and it is therefore preferable to the three-drug combination for the prophylaxis of bacterial infection.

  9. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol

    DEFF Research Database (Denmark)

    Raja, Raheel A; Schmiegelow, Kjeld; Albertsen, BK

    2014-01-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis...... ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m(2) /dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed...... with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve...

  10. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

    Science.gov (United States)

    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

    2011-08-03

    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 programs. 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 states. 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.

  11. In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals

    International Nuclear Information System (INIS)

    Inoue, Yusuke; Okubo, Toshiyuki; Tojo, Arinobu; Sekine, Rieko; Soda, Yasushi; Kobayashi, Seiichiro; Nomura, Akiko; Izawa, Kiyoko; Kitamura, Toshio; Ohtomo, Kuni

    2006-01-01

    The application of in vivo bioluminescence imaging to non-invasive, quantitative monitoring of tumour models relies on a positive correlation between the intensity of bioluminescence and the tumour burden. We conducted cell culture studies to investigate the relationship between bioluminescent signal intensity and viable cell numbers in murine leukaemia model cells. Interleukin-3 (IL-3)-dependent murine pro-B cell line Ba/F3 was transduced with firefly luciferase to generate cells expressing luciferase stably under the control of a retroviral long terminal repeat. The luciferase-expressing cells were transduced with p190 BCR-ABL to give factor-independent proliferation. The cells were cultured under various conditions, and bioluminescent signal intensity was compared with viable cell numbers and the cell cycle stage. The Ba/F3 cells showed autonomous growth as well as stable luciferase expression following transduction with both luciferase and p190 BCR-ABL, and in vivo bioluminescence imaging permitted external detection of these cells implanted into mice. The bioluminescence intensities tended to reflect cell proliferation and responses to imatinib in cell culture studies. However, the luminescence per viable cell was influenced by the IL-3 concentration in factor-dependent cells and by the stage of proliferation and imatinib concentration in factor-independent cells, thereby impairing the proportionality between viable cell number and bioluminescent signal intensity. Luminescence per cell tended to vary in association with the fraction of proliferating cells. Although in vivo bioluminescence imaging would allow non-invasive monitoring of leukaemia model animals, environmental factors and therapeutic interventions may cause some discrepancies between tumour burden and bioluminescence intensity. (orig.)

  12. In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Yusuke; Okubo, Toshiyuki [University of Tokyo, Department of Radiology, Institute of Medical Science, Tokyo (Japan); Tojo, Arinobu; Sekine, Rieko; Soda, Yasushi; Kobayashi, Seiichiro; Nomura, Akiko; Izawa, Kiyoko [University of Tokyo, Division of Molecular Therapy, Advanced Clinical Research Centre, Tokyo (Japan); Kitamura, Toshio [University of Tokyo, Division of Cellular Therapy, Advanced Clinical Research Centre, Tokyo (Japan); Ohtomo, Kuni [University of Tokyo, Department of Radiology, Graduate School of Medicine, Tokyo (Japan)

    2006-05-15

    The application of in vivo bioluminescence imaging to non-invasive, quantitative monitoring of tumour models relies on a positive correlation between the intensity of bioluminescence and the tumour burden. We conducted cell culture studies to investigate the relationship between bioluminescent signal intensity and viable cell numbers in murine leukaemia model cells. Interleukin-3 (IL-3)-dependent murine pro-B cell line Ba/F3 was transduced with firefly luciferase to generate cells expressing luciferase stably under the control of a retroviral long terminal repeat. The luciferase-expressing cells were transduced with p190 BCR-ABL to give factor-independent proliferation. The cells were cultured under various conditions, and bioluminescent signal intensity was compared with viable cell numbers and the cell cycle stage. The Ba/F3 cells showed autonomous growth as well as stable luciferase expression following transduction with both luciferase and p190 BCR-ABL, and in vivo bioluminescence imaging permitted external detection of these cells implanted into mice. The bioluminescence intensities tended to reflect cell proliferation and responses to imatinib in cell culture studies. However, the luminescence per viable cell was influenced by the IL-3 concentration in factor-dependent cells and by the stage of proliferation and imatinib concentration in factor-independent cells, thereby impairing the proportionality between viable cell number and bioluminescent signal intensity. Luminescence per cell tended to vary in association with the fraction of proliferating cells. Although in vivo bioluminescence imaging would allow non-invasive monitoring of leukaemia model animals, environmental factors and therapeutic interventions may cause some discrepancies between tumour burden and bioluminescence intensity. (orig.)

  13. Stem cell targets and dosimetry for radiation-induced leukaemia and bone cancer

    International Nuclear Information System (INIS)

    Richardson, R.B.

    2007-01-01

    The ICRP are proposing changes to the assumed targets for the induction of bone cancer and leukaemias as described by Harrison et al in an accompanying article. This study of radiation targets in the skeleton finds that the endosteum of the long bone medullary cavities is not an important target, especially in the adult, as it supports a very low stem cell population associated with high adiposity, whereas the periosteum has a strong mesenchymal stem cell population throughout lifetime. Quiescent stem cells are found to be preferentially located close to the trabecular bone surface in the osteoblastic niche, whereas progenitors of stem cells prefer to reside in perivascular niches. Evidence is given in support of the suggestion that the absence of excess bone-cancer in atomic bomb survivors may be related to the extremely low prevalence of Paget's disease in Japan. The hypoxic conditions of the endosteum adjacent to quiescent bone surfaces provide a radioprotective stem cell microenvironment by a factor of 2-3 fold, whereas greater radiosensitivity is prevalent in the young and individuals with benign diseases of bone. Increasing the volume of the bone cancer target from a 10 μm thick endosteum to a 50 μm peripheral marrow layer will result in an approximately three-fold decline in the mean dose from alpha-emitters in bone. These new observations are shown to go some way in explaining the low incidences for leukaemia and especially bone cancer in radium dial painters, Thorotrast patients and Mayak nuclear workers. (author)

  14. The risks of leukaemia and non-cancer mortality in the offspring of the Japanese bomb survivors and a comparison of leukaemia risks with those in the offspring of the Sellafield workforce

    International Nuclear Information System (INIS)

    Little, M.P.

    1992-01-01

    The incidence of leukaemia and mortality from various causes other than cancer observed in offspring of the Japanese bomb survivors are analysed using linear and exponential forms of a relative risk model. Relative risk coefficients for leukaemia as a function of total pre-conception dose in the offspring of the Japanese and those for children of the Sellafield workforce are compared, and statistically significant differences are found. The statistical significance of these differences is no less marked if attention is restricted to those born before the end of 1950 in the Japanese cohort; therefore it is unlikely that the differences between the preconception irradiation leukamia risks in the Japanese and Sellafield datasets are a result of different distributions of parental ages at exposure in the two groups, or of different lengths of time between exposures of spermatogonia and conception. (Author)

  15. Trends in infant leukaemia in West Germany in relation to in utero exposure due to Chernobyl accident.

    Science.gov (United States)

    Steiner, M; Burkart, W; Grosche, B; Kaletsch, U; Michaelis, J

    1998-07-01

    A temporary increase in the incidence of infant leukaemia in Greece was reported by Petridou et al., which was attributed to in utero exposure to ionising radiation resulting from the Chernobyl accident. We performed a similar analysis based on the data of the German Childhood Cancer Registry in order to check whether the observation could be confirmed by means of independent data. Applying the same definitions as Petridou et al., we also observed an increased incidence of infant leukaemia in a cohort of children born after the Chernobyl accident. More detailed analyses, regarding areas with different contamination levels and dose rate gradients over time after the accident, showed, however, no clear trend with regard to exposure. It would therefore appear less likely that the observed effect was caused by exposure to ionising radiation due to the Chernobyl accident.

  16. Trends in infant leukaemia in West Germany in relation to in utero exposure due to the Chernobyl accident

    International Nuclear Information System (INIS)

    Steiner, M.; Burkart, W.; Grosche, B.; Kaletsch, U.; Michaelis, J.

    1998-01-01

    A temporary increase in the incidence of infant leukaemia in Greece was reported by Petridou et al., which was attributed to in utero exposure to ionising radiation resulting from the Chernobyl accident. We performed a similar analysis based on the data of the German Childhood Cancer Registry in order to check whether the observation could be confirmed by means of independent data. Applying the same definitions as Petridou et al., we also observed an increased incidence of infant leukaemia in a cohort of children born after the Chernobyl accident. More detailed analyses, regarding areas with different contamination levels and dose rate gradients over time after the accident, showed, however, no clear trend with regard to exposure. It would therefore appear less likely that the observed effect was caused by exposure to ionising radiation due to the Chernobyl accident. (orig.)

  17. Clinico-pathological profile of acute promyelocytic leukaemia at Al-Amal Oncology-Haematology Centre, Qatar.

    Science.gov (United States)

    Ibrahim, F A; Yassin, M A; El-Ayoubi, H R; Alhiji, I A; Albinali, A S; Almansour, S M; Qafoud, F M

    2010-09-01

    This cases series describes the profile of adult patients with acute promyelocytic leukaemia (APt) at a referral hospital in Qatar. Of 34 acute myeloid leukaemia (AML) cases diagnosed, 11(32%) were classified as APt. Disseminated intravascular coagulation was common at presentation (91%). Severe thrombocytopenia was seen in 73%, leukocytosis in 55% and severe anaemia in 45%. Only 2 patients were of the classic hypergranular type. In the remaining 9 patients, 3 morphological subtypes were recognized: microgranular variant (6 patients), hyperbasophilic (2 patients) and regular nuclear outline M3r (1 patient). Translocation t(15;17) was detected in 63% of cases. APL constitutes a high proportion of AML cases in Qatar, with considerable morphological heterogeneity and a oredominance of APL variants with unfavourable oresenting features.

  18. The prevalence of antibodies of Brucella abortus, Dermatophilus congolensis and bovine leukaemia virus in Nigerian slaughter cattle.

    Science.gov (United States)

    Oyejide, A; Adu, F D; Makinde, A A; Ezeh, E N

    1987-01-01

    In a pilot survey to compare the relative prevalence of three diseases in apparently healthy White Fulani Zebu (WFZ) cattle slaughtered in Nigeria, sera from 80 randomly selected animals with no significant gross lesions on ante mortem and post mortem inspection were examined for antibodies to Brucella abortus, Dermatophilus congolensis and bovine leukaemia virus. Of the samples screened, 5.0, 8.8 and 2.0% showed serological evidence for brucellosis, cutaneous streptothricosis and bovine leukosis respectively.

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

    Science.gov (United States)

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

    Science.gov (United States)

    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.

  1. Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria

    International Nuclear Information System (INIS)

    Gardner, M.J.; Snee, M.P.; Hall, A.J.; Powell, C.A.; Downes, S.

    1990-01-01

    The raised incidence of leukaemia, particularly, and non-Hodgkin's lymphoma among children near Sellafield was associated with paternal employment and recorded external dose of whole body penetrating radiation during work at the plant before conception. The association can explain statistically the observed geographical excess. This result suggests an effect of ionising radiation on fathers that may be leukaemogenic in their offspring, though other, less likely, explanations are possible. (author)

  2. Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  4. Andrographolide inhibits growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis.

    Science.gov (United States)

    Manikam, Shiamala D; Manikam, Shiamala T; Stanslas, Johnson

    2009-01-01

    The growth inhibiting potential of andrographolide was evaluated in three acute promyelocytic leukaemia cell line models (HL-60, NB4 and all-trans retinoic acid (ATRA)-resistant NB4-R2). In elucidating the mechanisms of growth inhibition, a special emphasis was placed on assessing the induction of differentiation and apoptosis by andrographolide in the primary acute promyelocytic leukaemia NB4 cells. The compound was 2- and 3-fold more active in inhibiting the growth of HL-60 and NB4-R2 cells compared with NB4 cells, respectively. At IC50 (concentration at which growth of 50% of the cells (compared with medium only treated control cells) is inhibited; 4.5 microM) the compound exhibited strong cell-differentiating activity in NB4 cells, similar to ATRA (IC50 1.5 microM). In the presence of a pure retinoic acid receptor antagonist AGN193109, the growth inhibition of NB4 cells by ATRA was reversed, whereas the activity of andrographolide was not affected. This clearly suggested that andrographolide's cell differentiating activity to induce growth inhibition of NB4 cells most likely occurred via a retinoic acid receptor-independent pathway. At higher concentration (2xIC50), andrographolide was an efficient inducer of apoptosis in NB4 cells. Taken together, these results suggest andrographolide and its derivatives, apparently with a novel cell differentiating mechanism and with ability to induce apoptosis, might be beneficial in the treatment of primary and ATRA-resistant acute promyelocytic leukaemia.

  5. Profile of Skin pH in Leukaemia's Children with Chemotherapy Treatments at Haji Adam Malik General Hospital, Medan.

    Science.gov (United States)

    Siregar, Radha; Purnama, Sri; Lakswinar, Salia

    2017-12-15

    One of the treatments for leukaemia is chemotherapy. Side effects and toxicity of this treatment can be seen on the skin, adnexal, and mucous membranes. They might increase potential hydrogen (pH) value on the skin surface, therefore, disrupting epidermal barrier defences. To describe the pH of the skin in children with leukaemia who received chemotherapy. This study was an observational descriptive, cross-sectional study, conducted from March until December 2016 with 32 children with leukaemia who treated at Haji Adam Malik General Hospital, Medan as subjects. Skin pH was measured by a pH meter. We found mean skin pH in ALL (6.28 ± 0.58), CML (5.9 ± 0) and AML (6.5 ± 0.50). The mean skin pH after 1-5 weeks of chemotherapy was 6.13 ± 0.49, at 6-10 weeks (6.32 ± 0.51), and at 11-15 weeks (7.12 ± 0.36). The mean skin pH of patients with two drugs (5.98 ± 0.44), four drugs (6.28 ± 0.55), and six drugs (6.63 ± 0.56). The highest mean of skin pH were obtained in AML group, 11-15 weeks length of chemotherapy and group with six drugs regimen.

  6. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

    Science.gov (United States)

    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.

  7. Procoagulant activity of extracellular vesicles as a potential biomarker for risk of thrombosis and DIC in patients with acute leukaemia.

    Science.gov (United States)

    Gheldof, Damien; Haguet, Hélène; Dogné, Jean-Michel; Bouvy, Céline; Graux, Carlos; George, Fabienne; Sonet, Anne; Chatelain, Christian; Chatelain, Bernard; Mullier, François

    2017-02-01

    Haemostatic complication is common for patients with hematologic malignancies. Recent studies suggest that the procoagulant activity (PCA) of extracellular vesicles (EV) may play a major role in venous thromboembolism and disseminated intravascular coagulation (DIC) in acute leukaemia. To study the impact of EVs from leukaemic patients on thrombin generation and to assess EV-PCA as a potential biomarker for thrombotic complications in patients with acute leukaemia. Blood samples from a cohort of patients with newly diagnosed acute leukaemia were obtained before treatment (D-0), 3 and 7 days after treatment (D-3 and D-7). Extracellular vesicles were isolated and concentrated by ultracentrifugation. EV-PCA was assessed by thrombin generation assay, and EV-associated tissue factor activity was measured using a commercial bio-immunoassay (Zymuphen MP-TF®). Of the 53 patients, 6 had increased EV-PCA at D-0 and 4 had a thrombotic event. Patients without thrombotic events (n = 47) had no elevated EV-PCA. One patient had increased EVs with procoagulant activity at D-3 and developed a DIC at D-5. This patient had no increased EVs-related tissue factor activity from D-0 to D-7 (2 pg/ml), of these, four had a thrombosis and two had haemorrhages. Procoagulant activity of extracellular vesicles could have a predictive value in excluding the risk of thrombotic events. Our findings also suggest a possible association between thrombotic events and EV-PCA.

  8. PERCENTAGE OF CIPROFLOXACIN-RESISTANT STRAINS OF CITROBACTER FREUNDII IN ACUTE LEUKAEMIA PATIENTS WITH CIPROFLOXACIN PROPHYLAXIS

    Directory of Open Access Journals (Sweden)

    Rika Strauch

    2004-12-01

    Full Text Available Background. Authors tried to determine an efficiency of ciprofloxacin as infection prophylaxis in patients with acute leukaemia treated at the Department of Haematology in Clinical Center of Ljubljana. Due to cytotoxic chemotherapy, aplasia of bone marrow is inevitable. Therefore, these patients are at high risk for bacterial and fungal infection. The authors have noticed a rise in the number of ciprofloxacin-resistant strains of Citrobacter freundii and decided to find out if ciprofloxacin is still usable in this setting.Patients and methods. 45 patients with acute leukaemia were admitted to the Department of Haematology in the Clinical Center of Ljubljana during the year 2001 and 2002. All the patients received ciprofloxacin 2 × 500 mg on a daily basis. Citrobacter freundii was isolated in 11 patients, to whom we determined the proportion of ciprofloxacin-resistant strains of Citrobacter freundii and other Enterobacteriaceae. Susceptibility testing was done by the NCCCLS standards by the disc diffusion method and minimal inhibitory concentration.Results. C. freundii was isolated in 11 patients with AL. Extended-spectrum beta-lactamases (ESBL C. freundii was isolated in 6 patients (54.5%. Ciprofloxacin-resistant C. freundii was isolated in 6 patients (54.5%. Six patients (54.5% had ciprofloxacin-resistant C. freundii which was ESBL positive at the same time. In AL patients with C. freundii (n = 11 almost half of isolated bacteria were Gram negative bacilli (45.2%, n = 292, mostly from the family of Enterobacteriaceae. More than half of enterobacteria were ciprofloxacin-resistant, one third of them were also ESBL positive. Out of 131 enterobacteria, C. freundii was isolated 37 times. (28.2%.Conclusions. C. freundii was isolated in one fourth of AL patients. Half of the isolates were ciprofloxacin-resistant. The same was true for isolated enterobacteria. Almost all of ciprofloxacin-resistant bacteria were ESBL positive. There is a question

  9. Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

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    Alexopoulos Evangelos C

    2006-07-01

    Full Text Available Abstract 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

  10. An analysis of leukaemia, lymphoma and other malignancies together with certain categories of non-cancer mortality in the first generation offspring (F1) of the Japanese bomb survivors

    International Nuclear Information System (INIS)

    Little, M.P.; Wakeford, R.; Charles, M.W.

    1994-01-01

    The absence of any significant excess of childhood leukaemia in the offspring of the Japanese bomb survivors has provided strong evidence against a causal interpretation of the association between paternal preconception radiation dose and the incidence of childhood leukaemia in the offspring of employees at the Sellafield nuclear installation, West Cumbria. The use of the Japanese data has, however, been questioned on the basis that leukaemia cases may have been under-recorded in the years immediately following the bombings. In order to investigate possible misdiagnoses of leukaemia cases in the first generation offspring (F 1 ) of the Japanese bomb survivors, analyses have been undertaken of cases of leukaemia, non-Hodgkin's lymphoma (NHL), and all other malignancies, together with deaths due to blood diseases, deaths due to infectious diseases and deaths from unknown causes. (author)

  11. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images

    Science.gov (United States)

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-10-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method.

  12. Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome. Conceptual chances

    International Nuclear Information System (INIS)

    Buchmann, I.; Helisch, A.; Bartenstein, P.; Meyer, R.G.; Herr, W.

    2005-01-01

    The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myelblative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand. (orig.)

  13. Large granular lymphocytic leukaemia complicated with histiocytic sarcoma in a dog : clinical communication

    Directory of Open Access Journals (Sweden)

    T. Maruo

    2009-05-01

    Full Text Available A 10-year-old castrated male Golden retriever, weighing 36.3 kg was referred for evaluation owing to a decline in general condition. Findings from the complete blood count revealed a marked lymphocytosis (113 000/µℓ. Examination of Wright-Giemsa-stained films of peripheral blood revealed the presence of large granular lymphocytes (LGL. Seventy-two per cent (81 360/µℓ of the lymphocytes were found to be 12-17 µm in diameter, containing nuclei with mature clumped chromatin and abundant lightly basophilic cytoplasm with a variable number of fine azurophilic granules. Based on these findings this case was diagnosed as LGL leukaemia. As a result of multiple-agent chemotherapy, the markedly elevated levels of lymphocytes gradually decreased to 7500/µℓ on day 122 and the patient maintained a good quality of life for the following 3 months. However, on around day 237, a soft, raised, bosselated mass on the labial region was noted. The dog was diagnosed as having histiocytic sarcoma based on cytological and histological examination of the mass. Shortly after diagnosis, the dog developed sudden onset of central nervous system signs and died on day 270. A common outcome of canine LGL is the development of acute blast crisis or lymphoma. However, this case was notable for complication with histiocytic sarcoma from another origin.

  14. Dose-adjusted arsenic trioxide for acute promyelocytic leukaemia in chronic renal failure.

    Science.gov (United States)

    Firkin, Frank; Roncolato, Fernando; Ho, Wai Khoon

    2015-10-01

    To determine the potential for arsenic trioxide (ATO) to be safely and effectively incorporated into induction therapy of newly diagnosed acute promyelocytic leukaemia (APL) in patients with severe chronic renal failure (CRF) by reduction of the ATO dosage to compensate for reduced renal elimination of arsenic in CRF. Two of the four CRF patients with APL in the study were dialysis-dependent, and two had eGFRs of 18 and 19 mL/min/1.73 m(2) . ATO dosage schedules were adjusted to obtain comparable whole-blood arsenic levels to those in APL patients with normal renal function who achieved molecular remission (MR) while receiving 10 mg ATO daily for 28 d. Average ATO administered per day in CRF patients ranged from 36 to 50% of the ATO administered to APL patients with normal renal function. No clinically significant cardiac, hepatic or other toxicities were detected. RT-PCR-negative MR was achieved after one treatment course in two patients and after two courses in the others. Relapse-free survival is 155, 60, 43 and 5 months. The observations in this pilot study have demonstrated whole-blood arsenic levels can provide a guide to adjustments of ATO dosage schedules that permit safe and effective therapeutic outcomes in APL patients with severely compromised renal function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia

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    Lazić Jelena

    2009-01-01

    Full Text Available Introduction. Acute lymphoblastic leukaemia (ALL is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR. MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.

  16. All trans retinoic acid abrogates spontaneous monocytic growth in juvenile chronic myelomonocytic leukaemia.

    Science.gov (United States)

    Cambier, N; Menot, M L; Schlageter, M H; Balitrand, N; Leblanc, T; Bordigoni, P; Rohrlich, P; Lamagnère, J P; Donadieu, J; Herbelin, C; Puissant, C; Gourand, F; Baruchel, A; Chomienne, C

    2001-01-01

    All trans retinoic acid, the active metabolite of vitamin A, exerts profound effects on cell differentiation. On normal myeloid progenitors, retinoids switch the differentiation program of granulo-macrophagic progenitors towards the granulocytic lineage and consequently reduce CFU-M colony formation. Bone marrow and peripheral blood mononuclear cells from children with Juvenile Chronic Myelomonocytic Leukaemia show typical spontaneous monocytic growth. We questioned whether in this disease, retinoids could switch myelomonocytic growth and inhibit the abnormal CFU-M colony proliferation. Ten JCML samples were studied in the presence of ATRA in methyl cellulose colony assay, before (CFU-C) or after (pre-CFU) liquid suspension culture. In vitro characteristics of JCML such as spontaneous monocytic growth in the absence of growth factor was noted in all patients. In the presence of leucocyte-conditioned medium, nine samples showed only CFU-M growth and one sample CFU-GM growth. Incubation with ATRA inhibited CFU-M colony formation in nine cases. Enhancement of granulocytic differentiation (CFU-G) was noted in nine cases. ATRA also inhibited CD34+ JCML monocytic growth and GM-CSF hypersensitivity. These data suggest that, in JCML progenitors, retinoid pathways are functional and inhibition of immature monocytic progenitors cells may be achieved with retinoids, without impeding granulocytic cell growth.

  17. The effect of game-based exercise on infant acute lymphocytic leukaemia patients

    Directory of Open Access Journals (Sweden)

    Édgar Cortés Reyes

    2013-10-01

    Full Text Available Objective. To establish the effect of a game-based exercise programme on Physical Deconditioning Syndrome (PDS in 5 to 12 year-old children suffering Acute Lymphocytic Leukaemia (ALL. Materials and methods. This was a quasi-experimental study involving seven children being treated for ALL at the National Cancer Institute (NCI in Bogotá, Colombia. Fitness determinants (aerobic capacity, muscle strength, flexibility, motor skills and proprioception were initially assessed to establish their exercise regime category, classifying subjects into three levels. Post-intervention assessment at the end of the programme verified changes in such determinants. Results. Seven children aged 5 to 12 years-old (9±2.13 years suffering from ALL (4 girls and 3 boys met the inclusion criteria. Most determinants underwent changes leading to an increase in patients’ evaluation scores (except for muscle strength, which remained constant. Whilst determinant variation was important, a greater difference was found when the overall score was analysed (p=0.05, signifying that the intervention had changed these children’s health status. Conclusion. Game-based exercise was useful for managing PDS in 5 to12 year-old ALL patients and suggested new ways of providing an intervention concerning physical therapy. However, studies involving a larger target population and longer intervention time are needed to identify new findings in this field.

  18. Bypass mechanisms of resistance to tyrosine kinase inhibition in chronic myelogenous leukaemia.

    Science.gov (United States)

    Marfe, Gabriella; Di Stefano, Carla

    2014-06-01

    Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patients can now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significant proportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiple molecular mechanisms of resistance have been identified and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain. The second is activation of alternative molecules that maintain the signalling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

  19. Site- and allele-specific polycomb dysregulation in T-cell leukaemia

    Science.gov (United States)

    Navarro, Jean-Marc; Touzart, Aurore; Pradel, Lydie C.; Loosveld, Marie; Koubi, Myriam; Fenouil, Romain; Le Noir, Sandrine; Maqbool, Muhammad Ahmad; Morgado, Ester; Gregoire, Claude; Jaeger, Sebastien; Mamessier, Emilie; Pignon, Charles; Hacein-Bey-Abina, Salima; Malissen, Bernard; Gut, Marta; Gut, Ivo G.; Dombret, Hervé; Macintyre, Elizabeth A.; Howe, Steven J.; Gaspar, H. Bobby; Thrasher, Adrian J.; Ifrah, Norbert; Payet-Bornet, Dominique; Duprez, Estelle; Andrau, Jean-Christophe; Asnafi, Vahid; Nadel, Bertrand

    2015-01-01

    T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1+ cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1+ T-ALLs. Sequencing reveals that >20% of monoallelic TAL1+ patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5′ to TAL1. Using ‘allelic-ChIP’ and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation. PMID:25615415

  20. Analysis of ZAP70 expression in adult acute lymphoblastic leukaemia by real time quantitative PCR

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    Chakupurakal Geothy

    2012-05-01

    Full Text Available Abstract Background ZAP70 gene expression is associated with poor prognosis in B-cell lymphoproliferative disorders especially chronic lymphocytic leukaemia (CLL but its role in adult B-ALL has not been established. On diagnostic samples from 76 patients with adult ALL (65 with B-ALL and 11 with T-ALL ZAP70 mRNA expression levels were studied by real time-quantitative PCR (RT-qPCR analysis. Findings A broad distribution of ZAP70 expression was observed in ALL, ranging from 0.002 to 5.3 fold that of the ZAP70 positive Jurkat reference cell line. No association was observed between expression levels and the presence of specific cytogenetic abnormalities. Five cases, including one case of T-ALL, had ZAP70 expression above the level of the Jurkat reference cell line. Conclusions Our results confirm the frequent expression of ZAP70 in adult ALL. Limited comparisons made did highlight poor-risk patients with high ZAP70 expression, but due to lack of clinical information on patient samples we were unable to directly assess the impact on disease prognosis. ZAP-70 may be an important laboratory assay in adult ALL and further studies are warranted to study a potential correlation with cytogenetic and other genetic markers.

  1. Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells

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    Tao Zhang

    2015-11-01

    Full Text Available The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic-binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS. More than 40 arsenic-binding proteins were separated, and redox-related proteins, glutathione S-transferase P1 (GSTP1, heat shock 70 kDa protein 9 (HSPA9 and pyruvate kinase M2 (PKM2, were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL.

  2. Childhood leukaemia close to high-voltage power lines--the Geocap study, 2002-2007.

    Science.gov (United States)

    Sermage-Faure, C; Demoury, C; Rudant, J; Goujon-Bellec, S; Guyot-Goubin, A; Deschamps, F; Hemon, D; Clavel, J

    2013-05-14

    High-voltage overhead power lines (HVOLs) are a source of extremely low-frequency magnetic fields (ELF-MFs), which are classified as possible risk factors for childhood acute leukaemia (AL). The study was carried out to test the hypothesis of an increased AL incidence in children living close to HVOL of 225-400 kV (VHV-HVOL) and 63-150 kV (HV-HVOL). The nationwide Geocap study included all the 2779 cases of childhood AL diagnosed in France over 2002-2007 and 30 000 contemporaneous population controls. The addresses at the time of inclusion were geocoded and precisely located around the whole HVOL network. Increased odds ratios (ORs) were observed for AL occurrence and living within 50 m of a VHV-HVOL (OR=1.7 (0.9-3.6)). In contrast, there was no association with living beyond that distance from a VHV-HVOL or within 50 m of a HV-HVOL. The present study, free from any participation bias, supports the previous international findings of an increase in AL incidence close to VHV-HVOL. In order to investigate for a potential role of ELF-MF in the results, ELF-MF at the residences close to HVOL are to be estimated, using models based on the annual current loads and local characteristics of the lines.

  3. Family circumstances and survival from childhood acute lymphoblastic leukaemia in West Germany.

    Science.gov (United States)

    Erdmann, Friederike; Kaatsch, Peter; Schüz, Joachim

    2015-04-01

    Little is known about the relationship between family characteristics and survival from childhood acute lymphoblastic leukaemia (ALL), which we studied for the first time in German children. ALL cases were diagnosed between 1992 and 1994 and information on family characteristics was collected during a previously conducted nationwide case-control study. Children were followed for 10 years after diagnosis, as few disease-related events occur afterwards. Cox proportional hazards models estimating hazard ratios (HR) were calculated using overall as well as event-free survival methods. Second born children showed statistically significant better survival compared to first or later born children, with HRs ranging between 0.54 and 0.64 compared to firstborns. Somewhat poorer survival was observed for children having 3 or more siblings. A relationship was found for parental age at child's diagnosis, with poorer survival for children with younger parents (≤25 years of age at child's diagnosis), or with older fathers. The HR was statistically significant for fathers being ≥41years of age (HR of 2.1). No relationship between degree of urbanization of the place of residence at diagnosis and ALL survival was observed. Family circumstances may have an impact on survival from childhood ALL in Germany. Further research is warranted to elaborate the relationship of specific family characteristics and ALL survival and to investigate possible differential adherence to therapy and interactions with physicians. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Ultraviolet B irradiation of human leukaemia HL-60 cells in vitro induces apoptosis

    International Nuclear Information System (INIS)

    Martin, S.J.; Cotter, T.G.

    1991-01-01

    UV radiation is known to be a potent agent for the induction of programmed cell death (apoptosis) in human skin. However, the mechanistic aspects of UV-induced apoptosis remain ill-defined. In this study the effects of varying periods of UV-irradiation on the human leukaemia HL-60 cell line and on five other human cell lines were investigated.HL-60 cells were found to rapidly undergo apoptosis en masse after short periods of UV-irradiation whereas prolonged exposure of these cells to this form of radiation induced a more rapid form of cell death which was suggestive of necrosis, the pathological mode of cell death. UV-induced apoptosis in cell lines was characterized by morphological changes as well as DNA fragmentation into unit multiples of ∼ 200 bp, which was indicative of endogenous endonuclease activation. This DNA fragmentation pattern was not detected in cells immediately after UV-irradiation, and was therefore not the result of direct UV-induced DNA damage. UV-induced apoptosis of the HL-60 cell line was found to require extracellular calcium and to be inhibited in a dose-dependent way by zinc added to the culture medium. (author)

  5. Osteonecrosis following treatment for childhood acute lymphoblastic leukaemia: The Southampton Children's Hospital experience.

    Science.gov (United States)

    Rhodes, A; Gray, J; Harvey, N; Davies, J H; Oreffo, R O C; Reading, I; Clarke, N M P; Aarvold, A

    2017-12-01

    To determine the prevalence of osteonecrosis (ON) in children following treatment of acute lymphoblastic leukaemia (ALL), characterise these cases and review treatment methods. All children diagnosed and treated for ALL between 01 January 2003 and 31 December 2013 at our centre were retrospectively reviewed. Logistic regression was used to investigate risk factors for ON occurrence. Of 235 children treated for ALL, 48/235 (20.4%) children suffered musculoskeletal symptoms necessitating radiological investigation. A total of 13 (5.5%) had MRI-diagnosed ON, with a median diagnosis time of 12 months (interquartile range 10 to 14) following initiation of chemotherapy.ON affected 40 joints in 13 children. The most commonly involved joints were hips (14 joints in eight patients) and knees (12 joints in seven patients).Older age at ALL diagnosis was associated with significantly increased risk of development of ON per year (odds ratio 1.35, 95% confidence interval 1.17 to 1.57, p < 0.001).Eight children underwent at least one surgical intervention. Joint arthroplasty was undertaken in nine joints of four children at a mean age of 18.3 years. All patients who underwent hip arthroplasty had previously received core decompression, with a mean time of 27.8 months (18 to 33) between treatments. ON is a significant complication of ALL treatment. Our results suggest risk stratification for development of ON by age, and targeted monitoring of high-risk joints is possible. ON treatment is varied with little evidence base.

  6. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images

    Science.gov (United States)

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-01-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method. PMID:26450665

  7. Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Mansour, Marc R; Reed, Casie; Eisenberg, Amy R; Tseng, Jen-Chieh; Twizere, Jean-Claude; Daakour, Sarah; Yoda, Akinori; Rodig, Scott J; Tal, Noa; Shochat, Chen; Berezovskaya, Alla; DeAngelo, Daniel J; Sallan, Stephen E; Weinstock, David M; Izraeli, Shai; Kung, Andrew L; Kentsis, Alex; Look, A Thomas

    2015-01-01

    Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T-ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R-mutant DND-41 cells as assessed by non-reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND-41 cells, and Ba/F3 cells transformed by an IL7R-mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND-41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T-ALL. © 2014 John Wiley & Sons Ltd.

  8. Current challenges and opportunities in treating adult patients with Philadelphia-negative acute lymphoblastic leukaemia.

    Science.gov (United States)

    Wolach, Ofir; Amitai, Irina; DeAngelo, Daniel J

    2017-12-01

    Significant advances have been made in recent years in the field of Philadelphia-negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk-stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric-inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk-adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk-stratification, choice of induction and post-remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL. © 2017 John Wiley & Sons Ltd.

  9. A study on the predictability of acute lymphoblastic leukaemia response to treatment using a hybrid oncosimulator.

    Science.gov (United States)

    Ouzounoglou, Eleftherios; Kolokotroni, Eleni; Stanulla, Martin; Stamatakos, Georgios S

    2018-02-06

    Efficient use of Virtual Physiological Human (VPH)-type models for personalized treatment response prediction purposes requires a precise model parameterization. In the case where the available personalized data are not sufficient to fully determine the parameter values, an appropriate prediction task may be followed. This study, a hybrid combination of computational optimization and machine learning methods with an already developed mechanistic model called the acute lymphoblastic leukaemia (ALL) Oncosimulator which simulates ALL progression and treatment response is presented. These methods are used in order for the parameters of the model to be estimated for retrospective cases and to be predicted for prospective ones. The parameter value prediction is based on a regression model trained on retrospective cases. The proposed Hybrid ALL Oncosimulator system has been evaluated when predicting the pre-phase treatment outcome in ALL. This has been correctly achieved for a significant percentage of patient cases tested (approx. 70% of patients). Moreover, the system is capable of denying the classification of cases for which the results are not trustworthy enough. In that case, potentially misleading predictions for a number of patients are avoided, while the classification accuracy for the remaining patient cases further increases. The results obtained are particularly encouraging regarding the soundness of the proposed methodologies and their relevance to the process of achieving clinical applicability of the proposed Hybrid ALL Oncosimulator system and VPH models in general.

  10. Developing "Care Assistant": A smartphone application to support caregivers of children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Wang, Jingting; Yao, Nengliang; Wang, Yuanyuan; Zhou, Fen; Liu, Yanyan; Geng, Zhaohui; Yuan, Changrong

    2016-04-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. Caring for children with ALL is an uncommon experience for parents without medical training. They urgently need professional assistance when their children are recovering at home. This paper documents the process of developing an Android application (app) "Care Assistant" for family caregivers of children with ALL. Key informant interviews and focus group studies were used before programming the app. The key informants and focus group members included: caregivers of children with ALL, cancer care physicians and nurses, and software engineers. We found several major challenges faced by caregivers: limited access to evidence-based clinic information, lack of financial and social assistance, deficient communications with doctors or nurses, lack of disease-related knowledge, and inconvenience of tracking treatments and testing results. This feedback was used to develop "Care Assistant". This app has eight modules: personal information, treatment tracking, family care, financial and social assistance, knowledge centre, self-assessment questionnaires, interactive platform, and reminders. We have also developed a web-based administration portal to manage the app. The usability and effectiveness of "Care Assistant" will be evaluated in future studies. © The Author(s) 2015.

  11. Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques.

    Science.gov (United States)

    Oliveira, Joao Batista A; Vagnini, Laura D; Petersen, Claudia G; Renzi, Adriana; Oliveira-Pelegrin, Gabriela R; Mauri, Ana L; Ricci, Juliana; Massaro, Fabiana C; Dieamant, Felipe; Cavagna, Mario; Baruffi, Ricardo L R; Franco, Jose G

    2016-01-01

    Certain gene polymorphisms are associated with implantation failure and pregnancy loss. Studies of leukaemia inhibitory factor (LIF) gene polymorphisms are scarce. The LIF single nucleotide polymorphism (SNP) thymine (T)/guanine (G) (rs929271) was studied in women to determine whether an association existed with pregnancy outcomes after intracytoplasmic sperm injection (ICSI); 411 women who underwent ICSI were recruited. DNA was extracted from the peripheral blood, and the LIF gene SNP T/G (rs929271) was genotyped using real-time polymerase chain reaction. Participants were divided into three groups according to their LIF genotype: T/T (n = 168), T/G (n = 202) and G/G (n = 41). All IVF and ICSI procedures were carried out under the same clinical and laboratory conditions. The ICSI cumulative results (from fresh plus frozen cycles) of each genotype group were analysed. The G/G genotype in women was associated with a higher implantation rate (T/T: 15.9%, T/G: 16.2%, G/G: 27.0%; P Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  12. A comparison of busulphan versus total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Ringden, O. [Huddinge Hospital, Stockholm (Sweden). Dept. of Clinical Immunology; Labopin, M.; Gorin, N.C. [Hopital Saint-Antoine, Paris (France). Centre International Greffes de Moelle; Tura, S. [Orsola University Hospital, Bologna (Italy); Arcese, W. [University `La Sapienza`, Rome (Italy). Haematology; Iriondo, A. [Hospital National, Santander (Spain); Zittoun, R. [Hotel-Dieu, Paris (France). Service d`Hematologie; Sierra, J. [Hospital Clinic, Barcelona (Spain)

    1996-06-01

    We retrospectively compared the outcome in patients in the EBMT database transplanted for acute leukaemia from January 1987 to January 1994 who received busulphan and cyclophosphamide (BU/CY) as a pretransplant regimen versus those who received cyclophosphamide and total-body irradiation (CY-TBI). The patients were matched for type of transplant (autologous bone marrow transplantation (ABMT) versus allogenic (BMT)), diagnosis (acute lymphoblast leukaemia (ALL) ora cute myeloid leukaemia (AML)), status (early first complete remission, CR-1) versus intermediate (second or later remission, first relapse), age, FAB classification for AML, prevention of graft-versus-host disease and year of transplantation. BU/CY and CY/TBI as pretransplant regimens gave similar results in all situations, except ABMT for ALL intermediate stages with more than 2 years from diagnosis to transplantation, where a lower RI and a higher LFS were associated with CY/TBI. (author).

  13. A comparison between the risks of childhood leukaemia from parental exposure to radiation in the Sellafield workforce and those displayed among the Japanese bomb survivors

    International Nuclear Information System (INIS)

    Little, M.P.

    1990-01-01

    The cases of childhood leukaemia found near the Sellafield plant and those observed in the offspring of the Japanese bomb survivors are analysed using a relative risk model. The leukaemia relative risk coefficients for total paternal (whole-body) pre-conception exposure for the Sellafield children are found to be about 50 to 80 times higher than the (gonadal) coefficients applying to the offspring of the bomb survivors. This difference is statistically significant, and in particular the risk coefficients for the Sellafield cohort are significantly positive, unlike those for the Japanese. If the assumption is made that the excess relative risk estimated from the Sellafield data lasts for the whole of the life of the offspring, the apparent population leukaemia risk to the first-generation offspring (for an England and Wales population) would be between 4% Sv -1 and 5% Sv -1 . (author)

  14. Neutrophil Gelatinase-Associated Lipocalin (NGAL), Pro-Matrix Metalloproteinase-9 (pro-MMP-9) and Their Complex Pro-MMP-9/NGAL in Leukaemias

    Energy Technology Data Exchange (ETDEWEB)

    Bouchet, Sandrine; Bauvois, Brigitte, E-mail: brigitte.bauvois@crc.jussieu.fr [INSERM U1138, Université Pierre et Marie Curie, Université Paris-Descartes, Centre de Recherche des Cordeliers, Paris 75006 (France)

    2014-04-04

    Matrix metalloproteinase (MMP)-9 and neutrophil gelatinase-associated lipocalin (NGAL) have gained attention as cancer biomarkers. The inactive zymogen form of MMP-9 (pro-MMP-9) also exists as a disulphide-linked heterodimer bound to NGAL in humans. Leukaemias represent a heterogeneous group of neoplasms, which vary in their clinical behavior and pathophysiology. In this review, we summarize the current literature on the expression profiles of pro-MMP-9 and NGAL as prognostic factors in leukaemias. We also report the expression of the pro-MMP-9/NGAL complex in these diseases. We discuss the roles of (pro)-MMP-9 (active and latent forms) and NGAL in tumour development, and evaluate the mechanisms by which pro-MMP-9/NGAL may influence the actions of (pro)-MMP-9 and NGAL in cancer. Emerging knowledge about the coexpression and the biology of (pro)-MMP-9, NGAL and their complex in cancer including leukaemia may improve treatment outcomes.

  15. Risk of leukaemia and residential exposure to air pollution in an industrial area in Northern Italy: a case-control study.

    Science.gov (United States)

    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.

  16. Sinonasal Lymphoma Presenting as a Probable Sanctuary Site for Relapsed B Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    W. Y. Lim

    2015-01-01

    Full Text Available Sinonasal lymphoma is a non-Hodgkin lymphoma (NHL representing 1.5% of all lymphomas. It presents as an unremitting ulceration with progressive destruction of midline sinonasal and surrounding structures. Poor prognosis warrants early treatment although diagnosis is challenging and frequently delayed. It is usually primary in origin and to our knowledge the sinonasal region has never been reported as a sanctuary site in leukaemia/lymphoma relapse. We present a unique case of B-cell ALL (acute lymphoblastic leukaemia with late relapse to the nasal septum as a sinonasal lymphoblastic lymphoma and with genetic support for this as a sanctuary site.

  17. Anti-proliferative effect of rosiglitazone in the human T-lymphocyte leukaemia cell line Jurkat cells.

    Science.gov (United States)

    Wei, Rui; Yu, Fei; Yang, Jin; Gao, Hongwei; Wang, Haining; Hong, Tianpei

    2017-12-23

    Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in various types of human cancer cells including leukaemia cells, and activation of PPARγ can inhibit cancer cell growth. However, whether PPARγ is expressed in Jurkat cells, a human T-lymphocyte leukaemia cell line, and whether activation of PPARγ affects cell biological behaviors remains to be clarified. In this study, we investigated the effect of a PPARγ activator rosiglitazone, under clinically relevant pharmacological concentrations, on the growth and apoptosis of Jurkat cells in vitro and explored the possible mechanism. Metformin was also included as a positive control for the anti-proliferative and pro-apoptotic effects. We found that PPARγ mRNA was transcribed in Jurkat cells. Treatment with rosiglitazone (5 µM, 10 µM, and 20 µM) or metformin (1 mM and 10 mM) inhibited cell proliferation, and induced cell cycle arrest at G0/G1 or S phase, respectively, in a dose-dependent manner. Although metformin significantly upregulated the protein levels of the pro-apoptotic markers cleaved-caspase 3 and Bax in Jurkat cells, rosiglitazone did not have such an effect. Moreover, rosiglitazone significantly upregulated the level of PPARγ, and downregulated the expression of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) in a dose-dependent manner. Our data indicate that rosiglitazone has an anti-proliferative effect in Jurkat cells, which may be at least partly mediated via downregulating IR and IGF-1R expression. Therefore, rosiglitazone may have a potential role not only for management of hyperglycaemia but also for control of tumor progression in patients with T-lymphocyte leukaemia and diabetes. © 2017 International Federation for Cell Biology.

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

    Energy Technology Data Exchange (ETDEWEB)

    Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor, E-mail: manzoork@aims.amrita.edu, E-mail: ullasmony@aims.amrita.edu [Amrita Centre for Nanoscience and Molecular Medicine, Amrita Institute of Medical Science, Cochin 682 041 (India)

    2011-07-15

    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 {approx} 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of {approx} 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 {approx} 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of {approx} 12 nm retained bright fluorescence over an extended duration of {approx} 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 {approx} 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of {approx} 8.2% in human peripheral blood cells (PBMCs) which are CD33{sup low}. 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.

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

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

    2011-01-01

    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 CD33 low . 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.

  1. FISH Detection of PML-RARA Fusion in ins(15;17 Acute Promyelocytic Leukaemia Depends on Probe Size

    Directory of Open Access Journals (Sweden)

    Lynda J. Campbell

    2013-01-01

    Full Text Available The diagnosis of acute promyelocytic leukaemia (APL is usually confirmed by cytogenetics showing the characteristic t(15;17, but a minority of patients have a masked PML/RARA fusion. We report ten patients with APL and no evidence of the t(15;17, in whom the insertion of RARA into PML could not be demonstrated by initial FISH studies using a standard dual fusion probe but was readily identified using smaller probes. Given the need for rapid diagnosis of APL, it is important to be aware of the false negative rate for large PML/RARA FISH probes in the setting of masked rearrangements.

  2. Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

    Directory of Open Access Journals (Sweden)

    Denise Niewerth

    2016-09-01

    Full Text Available Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML and acute lymphocytic leukaemia (ALL. Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1 and AML (COG-AAML07P1. Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12 obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001. These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028 between patients who did (n = 4 and did not reach complete remission (CR (n = 8, although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.

  3. Potentially avoidable hospital admissions in older patients with acute myeloid leukaemia in the USA: a retrospective analysis.

    Science.gov (United States)

    El-Jawahri, Areej; Keenan, Tanya; Abel, Gregory A; Steensma, David P; LeBlanc, Thomas W; Chen, Yi-Bin; Hobbs, Gabriela; Traeger, Lara; Fathi, Amir T; DeAngelo, Daniel J; Wadleigh, Martha; Ballen, Karen K; Amrein, Philip C; Stone, Richard M; Temel, Jennifer S

    2016-06-01

    Older adults (≥60 years of age) with acute myeloid leukaemia spend a substantial proportion of their life in hospital after diagnosis. We examined reasons for their hospital admissions and identified potentially avoidable hospital admissions (PAH) in this age group in the USA. In this retrospective analysis, we examined the reasons for hospital admissions in older patients diagnosed with and treated for acute myeloid leukaemia at two tertiary care hospitals in the USA. We included patients receiving intensive induction chemotherapy or non-intensive treatment. We excluded those with acute promyelocytic leukaemia, those seen only for a one-time consultation who received primary treatment elsewhere, and those who received supportive care alone. We identified the eligible cohort using the Dana-Farber Cancer Institute and Massachusetts General Hospital Leukemia Clinical Research Information Systems database. Practising oncologists used a consensus-driven medical record review process to identify the primary reason for each hospital admission and categorise it as potentially avoidable or not avoidable on the basis of an adaptation of Graham's criteria for PAH. We used multivariable logistic regression analyses to identify predictors of PAH. Between May 1, 2005, and Dec 23, 2011, we assessed 1040 hospital admissions (excluding initial admission for diagnosis) in 329 consecutively admitted patients. The most common primary reasons for hospital admissions were: fever or infection (396 [38%]), planned admission for chemotherapy or transplantation (391 [38%]), and uncontrolled symptoms (102 [10%]). We identified 172 (27%) of 649 unplanned hospital admissions as potentially avoidable; among these admissions, 82 (48%) were readmissions because of previous premature hospital discharge, 32 (19%) because of problems that could have been managed in the outpatient setting, and 26 (15%) because of failure of timely outpatient follow-up. In a mixed logistic regression model, higher

  4. New Complex Chromosomal Translocation in Chronic Myeloid Leukaemia: t(9;18;22(q34;p11;q11

    Directory of Open Access Journals (Sweden)

    Abdeljabar El Andaloussi

    2007-01-01

    Full Text Available A Chronic myeloid leukaemia (CML case with a new complex t(9;18;22(q34;p11;q11 of a 29-year-old man is being reported. For the first time, this translocation has been characterized by karyotype complemented with fluorescence in situ hybridization (FISH. In CML, the complex and standard translocations have the same prognosis. The patient was treated with standard initial therapy based on hydroxyurea before he died due to heart failure four months later. Our finding indicates the importance of combined cytogenetic analysis for diagnosis and guidance of treatment in clinical diagnosis of CML.

  5. Phenotypically Dormant and Immature Leukaemia Cells Display Increased Ribosomal Protein S6 Phosphorylation.

    Directory of Open Access Journals (Sweden)

    Monica Pallis

    Full Text Available Mechanistic/mammalian target of rapamycin (mTOR activity drives a number of key metabolic processes including growth and protein synthesis. Inhibition of the mTOR pathway promotes cellular dormancy. Since cells from patients with acute myeloid leukaemia (AML can be phenotypically dormant (quiescent, we examined biomarkers of their mTOR pathway activity concurrently with Ki-67 and CD71 (indicators of cycling cells by quantitative flow cytometry. Using antibodies to phosphorylated epitopes of mTOR (S2448 and its downstream targets ribosomal protein S6 (rpS6, S235/236 and 4E-BP1 (T36/45, we documented that these phosphorylations were negligible in lymphocytes, but evident in dormant as well as proliferating subsets of both mobilised normal stem cell harvest CD34+ cells and AML blasts. Although mTOR phosphorylation in AML blasts was lower than that of the normal CD34+ cells, p-4E-BP1 was 2.6-fold higher and p-rpS6 was 22-fold higher. Moreover, in contrast to 4E-BP1, rpS6 phosphorylation was higher in dormant than proliferating AML blasts, and was also higher in the immature CD34+CD38- blast subset. Data from the Cancer Genome Atlas show that rpS6 expression is associated with that of respiratory chain enzymes in AML. We conclude that phenotypic quiescence markers do not necessarily predict metabolic dormancy and that elevated rpS6 ser235/236 phosphorylation is characteristic of AML.

  6. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  7. Morphological and immunophenotypical features of hairy cell leukaemia involving lymph nodes and extranodal tissues.

    Science.gov (United States)

    Cortazar, Jacqueline M; DeAngelo, Daniel J; Pinkus, Geraldine S; Morgan, Elizabeth A

    2017-07-01

    Hairy cell leukaemia (HCL) is a rare B cell neoplasm that mainly affects bone marrow (BM), peripheral blood (PB) and spleen. Involvement of lymph nodes and extranodal structures is considered infrequent. Herein we describe our institutional experience of nodal (n = 10) and extranodal (n = 3) HCL during a 30-year period. Ten patients had prior evidence of HCL within the BM or PB at a median 35.8 months before nodal/extranodal diagnosis (range: <1-175 months), and HCL was diagnosed concurrently within the bone marrow of one additional patient. Nodal involvement showed distinct architectural patterns, including diffuse (62% of cases), sinusoidal (25%) and nodular (13%). Extranodal involvement was characterized as diffuse infiltration through underlying structures in all cases. Morphological features ranged from classic 'fried-egg' cytology to a plasmacytoid appearance. Nodal/extranodal disease showed an overlapping immunophenotypical profile with other small B cell lymphomas, including expression of cyclin D1 (70%), CD43 (55%), CD10 (38%) and CD5 (8%). Rates of both CD43 and CD10 reactivity were higher than described previously in leukaemic HCL, suggesting that expression may be enriched in cases with extramedullary extension. Although uncommon, HCL should be considered in the differential diagnosis of small B cell neoplasms involving nodal/extranodal sites, given the therapeutic implications. In particular, recent discoveries including detection of the BRAF V 600E mutation in nearly all cases of HCL and the availability of an antibody to CD103 for use in paraffin-embedded tissues will facilitate the distinction of HCL from other small B cell lymphomas in the nodal/extranodal setting. © 2017 John Wiley & Sons Ltd.

  8. Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

    Science.gov (United States)

    Ridinger-Saison, M; Evanno, E; Gallais, I; Rimmelé, P; Selimoglu-Buet, D; Sapharikas, E; Moreau-Gachelin, F; Guillouf, C

    2013-01-01

    Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. PMID:23852375

  9. [Acute pancreatitis during chemotherapy of acute lymphoblastic leukaemia complicated with pseudocyst].

    Science.gov (United States)

    Sikorska-Fic, Barbara; Stańczak, Elzbieta; Matysiak, Michał; Kamiński, Andrzej

    2008-01-01

    The incidence of pancreatitis in patients with haematopoetic neoplasms who are treated with L-asparaginase is fom 2 to 24%. In majority of cases the pancreatitis is oedematous and self-limiting. Acute haemorrhagic or necrotizing pancreatitis caused by L-asparaginase is rare but potentially life-threatening complication. We present 2 cases of acute pancreatitis in children aged 2 and 4 years. They were diagnosed to have acute lymphoblastic leukaemia and were treated according to the ALLLIC BFM 2002 protocol. Acute pancreatitis developed in these children after induction therapy and was followed by formation of a pseudocyst. In both cases the diagnosis of this complication was made directly after phase I of the protocol I (after eighth dose of L-Asparaginase). In the first case the course of acute pancreatitis was mild. Normalization of the amylase levels occurred after 7 days and the diagnosis of post inflammatory cyst was made 15 days after the first signs of the disease. But thereafter, during the additional complication (pneumonia with Pseudomonas aeruginosa bacteriemia) the pancreatic cyst became infected. In the second case acute pancreatitis had a severe course and the child required treatment in the Intensive Care Unit for 21 days. The cyst was diagnosed after 20 days from the beginning of symptoms. The surgical procedure, applied in both cases was internal drainage by anastomosis of the cyst with the back wall of the stomach. Antileukaemic treatment was recommenced after 6-8 weeks when complications resolved. Currently both children are well and remain in haematological remission and continue maintenance chemotherapy.

  10. The implications of an incidental chronic lymphocytic leukaemia in a resection specimen for colorectal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Alberts Justin C

    2007-10-01

    Full Text Available Abstract Background Colorectal cancer and B cell chronic lymphocytic leukaemia (CLL have a significant incidence, which are increasing with the aging population. Evidence has been presented in the literature to suggest that the synchronous presentation of colorectal cancer and B cell CLL may be more than simply coincidental for these two common malignancies. We report an unusual case of a presumed B cell CLL diagnosed on the basis of histological analysis of lymph nodes recovered from a resection specimen for rectal adenocarcinoma. We considered aetiological factors which may have linked the synchronous diagnosis of the two malignancies and the potential implications for the natural history of the two malignancies on one another. Case presentation A 70-year-old male underwent low anterior resection with total mesorectal excision for a rectal adenocarcinoma. His co-morbid conditions were chronic obstructive airways disease and ischaemic heart disease. General examination revealed no lymphadenopathy. Full blood count, urea and electrolytes and liver function tests were all within normal limits. As well as confirming a pT3 N1 adenocarcinoma, histological analysis showed lymph nodes with an infiltrate of small lymphoid cells. Immunohistochemical studies showed these cells to be in keeping with B cell CLL. Conclusion Whilst unable to identify any common aetiological factors in the two malignancies in our patient, immunosuppression and genetic abnormalities have been identified as possible bases for an observed epidemiological association between colorectal cancer and haematological malignancies. Examples such as our case of synchronous diagnosis of two malignancies in a patient are likely to increase with the aging population. The potential affects of one malignancy on the natural history of the other warrants further study. In our case, we considered that slow progression of the B cell CLL may increase the risk of recurrent rectal adenocarcinoma.

  11. Survival of Mexican Children with Acute Myeloid Leukaemia Who Received Early Intensification Chemotherapy and an Autologous Transplant

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    Elva Jiménez-Hernández

    2015-01-01

    Full Text Available Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients, diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients, diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy. Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P=0.041. Overall survival for Group A (18, 90% was higher than that for Group B (60%. Complete remission continued for two years of follow-up. Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy.

  12. Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Garofalo, Michela; Romano, Giulia; Quintavalle, Cristina; Romano, Maria Fiammetta; Chiurazzi, Federico; Zanca, Ciro; Condorelli, Gerolama

    2007-03-15

    B-cell chronic lymphocytic leukaemia (B-CLL) cells fail to undergo apoptosis. The mechanism underlying this resistance to cell death is still largely unknown. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells, and thus represents an attractive tool for the treatment of cancer. Unfortunately, lymphocytes from B-CLL patients are resistant to TRAIL-mediated apoptosis. Thus, we aimed to study the involvement of PED, a DED-family member with a broad antiapoptotic action, in this resistance. We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED. Treatment of B-CLL cells with specific PED antisense oligonucleotides, a protein synthesis inhibitor or HDAC inhibitors, induced a significant downregulation of PED and sensitized these cells to TRAIL-induced cell death. These findings suggest a direct involvement of PED in resistance to TRAIL-induced apoptosis in B-CLL. It also identifies this DED-family member as a potential therapeutic target for this form of leukaemia. (c) 2006 Wiley-Liss, Inc.

  13. Cyclooxygenase-2 (COX-2 Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1 Activity in Acute Myeloid Leukaemia Cells

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    Sergio Rutella

    2013-08-01

    Full Text Available Indoleamine 2,3-dioxygenase 1 (IDO1 metabolizes L-tryptophan to kynurenines (KYN, inducing T-cell suppression either directly or by altering antigen-presenting-cell function. Cyclooxygenase (COX-2, the rate-limiting enzyme in the synthesis of prostaglandins, is over-expressed by several tumours. We aimed at determining whether COX-2 inhibitors down-regulate the IFN-g-induced expression of IDO1 in acute myeloid leukaemia (AML cells. IFN-γ at 100 ng/mL up-regulated COX-2 and IDO1 in HL-60 AML cells, both at mRNA and protein level. The increased COX-2 and IDO1 expression correlated with heightened production of prostaglandin (PGE2 and kynurenines, respectively. Nimesulide, a preferential COX-2 inhibitor, down-regulated IDO1 mRNA/protein and attenuated kynurenine synthesis, suggesting that overall IDO inhibition resulted both from reduced IDO1 gene transcription and from inhibited IDO1 catalytic activity. From a functional standpoint, IFN-g-challenged HL-60 cells promoted the in vitro conversion of allogeneic CD4+CD25− T cells into bona fide CD4+CD25+FoxP3+ regulatory T cells, an effect that was significantly reduced by treatment of IFN-γ-activated HL-60 cells with nimesulide. Overall, these data point to COX-2 inhibition as a potential strategy to be pursued with the aim at circumventing leukaemia-induced, IDO-mediated immune dysfunction.

  14. Chronic lymphocytic leukaemia and radiation: findings among workers at five US nuclear facilities and a review of the recent literature.

    Science.gov (United States)

    Schubauer-Berigan, Mary K; Daniels, Robert D; Fleming, Donald A; Markey, Andrea M; Couch, James R; Ahrenholz, Steven H; Burphy, Jenneh S; Anderson, Jeri L; Tseng, Chih-Yu

    2007-12-01

    The aetiology of chronic lymphocytic leukaemia (CLL) is largely unknown. Despite compelling evidence for ionising radiation as a cause of most forms of leukaemia, CLL was not found to be radiogenic in early studies. Herein we describe the recent evidence for causation of CLL by ionising and non-ionising radiation, including a nested case-control study conducted within a cohort of 94 517 US workers at four nuclear weapons facilities and a nuclear naval shipyard. Forty-three cases of CLL deaths and 172 age-matched controls were identified with follow-up up to between 1990 and 1996. Radiation exposure from external sources and plutonium (lagged 10 years) was assessed for each worker, based on monitoring records. The excess relative rate (ERR) was estimated for workers receiving elevated doses compared to unexposed workers, controlling for possible risk factors. The ERR per 10 mSv was -0.020 (95% confidence interval: <0, 0.14) based on all exposed workers. However, for workers receiving <100 mSv, the ERR per 10 mSv was 0.20 (-0.035, 0.96). Recent studies of uranium miners and other populations have shown elevations of CLL possibly associated with ionising and non-ionising radiation. New studies should use incident cases and sufficient latency to account for the expected lengthy induction period for CLL.

  15. Rural population mixing and childhood leukaemia: effects of the North Sea oil industry in Scotland, including the area near Dounreay nuclear site

    International Nuclear Information System (INIS)

    Kinlen, L.J.; O'Brien, F.; Clarke, K.; Balkwill, A.; Matthews, F.

    1993-01-01

    The objective of this study was to determine if any excess of childhood leukaemia and non-Hodgkin's lymphoma was associated with certain striking examples of population mixing in rural Scotland produced by the North Sea oil industry. Details were traced for over 30 000 workers (25 yrs old) involved in the construction of the large oil terminals in the Shetland and Orkney islands in northern Scotland or employed offshore. Home addresses of the 17160 Scottish residents were postcoded, integrated with census data, and then classified as urban or rural. Rural postcode sectors, ranked by proportion of oil workers, were grouped into three categories with similar numbers of children but contrasting densities of oil workers. The incidence of leukaemia and non-Hodgkin's lymphoma was examined in these rural (and also in urban) categories in the periods 1974-8, 1979-83 and 1984-8. A significant excess of leukaemia and non-Hodgkin's lymphoma was found in 1979-83 in the group of rural home areas with the largest proportion of oil workers, following closely on large increases in the workforce. The area near the Dounreay nuclear installation, where an excess of leukaemia is already well known, was within the rural high oil category. (Author)

  16. Leukaemia inhibitory factor (LIF) gene mutations in women diagnosed with unexplained infertility and endometriosis have a negative impact on the IVF outcome a pilot study

    Czech Academy of Sciences Publication Activity Database

    Novotný, Z.; Křižan, Jiří; Šíma, R.; Šíma, Petr; Uher, P.; Zech, N.; Huttelová, R.; Baborová, P.; Ulčová-Gallová, Z.; Šubrt, I.; Ulmanová, E.; Houdek, Z.; Rokyta, Z.; Babuška, V.; Králíčková, M.

    2009-01-01

    Roč. 55, č. 3 (2009), s. 92-97 ISSN 0015-5500 R&D Projects: GA MZd NR9135 Institutional research plan: CEZ:AV0Z50200510 Keywords : leukaemia inhibitory factor * infertility * mutation Subject RIV: EC - Immunology Impact factor: 0.924, year: 2009

  17. PCR-positivity in harvested bone marrow predicts relapse after transplantation with autologous purged bone marrow in children in second remission of precursor B-cell acute leukaemia

    NARCIS (Netherlands)

    Vervoordeldonk, S. F.; Merle, P. A.; Behrendt, H.; Steenbergen, E. J.; van den Berg, H.; van Wering, E. R.; von dem Borne, A. E.; van der Schoot, C. E.; van Leeuwen, E. F.; Slaper-Cortenbach, I. C.

    1997-01-01

    Purging of autologous bone marrow (BM) grafts of children in second remission after a relapse of precursor B acute lymphoblastic leukaemia (ALL) in the BM has been carried out in our laboratory since 1987, initially by complement mediated cell lysis. This protocol was extended by performing an

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

    NARCIS (Netherlands)

    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.; Meulendijks, Ine; Cornelisse, Petra; van Hooije, Christel; Biaggi, Christine; van der Holt, Bronno; Labopin, Myriam; de Bock, B.; Breems, D. A.; Zachee, P.; Ferrant, A.; Vekemans, M. C.; Mineur, P.; Delannoy, A.; Maertens, J.; Verhoef, G.; van Steenweghen, S.; Bosly, A.; Graux, C.; Jaeger, E.; Theobald, M.; Beck, J.; Fischer, Th; Gjertsen, B. T.; Bargetzi, M.; Wernli, M.; Passweg, J.; Gratwohl, A.; Leoncini-Francini, L.; Marini, G.; Fey, M. F.; Pabst, T.; Chapuis, B.; Chalandon, Y.; Herr, A.; Wuillemin, W. A.; Gregor, M.; Piquet, D.; Zimmerli-Schwab, B.; Hess, U.; Binder, D.; Kroner, Th; Mantz, M.; Jacky, E.; Schanz, U.; Wittebol, S.; van der Lelie, J.; Leeksma, O. C.; Janssen, J. J. W. M.; Ossenkoppele, G. J.; Huijgens, P. C.; Deenik, W.; Posthuma, W.; Wijermans, P. W.; Schaafsma, M. R.; Legdeur, M.; Huls, G.; Vellenga, E.; Daenen, S. M. G. J.; Voogt, P. J.; Joosten, P.; Schouten, H. C.; Laterveen, L.; Biesma, D. H.; de Weerdt, O.; Löwenberg, B.; Cornelissen, J. J.; Sonneveld, P.; Zijlmans, J.; Jongen-Lavrencic, M.; de Greef, G. E.; van Zaanen, H.; Verdonck, L. F.; Kuball, J.; van Marwijk Kooy, M.

    2015-01-01

    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

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

    NARCIS (Netherlands)

    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; Lowenberg, Bob; Ossenkoppele, Gert; Vellenga, Edo; Cornelissen, Jan J.

    2015-01-01

    Background 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,

  20. Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value : results from a prospective clinical trial

    NARCIS (Netherlands)

    van der Holt, Bronno; Breems, Dimitri A.; Beverloo, H. Berna; van den Berg, Eva; Burnett, Alan K.; Sonneveld, Pieter; Lowenberg, Bob

    Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed

  1. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Directory of Open Access Journals (Sweden)

    Virijevic Marijana

    2016-12-01

    Full Text Available Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2 genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK. The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up.

  2. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study

    NARCIS (Netherlands)

    Fink, Anna Maria; Bahlo, Jasmin; Robrecht, Sandra; Al-Sawaf, Othman; Aldaoud, Ali; Hebart, Holger; Jentsch-Ullrich, Kathleen; Dörfel, Steffen; Fischer, Kirsten; Wendtner, Clemens-Martin; Nösslinger, Thomas; Ghia, Paolo; Bosch, Francesc; Kater, Arnon P.; Döhner, Hartmut; Kneba, Michael; Kreuzer, Karl-Anton; Tausch, Eugen; Stilgenbauer, Stephan; Ritgen, Matthias; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

    2017-01-01

    Background The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. Methods In this

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

    DEFF Research Database (Denmark)

    Villumsen, Marie; Sørup, Signe; Jess, Tine

    2009-01-01

    . 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......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...... 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...

  4. Effectiveness of environmental control measures to decrease the risk of invasive aspergillosis in acute leukaemia patients during hospital building work.

    Science.gov (United States)

    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.

  5. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response : A randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON)

    NARCIS (Netherlands)

    Thielen, Noortje; van der Holt, Bronno; Cornelissen, Jan J.; Verhoef, Gregor E. G.; Gussinklo, Titia; Biemond, Bart J.; Daenen, Simon M. G.; Deenik, Wendy; Kooy, Rien van Marwijk; Petersen, Eefke; Smit, Willem M.; Valk, Peter J. M.; Ossenkoppele, Gert J.; Janssen, Jeroen J. W. M.

    2013-01-01

    Background: Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR4.5, quantitative reverse-transcription polymerase chain

  6. Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: A randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON)

    NARCIS (Netherlands)

    Thielen, Noortje; van der Holt, Bronno; Cornelissen, Jan J.; Verhoef, Gregor E. G.; Gussinklo, Titia; Biemond, Bart J.; Daenen, Simon M. G.; Deenik, Wendy; van Marwijk Kooy, Rien; Petersen, Eefke; Smit, Willem M.; Valk, Peter J. M.; Ossenkoppele, Gert J.; Janssen, Jeroen J. W. M.

    2013-01-01

    Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR(4.5), quantitative reverse-transcription polymerase chain reaction

  7. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

    NARCIS (Netherlands)

    Hungate, Eric A.; Vora, Sapana R.; Gamazon, Eric R.; Moriyama, Takaya; Best, Timothy; Hulur, Imge; Lee, Younghee; Evans, Tiffany-Jane; Ellinghaus, Eva; Stanulla, Martin; Rudant, Jéremie; Orsi, Laurent; Clavel, Jacqueline; Milne, Elizabeth; Scott, Rodney J.; Pui, Ching-Hon; Cox, Nancy J.; Loh, Mignon L.; Yang, Jun J.; Skol, Andrew D.; Onel, Kenan

    2016-01-01

    Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3

  8. Expression of leukaemia inhibitory factor at the conceptus-maternal interface during preimplantation development and in the endometrium during the oestrous cycle in the mare

    NARCIS (Netherlands)

    De Ruijter-Villani, M.; Deelen, C.; Stout, T. A E

    2016-01-01

    Leukaemia inhibitory factor (LIF) plays a critical role in blastocyst development and implantation in several species. The present study investigated mRNA and protein expression for LIF, as well as the low-affinity LIF receptor (LIFR) and interleukin-6 signal transducer (IL6ST), in equine

  9. High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies

    DEFF Research Database (Denmark)

    Vaitkeviciene, G; Forestier, E; Hellebostad, M

    2011-01-01

    Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1–15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland...

  10. Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

    Directory of Open Access Journals (Sweden)

    Bernhard F Gibbs

    Full Text Available Stem cell factor (SCF is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1 in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

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

    Directory of Open Access Journals (Sweden)

    Suzanne E Brooks

    Full Text Available 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.

  12. Allergic complications of L-asparaginase therapy in children with acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Konstantinidis Georgios

    2011-01-01

    Full Text Available Introduction. L-asparaginase (L-ASP is one of the most effective medications for the treatment of acute lymphoblastic leukaemia (ALL in children, and allergic reactions to the therapy are considered the most significant side effects. Objective. The aim of this study was to determine the prevalence and type of allergic reactions, as well as to identify potential risk factors for the development of allergic reactions during L-ASP therapy in children with ALL. Methods. The study encompassed 70 patients under 18 years of age, who were treated at the Institute for Child and Youth Healthcare of Vojvodina, Novi Sad in the period January 2000 - June 2009. We analyzed the frequency and type of allergic reactions during the administration of L-ASP, the onset of allergic reaction in relation to the phase of therapy of underlying disease, as well as the prevalence of allergic reactions in relation to drug administration method. Results. Allergic reaction manifested in 17 patients (24%. In 14 patients (82% allergic reaction to L-ASP manifested as urticaria, bronchospasm or anaphylaxis, whereas a mild local reaction was observed in only three patients (18%. In a group treated, according to the high-risk protocol, the prevalence of allergic reactions was statistically significantly higher in the intermediate-risk group of patients (p<0.01, i.e. statistically significantly more frequent, as compared to the standard-risk group of patients (p<0.05. The majority of patients (11; 65% developed allergic reactions to the 9th dose of L-ASP, i.e. the first dose during the reinduction phase. The time interval between the last L-ASP dose in the induction phase and the 1st dose in the reinduction phase was at least four weeks. With respect to administration method, the majority of patients (16; 94% developed allergic reaction after intravenous application of L-ASP. Conclusion. Potential risk factors for the development of allergic reaction to L-ASP are a high-risk therapy

  13. Prevalence and risk factors of feline leukaemia virus and feline immunodeficiency virus in peninsular Malaysia.

    Science.gov (United States)

    Bande, Faruku; Arshad, Siti Suri; Hassan, Latiffah; Zakaria, Zunita; Sapian, Nurul Asyikin; Rahman, Noor Alimah; Alazawy, Amer

    2012-03-22

    Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) are major causes of morbidity and mortality in domestic and wild felids. Despite the clinical importance of feline retroviruses and the growing interest in cats as pets, information about FeLV and FIV in Malaysia is presently insufficient to properly advise veterinarians and pet owners. A cross-sectional study was carried out from January 2010 to December 2010 to determine the prevalence and risk factors associated with FeLV and FIV among domestic cats in peninsular Malaysia. Plasma samples were harvested from the blood of 368 domestic cats and screened for evidence of FeLV p27 antigen and FIV antibodies, using an immunochromatographic kit. Additionally, data on cat demographics and health were collected using a structured questionnaire, and were evaluated as potential risk factors for FeLV or FIV status. Of the 368 cats that were evaluated in this study, 12.2% (45/368; 95% CI = 8.88 - 15.58) were positive for FeLV p27 antigen, 31.3%, (115/368; 95% CI = 26.51 - 35.99) were seropositive to FIV antibodies, and 4.3% (16/368; 95% CI = 2.27 - 6.43) had evidence of both viruses. Factors found to significantly increase the risk for FeLV seropositivity include sex, age, behaviour, sickness, and living in a multi-cat household. Seropositive response to FIV was significantly associated with sex, neuter status, age, behaviour, and health status. The present study indicates that FeLV and FIV are common among domestic cats in peninsular Malaysia, and that factors related to cat demographics and health such as age, sex, behaviour, health status and type of household are important predictors for seropositive status to FeLV or FIV in peninsular Malaysia. High prevalence of FeLV or FIV observed in our study is of concern, in view of the immunosuppressive potentials of the two pathogens. Specific measures for control and prevention such as screening and routine vaccination are needed to ensure that FeLV and FIV

  14. Prevalence and risk factors of feline leukaemia virus and feline immunodeficiency virus in peninsular Malaysia

    Directory of Open Access Journals (Sweden)

    Bande Faruku

    2012-03-01

    Full Text Available Abstract Background Feline leukaemia virus (FeLV and feline immunodeficiency virus (FIV are major causes of morbidity and mortality in domestic and wild felids. Despite the clinical importance of feline retroviruses and the growing interest in cats as pets, information about FeLV and FIV in Malaysia is presently insufficient to properly advise veterinarians and pet owners. A cross-sectional study was carried out from January 2010 to December 2010 to determine the prevalence and risk factors associated with FeLV and FIV among domestic cats in peninsular Malaysia. Plasma samples were harvested from the blood of 368 domestic cats and screened for evidence of FeLV p27 antigen and FIV antibodies, using an immunochromatographic kit. Additionally, data on cat demographics and health were collected using a structured questionnaire, and were evaluated as potential risk factors for FeLV or FIV status. Results Of the 368 cats that were evaluated in this study, 12.2% (45/368; 95% CI = 8.88 - 15.58 were positive for FeLV p27 antigen, 31.3%, (115/368; 95% CI = 26.51 - 35.99 were seropositive to FIV antibodies, and 4.3% (16/368; 95% CI = 2.27 - 6.43 had evidence of both viruses. Factors found to significantly increase the risk for FeLV seropositivity include sex, age, behaviour, sickness, and living in a multi-cat household. Seropositive response to FIV was significantly associated with sex, neuter status, age, behaviour, and health status. Conclusions The present study indicates that FeLV and FIV are common among domestic cats in peninsular Malaysia, and that factors related to cat demographics and health such as age, sex, behaviour, health status and type of household are important predictors for seropositive status to FeLV or FIV in peninsular Malaysia. High prevalence of FeLV or FIV observed in our study is of concern, in view of the immunosuppressive potentials of the two pathogens. Specific measures for control and prevention such as screening and

  15. Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia.

    Science.gov (United States)

    Keating, Gillian M

    2012-05-28

    Azacitidine (Vidaza®) is a pyrimidine nucleoside analogue of cytidine. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), as well as summarizing its pharmacological properties. The randomized, multicentre Cancer and Leukemia Group B 9221 trial compared the efficacy of subcutaneous azacitidine with that of supportive care alone in patients with MDS fulfilling French-American-British (FAB) classification criteria. The overall response rate, the complete response rate and the complete plus partial response rate were significantly higher in patients receiving azacitidine than in those receiving supportive care alone. The randomized, open-label, multicentre AZA-001 trial compared the efficacy of subcutaneous azacitidine with that of conventional care in adults with higher-risk (i.e. International Prognostic Scoring System intermediate-2-risk or high-risk classification) MDS/AML. Prior to randomization, investigators preselected patients to the conventional care strategy considered most appropriate (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). The median duration of overall survival was significantly prolonged by 9.4 months in patients with higher-risk MDS receiving azacitidine versus those receiving conventional care. The survival benefit seen with azacitidine versus conventional care was maintained across various patient subgroups (e.g. in patients aged ≥75 years, in those who did not achieve complete remission and in patients with WHO-defined AML). The efficacy of subcutaneous or intravenous azacitidine was also shown in a noncomparative trial in Japanese patients with MDS fulfilling FAB classification criteria, and registry programmes in various countries support the efficacy of azacitidine in patients with MDS. Azacitidine was generally well tolerated in patients with MDS, including in the elderly. Across trials

  16. Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey

    Directory of Open Access Journals (Sweden)

    Kodama Yuko

    2012-04-01

    Full Text Available Abstract Background The financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML who have been treated with imatinib. Methods A questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008. Results A total of 577 patients completed the questionnaire. Their median age was 61 years (range, 15–94. A financial burden was felt by 41.2 % (28 of 68 of the patients treated with imatinib in 2000, 70.8 % (201 of 284 in 2005, and 75.8 % (400 of 528 in 2008. Overall, 182 patients (31.7 % considered its discontinuation because of the financial burden and 15 (2.6 % temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients’ median annual household incomes were 49,615 US Dollars (USD, 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR = 0.96, 95 % CI: 0.95–0.98, p ≪ 0.0001 for 1-year increments, and patients with higher household incomes (OR = 0.92, 95 % CI: 0.85–0.99, p = 0.03 for 10,000 USD-increments were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR = 2.21, 95 % CI: 1.28–4.28, p = 0.004 for 10,000 USD-increments were more likely to have considered discontinuing their imatinib treatment. Conclusions The proportion of CML patients who sensed a financial burden increased between 2000 and 2008

  17. Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

    International Nuclear Information System (INIS)

    Reske, S.N.; Buchmann, I.; Seitz, U.; Glatting, G.; Neumaier, B.; Kotzerke, J.; Buck, A.; Martin, H.; Bergmann, L.

    2001-01-01

    Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates ( 188 Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2±2.1 (range 6.9-15.8) GBq 188 Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4±5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188 Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia. (orig.)

  18. Azole-based chemoprophylaxis of invasive fungal infections in paediatric patients with acute leukaemia: an internal audit.

    Science.gov (United States)

    Yunus, Sara; Pieper, Stephanie; Kolve, Hedwig; Goletz, Grazyna; Jürgens, Heribert; Groll, Andreas H

    2014-03-01

    Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs) are at high risk of life-threatening invasive fungal infections (IFIs). We analysed implementation, safety and efficacy of a standard operating procedure for oral, azole-based, mould-active antifungal prophylaxis. Patients with AML and RALs aged ≥13 years received 200 mg of posaconazole three times daily and patients aged 2-12 years received 200 mg of voriconazole two times daily from the completion of chemotherapy until haematopoietic recovery. Algorithms for fever or focal findings in all patients with haematological malignancies included blood cultures, high-resolution CT and other appropriate imaging, serial serum galactomannan, invasive diagnostics and pre-emptive therapy with change in class if on antifungal medication. From 2006 to 2010, 40 patients (0.8-17 years; 21 males) with newly diagnosed AML (n = 31) or RAL (n = 9) were admitted, of whom 36 received a total of 149 courses of chemotherapy (reasons for exclusion: contraindications and early death ≤3 days). Azole prophylaxis was given in 87.2% (n = 130/149) of episodes. Pre-emptive antifungal therapy for pulmonary infiltrates was initiated in 5/36 (13.9%) patients or 6/130 (4.6%) episodes for a duration of 3-22 days. No proven or probable IFIs occurred. Adverse events (AEs) were common but mostly low grade and reversible. Three courses (2.3%) were discontinued due to AEs. In simultaneously admitted new patients with acute lymphatic leukaemia (ALL; n = 101) and paediatric lymphomas (n = 29) not receiving standard antifungal prophylaxis, proven/probable IFIs occurred in 4 patients with ALL (4.0%) and 7/130 patients (5.4%) received pre-emptive therapy. Azole-based, mould-active antifungal prophylaxis in high-risk paediatric patients with AML and RALs was satisfactorily implemented, well tolerated and effective. The low rate of IFIs in patients with ALL/lymphoma supports the lack of a general indication for

  19. Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

    Directory of Open Access Journals (Sweden)

    Kosinski Marek

    2011-04-01

    Full Text Available Abstract 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

  20. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

    Science.gov (United States)

    Iland, Harry J; Collins, Marnie; Bradstock, Ken; Supple, Shane G; Catalano, Alberto; Hertzberg, Mark; Browett, Peter; Grigg, Andrew; Firkin, Frank; Campbell, Lynda J; Hugman, Amanda; Reynolds, John; Di Iulio, Juliana; Tiley, Campbell; Taylor, Kerry; Filshie, Robin; Seldon, Michael; Taper, John; Szer, Jeff; Moore, John; Bashford, John; Seymour, John F

    2015-09-01

    Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. 124

  1. Transcriptional activation of immediate-early gene ETR101 by human T-cell leukaemia virus type I Tax

    DEFF Research Database (Denmark)

    Chen, Li; Ma, Shiliang; Li, Bo

    2003-01-01

    Human T-cell leukaemia virus type I (HTLV-I) Tax regulates viral and cellular gene expression through interactions with multiple cellular transcription pathways. This study describes the finding of immediate-early gene ETR101 expression in HTLV-I-infected cells and its regulation by Tax. ETR101...... was persistently expressed in HTLV-I-infected cells but not in HTLV-I uninfected cells. Expression of ETR101 was dependent upon Tax expression in the inducible Tax-expressing cell line JPX-9 and also in Jurkat cells transiently transfected with Tax-expressing vectors. Tax transactivated the ETR101 gene promoter...... in a transient transfection assay. A series of deletion and mutation analyses of the ETR101 gene promoter indicated that a 35 bp region immediately upstream of the TATA-box sequence, which contains a consensus cAMP response element (CRE) and a G+C-rich sequence, is the critical responsive element for Tax...

  2. Results obtained from the treatment of the acute lymphoid leukaemia (ALL) to children from areas affected by the Chernobyl accident

    International Nuclear Information System (INIS)

    Gonzalez, A.

    1993-01-01

    Since march 1990, 103 children with acute lymphoid leukaemia (ALL) have received medical treatment in Cuba. All the patients had arrived with a previous treatment, which had them go through different stages of the therapeutic scheme which was in force in our country, the 7-ALL-87. The statistical study by the Kaplan Meler method showed a complete remission period of a 64% at 24 months. The event-free survival was of a 64%, and the global survival was of an 89%. In 25 children (24,2%), a relapse in the bone marrow was produced, where as 4 children (3,8%) underwent a relapse in the central nervous system. Eleven patients died, mostly because of a progression in the disease; 73 (70,8%) are under remission for periods of 3-32 months. Bone marrow autologous transplant was performed in five children with high risk; 2 died and the other 3 are under remission

  3. Haemostatic function and biomarkers of endothelial damage before and after platelet transfusion in patients with acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Larsen, A M; Leinøe, E B; Johansson, P I

    2015-01-01

    and after platelet transfusion in patients with acute myeloid leukaemia. MATERIALS AND METHODS: Blood was sampled before, 1 and 24 h after platelet transfusion. Primary and secondary haemostasis was evaluated by whole blood aggregometry (Multiplate) and thromboelastography (TEG). Endothelial biomarkers (s......OBJECTIVES: The beneficial effect of platelet transfusion on haemostasis is well established, but there is emerging evidence that platelet transfusion induces an inflammatory response in vascular endothelial cells. BACKGROUND: We investigated haemostatic function and endothelial biomarkers before......ICAM-1, syndecan-1, sThrombomodulin, sVE-Cadherin) and platelet activation biomarkers (sCD40L, TGF-beta) were investigated along with haematology/biochemistry analyses. RESULTS: Twenty-two patients were included. Despite continued low platelet counts, platelet transfusion normalised the median values...

  4. Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Jankovic, Momcilo; Masera, G.; Brouwers, Pim

    1994-01-01

    Cranial radiation therapy in childhood acute lymphoblastic leukaemia has been associated with adverse neuropsychological effects, such as low intelligence. We evaluated 203 children for six years in a multi-centre European study. The patients were divided into two groups: 129 children treated with 1800 cGy of cranial radiation therapy and 74 children who received high-dose methotrexate but no radiation therapy. We found a significant decline in full scale intelligence quotient in the irradiated group that increased with the length of time from diagnosis. Younger age at diagnosis was associated with lower full scale intelligence quotient in the radiated group. Our results indicate that a radiation dose of 1800 cGy can have negative effects on neurocognitive function and we continue to question the benefit of low-dose cranial radiation therapy. (author)

  5. SWOG S0910: A Phase 2 Trial of Clofarabine/Cytarabine/Epratuzumab for Relapsed/Refractory Acute Lymphocytic Leukaemia

    Science.gov (United States)

    Advani, Anjali S.; McDonough, Shannon; Coutre, Steven; Wood, Brent; Radich, Jerald; Mims, Martha; O’Donnell, Margaret; Elkins, Stephanie; Becker, Michael; Othus, Megan; Appelbaum, Frederick R.

    2014-01-01

    Summary Precursor B-acute lymphoblastic leukaemias (pre-B ALLs) comprise the majority of ALLs and virtually all blasts express CD22 in the cytoplasm and on the cell surface. In the present study (Southwestern Oncology Group S0910), we evaluated the addition of epratuzumab, a humanized monoclonal antibody against CD22, to the combination of clofarabine and cytarabine in adults with relapsed/refractory pre-B ALL. The response rate [complete remission and complete remission with incomplete count recovery ] was 52%, significantly higher than our previous trial with clofarabine/cytarabine alone, where the response rate was 17%. This result is encouraging and suggests a potential benefit to adding epratuzumab to chemotherapy for ALL; however, a randomized trial will be needed to answer this question. PMID:24579885

  6. A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study.

    Science.gov (United States)

    Chevallier, P; Labopin, M; Turlure, P; Prebet, T; Pigneux, A; Hunault, M; Filanovsky, K; Cornillet-Lefebvre, P; Luquet, I; Lode, L; Richebourg, S; Blanchet, O; Gachard, N; Vey, N; Ifrah, N; Milpied, N; Harousseau, J-L; Bene, M-C; Mohty, M; Delaunay, J

    2011-06-01

    A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy+Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36±4%, respectively. Disease status (relapse Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.

  7. ATP concentration as possible marker of liver damage at leukaemia treatment: confocal microscopy-based experimental study and numerical simulations

    Science.gov (United States)

    Malashchenko, V.; Zyubin, A.; Babak, S.; Lavrova, A.

    2017-04-01

    We consider the method of confocal microscopy as a convenient instrument for determination of chemical compounds in biological tissues and cells. In particular, we study the dynamics of adenosine triphosphate (ATP) concentration that could be used as a bio-marker of energy metabolism pathologies at the treatment of acute lymphoblastic leukaemia (ALL). On the basis of data obtained by the confocal microscopy, the values of ATP concentration have been calculated for each case. Possible correlations with other characteristics of pathology processes obtained from plasma of leukemia patients show that ATP value could be a prognostic factor of the treatment success. The role of ATP in the drug metabolism switching is also discussed within the context of kinetic modelling of metabolism processes leading to the production of 6-Thioguanosine monophosphate, which is a principal acting agent in chemotherapy.

  8. Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Haslam, K

    2012-02-01

    BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

  9. The use of 125I-labelled protein A for the detection of humoral immunity of gross murine leukaemia virus

    International Nuclear Information System (INIS)

    Holmes, H.C.; Tuffrey, M.; Barnes, R.D.; Steuden, J.; Hilgers, J.

    1980-01-01

    A solid-phase radioimmunoassay utilising binding of 125 I-labelled protein A to antibodies bound to virus adsorbed onto microtitre plates was shown to be suitable for detection of humoral immunity to Gross murine leukaemia virus (MuLV). The specificity of the reaction was shown by the fact that only homologous or closely related viruses effectively inhibited binding of antibodies to adsorbed virus. With this method a low level of spontaneous humoral immunity was demonstrated in sera from AKR/Crc mice, a strain with high concentrations of endogenous virus, whereas little or no anti-viral activity was found in CBA/H-T6Crc, a subline that does not appear to express MuLV. (Auth.)

  10. Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

    Science.gov (United States)

    Naka, Kazuhito; Jomen, Yoshie; Ishihara, Kaori; Kim, Junil; Ishimoto, Takahiro; Bae, Eun-Jin; Mohney, Robert P.; Stirdivant, Steven M.; Oshima, Hiroko; Oshima, Masanobu; Kim, Dong-Wook; Nakauchi, Hiromitsu; Takihara, Yoshihiro; Kato, Yukio; Ooshima, Akira; Kim, Seong-Jin

    2015-01-01

    Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK–Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment. PMID:26289811

  11. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma.

    Science.gov (United States)

    Park, Myoung-Ja; Taki, Tomohiko; Oda, Megumi; Watanabe, Tomoyuki; Yumura-Yagi, Keiko; Kobayashi, Ryoji; Suzuki, Nobuhiro; Hara, Junichi; Horibe, Keizo; Hayashi, Yasuhide

    2009-04-01

    Mutation analysis of FBXW7 and NOTCH1 genes was performed in 55 T cell acute lymphoblastic leukaemia (T-ALL) and 14 T cell non-Hodgkin lymphoma (T-NHL) patients who were treated on the Japan Association of Childhood Leukaemia Study (JACLS) protocols ALL-97 and NHL-98. FBXW7 and/or NOTCH1 mutations were found in 22 (40.0%) of 55 T-ALL and 7 (50.0%) of 14 T-NHL patients. FBXW7 mutations were found in 8 (14.6%) of 55 T-ALL and 3 (21.4%) of 14 T-NHL patients, and NOTCH1 mutations in 17 (30.9%) of 55 T-ALL and 6 (42.9%) of 14 T-NHL patients. Three (5.4%) T-ALL and two (1.4%) T-NHL patients had mutations in both FBXW7 and NOTCH1. FBXW7 mutations included one insertion, one deletion, one deletion/insertion and nine missense mutations. NOTCH1 mutations were detected in the heterodimerization domain (HD) in 15 cases, in the PEST domain in seven cases, and in both the HD and PEST domains in one case. Five-year event-free survival and overall survival for patients with FBXW7 and/or NOTCH1 mutations were 95.5% (95% CI, 71.9-99.4%) and 100% respectively, suggesting that T-ALL patients with FBXW7 and/or NOTCH1 mutation represent a good prognosis compared to those without FBXW7 and/or NOTCH1 mutations (63.6%, P = 0.007 and 78.8%, P = 0.023, respectively).

  12. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).

    NARCIS (Netherlands)

    Amadori, S.; Suciu, S.; Selleslag, D.; Stasi, R.; Alimena, G.; Baila, L.; Rizzoli, V.; Borlenghi, E.; Gaidano, G.; Magro, D.; Torelli, G.; Muus, P.; Venditti, A.; Cacciola, E.; Lauria, F; Vignetti, M.; Witte, T.J.M. de

    2010-01-01

    This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best

  13. Prevention of central nervous system involvement with intrathecal 198Au colloid and methotrexate in non-Hodgkin lymphoma, acute non-lymphatic leukaemia and Ewing's sarcoma

    International Nuclear Information System (INIS)

    Metz, O.; Stoll, W.; Plenert, W.; Deckert, H.; Doege, H.; Doerffel, W.; Mittler, U.; Redemann, H.; Roenisch, P.; Zastrow, J.

    1982-01-01

    Intrathecal 198 Au colloid and methotrexate were administered to 27 children (between 1972 and 1981) with non-lymphatic leukaemia, 21 with non-Hodgkin lymphoma and two with Ewing's sarcoma to prevent CNS involvement. In one boy with non-lymphatic leukaemia a stable remission after a three-year period of cytostatic treatment ended with isolated CNS involvement. No isolated CNS recurrence occurred in children with non-Hodgkin lymphoma receiving regular radiogold administration. Combined iris and CNS recurrence occurred in one child with non-Hodkin lymphoma. Eleven of 21 children with non-Hodgkin lymphoma have been in complete initial remission for 4-39 months without cytostatic treatment. Late cerebral complications have not been observed after 198 Au colloid and methotrexate. (orig.) [de

  14. Chronic Subdural Hematoma development in Accelerated phase of Chronic Myeloid Leukaemia presenting with seizure and rapid progression course with fatal outcome

    Directory of Open Access Journals (Sweden)

    Raheja Amol

    2015-06-01

    Full Text Available Occurrence of chronic subdural hematoma (CSDH in leukemia is rare, and most reported cases occurred in relation with acute myeloid leukaemia; however, occurrence is extremely rare in accelerated phase of chronic myelogenous leukaemia (CML. Seizure as presentation of SDH development in CML cases is not reported in literature. Authors report an elderly male, who was diagnosed as CML, accelerated phase of developing SDH. Initially presented to local physician with seizure; urgent CT scan head was advised, but ignored and sensorium rapidly worsened over next day and reported to our emergency department in deeply comatose state, where imaging revealed chronic subdural hematoma with hypoxic brain injury with fatal outcome. Seizure, progressive worsening of headache, vomiting and papilloedema are harbinger of intracranial space occupying lesion and requires CT head in emergency medical department for exclusion, who are receiving treatment of haematological malignancy

  15. DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008)

    DEFF Research Database (Denmark)

    Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob

    2017-01-01

    analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T......-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m(2) once per day and methotrexate 20 mg/m(2) once per week, targeted to a leucocyte count...... Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation....

  16. Benefit of oral nutritional supplements for children with acute lymphoblastic leukaemia during remission-induction chemotherapy: a quasi-experimental study.

    Science.gov (United States)

    Liang, Rui; Chen, Gai-Yun; Fu, San-Xian; Zhong, Jie; Ma, Yan

    2018-01-01

    To determine the effect of oral nutritional supplements (ONS) on children with acute lymphoblastic leukaemia undergoing remission-induction chemotherapy. We included 127 paediatric patients who were diagnosed with acute lymphoblastic leukaemia and undergoing remission- induction chemotherapy in the First Affiliated Hospital of Zhengzhou University. Children from two paediatric wards who met the inclusion criteria were enrolled. One ward was randomly chosen as the intervention group and the other ward as the control group. Children in the two groups were matched for age and sex. The ONS group was administered Peptamen® (n=60) and the control group was administered a low-fat diet (n=67). The baseline information before treatment was not significantly different between groups (p>0.05). In the control group, weight loss at the end of chemotherapy was significantly higher than that of ONS group (poral nutritional supplements can improve the nutritional status of children, reduce the incidence of complications, and decrease the costs of hospitalization.

  17. Adapting a Vacuum Assisted Closure dressing to challenging wounds: negative pressure treatment for perineal necrotizing fasciitis with rectal prolapse in a newborn affected by acute myeloid leukaemia.

    Science.gov (United States)

    Negosanti, Luca; Aceti, Arianna; Bianchi, Tommaso; Corvaglia, Luigi; Negosanti, Francesca; Sgarzani, Rossella; Morselli, Paolo Giovanni; Cipriani, Riccardo; Negosanti, Massimino; Patrizi, Annalisa; Faldella, Giacomo

    2010-01-01

    We report the case of a newborn with acute myeloid leukaemia, who developed perineal necrotizing fasciitis due to Pseudomonas Aeruginosa, after twenty days of life. Following surgical debridement, she was effectively treated with topical negative pressure therapy (V.A.C.(R) device) with silver foam dressings, this achieved complete closure in thirteen days. Negative pressure therapy should be considered when conventional wound care fails to achieve complete wound closure, even in neonates.

  18. Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene

    NARCIS (Netherlands)

    von Lindern, M.; Fornerod, M.; Soekarman, N.; van Baal, S.; Jaegle, M.; Hagemeijer, A.; Bootsma, D.; Grosveld, G.

    1992-01-01

    The t(6;9) that characterizes a specific subtype of ANLL fuses the 3' part of a gene located on chromosome 9q34, CAN, to the 5' part of a gene located on chromosome 6p23, DEK. On the 6p- chromosome, the resulting DEK-CAN fusion gene is transcribed into a leukaemia-specific 5.5 kb chimaeric mRNA that

  19. Changes in the expression of FGFR3 in patients with chronic myeloid leukaemia receiving transplants of allogeneic peripheral blood stem cells

    Czech Academy of Sciences Publication Activity Database

    Dvořáková, D.; Krejčí, P.; Mayer, J.; Fajkus, Jiří; Hampl, Aleš; Dvořák, Petr

    2001-01-01

    Roč. 113, č. 3 (2001), s. 832-835 ISSN 0007-1048 R&D Projects: GA ČR GA312/97/0393; GA MŠk ME 198 Institutional research plan: CEZ:AV0Z5045916 Keywords : fibroblast growth factor receptor 3 * chronic myeloid leukaemia * stem cell transplantation Subject RIV: BO - Biophysics Impact factor: 2.815, year: 2001

  20. Splenic artery pseudoaneurysm due to acute pancreatitis in a 6-year-old boy with acute lymphoblastic leukaemia treated with L-aspariginase

    DEFF Research Database (Denmark)

    Larsen, Cæcilie Crawley; Laursen, Christian B; Dalby, Kasper

    2014-01-01

    Acute pancreatitis is a rare phenomenon in children but its incidence seems to be increasing. In children, it is generally caused due to systemic illness, biliary disease, trauma, idiopathy and side effects of medicines like L-aspariginase. Acute pancreatitis is difficult to diagnose in children...... pseudoaneurysm due to acute pancreatitis in a 6-year-old boy with acute lymphoblastic leukaemia treated with L-aspariginase. He presented with fever, irritability and pain in his left groin region....

  1. Leukaemia and non-Hodgkin's lymphoma: incidence in children and young adults resident in the Dounreay area of Caithness, Scotland in 1968-91

    International Nuclear Information System (INIS)

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

    1994-01-01

    The study objective was to review the incidence of leukaemia and non-Hodgkin's lymphoma in children and young adults in the area less than 25 km from the Dounreay nuclear installation and the remainder of the Kirkwall postcode area in the full time period for which data are now available (1968-91), and to determine whether the excess incidence reported in the period up to 1984 has continued in subsequent years. (author)

  2. Nutritional status and quality of life in patients with acute leukaemia prior to and after induction chemotherapy in three hospitals in Tehran, Iran: a prospective study.

    Science.gov (United States)

    Malihi, Z; Kandiah, M; Chan, Y M; Hosseinzadeh, M; Sohanaki Azad, M; Zarif Yeganeh, M

    2013-07-01

    The primary objective of the present study was to assess changes in the nutritional status and quality of life in acute leukaemia patients, aged ≥15 years, who had undergone induction chemotherapy. A preliminary and post-induction chemotherapy assessment of patients' nutritional status, quality of life, sociodemographic status and medical characteristics was conducted using the Patient Generated Subjective Global Assessment (PG-SGA) and the European Organization for Research and Treatment of Cancer quality of life (QOL-C30, version 3) questionnaires. The PG-SGA is a clinical nutrition assessment tool used to evaluate oncology patients. Patients with newly-diagnosed acute leukaemia, aged ≥15 years, at three hospitals in Tehran (from May 2009 to March 2010), were recruited for the present study. Sixty-three acute leukaemia patients [65% men and 35% women with a mean (SD) age of 33 (15.4) years] participated in the present study. A total of 19.4% were found to be malnourished prior to chemotherapy. After chemotherapy, 76.1% of patients were considered moderately malnourished, whereas 6.3% were severely malnourished. After induction chemotherapy, both the nutritional status and quality of life deteriorated in the majority of patients, as demonstrated by a paired t-test. A deteriorated nutritional status and quality of life was the result of the side effects posed by induction chemotherapy in the patients investigated in the present study. These findings highlight the need for an appropriate nutritional support programme to improve the nutritional status and quality of life in patients with leukaemia undergoing chemotherapy. © 2013 The Authors Journal of Human Nutrition and Dietetics © 2013 The British Dietetic Association Ltd.

  3. Paternal Occupational Exposure to Endocrine-Disrupting Chemicals as a Risk Factor for Leukaemia in Children: A Case-Control Study from the North of England

    Directory of Open Access Journals (Sweden)

    Mark S. Pearce

    2014-01-01

    Full Text Available Occupations with exposures to a variety of chemicals, including those thought to be potential endocrine disruptors, have been associated with an increased risk of leukaemia in offspring. We investigated whether an association exists between paternal occupations at birth involving such exposures and risk of leukaemia in offspring. Cases (n=958 were matched, on sex and year of birth, to controls from two independent sources, one other cancers, one cancer-free live births. Paternal occupations at birth were classified, using an occupational exposure matrix, as having “very unlikely,” “possible,” or “likely” exposure to six groups of potential endocrine-disrupting chemicals. There was a significantly increased risk of acute nonlymphocytic leukaemia (ANLL for polychlorinated organic compounds (OR 1.95, 95% CI 1.08–3.54 only in comparison with cancer-free controls, and for phthalates (OR 1.61, 95% CI 1.00–2.61 only with registry controls. A number of other, including inverse, associations were seen, but limited to one control group only. No associations were seen with likely paternal exposure to heavy metals. The associations identified in this study require further investigation, with better exposure and potential confounding (for example maternal variables information, to evaluate the likelihood of true associations to assess whether they are real or due to chance.

  4. Neutrophil Gelatinase-Associated Lipocalin (NGAL, Pro-Matrix Metalloproteinase-9 (pro-MMP-9 and Their Complex Pro-MMP-9/NGAL in Leukaemias

    Directory of Open Access Journals (Sweden)

    Sandrine Bouchet

    2014-04-01

    Full Text Available Matrix metalloproteinase (MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL have gained attention as cancer biomarkers. The inactive zymogen form of MMP-9 (pro-MMP-9 also exists as a disulphide-linked heterodimer bound to NGAL in humans. Leukaemias represent a heterogeneous group of neoplasms, which vary in their clinical behavior and pathophysiology. In this review, we summarize the current literature on the expression profiles of pro-MMP-9 and NGAL as prognostic factors in leukaemias. We also report the expression of the pro-MMP-9/NGAL complex in these diseases. We discuss the roles of (pro-MMP-9 (active and latent forms and NGAL in tumour development, and evaluate the mechanisms by which pro-MMP-9/NGAL may influence the actions of (pro-MMP-9 and NGAL in cancer. Emerging knowledge about the coexpression and the biology of (pro-MMP-9, NGAL and their complex in cancer including leukaemia may improve treatment outcomes.

  5. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study.

    Science.gov (United States)

    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], ppancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting

  6. Effectiveness of imatinib mesylate over etoposide in the treatment of sensitive and resistant chronic myeloid leukaemia cellsin vitro.

    Science.gov (United States)

    Husaini, Roslina; Ahmad, Munirah; Zakaria, Zubaidah

    2017-06-01

    Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin-resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492±0.024 and 0.378±0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6±16.5 and 194±8.46 µM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3±0.2 and 31.9±16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3±8.35%) relative to K562/ADM cells (5.17±3.3%). In addition, the MDR genes in K562/ADM cells were knocked

  7. Loss of variation of state detected in soybean metabolic and human myelomonocytic leukaemia cell transcriptional networks under external stimuli

    KAUST Repository

    Sakata, Katsumi

    2016-10-24

    Soybean (Glycine max) is sensitive to flooding stress, and flood damage at the seedling stage is a barrier to growth. We constructed two mathematical models of the soybean metabolic network, a control model and a flooded model, from metabolic profiles in soybean plants. We simulated the metabolic profiles with perturbations before and after the flooding stimulus using the two models. We measured the variation of state that the system could maintain from a state–space description of the simulated profiles. The results showed a loss of variation of state during the flooding response in the soybean plants. Loss of variation of state was also observed in a human myelomonocytic leukaemia cell transcriptional network in response to a phorbol-ester stimulus. Thus, we detected a loss of variation of state under external stimuli in two biological systems, regardless of the regulation and stimulus types. Our results suggest that a loss of robustness may occur concurrently with the loss of variation of state in biological systems. We describe the possible applications of the quantity of variation of state in plant genetic engineering and cell biology. Finally, we present a hypothetical “external stimulus-induced information loss” model of biological systems.

  8. In vitro testing of chemotherapeutic drug combinations in acute myelocytic leukaemia using the fluorometric microculture cytotoxicity assay (FMCA).

    Science.gov (United States)

    Larsson, R; Fridborg, H; Kristensen, J; Sundström, C; Nygren, P

    1993-05-01

    The fluorometric microculture cytotoxicity assay (FMCA) was employed for analysing the effect of different chemotherapeutic drug combinations and their single constituents in 44 cases of acute myelocytic leukaemia (AML). A large heterogeneity with respect to cell kill was observed for all combinations tested, the interactions ranging from antagonistic to synergistic in terms of the multiplicative concept for drug interactions. However, an 'additive' model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) for several common antileukaemic drug combinations. When the two interaction models were related to treatment outcome 38% of the non-responders showed preference for the additive model whereas the corresponding figure for responders was 80%. Overall, in 248 of 290 (85%) tests performed with drug combinations, there was an agreement between the effect of the combination and that of the most active single component. Direct comparison of Dmax and the combination for correlation with clinical outcome demonstrated only minor differences in the ability to predict drug resistance. The results show that FMCA appear to report drug interactions in samples from patients with AML in accordance with clinical experience. Furthermore, testing single agents as a substitute for drug combinations may be adequate for detection of clinical drug resistance to combination therapy in AML.

  9. Primary angiocentric/angioinvasive T-cell lymphoma of the tympanic bulla in a feline leukaemia virus-positive cat

    Directory of Open Access Journals (Sweden)

    Sara F Santagostino

    2015-07-01

    Full Text Available 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.

  10. Antileukaemia effect of rapamycin alone or in combination with daunorubicin on Ph+ acute lymphoblastic leukaemia cell line.

    Science.gov (United States)

    Yang, Xi; Lin, Juan; Gong, Yuping; Ma, Hongbing; Shuai, Xiao; Zhou, Ruiqing; Guo, Yong; Shan, Qingqing; He, Guangcui

    2012-09-01

    The translocation (9;22) (q34;q11), known as the Philadelphia (Ph) chromosome and bcr-abl fusion gene, is the common cytogenetic abnormality and an unfavourable prognosis in adult acute lymphoblastic leukaemia (ALL). Although chemotherapeutic treatment produced high rates of complete response in approximately 70%-80% of newly diagnosed Ph+ ALL, the onset of resistance and clinical relapse is rapid. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we aimed to assess the antileukemic activity of rapamycin (RAPA) (Sigma-Aldrich Corporation, MO, USA), a mammalian target of rapamycin inhibitor, alone and in combination with daunorubicin (DNR) (Pharmacia & Upjohn Company, Germany) in a Ph+ acute lymphoblastic cell line SUP-B15 and a primary Ph+ ALL sample in vitro. Here, we demonstrated that 50 nmol/L of RAPA significantly intensified the inhibition induced by DNR on both Ph+ ALL cell line and a primary Ph+ ALL sample. Notably, we reported that the consequence of DNR treatment induced the over expression of the components of mammalian target of rapamycin signalling pathway, whereas RAPA effectively eliminated this deleterious side effect of DNR, which might enhance DNR's ability to kill drug-resistant cancer. The synergistic effect was also associated with the increase in autophagy, blockage of cell cycle progression in the G1 phase. Altogether, our results suggest that DNR in combination with RAPA is more effective in the treatment of Ph+ ALL compared with DNR alone. Copyright © 2011 John Wiley & Sons, Ltd.

  11. Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids

    Energy Technology Data Exchange (ETDEWEB)

    Amos, T.A.S.; Lewis, J.L.; Grand, F.H.; Gooding, R.P.; Goldman, J.M.; Gordon, M.Y. [Royal Postgraduate Medical School, London (United Kingdom)

    1995-10-01

    Inhibition of apoptosis (genetically programmed active cell death) by p210 BCR-ABL expression is a mechanism that might contribute to clonal expansion in chronic myeloid leukaemia (CML). Since cell death following exposure to ionizing radiation and many chemotherapeutic agents can occur by the apoptotic pathway, inhibition of apoptosis would be expected to confer a relative resistance to these treatments. Similarly, cells deprived of growth factors in vitro die by apoptosis, and inhibition of apoptosis would therefore be expected to allow cells to survive better in growth factor-deprived conditions. We found that the survival of normal and CML myeloid progenitors was the same after in vitro incubation in deprived conditions and after treatment with X-irradiation or glucocorticoids. We also found that mature cells in colonies produced by CML progenitors (CFU-GM) did not survive better than those produced by normal progenitor cells. Flow cytometric analysis of propidium iodide-stained cells provided a direct indication that the degree of apoptosis may correspond to the degree of deprivation. These results suggest that inhibition of apoptosis may not be the primary mechanism whereby BCR-ABL influences the expansion of the malignant clone in CML. (Author).

  12. Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia.

    Directory of Open Access Journals (Sweden)

    Edwin D Hawkins

    Full Text Available In epithelial and stem cells, lethal giant larvae (Lgl is a potent tumour suppressor, a regulator of Notch signalling, and a mediator of cell fate via asymmetric cell division. Recent evidence suggests that the function of Lgl is conserved in mammalian haematopoietic stem cells and implies a contribution to haematological malignancies. To date, direct measurement of the effect of Lgl expression on malignancies of the haematopoietic lineage has not been tested. In Lgl1⁻/⁻ mice, we analysed the development of haematopoietic malignancies either alone, or in the presence of common oncogenic lesions. We show that in the absence of Lgl1, production of mature white blood cell lineages and long-term survival of mice are not affected. Additionally, loss of Lgl1 does not alter leukaemia driven by constitutive Notch, c-Myc or Jak2 signalling. These results suggest that the role of Lgl1 in the haematopoietic lineage might be restricted to specific co-operating mutations and a limited number of cellular contexts.

  13. Silencing of TESTIN by dense biallelic promoter methylation is the most common molecular event in childhood acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Song Sarah

    2010-06-01

    Full Text Available Abstract Background Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL and has the potential to contribute to its onset and outcome. However, few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. By screening candidate genes, we have detected frequent and dense methylation of the TESTIN (TES promoter. Results Bisulfite sequencing showed that 100% of the ALL samples (n = 20 were methylated at the TES promoter, whereas the matched remission (n = 5, normal bone marrow (n = 6 and normal PBL (n = 5 samples were unmethylated. Expression of TES in hyperdiploid, TEL-AML+, BCR-ABL+, and E2A-PBX+ subtypes of B lineage ALL was markedly reduced compared to that in normal bone marrow progenitor cells and in B cells. In addition TES methylation and silencing was demonstrated in nine out of ten independent B ALL propagated as xenografts in NOD/SCID mice. Conclusion In total, 93% of B ALL samples (93 of 100 demonstrated methylation with silencing or reduced expression of the TES gene. Thus, TES is the most frequently methylated and silenced gene yet reported in ALL. TES, a LIM domain-containing tumour suppressor gene and component of the focal adhesion complex, is involved in adhesion, motility, cell-to-cell interactions and cell signalling. Our data implicate TES methylation in ALL and provide additional evidence for the involvement of LIM domain proteins in leukaemogenesis.

  14. Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib.

    Science.gov (United States)

    Giallongo, Cesarina; Parrinello, Nunziatina L; La Cava, Piera; Camiolo, Giuseppina; Romano, Alessandra; Scalia, Marina; Stagno, Fabio; Palumbo, Giuseppe A; Avola, Roberto; Li Volti, Giovanni; Tibullo, Daniele; Di Raimondo, Francesco

    2018-02-01

    Myeloid suppressor cells are a heterogeneous group of myeloid cells that are increased in patients with chronic myeloid leukaemia (CML) inducing T cell tolerance. In this study, we found that therapy with tyrosine kinase inhibitors (TKI) decreased the percentage of granulocytic MDSC, but only patients treated with dasatinib showed a significant reduction in the monocytic subset (M-MDSC). Moreover, a positive correlation was observed between number of persistent M-MDSC and the value of major molecular response in dasatinib-treated patients. Serum and exosomes from patients with CML induced conversion of monocytes from healthy volunteers into immunosuppressive M-MDSC, suggesting a bidirectional crosstalk between CML cells and MDSC. Overall, we identified M-MDSC as prognostic factors in patients treated with dasatinib. It might be of interest to understand whether MDSC may be a candidate predictive markers of relapse risk following TKI discontinuation, suggesting their potential significance as practice of precision medicine. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  15. Catanionic drug-derivative nano-objects constructed by chlorambucil and its derivative for efficient leukaemia therapy.

    Science.gov (United States)

    Ji, Xiaoqing; Shi, Chunhuan; Li, Nuannuan; Wang, Kaiming; Li, Zhonghao; Luan, Yuxia

    2015-12-01

    A new carrier-free catanionic drug-derivative nano-object strategy is developed for leukaemia therapy. The as-prepared drug-derivative nano-objects are formed by ionic pairs of hydrophobic anticancer drug chlorambucil (CLB) and its derivative N-(2-Amino-ethyl)-4-{4-[bis-(2-chloro-ethyl)-amino]-phenyl}-butyramide (CLBM). The designed drug delivery system has the advantage of 100% drug content without additional carrier materials. The ionic pairs are formed by proton exchange between CLB and CLBM. Due to the amphiphilicity of the ionic pairs, they can assemble into well-defined drug-derivative (CLB-CLBM) nano-objects. Series of techniques such as transmission electron microscopy (TEM), dynamic light scattering (DLS) and electrical conductivity are used to investigate the property of the solution and aggregation behaviour of as-prepared drug-derivative ionic pairs. In vitro drug release study of the as-prepared nano-objects shows their prolonged drug release behavior. Specifically, in vitro cytotoxicity results of these nano-objects show obviously higher cytotoxicity, which is promising for clinical efficacy. This study may pave the way for the fabrication of carrier-free drug delivery system with efficient cancer therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. The broad-spectrum caspase inhibitor Boc-Asp-CMK induces cell death in human leukaemia cells.

    Science.gov (United States)

    Frydrych, Ivo; Mlejnek, Petr; Dolezel, Petr; Zoumpourlis, Vassilis; Krumpochova, Petra

    2008-08-01

    Synthetic caspase inhibitors and particularly broad-spectrum caspase inhibitors can prevent cells from death or at least slow down cell death process and abrogate some apoptotic hallmarks [Kitanaka, C., Kuchino, Y., 1999. Caspase-independent programmed cell death with necrotic morphology. Cell Death and Differentiation 6, 508-515]. However, not all synthetic caspase inhibitors diminish cell death. We have found that the broad-spectrum caspase inhibitor Boc-Asp-CMK induced cell death at micromolar concentrations in human leukaemia cells. Interestingly, low concentrations of Boc-Asp-CMK induced cell death with apoptotic hallmarks. Increasing concentrations of Boc-Asp-CMK led to necrotic cell death. The switch between apoptosis and necrosis seemed to depend upon the degree of inhibition of executioner caspases, including caspase-3/7 with Boc-Asp-CMK. Interestingly, caspase-3 processing was not inhibited even for the highest concentration of Boc-Asp-CMK used. We assume, that toxic properties of Boc-Asp-CMK can be attributed to the chloromethylketone residuum in its molecule, as its analogue Boc-Asp-FMK with fluoromethylketone residuum was more than 13 times less toxic. Our results further indicated that toxicity of Boc-Asp-CMK might arise from its interference with mitochondrial metabolism.

  17. Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

    International Nuclear Information System (INIS)

    Yoon, J-Y; Szwajcer, D; Ishdorj, G; Benjaminson, P; Xiao, W; Kumar, R; Johnston, J B; Gibson, S B

    2013-01-01

    Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins

  18. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

    Science.gov (United States)

    Kirschbaum, Mark; Gojo, Ivana; Goldberg, Stuart L; Bredeson, Christopher; Kujawski, Lisa A; Yang, Allen; Marks, Peter; Frankel, Paul; Sun, Xing; Tosolini, Alessandra; Eid, Joseph E; Lubiniecki, Gregory M; Issa, Jean-Pierre

    2014-10-01

    Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m(2) daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation. © 2014 John Wiley & Sons Ltd.

  19. Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids

    International Nuclear Information System (INIS)

    Amos, T.A.S.; Lewis, J.L.; Grand, F.H.; Gooding, R.P.; Goldman, J.M.; Gordon, M.Y.

    1995-01-01

    Inhibition of apoptosis (genetically programmed active cell death) by p210 BCR-ABL expression is a mechanism that might contribute to clonal expansion in chronic myeloid leukaemia (CML). Since cell death following exposure to ionizing radiation and many chemotherapeutic agents can occur by the apoptotic pathway, inhibition of apoptosis would be expected to confer a relative resistance to these treatments. Similarly, cells deprived of growth factors in vitro die by apoptosis, and inhibition of apoptosis would therefore be expected to allow cells to survive better in growth factor-deprived conditions. We found that the survival of normal and CML myeloid progenitors was the same after in vitro incubation in deprived conditions and after treatment with X-irradiation or glucocorticoids. We also found that mature cells in colonies produced by CML progenitors (CFU-GM) did not survive better than those produced by normal progenitor cells. Flow cytometric analysis of propidium iodide-stained cells provided a direct indication that the degree of apoptosis may correspond to the degree of deprivation. These results suggest that inhibition of apoptosis may not be the primary mechanism whereby BCR-ABL influences the expansion of the malignant clone in CML. (Author)

  20. Sensitivity and resistance towards isoliquiritigenin, doxorubicin and methotrexate in T cell acute lymphoblastic leukaemia cell lines by pharmacogenomics.

    Science.gov (United States)

    Youns, Mahmoud; Fu, Yu-Jie; Zu, Yuan-Gang; Kramer, Anne; Konkimalla, V Badireenath; Radlwimmer, Bernhard; Sültmann, Holger; Efferth, Thomas

    2010-09-01

    The development of drug resistance in cancer cells necessitates the identification of novel agents with improved activity towards cancer cells. In the present investigation, we compared the cytotoxicity of the chalcone flavonoide, isoliquiritigenin (ISL), with that of doxorubicin (DOX) and methotrexate (MTX) in five T cell acute lymphoblastic leukaemia (T-ALL) cell lines (Jurkat, J-Jhan, J16, HUT78 and Karpas 45). To gain insight into the molecular mechanisms which determine the response of T-ALL cells towards ISL, DOX and MTX, we applied array-based matrix comparative genomic hybridisation and microarray-based mRNA expression profiling and compared the genomic and transcriptomic profiles of the cell lines with their 50% inhibition (IC(50)) values for these three drugs. The IC(50) values for ISL did not correlate with those for DOX or MTX, indicating that ISL was still active in DOX- or MTX-unresponsive cell lines. Likewise, the genomic imbalances of chromosomal clones and mRNA expression profile significantly correlating with IC(50) values for ISL were different from thoses correlating with IC(50) values for DOX and MTX. In conclusion, ISL represents a cytotoxic natural product with activity towards T-ALL cell lines. There was no cross-resistance between ISL and DOX or MTX, and the genomic and transcriptomic profiles pointed to different molecular modes of action of ISL as compared to DOX and MTX, indicating that ISL may be a valuable adjunct for cancer therapy to treat otherwise drug-resistant tumours.

  1. 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).

    Science.gov (United States)

    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.

  2. Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

    Science.gov (United States)

    Baron, F; Ruggeri, A; Beohou, E; Labopin, M; Mohty, M; Sanz, J; Vigouroux, S; Furst, S; Bosi, A; Chevallier, P; Cornelissen, J J; Michallet, M; Sierra, J; Karakasis, D; Savani, B N; Gluckman, E; Nagler, A

    2018-02-01

    The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  3. Acute leukaemia with a pure erythroid phenotype: under-recognized morphological and cytogenetic signatures associated universally with primary refractory disease and a dismal clinical outcome.

    Science.gov (United States)

    Park, David C; Ozkaya, Neval; Lovitch, Scott B

    2017-08-01

    Pure erythroid leukaemia (PEL) is an extremely rare and aggressive subtype of acute myeloid leukaemia defined by the World Health Organization (WHO) as a neoplastic proliferation of immature cells committed exclusively to the erythroid lineage, comprising >80% of bone marrow cells and not meeting the criteria of other well-defined myeloid neoplasms. The aim of this study was to describe the clinicopathological features of acute leukaemias with a pure erythroid phenotype (ALPEP) irrespective of their WHO classification and to determine if ALPEP represents a distinct clinicopathological entity. We identified seven cases of ALPEP, in which immature cells fulfilled WHO morphological and immunophenotypical criteria for PEL. All patients except one were male, with a median age of 60 years. Three cases represented de novo PEL, three were therapy-related myeloid neoplasms and one was a blast phase of a myeloproliferative neoplasm. Extensive tumour necrosis was present in five cases (71%). Five cases with available modal karyotypes all demonstrated a complex karyotype involving the TP53 gene locus, with three cases (60%) also showing a monosomy 5 or deletion 5q and additional material on chromosome 19q13. All patients died of their disease, with a mean overall survival of 189 and 64.7 days in cases without and with necrosis on the initial biopsy, respectively. We describe previously unreported but relatively common findings of extensive tumour necrosis and recurring cytogenetic abnormalities in ALPEP. Our findings suggest strongly that ALPEP represents a distinct clinicopathological entity regardless of its WHO classification. © 2017 John Wiley & Sons Ltd.

  4. P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients

    International Nuclear Information System (INIS)

    Tang, Ruoping; Legrand, Ollivier; Marie, Jean-Pierre; Cohen, Simy; Perrot, Jean-Yves; Faussat, Anne-Marie; Zuany-Amorim, Claudia; Marjanovic, Zora; Morjani, Hamid; Fava, Fanny; Corre, Elise

    2009-01-01

    AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC 50 > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633

  5. Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01

    Science.gov (United States)

    Jiménez-Hernández, Elva; Jaimes-Reyes, Ethel Zulie; Arellano-Galindo, José; García-Jiménez, Xochiketzalli; Tiznado-García, Héctor Manuel; Sánchez-Jara, Berenice; Bekker-Méndez, Vilma Carolina; Ortíz-Torres, María Guadalupe; Ortíz-Fernández, Antonio; Marín-Palomares, Teresa; Mejía-Aranguré, Juan Manuel

    2015-01-01

    Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count 100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population. PMID:25922837

  6. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10)

    DEFF Research Database (Denmark)

    Eichhorst, Barbara; Fink, Anna-Maria; Bahlo, Jasmin

    2016-01-01

    BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less....... The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included...... AG, Mundipharma, German Federal Ministry of Education and Research....

  7. Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival

    DEFF Research Database (Denmark)

    Forestier, Erik; Heyman, Mats; Andersen, Mette K

    2008-01-01

    The prognostic impact of t(12;21)(p13;q22) [ETV6/RUNX1 fusion] in paediatric acute lymphoblastic leukaemia (ALL) has been extensively debated, particularly with regard to the frequency of late relapses and appropriate treatment regimens. We have retrospectively collected 679 ALLs with known ETV6....../RUNX1 status, as ascertained by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction, treated according to the Nordic Society of Paediatric Haematology and Oncology -ALL-1992 protocol. The assigned risk groups/treatment modalities for the 171 (25%) patients with t(12...

  8. Ponatinib for Treating Chronic Myeloid Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    Science.gov (United States)

    Pandor, Abdullah; Stevenson, Matt; Stevens, John; James, Marrissa Martyn-St; Hamilton, Jean; Byrne, Jenny; Rudin, Claudius; Rawdin, Andrew; Wong, Ruth

    2018-02-26

    As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures ponatinib (Inclusig ® ; Incyte Corporation) to submit evidence for the clinical and cost effectiveness for previously treated chronic myeloid leukaemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). This paper focusses on the three phases of CML: the chronic phase (CP), the accelerated phase (AP) and the blast crisis phase (BP). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. Clinical evidence for ponatinib was derived from a phase II, industry-sponsored, single-arm, open-label, multicentre, non-comparative study. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment (in terms of major cytogenetic response and major haematological response) with an acceptable safety profile for patients with CML. Given the absence of any head-to-head studies comparing ponatinib with other relevant comparators, the company undertook a matching-adjusted indirect comparison (MAIC) of ponatinib with bosutinib. The approach was only used for patients with CP-CML because comprehensive data were not available for the AP- or BP-CML groups to allow the matching technique to be used. Despite the uncertainty about the MAIC approach, ponatinib was considered likely to offer advantages over bosutinib in the third-line setting, particularly for complete cytogenetic response. The company developed two health economic models to assess the cost effectiveness of ponatinib for the treatment of patients in CP-CML or in advanced CML (AP- or BP-CML, which were modelled separately). The company did

  9. B-cell chronic lymphocytic leukaemia: prognostic value of the immunophenotype and the clinico-haematological features.

    Science.gov (United States)

    Orfao, A; Gonzalez, M; San Miguel, J F; Rios, A; Canizo, M C; Hernandez, J; Maricato, M L; Lopez Borrasca, A

    1989-05-01

    Sixty-two previously untreated patients with B-cell chronic lymphocytic leukaemia were analysed to study the prognostic value of both the immunologic phenotype and the clinicobiologic characteristics. Univariate studies showed that none of the immunological markers analysed, sheep-rosette, mouse-rosette, slg, and HLA/DR, CD20, FMC7, CD5, and CD9 antigens, had a significant influence on survival. On the other hand, several clinical and haematological characteristics were identified as being associated with survival: 1) clinical features--presence of lymphadenopathies (P less than .05) and hepatomegaly and/or splenomegaly (P less than .04); 2) haematologic parameters--presence of anaemia and/or thrombopenia (P less than .05), the absolute peripheral blood lymphocyte count (P less than .03), and the presence of hypogammaglobulinemia (P less than .08); 3) biochemical parameters--serum uric acid (P less than .03); and 4) bone marrow histopathological features--biopsy pattern (P less than .04) and the percentage of lymphocytes in bone marrow aspirate (P less than .03). Both the Rai staging and the International Workshop on CLL staging systems were effective in identifying groups of patients with significantly different prognoses (P less than .05). Multivariate regression analysis demonstrated that the combination of three clinicopathologic characteristics (bone marrow histopathologic pattern, absolute peripheral blood lymphocyte count, and the presence or not of hypogammaglobulinaemia) had the strongest predictive relationship with survival time. In summary, our findings show that the clinicobiological and anatomopathologic parameters have much more prognostic relevance than the immunological markers analysed in the present study.

  10. Impact of hydrochloric acid instillation on salvage of infected central venous catheters in children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Madsen, Mette; Rosthøj, Steen

    2013-01-01

    Bacteraemia associated with indwelling central venous catheters (CVC) causes significant morbidity in children with cancer. Hydrochloric acid (HCl) instillations have been reported to salvage CVCs with antibiotic-refractory infection. We implemented this treatment in 2002. The impact on the survival of CVCs has been evaluated in a retrospective cohort study of children with acute lymphoblastic leukaemia (ALL). Children with newly diagnosed ALL during 1999-2005 having their first CVC inserted before (n = 16) and after (n = 24) the introduction of the procedure were studied. All bacteraemic episodes were reviewed, recording bacteriological findings and treatment, and the time to premature or planned removal of the CVC was determined. In the comparison cohort, 31.0% (9/29) of bacteraemic episodes led to removal of the CVC, compared to 5.5% (2/36) in the intervention cohort (p = 0.01). Thus, the rate of catheter loss due to infection fell from 56.3% (9/16) to 8.3% (2/24) after introducing HCl treatment (p = 0.0025). Overall, the premature catheter removal rate fell from 75.0% (12/16) to 45.8% (11/24) (p = 0.10). Analysed in a CUSUM plot the reduced frequency of premature CVC removal evidently coincided with the introduction of the procedure. In a subgroup analysis of 21 monobacterial infections with coagulase-negative staphylococci, a decrease in systemic and lock antibiotic therapy was found. No adverse events were noted. HCl instillations significantly reduced the need to remove and replace CVCs. The procedure is practical, appears to be safe, and may reduce the consumption of antibiotics.

  11. Simultaneous clinical resolution of focal segmental glomerulosclerosis associated with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab

    Directory of Open Access Journals (Sweden)

    Karasavvidou Foteini

    2011-07-01

    Full Text Available Abstract Background Although renal involvement in advanced haematological malignancies is common, glomerulonephritis associated with lymphoproliferative disorders is rare, and the related pathogenetic mechanisms are still poorly understood. We present a rare case of chronic lymphocytic leukaemia(CLL-associated focal segmental glomerulosclerosis with nephrotic-range proteinuria. Case presentation A 53-year-old Caucasian man, previously healthy, with no history of hypertension, alcohol use or smoking presented with rapid weight gain, massive peripheral oedema, and hypertension. Laboratory findings included a white blood cell count of 49,800 cells/mm3 with an absolute lymphocyte count of 47,000 cells/mm3, serum albumin of 2.3 g/dL, urea 65 mg/dL, and creatinine 1.5 mg/dL. A 24-hour urine collection contained 7.1 g protein and significant haematuria. A peripheral blood smear showed mature lymphocytosis and smudge cells. Diagnostic imaging showed mild paraaortic lymphadenopathy with no renal abnormalities. Bone marrow aspiration and trephine biopsy showed diffuse and focal infiltration with B-CLL lymphocytes. Percutaneous renal biopsy revealed total sclerosis in 3/21(14% of the glomeruli and focal and segmental solidification and sclerosis in 4/21 (19% glomeruli. A regimen of fludarabine, cyclophosphamide and rituximab was successful in inducing remission of the CLL and clinical resolution of the nephritic-range proteinuria. Conclusions A multidisciplinary approach to monitor both the malignancy and the glomerular lesions is crucial for the optimal management of paraneoplastic glomerulonephritis. Although chemotherapy with fludarabine, cyclophosphamide and rituximab successfully treated CLL-associated nephrotic syndrome in our patient, further studies are required to confirm efficacy in this setting.

  12. Bovine leukaemia virus genotypes 5 and 6 are circulating in cattle from the state of São Paulo, Brazil.

    Science.gov (United States)

    Gregory, Lilian; Carrillo Gaeta, Natália; Araújo, Jansen; Matsumiya Thomazelli, Luciano; Harakawa, Ricardo; Ikuno, Alice A; Hiromi Okuda, Liria; de Stefano, Eliana; Pituco, Edviges Maristela

    2017-12-01

    Enzootic bovine leucosis (EBL) is a silent disease caused by a retrovirus [bovine leukaemia virus (BLV)]. BLV is classified into almost 10 genotypes that are distributed in several countries. The present research aimed to describe two BLV gp51 env sequences of strains detected in the state of São Paulo, Brazil and perform a phylogenetic analysis to compare them to other BLV gp51 env sequences of strains around the world. Two bovines from different herds were admitted to the Bovine and Small Ruminant Hospital, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil. In both, lymphosarcoma was detected and the presence of BLV was confirmed by nested PCR. The neighbour-joining algorithm distance method was used to genotype the BLV sequences by phylogenetic reconstruction, and the maximum likelihood method was used for the phylogenetic reconstruction. The phylogeny estimates were calculated by performing 1000 bootstrap replicates. Analysis of the partial envelope glycoprotein (env) gene sequences from two isolates (25 and 31) revealed two different genotypes of BLV. Isolate 25 clustered with ten genotype 6 isolates from Brazil, Argentina, Thailand and Paraguay. On the other hand, isolate 31 clustered with two genotype 5 isolates (one was also from São Paulo and one was from Costa Rica). The detected genotypes corroborate the results of previous studies conducted in the state of São Paulo, Brazil. The prediction of amino acids showed substitutions, particularly between positions 136 and 150 in 11 out of 13 sequences analysed, including sequences from GenBank. BLV is still important in Brazil and this research should be continued.

  13. Relationship between cigarette smoking and risk of chronic myeloid leukaemia: a meta-analysis of epidemiological studies.

    Science.gov (United States)

    Qin, Ling; Deng, Hui-Yang; Chen, Sheng-Jiang; Wei, Wei

    2017-05-01

    Previous epidemiologic studies that have been reported on the association between cigarette smoking and risk of chronic myeloid leukaemia (CML) have remained controversial. A comprehensive meta-analysis was performed to evaluate smoking as a potential relationship factor and incidence of CML. Systematic literatures collected from articles published before August 2015 were searched from PubMed, EMBASE and the Cochrane Library. A total of 10 studies (nine case-controls and one cohort) met inclusion criteria of this meta-analysis. Odds ratios (ORs) with 95% confidence interval (CI) were calculated to assess the strength of the association between cigarette smoking and risk of CML in this study. Quality assessments were performed on the studies with the Newcastle-Ottawa Scale. I2 index was used to evaluate heterogeneity. Finally, publication bias was assessed through funnel plots and Begger's test. No significant association was observed between ever-smokers and CML when compared among non-smokers (OR = 1.13, 95% CI: 0.99-1.29) or between subgroups stratified by smoking history, gender, geographical region, study design and source of patients. Our results demonstrate that this association was stronger in individuals who smoked smoked >20 cigarettes/day (OR = 1.24, 95% CI: 0.55-2.81). Moreover, cumulative smoking of 30 pack-years was associated with ORs of 1.22, 1.32 and 1.39, respectively (P smoking may significantly increase the risk of CML in a dose-dependent manner. However, additional well-designed, prospective cohort studies are required to verify these findings and identify other risk factors associated with CML.

  14. Epidemiology and clinical outcomes of feline immunodeficiency virus and feline leukaemia virus in client-owned cats in New Zealand

    Directory of Open Access Journals (Sweden)

    Claire Luckman

    2017-09-01

    Full Text Available Objectives The objectives were to collect baseline data on the occurrence, testing and vaccination practices, and clinical outcomes of feline leukaemia virus (FeLV and feline immunodeficiency virus (FIV in New Zealand Methods A cross-sectional survey of 423 veterinary practices in New Zealand was performed to collect data on FeLV and FIV testing and vaccination during the 2015 calendar year. Clinical records from 572 cats tested using a point-of-care ELISA at a first-opinion veterinary practice between 7 April 2010 and 23 June 2016 were also obtained and multivariable logistic regression models were constructed to identify risk factors for test positivity. Survival times were estimated using Kaplan–Meier methods. Results The survey was completed by 112 clinics (26.4% of which 72 performed in-house testing. Of the 2125 tests performed, 56 (2.6% were positive for FeLV and 393 (18.5% were positive for FIV. Fewer than 1% of cats were vaccinated for FeLV, with veterinarians citing low perceived prevalence as the primary reason for not vaccinating. Being male compared with being female and having clinical evidence of immunosuppression were significant risk factors for both FeLV and FIV test positivity. The median survival times of FeLV and FIV test-positive cats were 10 days (95% confidence interval [CI] 0–16 and 650 days (95% CI 431–993, respectively. Conclusions and relevance Testing and vaccination for FeLV and FIV in New Zealand appears targeted towards high-risk animals, which may bias prevalence estimates. Baseline data should be monitored for changes in FeLV epidemiology now commercial vaccines are no longer available.

  15. Outcome of Childhood Acute Lymphoblastic Leukaemia after Induction Therapy --- Three-Year Experience in a Tertiary Care Hospital in Bangladesh

    Directory of Open Access Journals (Sweden)

    M Belayet Hossain

    2017-01-01

    Full Text Available Background: The incidence of different malignancies is increasing among the world populations. Acute lymphoblastic leukaemia (ALL is the most common of all the paediatric malignancies. Response to induction therapy is one of the most important predictors of long term outcome of ALL. Objective: To see the immediate outcome of paediatric ALL patients following induction therapy. Materials and Methods: This retrospective study was conducted from January 2013 to December 2015. Total 221 paediatric ALL patients were included in this study. Diagnosis was based on history, examination, blast cells count on peripheral blood film and bone marrow study, CSF study and immunophenotyping of peripheral blood/bone marrow aspirate in patients who were financially capable. Among them, parents of 40 (18% patients did not agree to start chemotherapy. According to Modified UK ALL 2003 protocol (Regimen A & B 181 patients were given induction therapy (vincristine, prednisolone, L-asparaginase, and daunomycin in high risk patients. Among them 14 patients discontinued, 10 patients died during chemotherapy and rest 157 patients completed induction phase. Bone marrow study was repeated after completion of induction therapy and remission pattern was seen. Results: Out of 157 chemotherapy completed patients, 137 (87% went into complete remission (25% blast cells in the bone marrow. Ten (5.5% patients died due to bleeding, febrile neutropenia and sepsis during the course of induction therapy. Conclusion: ALL in children is curable with effective chemotherapy. Poverty, ignorance and misconception regarding outcome are responsible for refusal and discontinuation of chemotherapy in third world countries like Bangladesh. Mortality and treatment cost can be reduced with the improvement of the facilities for isolation, barrier nursing and supportive treatment, and by creating awareness.

  16. Label-free imaging and identification of typical cells of acute myeloid leukaemia and myelodysplastic syndrome by Raman microspectroscopy.

    Science.gov (United States)

    Vanna, R; Ronchi, P; Lenferink, A T M; Tresoldi, C; Morasso, C; Mehn, D; Bedoni, M; Picciolini, S; Terstappen, L W M M; Ciceri, F; Otto, C; Gramatica, F

    2015-02-21

    In clinical practice, the diagnosis and classification of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) start from the manual examination of stained smears of bone marrow (BM) and peripheral blood (PB) by using an optical microscope. This step is subjective and scarcely reproducible. Therefore, the development of subjective and potentially automatable methods for the recognition of typical AML/MDS cells is necessary. Here we have used Raman spectroscopy for distinguishing myeloblasts, promyelocytes, abnormal promyelocytes and erhytroblasts, which have to be counted for a correct diagnosis and morphological classification of AML and MDS. BM samples from patients affected by four different AML subtypes, mostly characterized by the presence of the four subpopulations selected for this study, were analyzed. First, each cell was scanned by acquiring 4096 spectra, thus obtaining Raman images which demonstrate an accurate description of morphological features characteristic of each subpopulation. Raman imaging coupled with hierarchical cluster analysis permitted the automatic discrimination and localization of the nucleus, the cytoplasm, myeloperoxidase containing granules and haemoglobin. Second, the averaged Raman fingerprint of each cell was analysed by multivariate analysis (principal component analysis and linear discriminant analysis) in order to study the typical vibrational features of each subpopulation and also for the automatic recognition of cells. The leave-one-out cross validation of a Raman-based classification model demonstrated the correct classification of myeloblasts, promyelocytes (normal/abnormal) and erhytroblasts with an accuracy of 100%. Normal and abnormal promyelocytes were distinguished with 95% accuracy. The overall classification accuracy considering the four subpopulations was 98%. This proof-of-concept study shows that Raman micro-spectroscopy could be a valid approach for developing label-free, objective and automatic

  17. Chronic myeloid leukaemia in Spain: Its presentation characteristics have changed. Spanish section of the EUTOS population-based registry.

    Science.gov (United States)

    Osorio, S; Casado, L F; Giraldo, P; Maestro, B; Andrade, M; Redondo, S; García-Gutiérrez, V; Ayala, R; Garcia, N; Steegmann, J L

    2016-01-01

    To provide more reliable data on the epidemiology of chronic myeloid leukaemia (CML) in Spain than are currently available. The EUTOS population-based project of European LeukemiaNet is a population registry of new CML cases in patients 18 years of age or older from 22 European areas. The Spanish section included the autonomous communities of Madrid, Castilla-La Mancha and Aragon, from 1-2-2010 to 31-12-2012. A total of 250 cases were recorded in 35 months. The overall incidence was 1.08 cases/10(5) inhabitants-year, with a predominance of men (58%) and clear differences among the communities. The incidence standardised by age was similar (overall, 1.04; men, 1.31; women, 0.81). The median age was 54 years. The incidence increased with age, reaching a peak at>65 years, although 31.7% of cases appeared between the ages of 20 and 44 years. Four percent of cases were diagnosed in advanced stages (2.4% in accelerated phase, 1.6% in blast crisis), 56% were asymptomatic, 38% had splenomegaly, and the Sokal score was high in 11% (lower than what was previously reflected in the literature). The current incidence of CML in Spain is higher than previously reported and similar to that of the European studies. Unlike the classical descriptions, CML presented mostly in asymptomatic form, with no splenomegaly, less leucocytosis and in stages with better prognosis. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  18. Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival.

    Science.gov (United States)

    Mughal, Muhammad Kashif; Akhter, Ariz; Street, Lesley; Pournazari, Payam; Shabani-Rad, Meer-Taher; Mansoor, Adnan

    2017-09-01

    Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Smoking and subsequent risk of acute myeloid leukaemia: A pooled analysis of 9 cohort studies in Japan.

    Science.gov (United States)

    Ugai, Tomotaka; Matsuo, Keitaro; Oze, Isao; Ito, Hidemi; Wakai, Kenji; Wada, Keiko; Nagata, Chisato; Nakayama, Tomio; Liu, Rong; Kitamura, Yuri; Tamakoshi, Akiko; Tsuji, Ichiro; Sugawara, Yumi; Sawada, Norie; Sadakane, Atsuko; Tanaka, Keitaro; Mizoue, Tetsuya; Inoue, Manami; Tsugane, Shoichiro; Shimazu, Taichi

    2018-02-01

    Smoking has been identified as a significant risk factor for acute myeloid leukaemia (AML). However, epidemiological evidence for the effect of smoking on the risk of AML among Asians is scarce. Here, we investigated the impact of smoking habits on the risk of AML by conducting a pooled analysis of 9 population-based prospective cohort studies in Japan. We analysed original data on smoking habits at baseline from 9 cohort studies. Hazard ratios (HRs) in the individual studies were calculated using a Cox proportional hazard model adjusted for potential confounders and combined using a random-effects model. During 4 808 175 person-years of follow-up for a total of 344 676 participants (165 567 men and 179 109 women), 245 AML cases (139 men and 106 women) were identified. For both sexes combined, current smokers had a marginally significant increased risk of AML compared to never smokers (HR = 1.44, 95% confidence interval [CI], 0.97-2.14). Ever smokers with more than 30 pack-years had a statistically significant increased risk of AML compared to never smokers among both sexes combined (HR = 1.66, 95% CI, 1.06-2.63). By sex, this significant association was observed only among men, with an HR of 1.69 (95% CI, 1.00-2.87) for ever smokers with more than 30 pack-years relative to never smokers. In conclusion, this study confirmed that cigarette smoking increases the risk of AML in Japanese. This study provides important evidence that smoking increases the risk of AML among Asians, which has already been shown in Western populations. Copyright © 2017 John Wiley & Sons, Ltd.

  20. Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study.

    Science.gov (United States)

    Ishida, Yasushi; Maeda, Miho; Urayama, Kevin Y; Kiyotani, Chikako; Aoki, Yuki; Kato, Yoko; Goto, Shoko; Sakaguchi, Sachi; Sugita, Kenichi; Tokuyama, Mika; Nakadate, Naoya; Ishii, Eizaburo; Tsuchida, Masahiro; Ohara, Akira

    2014-01-01

    With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Children's Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty-seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non-Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow-up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7-1·4%) at 10 years and 2·4% (95% CI, 1·5-3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5-12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols. © 2013 John Wiley & Sons Ltd.

  1. Geographic and ethnic differences in childhood leukaemia and lymphoma survival: comparisons of Philippine residents, Asian Americans and Caucasians in the United States.

    Science.gov (United States)

    Redaniel, M T; Laudico, A; Mirasol-Lumague, M R; Alcasabas, A P; Pulte, D; Brenner, H

    2010-06-29

    Childhood cancer survival estimates from developing nations are rare. Using the US SEER and the Manila and Rizal Cancer Registry databases in the Philippines, 5-year survival for childhood leukaemia and lymphoma in 2001-2005 among Asian Americans were compared with both Filipinos and Caucasians in the United States. Estimates for patients in the United States in earlier time periods were compared with that of Philippine residents to estimate delay in achievements of comparable levels of survival. Childhood leukaemia and lymphoma relative survival was much lower in Filipinos living in the Philippines (32.9 and 47.7%) than in Asian Americans (80.1 and 90.5%) and Caucasians (81.9 and 87%). Achievement of comparable survival rates of Philippine residents lagged behind by 20 to >30 years compared with patients in the United States. The large differences in survival estimates of US populations and Philippine residents highlight the deficiencies of paediatric cancer care delivery in the Philippines. The long survival lag underlines the need for major improvements in access to diagnostic and treatment facilities.

  2. Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.

    Science.gov (United States)

    Bacher, Nicole; Tiefenthaler, Martin; Sturm, Sonja; Stuppner, Hermann; Ausserlechner, Michael J; Kofler, Reinhard; Konwalinka, Günther

    2006-03-01

    Natural products are still an untapped source of promising lead compounds for the generation of antineoplastic drugs. Here, we investigated for the first time the antiproliferative and apoptotic effects of highly purified oxindole alkaloids, namely isopteropodine (A1), pteropodine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5) obtained from Uncaria tomentosa, a South American Rubiaceae, on human lymphoblastic leukaemia T cells (CCRF-CEM-C7H2). Four of the five tested alkaloids inhibited proliferation of acute lymphoblastic leukaemia cells. Furthermore, the antiproliferative effect of the most potent alkaloids pteropodine (A2) and uncarine F (A4) correlated with induction of apoptosis. After 48 h, 100 micromol/l A2 or A4 increased apoptotic cells by 57%. CEM-C7H2 sublines with tetracycline-regulated expression of bcl-2, p16ink4A or constitutively expressing the cowpox virus protein crm-A were used for further studies of the apoptosis-inducing properties of these alkaloids. Neither overexpression of bcl-2 or crm-A nor cell-cycle arrest in G0/G1 phase by tetracycline-regulated expression of p16INK4A could prevent alkaloid-induced apoptosis. Our results show the strong apoptotic effects of pteropodine and uncarine F on acute leukaemic lymphoblasts and recommend the alkaloids for further studies in xenograft models.

  3. The relationship between pain, fatigue, sleep disorders and quality of life in adult patients with acute leukaemia: During the first year after diagnosis.

    Science.gov (United States)

    Miladinia, Mojtaba; Baraz, Shahram; Ramezani, Monir; Malehi, Amal Saki

    2018-01-01

    The aim of this study was to investigate the relationship between pain, fatigue, sleep disorders and quality of life and assess the most powerful predictor of quality of life in patients with acute leukaemia. In this cross-sectional multicentre study, 406 patients were recruited. Data were collected using the Iranian Short-Form 36-item Health Survey, the Pittsburgh Sleep Quality Index, and the Numeric Rating Scale for Pain and Fatigue Intensity. It was found that pain and fatigue had direct relationship with sleep disorders. Statistically significant relationships were reported between pain, fatigue, sleep disorders and QoL. Also, a statistically significant relationship was found between pain and QoL (p sleep disorders in total had the predictive power for quality of life (R 2  = 36%). The most powerful predictor of quality of life was pain. It is suggested that healthcare professionals note the importance of patients' symptoms in clinical investigations and take appropriate measures for their management. The assessment of pain as the most powerful predictor of quality of life can be considered a basis for the improvement of quality of life, fatigue and sleep quality in patients with acute leukaemia. © 2017 John Wiley & Sons Ltd.

  4. A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience.

    Science.gov (United States)

    Maung, Su W; Burke, Cathie; Hayde, Jennifer; Walshe, Janice; McDermott, Ray; Desmond, Ronan; McHugh, Johnny; Enright, Helen

    2017-07-01

    To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.

  5. A novel RT-qPCR assay for quantification of the MLL-MLLT3 fusion transcript in acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Abildgaard, Lotte; Ommen, Hans Beier; Lausen, Birgitte Frederiksen

    2013-01-01

    OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because of the heter......OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because...... of the heterogeneity of translocation break points, the MLL-MLLT3 fusion gene is a challenging target. We hypothesised that MRD monitoring using MLL-MLLT3 as a RT-qPCR marker is feasible in the majority of patients with t(9;11)-positive AML. METHODS: Using a locked nucleic acid probe, we developed a sensitive RT-qPCR...... follow-up. Two patients relapsed, and both were MRD positive in BM after first induction course. A total of three relapses occurred, and they were detected by RT-qPCR 3 wks before haematological relapse was diagnosed. CONCLUSION: This MLL-MLLT3 RT-qPCR assay could be useful in MRD monitoring of a group...

  6. Epigenetic regulation of microRNA-128a expression contributes to the apoptosis-resistance of human T-cell leukaemia jurkat cells by modulating expression of fas-associated protein with death domain (FADD).

    Science.gov (United States)

    Yamada, Nami; Noguchi, Shunsuke; Kumazaki, Minami; Shinohara, Haruka; Miki, Kohei; Naoe, Tomoki; Akao, Yukihiro

    2014-03-01

    Increased expression of miR-128a is often observed in acute lymphoblastic leukaemia (ALL) compared with its expression in acute myeloid leukaemia (AML). The objective of this study was to investigate the role of miR-128a, especially that in the Fas-signalling pathway, in T-cell leukaemia cells. The role of miR-128a in Fas-mediated apoptosis was examined by using Fas-activating antibody (CH-11)-susceptible Jurkat cells and -resistant Jurkat/R cells. Whereas ectopic expression of miR-128a conferred Fas-resistance on Jurkat cells by directly targeting Fas-associated protein with death domain (FADD), antagonizing miR-128a expression sensitized Jurkat/R cells to the Fas-mediated apoptosis through derepression of FADD expression. Myeloid leukaemia HL60 and K562 cells were also CH-11-resistant, sharing a similar resistant mechanism with Jurkat/R cells. Furthermore, CH-11 induced demethylation of the promoter region of miR-128a with resultant up-regulation of miR-128a expression in Jurkat/R cells, which was shown to be a mechanism for the resistance ofJurkat/R cells to Fas-mediated apoptosis. Our results indicate that the induction of miR-128a expression by DNA demethylation is a novel mechanism of resistance to Fas-mediated apoptosis.

  7. The TEL-AML1 real-time quantitative polymerase chain reaction (PCR) might replace the antigen receptor-based genomic PCR in clinical minimal residual disease studies in children with acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    de Haas, V.; Breunis, W. B.; dee, R.; Verhagen, O. J. H. M.; Kroes, W.; van Wering, E. R.; van Dongen, J. J. M.; van den Berg, H.; van der Schoot, C. E.

    2002-01-01

    Prospective studies in children with B-precursor acute lymphoblastic leukaemia (ALL) have shown that polymerase chain reaction (PCR)-based detection of minimal residual disease (MRD) using immunoglobin (Ig) and T-cell receptor (TCR) gene rearrangements as targets can be used to identify patients

  8. Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 × 10(9) /l. The NOPHO experience 1984-2014

    DEFF Research Database (Denmark)

    Zeller, Bernward; Glosli, Heidi; Forestier, Erik

    2017-01-01

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on...

  9. Expression of co-stimulatory and adhesion molecules and chemokine or apoptosis receptors on acute myeloid leukaemia : high CD40 and CD11a expression correlates with poor prognosis

    NARCIS (Netherlands)

    Brouwer, RE; Hoefnagel, J; van der Burg, BB; Jedema, [No Value; Zwinderman, KH; Starrenburg, ICW; Kluin-Nelemans, HC; Barge, RMY; Willemze, R; Falkenburg, JHF

    2001-01-01

    The expression of adhesion and co-stimulatory molecules. and chemokine and death receptors such as tumour necrosis factor (TNF) and FAS on acute myeloid leukaemia (AML) may influence the biology of the disease and response to chemotherapy and immunotherapy. In this study, we analysed the expression

  10. Joint scientific publication by the INSERM and IRSN concerning child leukaemia about French nuclear power stations on the Internet site of the 'International Journal of Cancer' the 4 January 2012

    International Nuclear Information System (INIS)

    2012-01-01

    This document describes the cooperation between the INSERM and IRSN in the field of child leukaemia about nuclear power stations, and presents the published study: context and objectives, methodology (epidemiological data, geographical data), and obtained results (risks and comparison with a German study)

  11. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data.

    Science.gov (United States)

    2016-06-01

    The management of patients with chronic lymphocytic leukaemia is currently undergoing improvements due to novel therapies and a plethora of biological and genetic variables that add prognostic information to the classic clinical staging systems. We established an international consortium with the aim to create an international prognostic index for chronic lymphocytic leukaemia (CLL-IPI) that integrates the major prognostic parameters. We used results from a systematic search of the Cochrane Haematological Malignancies Group of MEDLINE, Embase, and Central databases for prospective, clinical phase 2 and 3 trials of chronic lymphocytic leukaemia, published between Jan 1, 1950, and Dec 31, 2010, which identified 13 trials. We contacted the principal investigators of these 13 trials, of which eight agreed to include individual patient data. We used the individual patient data from these phase 3 trials from France, Germany, Poland, the UK, and the USA to create the full analysis dataset. The full analysis dataset was randomly divided, using a random sample procedure, into training and internal-validation datasets. We did a univariate analysis and multivariate analyses using 27 baseline factors and overall survival as an endpoint. We assigned weighted risk scores to each factor included in the final multivariable model. We assessed the discriminatory value using C-statistics and also the validity and reproducibility of the CLL-IPI by subgroup analysis. We used two additional datasets from the Mayo Clinic (Rochester, MN, USA; MAYO cohort) and the SCALE Scandinavian population-based case-control study (SCAN cohort) as the external-validation datasets. 3472 treatment-naive patients were included in the full analysis dataset; 2308 were randomly segregated into the training dataset and 1164 into the internal-validation dataset. 838 patients were included in the MAYO cohort and 416 in the SCAN cohort. Median age of patients in the full analysis dataset was 61 years (range 27

  12. Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia

    International Nuclear Information System (INIS)

    Moskalev, Evgeny A; Pötz, Oliver; Joos, Thomas O; Hoheisel, Jörg D; Luckert, Katrin; Vorobjev, Ivan A; Mastitsky, Sergey E; Gladkikh, Aleena A; Stephan, Achim; Schrenk, Marita; Kaplanov, Kamil D; Kalashnikova, Olga B

    2012-01-01

    The Wnt/β-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/β-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect. The results suggest an

  13. The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia.

    Science.gov (United States)

    Basbous, Sara; Levescot, Anaïs; Piccirilli, Nathalie; Brizard, Françoise; Guilhot, François; Roy, Lydia; Bourmeyster, Nicolas; Gombert, Jean-Marc; Herbelin, André

    2016-11-01

    CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  14. Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

    Science.gov (United States)

    Law, Philip J.; Sud, Amit; Mitchell, Jonathan S.; Henrion, Marc; Orlando, Giulia; Lenive, Oleg; Broderick, Peter; Speedy, Helen E.; Johnson, David C.; Kaiser, Martin; Weinhold, Niels; Cooke, Rosie; Sunter, Nicola J.; Jackson, Graham H.; Summerfield, Geoffrey; Harris, Robert J.; Pettitt, Andrew R.; Allsup, David J.; Carmichael, Jonathan; Bailey, James R.; Pratt, Guy; Rahman, Thahira; Pepper, Chris; Fegan, Chris; von Strandmann, Elke Pogge; Engert, Andreas; Försti, Asta; Chen, Bowang; Filho, Miguel Inacio Da Silva; Thomsen, Hauke; Hoffmann, Per; Noethen, Markus M.; Eisele, Lewin; Jöckel, Karl-Heinz; Allan, James M.; Swerdlow, Anthony J.; Goldschmidt, Hartmut; Catovsky, Daniel; Morgan, Gareth J.; Hemminki, Kari; Houlston, Richard S.

    2017-01-01

    B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

  15. Promoter hypermethylation of the retinoic acid receptor beta2 gene is frequent in acute myeloid leukaemia and associated with the presence of CBFβ-MYH11 fusion transcripts

    DEFF Research Database (Denmark)

    Rethmeier, Anita; Aggerholm, Anni; Olesen, Lene Hyldahl

    2006-01-01

    Silencing of the putative tumour suppressor gene retinoic acid receptor beta2 (RARbeta2) caused by aberrant promoter hypermethylation has been identified in several solid tumours. In order to evaluate the extent of RARbeta2 hypermethylation and transcription in acute myeloid leukaemia (AML...... was unmethylated in 10/10 bone marrow and 7/7 blood samples from healthy individuals, the gene was hypermethylated in 43% of the AML patients. The RARbeta2 degree of promoter methylation differed between and within individuals, and the mRNA transcription levels of the gene varied inter-individually by a factor...... of 4000. A significant inverse correlation between promoter hypermethylation and gene expression could be established (t-test, P = 0.019). Comparison of methylation data with a series of other molecular alterations in the same patient materials revealed a correlation between hypermethylation...

  16. Real-time reverse transcription polymerase chain reaction detection and quantification of t(1;19) (E2A-PBX1) fusion genes associated with leukaemia.

    Science.gov (United States)

    Curry, J D; Glaser, M C; Smith, M T

    2001-12-01

    A real-time reverse transcription polymerase chain reaction (RT-PCR) method is described that enabled the detection and quantification of E2A-PBX1 fusion gene transcripts associated with t(1;19). The method was highly reproducible and offered exceptional sensitivity at 5 fg of fusion transcript per reaction, without the need for a nested PCR primer design. To illustrate the usefulness of this new technology the E2A-PBX1 fusion gene transcript expression level for several human leukaemia cell lines that are positive and negative for cytogenetically detectable t(1;19) was determined. The RCH-ACV had a threefold higher expression of E2A-PBX1 transcripts (600 transcripts per cell) than the other t(1;19) positive 697 (150 transcripts per cell). The only other cell line with detectable E2A-PBX1 was CEM, but the level of expression was < 1 transcript per cell.

  17. Risk of therapy-related leukaemia and preleukaemia after Hodgkin's disease. Relation to age, cumulative dose of alkylating agents, and time from chemotherapy

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J; Specht, L; Larsen, S O

    1987-01-01

    391 patients treated intensively for Hodgkin's disease were followed for up to 15 years to evaluate the risk of therapy-related acute non-lymphocytic leukaemia (t-ANLL) and preleukaemia. Only two independent factors, patient age and cumulative dose of alkylating agents, were related to the risk...... of t-ANLL. The hazard rate of t-ANLL was roughly proportional to the square of patient age and to the total cumulative dose of alkylating agents. In 320 patients treated with alkylating agents the cumulative risk of t-ANLL increased steadily from 1 year after the start of treatment and reached 13.......0% (SE 3.0) at 10 years after which time there were no further cases. Calculated from cessation of therapy with alkylating agents, however, the cumulative risk curve increased steeply during the first 1-2 years then gradually levelled out and no new cases were observed beyond 7 years. With a 15-year...

  18. Geographic and sociodemographic factors in the etiology of juvenile neoplasms: implications for leukaemia clusters of several factors including density, background radiation, infections and immunisations

    International Nuclear Information System (INIS)

    Kneale, G.W.

    1993-01-01

    This paper presents an analysis of data from the Oxford Survey of Childhood Cancers (OSCC) by the recently invented method of Fears and Brown, as modified (for correct variances of relative risk estimates) by Breslow and Zhao. The analysis has shown that, for OSCC cases, negative associations with population density, stillbirths and infant deaths were sufficiently strong for these alone to account for all but one of the leukaemia clusters so far reported in Britain as 'black hole' effects (the single exception being the Sellafield cluster). Finally, strong positive associations with regional levels of background radiation were found which have reinforced an earlier impression that these inevitable exposures are important causes of childhood cancer. (orig./MG)

  19. A novel BCR-ABL transcript e2a2 in a chronic myelogenous leukaemia patient with a duplicated Ph-chromosome and monosomy 7.

    Science.gov (United States)

    Leibundgut, E O; Jotterand, M; Rigamonti, V; Parlier, V; Mühlematter, D; Tobler, A; Solenthaler, M

    1999-09-01

    A novel BCR-ABL transcript was detected by multiplex RT-PCR in a patient with Philadelphia chromosome (Ph) positive chronic myelogenous leukaemia (CML) in accelerated phase. Sequencing of the aberrant transcript revealed an in-frame e2a2 fusion that included a 9 basepairs insertion. Cytogenetic analysis showed t(9;22), an additional Ph chromosome and monosomy 7. The clinical course was dismal: therapy was poorly tolerated, and the patient died in blast crisis 10 months after diagnosis. These data support the association of additional Ph and monosomy 7 with poor prognosis and suggest that the novel e2a2 BCR-ABL transcript may be related to an aggressive clinical course.

  20. Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms

    DEFF Research Database (Denmark)

    Klostergaard, Anja; Steffensen, Rudi; Møller, Jens K

    2010-01-01

    Infections after chemotherapy often cause significant morbidity in patients with acute myeloid leukaemia (AML). Chitotriosidase (CHIT) and mannose-binding lectin (MBL) are part of the innate immune system. Polymorphism in the CHIT-coding gene (CHIT1) may be associated with Gram-negative sepsis...... was a major concomitant factor for death. No significant associations between CHIT1 polymorphism and sepsis (P = 0.85) or death caused by sepsis (P = 0.14) were found. Furthermore, no significant associations between MBL2 polymorphism and sepsis (P = 0.76) or death caused by sepsis (P = 0.24) were observed...... in children with AML, and polymorphism in the MBL-coding gene (MBL2) seems to modify the risk of infections in several patient groups. The purpose of this study was to investigate the possible associations between polymorphisms in CHIT1, MBL2 and sepsis in adult patients treated with high-dose chemotherapy...

  1. Humoral immune failure defined by immunoglobulin class and immunoglobulin G subclass deficiency is associated with shorter treatment-free and overall survival in Chronic Lymphocytic Leukaemia.

    Science.gov (United States)

    Crassini, Kyle R; Zhang, Eva; Balendran, Shalini; Freeman, Jane A; Best, O Giles; Forsyth, Cecily J; Mackinlay, Naomi J; Han, Ping; Stevenson, William S; Mulligan, Stephen P

    2018-04-01

    Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment-free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL. © 2018 John Wiley & Sons Ltd.

  2. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study

    DEFF Research Database (Denmark)

    Tierens, Anne; Bjørklund, Elizabeth; Siitonen, Sanna

    2016-01-01

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society...... of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut-off level. RD-negative and -positive patients after...... first induction showed a 5-year EFS of 65 ± 7% and 22 ± 7%, respectively (P consolidation therapy had a 5-year EFS of 57 ± 7% and 11 ± 7%, respectively (P

  3. The risk of leukaemia in young children from exposure to tritium and carbon-14 in the discharges of German nuclear power stations and in the fallout from atmospheric nuclear weapons testing

    International Nuclear Information System (INIS)

    Wakeford, Richard

    2014-01-01

    Towards the end of 2007, the results were published from a case-control study (the ''KiKK Study'') of cancer in young children, diagnosed <5 years of age during 1980-2003 while resident near nuclear power stations in western Germany. The study found a tendency for cases of leukaemia to live closer to the nearest nuclear power station than their matched controls, producing an odds ratio that was raised to a statistically significant extent for residence within 5 km of a nuclear power station. The findings of the study received much publicity, but a detailed radiological risk assessment demonstrated that the radiation doses received by young children from discharges of radioactive material from the nuclear reactors were much lower than those received from natural background radiation and far too small to be responsible for the statistical association reported in the KiKK Study. This has led to speculation that conventional radiological risk assessments have grossly underestimated the risk of leukaemia in young children posed by exposure to man-made radionuclides, and particular attention has been drawn to the possible role of tritium and carbon-14 discharges in this supposedly severe underestimation of risk. Both 3 H and 14 C are generated naturally in the upper atmosphere, and substantial increases in these radionuclides in the environment occurred as a result of their production by atmospheric testing of nuclear weapons during the late 1950s and early 1960s. If the leukaemogenic effect of these radionuclides has been seriously underestimated to the degree necessary to explain the KiKK Study findings, then a pronounced increase in the worldwide incidence of leukaemia among young children should have followed the notably elevated exposure to 3 H and 14 C from nuclear weapons testing fallout. To investigate this hypothesis, the time series of incidence rates of leukaemia among young children <5 years of age at diagnosis has been examined from ten

  4. The risk of leukaemia in young children from exposure to tritium and carbon-14 in the discharges of German nuclear power stations and in the fallout from atmospheric nuclear weapons testing

    Energy Technology Data Exchange (ETDEWEB)

    Wakeford, Richard [The University of Manchester, Centre for Occupational and Environmental Health, Institute of Population Health, Manchester (United Kingdom)

    2014-05-15

    Towards the end of 2007, the results were published from a case-control study (the ''KiKK Study'') of cancer in young children, diagnosed <5 years of age during 1980-2003 while resident near nuclear power stations in western Germany. The study found a tendency for cases of leukaemia to live closer to the nearest nuclear power station than their matched controls, producing an odds ratio that was raised to a statistically significant extent for residence within 5 km of a nuclear power station. The findings of the study received much publicity, but a detailed radiological risk assessment demonstrated that the radiation doses received by young children from discharges of radioactive material from the nuclear reactors were much lower than those received from natural background radiation and far too small to be responsible for the statistical association reported in the KiKK Study. This has led to speculation that conventional radiological risk assessments have grossly underestimated the risk of leukaemia in young children posed by exposure to man-made radionuclides, and particular attention has been drawn to the possible role of tritium and carbon-14 discharges in this supposedly severe underestimation of risk. Both {sup 3}H and {sup 14}C are generated naturally in the upper atmosphere, and substantial increases in these radionuclides in the environment occurred as a result of their production by atmospheric testing of nuclear weapons during the late 1950s and early 1960s. If the leukaemogenic effect of these radionuclides has been seriously underestimated to the degree necessary to explain the KiKK Study findings, then a pronounced increase in the worldwide incidence of leukaemia among young children should have followed the notably elevated exposure to {sup 3}H and {sup 14}C from nuclear weapons testing fallout. To investigate this hypothesis, the time series of incidence rates of leukaemia among young children <5 years of age at diagnosis has been

  5. Beta-escin, a natural triterpenoid saponin from Chinese horse chestnut seeds, depresses HL-60 human leukaemia cell proliferation and induces apoptosis.

    Science.gov (United States)

    Niu, Yang P; Wu, Li M; Jiang, Yan L; Wang, Wen X; Li, Lian D

    2008-09-01

    Beta-escin, a natural triterpenoid saponin isolated from the seed of the horse chestnut, is known to generate a wide variety of biochemical and pharmacological effects. The purpose of the present study was to examine the apoptotic and antiproliferative activity of beta-escin in HL-60 human acute myeloid leukaemia cells. Antiproliferative activity was examined by soft agar colony assay and the trypan blue exclusion method. Apoptotic activity was evaluated by morphological analysis, annexin V analysis, DNA fragmentation analysis and flow cytometry cell cycle analysis. The results showed that beta-escin caused a significant inhibition of HL-60 cell proliferation in a dose- and time-dependent manner. Morphological evidence of apoptosis, including vacuolization, apoptotic nuclei fragmentation and apoptotic body formation, was observed in cells treated with 30 microg mL(-1) of beta-escin for 24, 48 and 72 h. A significant increase in the population of annexin V+ and PI- cells (early apoptotic) among the total cells was observed in cells treated with beta-escin (30-50 microg mL(-1)) for 24 h (Pescin (30-50 microg mL(-1)) for 48 h by agarose gel electrophoresis. Flow cytometry cell cycle analysis revealed that beta-escin (30-50 microg mL(-1)) induced G1-S arrest and led to a significant accumulation of the sub-G1 population in HL-60 cells (Pescin is a potent natural inhibitor of cell proliferation and inducer of apoptosis in HL-60 acute myeloid leukaemia cells. The results indicate that beta-escin may be a useful candidate agent for exploring potential antileukaemic drugs.

  6. Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.

    Science.gov (United States)

    Rao, Anupama; Hills, Robert K; Stiller, Charles; Gibson, Brenda E; de Graaf, Siebold S N; Hann, Ian M; O'Marcaigh, Aengus; Wheatley, Keith; Webb, David K H

    2006-03-01

    Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

  7. In vitro experimental 211At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin

    International Nuclear Information System (INIS)

    Petrich, Thorsten; Korkmaz, Zekiye; Krull, Doris; Meyer, Geerd J.; Knapp, Wolfram H.; Froemke, Cornelia

    2010-01-01

    Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. We labelled anti-CD33 antibodies with the alpha-emitter 211 At and compared survival of leukaemic HL-60 and K-562 cells treated with the 211 At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free 211 At. The mean labelling ratio of 211 At-labelled antibodies was 1:1,090 ± 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of 211 At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. 211 At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after 211 At-anti-CD33 (1:1,090) versus GO (1:1) treatment. Our results suggest that 211 At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase 211 At-anti-CD33 therapeutic effects. (orig.)

  8. In vitro experimental {sup 211}At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin

    Energy Technology Data Exchange (ETDEWEB)

    Petrich, Thorsten; Korkmaz, Zekiye; Krull, Doris; Meyer, Geerd J.; Knapp, Wolfram H. [Hanover University School of Medicine, Department of Nuclear Medicine, Hanover (Germany); Froemke, Cornelia [Hanover University School of Medicine, Department of Biometry, Hanover (Germany)

    2010-05-15

    Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. We labelled anti-CD33 antibodies with the alpha-emitter {sup 211}At and compared survival of leukaemic HL-60 and K-562 cells treated with the {sup 211}At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free {sup 211}At. The mean labelling ratio of {sup 211}At-labelled antibodies was 1:1,090 {+-} 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of {sup 211}At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. {sup 211}At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after {sup 211}At-anti-CD33 (1:1,090) versus GO (1:1) treatment. Our results suggest that {sup 211}At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase {sup 211}At-anti-CD33 therapeutic effects. (orig.)

  9. Temporal and Other Exposure Aspects of Residential Magnetic Fields Measurement in Relation to Acute Lymphoblastic Leukaemia in Children: The National Cancer Institute Children's Cancer Group Study (invited paper)

    International Nuclear Information System (INIS)

    Baris, D.; Linet, M.; Auvinen, A.; Kaune, W.T.; Wacholder, S.; Kleinerman, R.; Hatch, E.; Robison, L.; Niwa, S.; Haines, C.; Tarone, R.E.

    1999-01-01

    Case-control studies have used a variety of measurements to evaluate the relationship of children's exposure to magnetic fields (50 or 60 Hz) with childhood leukaemia and other childhood cancers. In the absence of knowledge about which exposure metrics may be biologically meaningful, studies during the past 10 years have often used time-weighted average (TWA) summaries of home measurements. Recently, other exposure metrics have been suggested, usually based on theoretical considerations or limited laboratory data. In this paper, the rationale and associated preliminary studies undertaken are described as well as feasibility and validity issues governing the choice of the primary magnetic field exposure assessment methods and summary metric used to estimate children's exposure in the National Cancer Institute/Children's Cancer Group (NCI/CCG) case-control study. Also provided are definitions and discussion of the strengths and weaknesses of the various exposure metrics used in exploratory analyses of the NCI/CCG measurement data. Exposure metrics evaluated include measures of central tendency (mean, median, 30th to 70th percentiles), peak exposures (90th and higher percentiles, peak values of the 24 h measurements), and measurements of short-term temporal variability (rate of change). This report describes correlations of the various metrics with the time-weighted average for the 24 h period (TWA-24-h). Most of the metrics were found to be positively and highly correlated with TWA-24-h, but lower correlations of TWA-24-h with peak exposure and with rate of change were observed. To examine further the relation between TWA and alternative metrics, similar exploratory analysis should be considered for existing data sets and for forthcoming measurement investigations of residential magnetic fields and childhood leukaemia. (author)

  10. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun, E-mail: xuejunshao@hotmail.com

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  11. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

    Science.gov (United States)

    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

    The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m 2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m 2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m 2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock

  12. Lymphatic Leukaemia* In Acute

    African Journals Online (AJOL)

    S. Afr. Med. J., 45, 867 (1971). Pneumocystis carinii is an organism which causes a diffuse pulmonary alveolar infestation in man. The organism was recognized and classified as a protozoan 60 years ago by. Chagas and CariniY This rare and usually fatal disease occurs in young babies;" or in individuals whose capacity.

  13. EDRP public local inquiry, UKAEA/BNFL precognition on: Review of the Scottish Health Service ISD report on 'Geographical distribution of leukaemia in young persons in Scotland 1968-1983'

    International Nuclear Information System (INIS)

    Wilkie, David

    1986-09-01

    The Scottish Health Service ISD Report is reviewed, with particular attention being paid to the statistical treatment of the data and its interpretation in relation to the location and frequency of occurrence of clusters of leukaemia identified in it. The sensitivity of cluster occurrence to the choice of sector boundaries and to the sub-division of the total time period of the study is considered, in general terms and by numerical experiment. (UK)

  14. The risk of leukaemia in young children from exposure to tritium and carbon-14 in the discharges of German nuclear power stations and in the fallout from atmospheric nuclear weapons testing.

    Science.gov (United States)

    Wakeford, Richard

    2014-05-01

    Towards the end of 2007, the results were published from a case-control study (the "KiKK Study") of cancer in young children, diagnosed nuclear power stations in western Germany. The study found a tendency for cases of leukaemia to live closer to the nearest nuclear power station than their matched controls, producing an odds ratio that was raised to a statistically significant extent for residence within 5 km of a nuclear power station. The findings of the study received much publicity, but a detailed radiological risk assessment demonstrated that the radiation doses received by young children from discharges of radioactive material from the nuclear reactors were much lower than those received from natural background radiation and far too small to be responsible for the statistical association reported in the KiKK Study. This has led to speculation that conventional radiological risk assessments have grossly underestimated the risk of leukaemia in young children posed by exposure to man-made radionuclides, and particular attention has been drawn to the possible role of tritium and carbon-14 discharges in this supposedly severe underestimation of risk. Both (3)H and (14)C are generated naturally in the upper atmosphere, and substantial increases in these radionuclides in the environment occurred as a result of their production by atmospheric testing of nuclear weapons during the late 1950s and early 1960s. If the leukaemogenic effect of these radionuclides has been seriously underestimated to the degree necessary to explain the KiKK Study findings, then a pronounced increase in the worldwide incidence of leukaemia among young children should have followed the notably elevated exposure to (3)H and (14)C from nuclear weapons testing fallout. To investigate this hypothesis, the time series of incidence rates of leukaemia among young children nuclear weapons testing, or that incidence rates are related to level of exposure to fallout, is apparent from these

  15. The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.

    Science.gov (United States)

    Main, C; Pitt, M; Moxham, T; Stein, K

    2010-10-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to

  16. A novel envelope mediated post entry restriction of murine leukaemia virus in human cells is Ref1/TRIM5α independent

    Directory of Open Access Journals (Sweden)

    McKnight Áine

    2010-10-01

    Full Text Available Abstract Background 'Intrinsic' resistance to retroviral infection was first recognised with the Friend virus susceptibility gene (Fv1, which determines susceptibility to murine leukaemia virus (MLV infection in different murine species. Similarly, the tripartite motif (TRIM family of proteins determine lentiviral restriction in a primate host-species specific manner. For example rhesus TRIM5α (rhTRIM5α can potently restrict HIV-1 infection while human TRIM5α (huTRIM5α only has a mild effect on SIVmac and HIV-1 infectivity (Lv1. Human TRIM5α is able to restrict MLV-N virus replication, but is ineffective against MLV-B or MLV-NB virus infection. Lv2 restriction of some HIV-2 viruses is seen in human cells. Like Lv1, Lv2 is a post-entry restriction factor, whose viral determinants have been mapped to the viral capsid (CA. Unlike Lv1, however, Lv2 is determined by envelope (Env in addition to CA. Here we present evidence of a novel Env determined post entry restriction to infection in human cells of pseudotyped MLV-B and MLV-NB cores. Results We generated retroviral vectors pseudotyped with various gamma and lentiviral Envs on MLV-B and -NB CAs containing a green fluorescent protein (GFP reporter. Flow cytometry was used to determine transduction efficiencies in NP2/CD4/CXCR4 (glioma cell line stably transduced with the HIV receptors and HeLa/CD4 cell lines. The HeLa/CD4 cell line restricted both MLV CAs in an Env dependent manner, compared to NP2/CD4/CXCR4 cells. Quantitative polymerase chain reaction (QT-PCR analysis of reverse transcription (RT transcripts demonstrates that this restriction occurs at a post entry and RT level. siRNA knockdown of huTRIM5α ruled out a direct role for this cellular component in mediating this restriction. We describe a previously unobserved Env determined restriction of MLV-B and MLV-NB CAs in HeLa/CD4 cells when pseudotyped with HIV-2 and RD114 Envs, but not gibbon ape leukaemia virus (GALV, HIV-1 or

  17. Meeting Report: Institute for Social Security and Services for State Workers (ISSSTE on Acute Lymphoblastic Leukaemia, Mexico City, Mexico, 3rd to 4th October 2016

    Directory of Open Access Journals (Sweden)

    Alvarado Ibarra Martha

    2017-06-01

    Full Text Available From October 3 to 4, 2016, the fourth meeting of haematologists who belonged to the institute for social security and services for state workers (ISSSTE was held, the meeting was held in Mexico City, Mexico. Attending this working meeting, medical fellows of the specialty of Haematology and Paediatric Haematology, as well as attached doctors of both specialties that work in different hospitals in Mexico City and the rest of the country, the purpose of the attendees to this consensus was discuss, update, and homogenize the protocols of diagnostic and therapeutic approach in patients with acute lymphoblastic leukaemia of all ages. All participants appreciated the opportunity to participate in one of the most important cooperation projects of the ISSSTE and to be able to offer updated treatment protocols to this population or, failing that, to send them a Medical Center that can provide hospital care as soon as possible. Physicians took advantage of this meeting for the scientific exchange, the discussion on projects in course and were planned the development of other consensuses being the closest the one of lymphomas. As in the previous consensuses that were published in a National magazine. The coordinator of this project raised to the attendees the possibility of a publication in magazines of greater prestige international since in countries like Mexico the cooperative work is not frequent and the group of haematologists belonging to ISSSTE are working towards this goal. This consensus was considered as a very well-organized platform to support the research of young fellows in the specialty to stimulate the team work in protocols of the different haematological pathologies and to inform the world the results achieved in a population of patients attended by the ISSSTE. In agreement with the main objective of this consensus on acute lymphoblastic leukaemia once finished and discussed throughout the haematological group, the coordinator for the

  18. Comparison of Health and Safety Executive and Cumbrian birth cohort studies of risk of leukaemia/non-Hodgkin's lymphoma in relation to paternal preconceptional irradiation

    International Nuclear Information System (INIS)

    Dickinson, H O; Hodgson, J T; Parker, L

    2003-01-01

    In 1993, a case-control study by the Health and Safety Executive (HSE) assessed the risk of leukaemia and non-Hodgkin's lymphoma (LNHL) among children of fathers employed at the Sellafield nuclear installation in relation to paternal preconceptional irradiation (PPI). It concluded that the statistical association between risk of LNHL and PPI was confined to children born in the village of Seascale, where the dose-response was extremely high and very significant. In contrast, in 2002, a Cumbrian birth cohort study, investigating largely the same cases, concluded that this statistical association was not significantly different among children born inside and outside Seascale and estimated the dose-response inside Seascale to be much lower. This review makes a detailed comparison of the two studies, considering their design, data and analyses. The differences between their findings are due to: (i) differences in the distribution of offspring-years which are differential with respect to dose category and Seascale birth status, (ii) a non-Seascale high-dose case included in the Cumbrian but not the HSE study, (iii) differences between analyses using categorical and continuous PPI dose and (iv) the presence of Seascale controls with PPI over 200 mSv in the Cumbrian but not the HSE study

  19. Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC).

    Science.gov (United States)

    Duchayne, Eliane; Fenneteau, Odile; Pages, Marie-Pierre; Sainty, Danielle; Arnoulet, Christine; Dastugue, Nicole; Garand, Richard; Flandrin, Georges

    2003-01-01

    Since the WHO classification of haematological malignancies recommended the description of global entities, we performed a national M7-AML study to correlate morphological, immunological and cytogenetic features, and to find new clinically relevant M7 entities. This study is based on accurate morphological and immunological study to select pure megakaryoblastic proliferations and to eliminate megakaryocytic participation in haemopathies. We collected 53 cases: 23 adults and 30 children. We confirm the wide heterogeneity of adult M7. In adults, the cytogenetic abnormalities are frequently those of secondary leukaemia while a few patients have a previous history and morphological features of dyshaematopoiesis; their outcome is very poor. Among children, besides the well-known Down syndrome M7, we in particular, studied ten t(1;22) M7 and one OTT-MAL transcript positive case with normal karyotype presenting specific features. We were already aware of their younger age, female and tumoral presentation, but we also found a lower percentage of bone marrow blasts, sometimes without any megakaryoblastic bone marrow involvement, but always, with a dysmegakaryocytopoiesis associated with micromegakaryocytes. They are generally good responders to intensive AML chemotherapy with very long disease-free survivals (DFS). Accordingly, OTT-MAL transcript study, in infant M7 with normal karyotype, is recommended and we feel that this entity should be added to the WHO AML classification.

  20. Detection of BCR-ABL and E2A-PBX1 fusion genes by RT-PCR in acute lymphoblastic leukaemia with failed or normal cytogenetics.

    Science.gov (United States)

    Devaraj, P E; Foroni, L; Kitra-Roussos, V; Secker-Walker, L M

    1995-02-01

    To evaluate the use of molecular analysis as a complement to karyotypic analysis in the detection of specific chromosomal abnormalities, the occurrence of t(1;19)(q23;p13) and t(9;22)(q34;q11) was investigated by RT-PCR in 43 diagnostic acute lymphoblastic leukaemia cases in whom cytogenetic investigations had failed (32 cases) or showed only a normal karyotype (> or = 20 normal metaphases, 11 cases). One child (aged 14 years) and five adults (aged 18-60 years) were BCR-ABL positive on first round for M-BCR-ABL (one case) or m-BCR-ABL (one case), or on nested PCR for m-BCR-ABL (three cases). Co-expression of M-BCR-ABL (first-round PCR) and m-BCR-ABL (nested PCR was seen in one case. One m-BCR-ABL-positive case also expressed the E2A-PBX1 fusion transcript. Patients positive for the transcript(s) were older, had higher white blood cell counts and a significantly poorer event-free survival (P < 0.001) than those negative for the transcript.

  1. Rapid Evolution to Blast Crisis Associated with a Q252H ABL1 Kinase Domain Mutation in e19a2 BCR-ABL1 Chronic Myeloid Leukaemia

    Directory of Open Access Journals (Sweden)

    Sarah L. McCarron

    2013-01-01

    Full Text Available A minority of chronic myeloid leukaemia (CML patients express variant transcripts of which the e19a2 BCR-ABL1 fusion is the most common. Instances of tyrosine kinase inhibitor (TKI resistance in e19a2 BCR-ABL1 CML patients have rarely been reported. A case of e19a2 BCR-ABL1 CML is described in whom imatinib resistance, associated with a Q252H ABL1 kinase domain mutation, became apparent soon after initiation of TKI therapy. The patient rapidly transformed to myeloid blast crisis (BC with considerable bone marrow fibrosis and no significant molecular response to a second generation TKI. The clinical course was complicated by comorbidities with the patient rapidly succumbing to advanced disease. This scenario of Q252H-associated TKI resistance with rapid BC transformation has not been previously documented in e19a2 BCR-ABL1 CML. This case highlights the considerable challenges remaining in the management of TKI-resistant BC CML, particularly in the elderly patient.

  2. Lower-limb MRI in the staging and re-staging of osteonecrosis in paediatric patients affected by acute lymphoblastic leukaemia after therapy

    International Nuclear Information System (INIS)

    Ippolito, D.; Masetto, A.; Franzesi, C.T.; Bonaffini, P.A.; Sironi, S.; Sala, A.; Biondi, A.

    2016-01-01

    To assess the diagnostic value of MRI examination in detecting and monitoring osteonecrotic lesions (ON) in childhood acute lymphoblastic leukaemia (ALL) after chemotherapy (CHT) and/or bone marrow transplantation (BMT). Seventy-three patients (37 males, mean age 12.4 years old) with ALL after treatment underwent a lower-limb MR examination between November 2006 and March 2012. In 47 there was clinical suspicion of ON, 26 were asymptomatic. Studies were performed with a 1 T and a 1.5 T scanner, acquiring short tau inversion recovery (STIR) and T1-weighted sequences in coronal plane from the hips to the ankles. The average acquisition time was 18 min. Considering baseline and follow-up examinations, the overall number of MRI studies was 195. Fifty-four of 73 patients showed ON at MRI study, with an overall number of 323 ON (89 involving articular surface, 24 with joint deformity, JD). Twenty-five of 47 symptomatic patients showed subchondral ON lesions, 11 developed JD. Three of 26 asymptomatic patients showed subchondral bone ON at baseline examination but no JD at follow-up. Twenty-two of 28 BMT, 32/45 CHT patients developed ON. Our MRI protocol proved to be feasible in evaluating ON in paediatric patients. Studies should be addressed only to symptomatic patients. (orig.)

  3. Lower-limb MRI in the staging and re-staging of osteonecrosis in paediatric patients affected by acute lymphoblastic leukaemia after therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ippolito, D.; Masetto, A.; Franzesi, C.T.; Bonaffini, P.A.; Sironi, S. [University of Milano-Bicocca Milan, School of Medicine, Monza (Italy); Department of Diagnostic Radiology, H. San Gerardo, Monza (Italy); Sala, A.; Biondi, A. [University of Milano-Bicocca Milan, School of Medicine, Monza (Italy); H. San Gerardo, Department of Paediatric Haematology, Monza (Italy)

    2016-04-15

    To assess the diagnostic value of MRI examination in detecting and monitoring osteonecrotic lesions (ON) in childhood acute lymphoblastic leukaemia (ALL) after chemotherapy (CHT) and/or bone marrow transplantation (BMT). Seventy-three patients (37 males, mean age 12.4 years old) with ALL after treatment underwent a lower-limb MR examination between November 2006 and March 2012. In 47 there was clinical suspicion of ON, 26 were asymptomatic. Studies were performed with a 1 T and a 1.5 T scanner, acquiring short tau inversion recovery (STIR) and T1-weighted sequences in coronal plane from the hips to the ankles. The average acquisition time was 18 min. Considering baseline and follow-up examinations, the overall number of MRI studies was 195. Fifty-four of 73 patients showed ON at MRI study, with an overall number of 323 ON (89 involving articular surface, 24 with joint deformity, JD). Twenty-five of 47 symptomatic patients showed subchondral ON lesions, 11 developed JD. Three of 26 asymptomatic patients showed subchondral bone ON at baseline examination but no JD at follow-up. Twenty-two of 28 BMT, 32/45 CHT patients developed ON. Our MRI protocol proved to be feasible in evaluating ON in paediatric patients. Studies should be addressed only to symptomatic patients. (orig.)

  4. Lower-limb MRI in the staging and re-staging of osteonecrosis in paediatric patients affected by acute lymphoblastic leukaemia after therapy.

    Science.gov (United States)

    Ippolito, D; Masetto, A; Franzesi, C Talei; Bonaffini, P A; Sala, A; Biondi, A; Sironi, S

    2016-04-01

    To assess the diagnostic value of MRI examination in detecting and monitoring osteonecrotic lesions (ON) in childhood acute lymphoblastic leukaemia (ALL) after chemotherapy (CHT) and/or bone marrow transplantation (BMT). Seventy-three patients (37 males, mean age 12.4 years old) with ALL after treatment underwent a lower-limb MR examination between November 2006 and March 2012. In 47 there was clinical suspicion of ON, 26 were asymptomatic. Studies were performed with a 1 T and a 1.5 T scanner, acquiring short tau inversion recovery (STIR) and T1-weighted sequences in coronal plane from the hips to the ankles. The average acquisition time was 18 min. Considering baseline and follow-up examinations, the overall number of MRI studies was 195. Fifty-four of 73 patients showed ON at MRI study, with an overall number of 323 ON (89 involving articular surface, 24 with joint deformity, JD). Twenty-five of 47 symptomatic patients showed subchondral ON lesions, 11 developed JD. Three of 26 asymptomatic patients showed subchondral bone ON at baseline examination but no JD at follow-up. Twenty-two of 28 BMT, 32/45 CHT patients developed ON. Our MRI protocol proved to be feasible in evaluating ON in paediatric patients. Studies should be addressed only to symptomatic patients.

  5. Development of an Epstein-Barr virus-associated lymphoproliferative disorder in a patient treated with azacitidine for chronic myelomonocytic leukaemia.

    Science.gov (United States)

    Menter, T; Schlageter, M; Bastian, L; Haberthür, R; Rätz Bravo, A E; Tzankov, A

    2014-03-01

    Some chemotherapeutic agents can cause iatrogenic lymphoproliferative disorders. In analogy to what has been observed with other nucleoside analogues such as cladribine and fludarabine, we document the first case of an Epstein-Barr virus-positive, iatrogenic immunodeficiency-associated, lymphoproliferative disease, formally resembling polymorphic post-transplant lymphoproliferative disease in a patient treated with azacitidine (Vidaza) for chronic myelomonocytic leukaemia (CMML). A 78-year-old female patient was diagnosed with CMML in January 2012, and treatment with azacitidine was initiated, which lasted for five cycles from February until June 2012. The patient was hospitalized in June 2012 under the suspicion of pneumonia. Transformation of the CMML was suspected at that time too. During hospitalization, a generalized enlargement of the lymph nodes and the spleen was noticed. The patient rapidly deteriorated and finally died of respiratory insufficiency. At autopsy, an Epstein-Barr virus-associated lymphoproliferative disorder, resembling polymorphic post-transplant lymphoproliferative disease with involvement of the lymph nodes, the spleen and the lung and causing necrotizing pneumonia, was diagnosed. Diagnostic criteria for diffuse large B-cell lymphoma or infectious mononucleosis-like lymphoproliferative disease were not met. This is the first documented case of an azacitidine-associated lymphoproliferative disease, raising awareness for possible not yet known side effects of this drug, which should be kept in mind by oncologists and pathologists. Copyright © 2013 John Wiley & Sons, Ltd.

  6. Direct X-ray radiogrammetry versus dual-energy X-ray absorptiometry: assessment of bone density in children treated for acute lymphoblastic leukaemia and growth hormone deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Rijn, Rick R. van; Wittenberg, Rianne [Academic Medical Centre Amsterdam, Department of Radiology, Amsterdam Zuid-Oost (Netherlands); Boot, Annemieke; Sluis, Inge M. van der; MuinckKeizer-Schrama, Sabine M.P.F. de [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Endocrinology, Rotterdam (Netherlands); Heuvel-Eibrink, Marry M. van den [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Haematology/Oncology, Rotterdam (Netherlands); Lequin, Maarten H. [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Radiology, Rotterdam (Netherlands); Kuijk, Cornelis Van [University Medical Centre ' Radboud' , Department of Radiology, Nijmegen (Netherlands)

    2006-03-15

    In recent years interest in bone densitometry in children has increased. To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA). A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed. In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of <0.001. During treatment a change in DXR-BMD was found in children with GHD. Our study showed that DXR in a paediatric population shows a strong correlation with DXA of the lumbar spine and total body and that it is able to detect a change in BMD during treatment. (orig.)

  7. An 8-year longitudinal sero-epidemiological study of bovine leukaemia virus (BLV) infection in dairy cattle in Turkey and analysis of risk factors associated with BLV seropositivity.

    Science.gov (United States)

    Şevik, Murat; Avcı, Oğuzhan; İnce, Ömer Barış

    2015-04-01

    Enzootic bovine leukosis (EBL) which is caused by bovine leukaemia virus (BLV) has an important economic impact on dairy herds due to reduced milk production and restrictions on livestock exports. This study was conducted to determine the BLV infection status in Central Anatolia Region of Turkey, an important milk production centre, and to examine the risk factors such as purchasing cattle, increasing cattle age, cattle breed and herd size associated with transmission of BLV infection. To estimate the rate of BLV infection, a survey for specific antibodies in 28,982 serum samples from animals belonging to 1116 different herds situated in Central Anatolia Region of Turkey were tested from January 2006 to December 2013. A generalized mixed linear model was used to evaluate the risk factors that influenced BLV seroprevalence. Antibodies against BLV were detected in 431 (2.28 %) of 18,822 Holstein and 29 (0.28 %) of 10,160 Brown Swiss cows. Among 1116 herds, 132 herds (11.82 %) had one or more positive animals. Also results of our study show that the prevalence of BLV infection increased from 2006 to 2011, and it tends to reduce with BLV control programme. Furthermore, we found positive associations between percentage of seropositive animal and increasing cattle age, herd size, cattle breed and purchased cattle. Age-specific prevalence showed that BLV prevalence increased with age. These factors should be taken into consideration for control of BLV infection.

  8. Melanoma and non-melanoma skin cancers in hairy cell leukaemia: a SEER population analysis and the 30-year experience at Memorial Sloan Kettering Cancer Center

    Science.gov (United States)

    Watts, Justin M; Kishtagari, Ashwin; Hsu, Meier; Lacouture, Mario E; Postow, Michael A; Park, Jae H; Stein, Eytan M; Teruya-Feldstein, Julie; Abdel-Wahab, Omar; Devlin, Sean M; Tallman, Martin S

    2016-01-01

    Few studies have examined melanoma and non-melanoma skin cancer (NMSC) incidence rates after a diagnosis of hairy cell leukaemia (HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and Surveillance, Epidemiology and End Results (SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10-year combined melanoma and NMSC skin cancer rate of 11.3%, melanoma 4.4% and NMSC 6.9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4,750 SEER patients with HCL, 55 (1.2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios (SIRs) did not show that melanoma was more common in HCL patients versus the general population (SIR 1.3, 95% CI 0.78–2.03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients. PMID:26115047

  9. Measurement of BCR-ABL1 by RT-qPCR in chronic myeloid leukaemia: findings from an International EQA Programme.

    Science.gov (United States)

    Scott, Stuart; Travis, Debbie; Whitby, Liam; Bainbridge, John; Cross, Nicholas C P; Barnett, David

    2017-05-01

    Sequential measurement of BCR-ABL1 mRNA levels by reverse transcription quantitative polymerase chain reaction (RT-qPCR) is embedded in the management of patients with chronic myeloid leukaemia (CML), and has played an important role in the remarkable improvement in patient outcomes seen in this disease. As a provider of external quality assessment (EQA) in this area, UK NEQAS for Leucocyte Immunophenotyping (UKNEQAS LI) has a unique perspective on the changing face of BCR-ABL1 testing in CML. To assess the impact of technical standardisation and the development of the International Scale (IS) upon the accuracy of BCR-ABL1 testing, we reviewed EQA trial data from 2007 to 2015. Comparison of participant results identified considerable variability at both high and low levels of disease, including therapeutically important decision points; however, results converted to the IS showed less variability compared to unconverted data sets. We also found that different methods of converting to the IS produce consistently different median results within UKNEQAS LI IS data sets. This data suggests that whilst the development of the IS has improved the comparability of results between centres, there is still the need for further improvement in the processes of converting raw results to the IS in order to fully realise the benefits of molecular monitoring of CML. © 2017 John Wiley & Sons Ltd.

  10. A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

    Science.gov (United States)

    Kennedy, Glen A; Morris, Kirk L; Subramonpillai, Elango; Curley, Cameron; Butler, Jason; Durrant, Simon

    2013-06-01

    This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity. © 2013 John Wiley & Sons Ltd.

  11. Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV and the Koala Retrovirus (KoRV

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    Joachim Denner

    2016-12-01

    Full Text Available Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1 is a well-known example. The gibbon ape leukaemia virus (GaLV and koala retrovirus (KoRV, two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from Melomys burtoni, the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs during xenotransplantation using pig cells, tissues or organs.

  12. Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV).

    Science.gov (United States)

    Denner, Joachim

    2016-12-20

    Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1) is a well-known example. The gibbon ape leukaemia virus (GaLV) and koala retrovirus (KoRV), two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from Melomys burtoni , the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs) during xenotransplantation using pig cells, tissues or organs.

  13. Chronic myelogenous leukaemia with a p53 mutation demonstrated neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly) and hypogranulation in the peripheral blood smear.

    Science.gov (United States)

    Shibusawa, Motoharu; Tadokoro, Jiro; Kojima, Masaru; Kashimura, Makoto

    2018-03-15

    A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein. On the basis of these findings, the patient was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase with a p53 mutation and treated with hydroxyurea, dasatinib and nilotinib. Neutrophilic granulocytes with the anomalies were no longer observed after achieving cytogenetic remission. To the best of our knowledge, this is the first report of CML case with the anomalies, in which a p53 mutation without chromosome 17 abnormalities was identified. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Acupuncture on the Endometrial Morphology, the Serum Estradiol and Progesterone Levels, and the Expression of Endometrial Leukaemia-inhibitor Factor and Osteopontin in Rats

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    Houju Fu

    2011-01-01

    Full Text Available Although it is well known that acupuncture has beneficial effects on a variety of medical conditions especially in pain relief, nausea, and vomiting, it remains controversial whether it has positive impact on the female reproduction. The present study aimed to evaluate whether the following endometrial receptivity factors: the endometrial morphology, the hormone concentrations, and the protein expression of endometrial leukaemia-inhibitory factor (LIF and osteopontin (OPN could be improved by the acupuncture in clomiphene citrate(CC-induced rat model during implantation period. Results showed that, compared with the CC group, glandular development advanced, the serum estradiol levels decreased significantly, and the glandular area and endometrial LIF and OPN expression were significantly higher in acupuncture group. There were no significant differences in serum progesterone levels, endometrial thickness, and stromal area between groups. These results suggest that acupuncture can improve certain aspects of endometrial receptivity in CC-induced rat model during implantation period, which might result in endometrial state better to female reproduction.

  15. An investigation into the seroprevalence of Toxoplasma gondii, Bartonella spp., feline immunodeficiency virus (FIV), and feline leukaemia virus (FeLV) in cats in Addis Ababa, Ethiopia.

    Science.gov (United States)

    Tiao, N; Darrington, C; Molla, B; Saville, W J A; Tilahun, G; Kwok, O C H; Gebreyes, W A; Lappin, M R; Jones, J L; Dubey, J P

    2013-05-01

    Toxoplasma gondii and Bartonella spp. are zoonotic pathogens of cats. Feline immunodeficiency virus (FIV), and feline leukaemia virus (FeLV) are immunosuppressive viruses of cats that can affect T. gondii oocyst shedding. In this study, the prevalence of antibodies to T. gondii, Bartonella spp., FIV, as well as FeLV antigens were determined in sera from feral cats (Felis catus) from Addis Ababa, Ethiopia. Using the modified agglutination test, IgG antibodies to T. gondii were found in 41 (85.4%) of the 48 cats with titres of 1:25 in one, 1:50 in one, 1:200 in six, 1:400 in six, 1:800 in six, 1:1600 in eight, and 1:3200 in 13 cats. Toxoplasma gondii IgM antibodies were found in 11/46 cats tested by ELISA, suggesting recent infection. Antibodies to Bartonella spp. were found in five (11%) of 46 cats tested. Antibodies to FIV or FeLV antigen were not detected in any of the 41 cats tested. The results indicate a high prevalence of T. gondii and a low prevalence of Bartonella spp. infection in cats in Ethiopia.

  16. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

    Science.gov (United States)

    Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

    2015-05-01

    This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

  17. The Frequency and Management of Asparaginase-Related Thrombosis in Paediatric and Adult Patients with Acute Lymphoblastic Leukaemia Treated On Dana-Farber Cancer Institute Consortium Protocols

    Science.gov (United States)

    Grace, Rachael F.; Dahlberg, Suzanne E.; Neuberg, Donna; Sallan, Stephen E.; Connors, Jean M.; Neufeld, Ellis J.; DeAngelo, Daniel J.; Silverman, Lewis B.

    2018-01-01

    SUMMARY The optimal management of asparaginase-associated thrombotic complications is not well-defined. We report the features, management, and outcome of paediatric (ages 0–18 years) and adult (18–50 years) patients with acute lymphoblastic leukaemia (ALL) with asparaginase-related venous thromboembolic events (VTE) treated at Dana-Farber Cancer Institute on clinical trials for newly diagnosed ALL between 1991–2008. Of 548 patients, 43 (8%) had VTE, including 27/501 (5%) paediatric and 16/47 (34%) adult patients. Sinus venous thrombosis occurred in 1.6% of patients. Age was the only significant predictor of VTE, with those aged >30 years at very high risk (VTE rate 42%). 74% of patients received low molecular weight heparin after VTE. Complications of anticoagulation included epistaxis (9%), bruising (2%), and, in two adult patients, major bleeding. 30 patients (70%) ultimately received at least 85% of the intended doses of asparaginase. 33% of patients experienced recurrent VTE (paediatric 17% vs. adults 47%, p=0.07). The 48-month event-free survival for patients with VTE was 85 ± 6% compared with 88 ± 2% for those without VTE (p=0.36). This study confirms that, after VTE, asparaginase can be restarted with closely monitored anticoagulation after imaging demonstrates clot stabilization or improvement. With this management strategy, a history of VTE does not appear to adversely impact prognosis. PMID:21210774

  18. BETULINIC ACID WAS MORE CYTOTOXIC TOWARDS THE HUMAN BREAST CANCER CELL LINE MDA-MB-231 THAN THE HUMAN PROMYELOCYTIC LEUKAEMIA CELL LINE HL-60

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    LATIFAH SAIFUL YAZAN

    2009-01-01

    Full Text Available Betulinic acid (BA is a pentacyclic triterpene found in several botanical sources that has been shown to cause apoptosis in a number of cell lines. This study was undertaken to determine the in vitro cytotoxic properties of BA towards the human mammary carcinoma cell line MDA-MB-231 and the human promyelocytic leukaemia cell line HL-60 and the mode of the induced cell death. The cytotoxicity and mode of cell death of BA were determined using the MTT assay and DNAfragmentation analysis, respectively. In our study, the compound was found to be cytotoxic to MDA-MB-231 and HL-60 cells with IC50 values of 58 μg/mL and 134 μg/mL, respectively. Cells treated with high concentrations of BA exhibited features characteristic of apoptosis such as blebbing, shrinking and a number of small cytoplasm body masses when viewed under an inverted light microscope after 24 h. The incidence of apoptosis in MDA-MB-231 was further confirmed bythe DNA fragmentation analysis, with the formation of DNA fragments of oligonucleosomal size (180-200 base pairs, giving a ladder-like pattern on agarose gel electrophoresis. BA was more cytotoxic towards MDA-MB-231 than HL-60 cells, and induced apoptosis in MDA-MB-231 cells.

  19. Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia

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    Federica Toscanini

    2011-01-01

    Full Text Available Hepatitis B virus (HBV reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity (anticore patients management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.

  20. Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia.

    Science.gov (United States)

    Toscanini, Federica; De Leo, Pasqualina; Calcagno, Giuseppe; Malfatti, Federica; Grasso, Alessandro; Anselmo, Marco

    2011-01-01

    Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.

  1. Treatment of acute lymphoblastic leukaemia with the second generation of CD19 CAR-T containing either CD28 or 4-1BB.

    Science.gov (United States)

    Li, Shiqi; Zhang, Jiasi; Wang, Meiling; Fu, Gang; Li, Yunyan; Pei, Li; Xiong, Zhouxing; Qin, Dabing; Zhang, Rui; Tian, Xiaobo; Wei, Zhihao; Chen, Run; Chen, Xuejiao; Wan, Jia; Chen, Jun; Wei, Xia; Xu, Yanmin; Zhang, Pei; Wang, Ping; Peng, Xi; Yang, Sainan; Shen, Junjie; Yang, Zhi; Chen, Jieping; Qian, Cheng

    2018-04-10

    T cells modified with anti-CD19 chimeric antigen receptor (CAR) containing either CD28 or 4-1BB (also termed TNFRSF9, CD137) costimulatory signalling have shown great potential in the treatment of acute lymphoblastic leukaemia (ALL). However, the difference between CD28 and 4-1BB costimulatory signalling in CAR-T treatment has not been well elucidated in clinical trials. In this study, we treated 10 relapsed or refractory ALL patients with the second generation CD19 CAR-T. The first 5 patients were treated with CD28-CAR and the other 5 patients were treated with 4-1BB CAR-T. All the 10 patients were response-evaluable. Three patients achieved complete remission and 1 patient with extramedullary disease achieved partial response after CD28-CAR-T treatment. In the 4-1BB CAR-T treatment group, 3 patients achieved complete remission. Furthermore, FLT-3 ligand (FLT3LG) was highly correlated with response time and may serve as a prognosis factor. No severe adverse events were observed in these 10 treated patients. Our study showed that both CD28 CAR-T and 4-1BB CAR-T both worked for response but they differed in response pattern (peak reaction time, reaction lasting time and reaction degree), adverse events, cytokine secretion and immune-suppressive factor level. © 2018 John Wiley & Sons Ltd.

  2. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.

    Science.gov (United States)

    Hungate, Eric A; Vora, Sapana R; Gamazon, Eric R; Moriyama, Takaya; Best, Timothy; Hulur, Imge; Lee, Younghee; Evans, Tiffany-Jane; Ellinghaus, Eva; Stanulla, Martin; Rudant, Jéremie; Orsi, Laurent; Clavel, Jacqueline; Milne, Elizabeth; Scott, Rodney J; Pui, Ching-Hon; Cox, Nancy J; Loh, Mignon L; Yang, Jun J; Skol, Andrew D; Onel, Kenan

    2016-02-12

    Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10(-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.

  3. A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.

    Science.gov (United States)

    Sutton, Rosemary; Venn, Nicola C; Law, Tamara; Boer, Judith M; Trahair, Toby N; Ng, Anthea; Den Boer, Monique L; Dissanayake, Anuruddhika; Giles, Jodie E; Dalzell, Pauline; Mayoh, Chelsea; Barbaric, Draga; Revesz, Tamas; Alvaro, Frank; Pieters, Rob; Haber, Michelle; Norris, Murray D; Schrappe, Martin; Dalla Pozza, Luciano; Marshall, Glenn M

    2018-02-01

    To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P 5 × 10 -5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL. © 2017 John Wiley & Sons Ltd.

  4. A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib.

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    Vanessa Augis

    Full Text Available BIM is essential for the response to tyrosine-kinase inhibitors (TKI in chronic myeloid leukaemia (CML patients. Recently, a deletion polymorphism in intron 2 of the BIM gene was demonstrated to confer an intrinsic TKI resistance in Asian patients. The present study aimed at identifying mutations in the BIM sequence that could lead to imatinib resistance independently of BCR-ABL mutations.BIM coding sequence analysis was performed in 72 imatinib-treated CML patients from a French population of our centre and in 29 healthy controls (reference population as a case-control study. Real-time quantitative PCR (RT qPCR was performed to assess Bim expression in our reference population.No mutation with amino-acid change was found in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP c465C>T (rs724710. A strong statistical link was found between the presence of the T allele and the high Sokal risk group (p = 0.0065. T allele frequency was higher in non responsive patients than in the reference population (p = 0.0049. Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (pT SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

  5. Direct X-ray radiogrammetry versus dual-energy X-ray absorptiometry: assessment of bone density in children treated for acute lymphoblastic leukaemia and growth hormone deficiency

    International Nuclear Information System (INIS)

    Rijn, Rick R. van; Wittenberg, Rianne; Boot, Annemieke; Sluis, Inge M. van der; MuinckKeizer-Schrama, Sabine M.P.F. de; Heuvel-Eibrink, Marry M. van den; Lequin, Maarten H.; Kuijk, Cornelis Van

    2006-01-01

    In recent years interest in bone densitometry in children has increased. To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA). A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed. In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of <0.001. During treatment a change in DXR-BMD was found in children with GHD. Our study showed that DXR in a paediatric population shows a strong correlation with DXA of the lumbar spine and total body and that it is able to detect a change in BMD during treatment. (orig.)

  6. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial.

    Science.gov (United States)

    Burnett, A K; Hills, R K; Grimwade, D; Jovanovic, J V; Craig, J; McMullin, M F; Kell, J; Wheatley, K; Yin, J A L; Hunter, A; Milligan, D; Russell, N H

    2013-04-01

    Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, PMRC arm. GO did not provide benefit. High white blood cell count (>10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

  7. Novel Thiazolo[5,4-b]phenothiazine Derivatives: Synthesis, Structural Characterization, and In Vitro Evaluation of Antiproliferative Activity against Human Leukaemia

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    Balazs Brem

    2017-06-01

    Full Text Available The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of N-(phenothiazin-3-yl-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-b]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT. In vitro activity as antileukemic agents of thiazolo[5,4-b]phenothiazine and N-(phenothiazine-3-yl-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-b]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.

  8. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

    Science.gov (United States)

    Vora, Ajay; Goulden, Nick; Wade, Rachel; Mitchell, Chris; Hancock, Jeremy; Hough, Rachael; Rowntree, Clare; Richards, Sue

    2013-03-01

    Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is

  9. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Science.gov (United States)

    Karan-Djurasevic, Teodora; Marjanovic, Irena; Tosic, Natasa; Mitrovic, Mirjana; Djunic, Irena; Colovic, Natasa; Vidovic, Ana; Suvajdzic-Vukovic, Nada; Tomin, Dragica; Pavlovic, Sonja

    2016-01-01

    Abstract Background Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. Patients and methods In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. Results IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. Conclusions Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection. PMID:27904446

  10. Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase

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    Hemant Malhotra

    2015-01-01

    Full Text Available Background & objectives: Imatinib is the standard first-line treatment for chronic myeloid leukaemia (CML patients. About 20 to 30 per cent patients develop resistance to imatinib and fail imatinib treatment. One of the mechanisms proposed is varying expression levels of the drug transporters. This study was aimed to determine the expression levels of imatinib transporter genes (OCT1, ABCB1, ABCG2 in CML patients and to correlate these levels with molecular response. Methods: Sixty three CML chronic phase patients who were on 400 mg/day imatinib for more than two years were considered for gene expression analysis study for OCT1, ABCB1 and ABCG2 genes. These were divided into responders and non-responders. The relative transcript expression levels of the three genes were compared between these two categories. The association between the expression values of these three genes was also determined. Results: No significant difference in the expression levels of OCT1, ABCB1 and ABCG2 was found between the two categories. The median transcript expression levels of OCT1, ABCB1 and ABCG2 genes in responders were 26.54, 10.78 and 0.64 versus 33.48, 7.09 and 0.53 in non-responders, respectively. A positive association was observed between the expression of the ABCB1 and ABCG2 transporter genes (r=0.407, P<0.05 while no association was observed between the expression of either of the ABC transporter genes with the OCT1 gene. Interpretation & conclusions: Our findings demonstrated that the mRNA expression levels of imatinib transporter genes were not correlated with molecular response in CML patients. Further studies need to be done on a large sample of CML patients to confirm these findings.

  11. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.

    Science.gov (United States)

    Eissa, Deena Samir; Ahmed, Tamer Mohamed

    2013-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome.

  12. Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Tholouli, Eleni [Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); MacDermott, Sarah [The Medical School, The University of Manchester, Oxford Road, M13 9PT Manchester (United Kingdom); Hoyland, Judith [School of Biomedicine, Faculty of Medical and Human Sciences, The University of Manchester, Oxford Road, M13 9PT Manchester (United Kingdom); Yin, John Liu [Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); Byers, Richard, E-mail: richard.byers@cmft.nhs.uk [School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester (United Kingdom)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Development of a quantitative high throughput in situ expression profiling method. Black-Right-Pointing-Pointer Application to a tissue microarray of 242 AML bone marrow samples. Black-Right-Pointing-Pointer Identification of HOXA4, HOXA9, Meis1 and DNMT3A as prognostic markers in AML. -- Abstract: Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p = 0.009), whilst high expression of HOXA9 (p < 0.0001), Meis1 (p = 0.005) and DNMT3A (p = 0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples.

  13. Anti-proliferative properties of commercial Pelargonium sidoides tincture, with cell-cycle G0/G1 arrest and apoptosis in Jurkat leukaemia cells.

    Science.gov (United States)

    Pereira, Andreia; Bester, Megan; Soundy, Puffy; Apostolides, Zeno

    2016-09-01

    Context Pelargonium sidoides DC (Geraniaceae) is an important medicinal plant indigenous to South Africa and Lesotho. Previous studies have shown that root extracts are rich in polyphenolic compounds with antibacterial, antiviral and immunomodulatory activities. Little is known regarding the anticancer properties of Pelargonium sidoides extracts. Objective This study evaluates the anti-proliferative effects of a Pelargonium sidoides radix mother tincture (PST). Materials and methods The PST was characterized by LC-MS/MS. Anti-proliferative activity was evaluated in the pre-screen panel of the National Cancer Institute (NCI-H460, MCF-7 and SF-268) and the Jurkat leukaemia cell line at concentrations of 0-150 μg/mL. The effect on cell growth was determined with sulphorhodamine B and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays after 72 h. The effect on cell cycle and apoptosis induction in Jurkat cells was determined by flow cytometry with propidium iodide and Annexin V: fluorescein isothiocyanate staining. Results Dihydroxycoumarin sulphates, gallic acid as well as gallocatechin dimers and trimers were characterized in PST by mass spectrometry. Moderate anti-proliferative effects with GI50 values between 40 and 80 μg/mL were observed in the NCI-pre-screen panel. Strong activity observed with Jurkat cells with a GI50 value of 6.2 μg/mL, significantly better than positive control 5-fluorouracil (GI50 value of 9.7 μg/mL). The PST arrested Jurkat cells at the G0/G1 phase of the cell cycle and increased the apoptotic cells from 9% to 21%, while the dead cells increased from 4% to 17%. Conclusion We present evidence that P. sidoides has cancer cell type-specific anti-proliferative effects and may be a source of novel anticancer molecules.

  14. Histamine reduces susceptibility to natural killer cells via down-regulation of NKG2D ligands on human monocytic leukaemia THP-1 cells

    Science.gov (United States)

    Nagai, Yasuhiro; Tanaka, Yukinori; Kuroishi, Toshinobu; Sato, Ryutaro; Endo, Yasuo; Sugawara, Shunji

    2012-01-01

    Natural killer (NK) group 2D (NKG2D) is a key activating receptor expressed on NK cells, whose interaction with ligands on target cells plays an important role in tumorigenesis. However, the effect of histamine on NKG2D ligands on tumour cells is unclear. Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A (MICA) and UL16-binding protein 1 on their surface, and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry. Interferon-γ augmented the surface expression of the NKG2D ligands, and this augmentation was significantly attenuated by histamine. The histamine H1 receptor (H1R) agonist 2-pyridylethylamine and H2R agonist dimaprit down-regulated the expression of NKG2D ligands, and activation of H1R and H2R signalling by A23187 and forskolin, respectively, had the same effect, indicating that the histamine-induced down-regulation of NKG2D ligands is mediated by H1R and H2R. Quantitative reverse transcription-PCR showed that mRNA levels of the NKG2D ligands and relevant microRNAs were not significantly changed by histamine. Histamine down-regulated the surface expression of endoplasmic reticulum protein 5, and inhibition of matrix metalloproteinases did not impair this down-regulation, indicating that proteolytic shedding was not involved. Instead, pharmacological inhibition of protein transport and proteasome abrogated it, and histamine enhanced ubiquitination of MICA. Furthermore, histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity. These results suggest that histamine down-regulates NKG2D ligands through the activation of an H1R- and H2R-mediated ubiquitin–proteasome pathway and consequently reduces susceptibility to NK cells. PMID:22304689

  15. Updated estimates of survival and cost effectiveness for imatinib versus interferon-alpha plus low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukaemia.

    Science.gov (United States)

    Reed, Shelby D; Anstrom, Kevin J; Li, Yanhong; Schulman, Kevin A

    2008-01-01

    For trials in which participants are followed beyond the main study period to assess long-term outcomes, economic evaluations conducted using short-term data should be systematically updated to reflect new information. We used 60-month survival data from the IRIS (International Randomized study of Interferon vs STI571) trial to update previously published cost-effectiveness estimates, based on 19 months of follow-up, of imatinib versus interferon (IFN)-alpha plus low-dose cytarabine in patients with chronic-phase chronic myeloid leukaemia. For patients treated with imatinib, we used the 60-month data to calibrate the survival curves generated from the original cost-effectiveness model. We used historical data to model survival for patients randomized to IFNalpha. We updated costs for medical resources using 2006 Medicare reimbursement rates and applied average wholesale prices (AWPs) and wholesale acquisition costs (WACs) to study medications. Five-year survival for patients randomized to imatinib was better than predicted in the original model (89.4% vs 83.2%). We estimated remaining life expectancy with first-line imatinib to be 19.1 life-years (3.8 life-years over the original model) and 15.2 QALYs (3.1 QALYs over the original estimate). Estimates for IFNalpha remained at 9.1 life-years and 6.3 QALYs. When we applied AWPs to study medications, incremental cost-effectiveness ratios (ICERs) were $US 51,800-57,500 per QALY. When we applied WACs, ICERs were $US 42,000-46,200 per QALY. Although the analysis revealed that the original survival estimates were conservative, the updated cost-effectiveness ratios were consistent with, or slightly higher than, the original estimates, depending on the method for assigning costs to study medications.

  16. Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study.

    Science.gov (United States)

    Jacola, Lisa M; Edelstein, Kim; Liu, Wei; Pui, Ching-Hon; Hayashi, Robert; Kadan-Lottick, Nina S; Srivastava, Deokumar; Henderson, Tara; Leisenring, Wendy; Robison, Leslie L; Armstrong, Gregory T; Krull, Kevin R

    2016-10-01

    Survivors of childhood acute lymphoblastic leukaemia (ALL) are at risk for neurocognitive deficits that affect development in adolescence and young adulthood, and influence educational attainment and future independence. We examined a large and diverse cohort of survivors to identify risk predictors and modifiers of these outcomes. In this cohort study, cognitive and behaviour symptoms were assessed via a standardised parent questionnaire for 1560 adolescent survivors of ALL diagnosed between 1970 and 1999. Clinically significant symptoms (≥90th percentile) and learning problems were compared between survivors and a sibling cohort. Multivariable regression models were used to examine associations with demographic and treatment characteristics. Models were adjusted for inverse probability of sampling weights to reflect undersampling of ALL survivors in the expansion cohort. In a subset of survivors with longitudinal data (n=925), we examined associations between adolescent symptoms or problems and adult educational attainment. Compared with siblings, survivors treated with chemotherapy only were more likely to demonstrate headstrong behaviour (155 [19%] of 752 survivors vs 88 [14%] of 610 siblings, p=0·010), inattention-hyperactivity (15 [19%] vs 86 [14%], plearning problems (191 [28%] vs 76 [14%], p4·3 g/m 2 ) conferred increased risk of inattention-hyperactivity (relative risk [RR] 1·53, 95% CI 1·13-2·08). Adolescent survivors with cognitive or behaviour problems and those with learning problems were less likely to graduate from college as young adults than adolescent survivors without cognitive or behaviour problems. Although modern therapy for childhood ALL has eliminated the use of cranial radiation therapy, adolescent survivors treated with chemotherapy only remain at increased risk for cognitive, behaviour, and academic problems that adversely affect adult education outcomes. National Cancer Institute, American Lebanese-Syrian Associated Charities

  17. Near infrared spectroscopy (NIRS as a new non-invasive tool to detect oxidative skeletal muscle impairment in children survived to acute lymphoblastic leukaemia.

    Directory of Open Access Journals (Sweden)

    Francesca Lanfranconi

    Full Text Available BACKGROUND: Separating out the effects of cancer and treatment between central and peripheral components of the O2 delivery chain should be of interest to clinicians for longitudinal evaluation of potential functional impairment in order to set appropriate individually tailored training/rehabilitation programmes. We propose a non-invasive method (NIRS, near infrared spectroscopy to be used in routine clinical practice to evaluate a potential impairment of skeletal muscle oxidative capacity during exercise in children previously diagnosed with acute lymphoblastic leukaemia (ALL. The purpose of this study was to evaluate the capacity of skeletal muscle to extract O2 in 10 children diagnosed with ALL, 1 year after the end of malignancy treatment, compared to a control group matched for gender and age (mean±SD = 7.8±1.5 and 7.3±1.4 years, respectively. METHODS AND FINDINGS: Participants underwent an incremental exercise test on a treadmill until exhaustion. Oxygen uptake ([Formula: see text], heart rate (HR, and tissue oxygenation status (Δ[HHb] of the vastus lateralis muscle evaluated by NIRS, were measured. The results showed that, in children with ALL, a significant linear regression was found by plotting [Formula: see text] vs Δ[HHb] both measured at peak of exercise. In children with ALL, the slope of the HR vs [Formula: see text] linear response (during sub-maximal and peak work rates was negatively correlated with the peak value of Δ[HHb]. CONCLUSIONS: The present study proves that the NIRS technique allows us to identify large inter-individual differences in levels of impairment in muscle O2 extraction in children with ALL. The outcome of these findings is variable and may reflect either muscle atrophy due to lack of use or, in the most severe cases, an undiagnosed myopathy.

  18. Histone deacetylase inhibition modulates deoxyribonucleotide pools and enhances the antitumor effects of the ribonucleotide reductase inhibitor 3'-C-methyladenosine in leukaemia cells.

    Science.gov (United States)

    Meli, Maria; Tolomeo, Manlio; Grifantini, Mario; Mai, Antonello; Cappellacci, Loredana; Petrelli, Riccardo; Rotili, Dante; Ferro, Arianna; Saiko, Philipp; Szekeres, Thomas; Dusonchet, Luisa

    2011-05-01

    Histone deacetylase (HDAC) inhibitors are a new class of epigenetic agents that were reported to enhance the cytotoxic effects of classical anticancer drugs through multiple mechanisms. However, which of the possible drug combinations would be the most effective and clinically useful are to be determined. We treated the HL60 and NB4 promyelocytic leukaemia cells with a combination of the ribonucleotide reductase (RR) inhibitor 3'-C-methyladenosine (3'-Me-Ado) and several hydroxamic acid-derived HDAC inhibitors, including two recently synthesized molecules, MC1864 and MC1879, and the reference compound trichostatin A (TSA). The results showed significant growth inhibitory and apoptotic synergistic effects with the combinations. Hence, we evaluated the effects of the combinations on cell cycle distribution and on the level of several proteins involved in the apoptotic process (p21, caspase-3, Bcl-2, Bax, AIF). Since HDAC inhibitors increased the G1-S transition block induced by 3'-Me-Ado, an effect on RR activity was hypothesized. Indeed, the HPLC evaluation of intracellular deoxyribonucleotide (dNTP) pools showed that both TSA and MC1864 induced a decrease in dNTPs, even if with a somewhat different pattern, suggesting that RR inhibition contributes to the observed synergism. Furthermore, while TSA was shown to activate the intrinsic apoptotic pathway, MC1864 induced a dose-dependent increase in ROS and AIF levels. Moreover, the treatment with the radical scavenger N-acetylcysteine determined a significant inhibition of MC1864- but not TSA-mediated synergistic effects. Hence, our findings are consistent with a possible role of HDAC inhibitor mediated-ROS induction in RR inhibition and in the potentiation of RR inhibitor-mediated apoptosis.

  19. Computer aided analysis of additional chromosome aberrations in Philadelphia chromosome positive acute lymphoblastic leukaemia using a simplified computer readable cytogenetic notation

    Directory of Open Access Journals (Sweden)

    Mohr Brigitte

    2003-01-01

    Full Text Available Abstract Background The analysis of complex cytogenetic databases of distinct leukaemia entities may help to detect rare recurring chromosome aberrations, minimal common regions of gains and losses, and also hot spots of genomic rearrangements. The patterns of the karyotype alterations may provide insights into the genetic pathways of disease progression. Results We developed a simplified computer readable cytogenetic notation (SCCN by which chromosome findings are normalised at a resolution of 400 bands. Lost or gained chromosomes or chromosome segments are specified in detail, and ranges of chromosome breakpoint assignments are recorded. Software modules were written to summarise the recorded chromosome changes with regard to the respective chromosome involvement. To assess the degree of karyotype alterations the ploidy levels and numbers of numerical and structural changes were recorded separately, and summarised in a complex karyotype aberration score (CKAS. The SCCN and CKAS were used to analyse the extend and the spectrum of additional chromosome aberrations in 94 patients with Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia (ALL and secondary chromosome anomalies. Dosage changes of chromosomal material represented 92.1% of all additional events. Recurring regions of chromosome losses were identified. Structural rearrangements affecting (pericentromeric chromosome regions were recorded in 24.6% of the cases. Conclusions SCCN and CKAS provide unifying elements between karyotypes and computer processable data formats. They proved to be useful in the investigation of additional chromosome aberrations in Ph-positive ALL, and may represent a step towards full automation of the analysis of large and complex karyotype databases.

  20. Evaluation of minimal residual disease in patients with chronic myeloid leukaemia on IFN-alpha 2b therapy using conventional cytogenetics and fluorescence in situ hybridization.

    Science.gov (United States)

    Talwar, Rashmi; Choudhry, V P; Jobanputra, Vaidehi; Kucheria, Kiran

    2002-01-01

    Chronic myeloid leukaemia (CML) is a haematopoietic malignancy characterized by the presence of the Philadelphia (Ph) chromosome that results from balanced reciprocal translocation between chromosomes 9 and 22 leading to the formation of the bcr/abl fusion gene. Studies have shown that interferon-alpha (IFN-alpha) therapy induces both cytogenetic (reduction in Ph+ cells) and molecular response (reduction in the bcr/abl positive cells) in a large proportion of patients, thereby improving their prognosis and survival. There are no reports available from India on the clinical management of CML patients using IFN-alpha therapy and molecular methods for the evaluation of residual disease. We evaluated the efficacy of IFN-alpha 2b therapy bysequential cytogenetic and molecularanalysis. Karyotypingwas done from G-banded metaphases obtained from 24-hour culture of bone marrow aspirates of 45 patients. Cytogenetic analysis was repeated at intervals of 4-6 months during the course of IFN-alpha therapy. Dual-colour fluorescence in situ hybridization (FISH) analysis using specific probes for bcr and abl genes was done to assess the molecular response. Eight patients achieved complete cytogenetic response with no Ph+ cells. Using FISH analysis, 4 of these patients were negative for the fusion gene implying a complete response, while the remaining 4 patients showed bcr/abl fusion signals that represent residual disease. Our study emphasizes the need for sequential cytogenetic and molecular analysis in the management of patients with CML and for the evaluation of minimal residual disease in patients on IFN-alpha therapy.

  1. Histamine reduces susceptibility to natural killer cells via down-regulation of NKG2D ligands on human monocytic leukaemia THP-1 cells.

    Science.gov (United States)

    Nagai, Yasuhiro; Tanaka, Yukinori; Kuroishi, Toshinobu; Sato, Ryutaro; Endo, Yasuo; Sugawara, Shunji

    2012-05-01

    Natural killer (NK) group 2D (NKG2D) is a key activating receptor expressed on NK cells, whose interaction with ligands on target cells plays an important role in tumorigenesis. However, the effect of histamine on NKG2D ligands on tumour cells is unclear. Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A (MICA) and UL16-binding protein 1 on their surface, and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry. Interferon-γ augmented the surface expression of the NKG2D ligands, and this augmentation was significantly attenuated by histamine. The histamine H1 receptor (H1R) agonist 2-pyridylethylamine and H2R agonist dimaprit down-regulated the expression of NKG2D ligands, and activation of H1R and H2R signalling by A23187 and forskolin, respectively, had the same effect, indicating that the histamine-induced down-regulation of NKG2D ligands is mediated by H1R and H2R. Quantitative reverse transcription-PCR showed that mRNA levels of the NKG2D ligands and relevant microRNAs were not significantly changed by histamine. Histamine down-regulated the surface expression of endoplasmic reticulum protein 5, and inhibition of matrix metalloproteinases did not impair this down-regulation, indicating that proteolytic shedding was not involved. Instead, pharmacological inhibition of protein transport and proteasome abrogated it, and histamine enhanced ubiquitination of MICA. Furthermore, histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity. These results suggest that histamine down-regulates NKG2D ligands through the activation of an H1R- and H2R-mediated ubiquitin-proteasome pathway and consequently reduces susceptibility to NK cells. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.

  2. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study.

    Science.gov (United States)

    Tierens, Anne; Bjørklund, Elizabeth; Siitonen, Sanna; Marquart, Hanne Vibeke; Wulff-Juergensen, Gitte; Pelliniemi, Tarja-Terttu; Forestier, Erik; Hasle, Henrik; Jahnukainen, Kirsi; Lausen, Birgitte; Jonsson, Olafur G; Palle, Josefine; Zeller, Bem; Fogelstrand, Linda; Abrahamsson, Jonas

    2016-08-01

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9-13·3] and OS (HR:7·0; 95%CI:2·0-24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials. © 2016 John Wiley & Sons Ltd.

  3. Increased megakaryocytic proliferation, pro-platelet deposition and expression of fibrosis-associated factors in children with chronic myeloid leukaemia with bone marrow fibrosis.

    Science.gov (United States)

    Hussein, K; Stucki-Koch, A; Göhring, G; Kreipe, H; Suttorp, M

    2017-07-01

    Paediatric chronic myeloid leukaemia (ped-CML) is rare and ped-CML with fibre accumulation in the bone marrow (MF) is thought to be even rarer. In adults (ad-CML), fibrosis represents an adverse prognostic factor. So far, the pro-fibrotic changes in the bone marrow microenvironment have not been investigated in detail in ped-CML. From a total of 66 ped-CML in chronic phase, biopsies were analysable and 10 had MF1/2 (MF1, n=8/10; MF2, n=2/10). We randomly selected 16 ped-CML and 16 ad-CML cases with and without fibrosis (each n=8) as well as 18 non-neoplastic controls. Bone marrow samples were analysed with a real-time PCR-based assay (including 127 genes for paediatric cases) and by immunohistochemistry. We found increased expression of megakaryocytic genes in ped-CML. The number of megakaryocytes and pro-platelets are increased in CML patients, but the most significant increase was noted for ped-CML-MF1/2. Anti-fibrotic MMP9 expression was lower in children than in adults. Cell mobilisation-related CXCL12 was decreased in young and adult patients with CML but not the corresponding receptor CXCR4. In summary, fibre accumulation in ped-CML-MF1/2 is associated with increased megakaryocytic proliferation and increased interstitial pro-platelet deposition. Deregulated expression of matrix-modulating factors shifts the bone marrow microenvironment towards fibrosis.

  4. Genetic variation of the gene coding for microRNA-204 (miR-204) is a risk factor in acute myeloid leukaemia.

    Science.gov (United States)

    Butrym, Aleksandra; Łacina, Piotr; Kuliczkowski, Kazimierz; Bogunia-Kubik, Katarzyna; Mazur, Grzegorz

    2018-01-30

    MicroRNAs (miRNAs or miRs) are small molecules known to be involved in post-transcriptional gene expression. Many of them have been shown to influence risk for various diseases. Recent studies suggest that lower expression of miR-204, a gene coding for miRNA-204, is correlated with shorter survival in patients with acute myeloid leukaemia (AML). This observation prompted us to analyse the effect of two polymorphisms of the miR-204 gene, one in the upstream flanking region (rs718447 A > G) and the other inside the gene itself (rs112062096 A > G), both also in intron 3 of the TRPM3 gene. The study was conducted on DNA samples isolated from AML patients (n = 95) and healthy individuals (n = 148), who were genotyped using the Light SNiP assays. The miR-204 rs718447 GG homozygosity was found to constitute a risk factor associated with susceptibility to AML (73/95 vs 92/148, AML patients vs healthy controls, OR = 2.020, p = 0.017). Additionally, this genotype was more frequent in patients with subtypes M0-M1 in the French-American-British (FAB) classification as compared to patients with subtypes M2-M7 (23/25 vs 39/57, p = 0.026). We also found that presence of allele A was linked to longer survival of AML patients. Our results show that polymorphism in miR-204 flanking region may constitute a risk and prognostic factor in AML.

  5. Integrating multiple immunogenetic data sources for feature extraction and mining somatic hypermutation patterns: the case of "towards analysis" in chronic lymphocytic leukaemia.

    Science.gov (United States)

    Kavakiotis, Ioannis; Xochelli, Aliki; Agathangelidis, Andreas; Tsoumakas, Grigorios; Maglaveras, Nicos; Stamatopoulos, Kostas; Hadzidimitriou, Anastasia; Vlahavas, Ioannis; Chouvarda, Ioanna

    2016-06-06

    Somatic Hypermutation (SHM) refers to the introduction of mutations within rearranged V(D)J genes, a process that increases the diversity of Immunoglobulins (IGs). The analysis of SHM has offered critical insight into the physiology and pathology of B cells, leading to strong prognostication markers for clinical outcome in chronic lymphocytic leukaemia (CLL), the most frequent adult B-cell malignancy. In this paper we present a methodology for integrating multiple immunogenetic and clinocobiological data sources in order to extract features and create high quality datasets for SHM analysis in IG receptors of CLL patients. This dataset is used as the basis for a higher level integration procedure, inspired form social choice theory. This is applied in the Towards Analysis, our attempt to investigate the potential ontogenetic transformation of genes belonging to specific stereotyped CLL subsets towards other genes or gene families, through SHM. The data integration process, followed by feature extraction, resulted in the generation of a dataset containing information about mutations occurring through SHM. The Towards analysis performed on the integrated dataset applying voting techniques, revealed the distinct behaviour of subset #201 compared to other subsets, as regards SHM related movements among gene clans, both in allele-conserved and non-conserved gene areas. With respect to movement between genes, a high percentage movement towards pseudo genes was found in all CLL subsets. This data integration and feature extraction process can set the basis for exploratory analysis or a fully automated computational data mining approach on many as yet unanswered, clinically relevant biological questions.

  6. Approach to derive doses for case-control studies of lung cancer and leukaemia among workers internally exposed to uranium and plutonium

    International Nuclear Information System (INIS)

    Thierry-Chef, Isabelle; Berard, Philippe; Bingham, Derek; Blanchardon, Eric; Challeton-de Vathaire, Cecile; Birchall, Alan; Puncher, Matthew; Bull, Richard; Hurtgen, Christian; Riddell, Tony; Vrijheid, Martine; Cardis, Elisabeth

    2008-01-01

    Case-control studies are currently conducted in 3 European countries (Belgium, France and the United Kingdom) to estimate the risk of lung cancer and leukaemia in relation to internal exposure to uranium and plutonium amongst workers in the nuclear industry. The project requires calculating doses absorbed by the lung and the bone marrow for many hundreds of cases and controls internally exposed. In order to establish a common approach to dose reconstruction, a detailed dosimetry protocol and a database of individual exposure were set up and will be presented. The dose reconstruction relies heavily on bioassay data, which are usually urine analysis, extending back over 50 years in some cases. Inevitably, data obtained over such a time span are of variable quality. It is important to review the monitoring practices at the various laboratories and to assess the reliability of these data in order to estimate possible biases as well as random uncertainties. Another key step in the reconstruction process is to decide upon the likely intake regimes consistent with the data. Generally, chronic intakes will be assumed and acute intakes will be added only when their existence is supported by operational data. Biokinetic models are used both to calculate intakes from bioassay data and to convert intakes to doses. The ICRP publication 66 respiratory tract model will be used along with the latest systemic models described by ICRP. These will be supplemented by the Leggett 2005 model for plutonium. These various models will be implemented by the code IMBA-Expert. Since it is essential to obtain central estimates for the doses, a particular problem is encountered with datasets consisting only of values below the limit of detection. For these cases Bayesian statistics will be employed using a non-informative prior probability distribution. (author)

  7. Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies

    Science.gov (United States)

    Salizzato, Valentina; Borgo, Christian; Cesaro, Luca; Pinna, Lorenzo A.; Donella-Deana, Arianna

    2016-01-01

    Chronic myeloid leukaemia (CML) is a myeloproliferative disorder promoted by the constitutive tyrosine kinase activity of Bcr-Abl oncoprotein. Although treatment with the Bcr-Abl-inhibitor imatinib represents the first-line therapy against CML, almost 20-30% of patients develop chemotherapeutic resistance and require alternative therapy. Here we show that a strong hyper-phosphorylation/activation of ERK1/2, Akt Ser473, and 40S ribosomal protein S6 (rpS6) is detectable in imatinib-resistant KCL22 and K562 CML cells as compared to the -sensitive cell variants. In imatinib-resistant CML cells, high concentration of imatinib is required to strongly inhibit Bcr-Abl, ERK1/2 and Akt Ser473 phosphorylation, but under these conditions the phosphorylation of rpS6, a common downstream effector of MEK/ERK1/2 and PI3K/Akt/mTOR pathways is only slightly reduced. By contrast, down-regulation of the protein kinase CK2 by the inhibitor CX-5011 or by silencing the CK2 subunits does not affect the activation state of MEK/ERK1/2 or PI3K/Akt/mTOR signalling, but causes a drop in rpS6 phosphorylation in parallel with reduced protein synthesis. CK2-inhibition by CX-5011 induces cell death by apoptosis and acts synergistically with imatinib or the MEK-inhibitor U0126 in reducing the viability of imatinib-resistant CML cells. The ternary mixture containing CX-5011, imatinib and U0126 represents the most effective synergistic combination to counteract CML cell viability. These results disclose a novel CK2-mediated mechanism of acquired imatinib-resistance resulting in hyper-phosphorylation of rpS6. We suggest that co-targeting CK2 and MEK protein kinases is a promising strategy to restore responsiveness of resistant CML cells to imatinib. PMID:26919095

  8. A survey of feline leukaemia virus antigenaemia among cats in eastern Austria: a retrospective analysis of serum samples routinely tested between 1996 and 2011

    Directory of Open Access Journals (Sweden)

    Clair L Firth

    2015-07-01

    Full Text Available Objectives The aim of this retrospective analysis was to determine the seroprevalence of feline leukaemia virus (FeLV antigenaemia among owned cats in Vienna and the surrounding area. Methods Samples were tested between 1996 and 2011 by the Department of Clinical Virology at the University of Veterinary Medicine, Vienna, Austria. All samples were sent to the university as part of routine diagnostic procedures, either to determine infection in clinically symptomatic individuals or to rule out infection prior to vaccination. To allow for statistical comparison, samples analysed between 2008 and 2011 were pooled into one population (n = 444 and evaluated against samples tested in 1996 (n = 840. Furthermore, analyses of subgroups were undertaken to determine the effect of sex and age on the prevalence of FeLV antigenaemia. Results With respect to the samples tested at the University of Veterinary Medicine in Vienna, it was determined that the level of FeLV antigenaemia in eastern Austria between 1996 and 2011 was 5.6%. The proportion of FeLV antigenaemic cats was highly variable and has not fallen significantly over this period, despite advances in vaccination, and the education of pet owners and animal welfare charities. Conclusions and relevance This study confirms the importance of continued and regular vaccination against FeLV among Austrian cats, particularly those allowed access to the outdoors. Within the remit of this retrospective study, it was not possible to follow-up results of repeat testing or of other assays (PCR of individual cats. As a result of this, no conclusions can be drawn as to the possibility of transient antigenaemic cats or false-positive enzyme-linked immunosorbent assay results.

  9. Comparison of loop-mediated isothermal amplification (LAMP) and nested-PCR assay targeting the RE and B1 gene for detection of Toxoplasma gondii in blood samples of children with leukaemia.

    Science.gov (United States)

    Fallahi, Shirzad; Seyyed Tabaei, Seyyed Javad; Pournia, Yadollah; Zebardast, Nozhat; Kazemi, Bahram

    2014-07-01

    Toxoplasmosis diagnosis constitutes an important measure for disease prevention and control. In this paper, a newly described DNA amplification technique, loop-mediated isothermal amplification (LAMP), and nested-PCR targeting the repeated element (RE) and B1 gene, were compared to each other for the detection of Toxoplasma gondii DNA in blood samples of children with leukaemia. One hundred ten blood samples from these patients were analyzed by LAMP and nested-PCR. Out of 50 seropositive samples (IgM+, IgG+), positive results were obtained with 92% and 86% on RE, B1-LAMP and 82% and 68% on RE, B1-nested PCR analyses, respectively. Of the 50 seronegative samples, three, two and one samples were detected positive by RE-LAMP, B1-LAMP and RE-nested PCR assays, respectively, while none were detected positive by B1-nested PCR. None of the 10 IgM-, IgG+ samples was detected positive after testing LAMP and nested-PCR assays in duplicate. This is the first report of a study in which the LAMP method was applied with high sensitivity and efficacy for the diagnosis of T. gonii in blood samples of children with leukaemia. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.

    Science.gov (United States)

    Shiba, Norio; Ohki, Kentaro; Kobayashi, Tohru; Hara, Yusuke; Yamato, Genki; Tanoshima, Reo; Ichikawa, Hitoshi; Tomizawa, Daisuke; Park, Myoung-Ja; Shimada, Akira; Sotomatsu, Manabu; Arakawa, Hirokazu; Horibe, Keizo; Adachi, Souichi; Taga, Takashi; Tawa, Akio; Hayashi, Yasuhide

    2016-02-01

    Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome. © 2015 John Wiley & Sons Ltd.

  11. The role of rehabilitation measures in reintegration of children with brain tumours or leukaemia and their families after completion of cancer treatment: a study protocol.

    Science.gov (United States)

    Peikert, Mona Leandra; Inhestern, Laura; Bergelt, Corinna

    2017-08-11

    For ill children as well as for their parents and siblings, childhood cancer poses a major challenge. Little is known about the reintegration into daily life of childhood cancer survivors and their families. The aim of this prospective observational study is to further the understanding of the role of rehabilitation measures in the reintegration process of childhood leukaemia or brain tumour survivors and their family members after the end of cancer treatment. This prospective observational study consists of three study arms: a quantitative study in cooperation with three German paediatric oncological study registries (study arm 1), a quantitative study in cooperation with a rehabilitation clinic that offers a family-oriented paediatric oncological rehabilitation programme (study arm 2) and a qualitative study at 12-month follow-up including families from the study arms 1 and 2 (study arm 3). In study arm 1, children, parents and siblings are surveyed after treatment (baseline), 4-6 months after baseline measurement and at 12-month follow-up. In study arm 2, data are collected at the beginning and at the end of the rehabilitation measure and at 12-month follow-up. Families are assessed with standardised questionnaires on quality of life, emotional and behavioural symptoms, depression, anxiety, fear of progression, coping and family functioning. Furthermore, self-developed items on rehabilitation aims and reintegration into daily life are used. Where applicable, users and non-users of rehabilitation measures will be compared regarding the outcome parameters. Longitudinal data will be analysed by means of multivariate analysis strategies. Reference values will be used for comparisons if applicable. Qualitative data will be analysed using thematic analysis. This study has been approved by the medical ethics committee of the Medical Chamber of Hamburg. Data will be published in peer-reviewed journals and presented at conferences. © Article author(s) (or their

  12. Are survival and mortality rates associated with recruitment to clinical trials in teenage and young adult patients with acute lymphoblastic leukaemia? A retrospective observational analysis in England.

    Science.gov (United States)

    Hough, Rachael; Sandhu, Sabrina; Khan, Maria; Moran, Anthony; Feltbower, Richard; Stiller, Charles; Stevens, Mike C G; Rowntree, Clare; Vora, Ajay; McCabe, Martin G

    2017-10-05

    Participation rates in clinical trials are low in teenagers and young adults (TYA) with cancer. Whilst the importance of clinical trials in informing best practice is well established, data regarding individual patient benefit are scarce. We have investigated the association between overall survival and trial recruitment in TYA patients with acute lymphoblastic leukaemia (ALL). Retrospective. National (England) TYA patients treated for ALL. 511 patients aged 15-24 years diagnosed with ALL between 2004 and 2010 inclusive, of whom 239 (46.7%) participated in the UKALL2003 trial. Patients were identified using National Clinical Trial (UKALL2003) and Cancer Registry (National Cancer Data Repository, English National Cancer Online Registration Environment) Databases. Relative survival rates were calculated for trial and non-trial patients and observed differences were modelled using a multiple regression approach. The numbers and percentages of deaths in those patients included in the survival analysis were determined for each 3-month period, p values were calculated using the two-tailed z-test for difference between proportions and 95% CIs for percentage deaths were derived using the binomial distribution based on the Wilson Score method. Patients treated on the trial had a 17.9% better 2-year survival (85.4% vs 67.5%, p<0.001) and 8.9% better 1-year survival (90.8% vs 81.9%, p=0.004) than those not on the trial. 35 (14.6%) patients recruited to the trial died in the 2 years following diagnosis compared with 86 (32.6%) of those not recruited (p<0.001). TYA patients recruited to the clinical trial UKALL 2003 in England had a lower risk of mortality and a higher overall survival than contemporaneous non-trial patients. These data underline the potential for individual patient benefit in participating in a clinical trial and the importance of international efforts to increase trial participation in the TYA age group. ISRCTN07355119. © Article author(s) (or their

  13. Independent analysis of the radiation risk for leukaemia in children and adults with mortality data (1950-2003) of Japanese A-bomb survivors

    Energy Technology Data Exchange (ETDEWEB)

    Kaiser, Jan Christian [German Research Centre for Environmental Health, Institute of Radiation Protection, Helmholtz Zentrum Muenchen, Oberschleissheim (Germany); Walsh, Linda [Federal Office for Radiation Protection, Department Radiation Protection and Health, Oberschleissheim (Germany); University of Manchester, The Faculty of Medical and Human Sciences, Manchester (United Kingdom)

    2013-03-15

    A recent analysis of leukaemia mortality in Japanese A-bomb survivors has applied descriptive models, collected together from previous studies, to derive a joint excess relative risk estimate (ERR) by multi-model inference (MMI) (Walsh and Kaiser in Radiat Environ Biophys 50:21-35, 2011). The models use a linear-quadratic dose response with differing dose effect modifiers. In the present study, a set of more than 40 models has been submitted to a rigorous statistical selection procedure which fosters the parsimonious deployment of model parameters based on pairwise likelihood ratio tests. Nested models were consequently excluded from risk assessment. The set comprises models of the excess absolute risk (EAR) and two types of non-standard ERR models with sigmoidal responses or two line spline functions with a changing slope at a break point. Due to clearly higher values of the Akaike Information Criterion, none of the EAR models has been selected, but two non-standard ERR models qualified for MMI. The preferred ERR model applies a purely quadratic dose response which is slightly damped by an exponential factor at high doses and modified by a power function for attained age. Compared to the previous analysis, the present study reports similar point estimates and confidence intervals (CI) of the ERR from MMI for doses between 0.5 and 2.5 Sv. However, at lower doses, the point estimates are markedly reduced by factors between two and five, although the reduction was not statistically significant. The 2.5 % percentiles of the ERR from the preferred quadratic-exponential model did not fall below zero risk in exposure scenarios for children, adolescents and adults at very low doses down to 10 mSv. Yet, MMI produced risk estimates with a positive 2.5 % percentile only above doses of some 300 mSv. Compared to CI from a single model of choice, CI from MMI are broadened in cohort strata with low statistical power by a combination of risk extrapolations from several models

  14. Independent analysis of the radiation risk for leukaemia in children and adults with mortality data (1950-2003) of Japanese A-bomb survivors.

    Science.gov (United States)

    Kaiser, Jan Christian; Walsh, Linda

    2013-03-01

    A recent analysis of leukaemia mortality in Japanese A-bomb survivors has applied descriptive models, collected together from previous studies, to derive a joint excess relative risk estimate (ERR) by multi-model inference (MMI) (Walsh and Kaiser in Radiat Environ Biophys 50:21-35, 2011). The models use a linear-quadratic dose response with differing dose effect modifiers. In the present study, a set of more than 40 models has been submitted to a rigorous statistical selection procedure which fosters the parsimonious deployment of model parameters based on pairwise likelihood ratio tests. Nested models were consequently excluded from risk assessment. The set comprises models of the excess absolute risk (EAR) and two types of non-standard ERR models with sigmoidal responses or two line spline functions with a changing slope at a break point. Due to clearly higher values of the Akaike Information Criterion, none of the EAR models has been selected, but two non-standard ERR models qualified for MMI. The preferred ERR model applies a purely quadratic dose response which is slightly damped by an exponential factor at high doses and modified by a power function for attained age. Compared to the previous analysis, the present study reports similar point estimates and confidence intervals (CI) of the ERR from MMI for doses between 0.5 and 2.5 Sv. However, at lower doses, the point estimates are markedly reduced by factors between two and five, although the reduction was not statistically significant. The 2.5 % percentiles of the ERR from the preferred quadratic-exponential model did not fall below zero risk in exposure scenarios for children, adolescents and adults at very low doses down to 10 mSv. Yet, MMI produced risk estimates with a positive 2.5 % percentile only above doses of some 300 mSv. Compared to CI from a single model of choice, CI from MMI are broadened in cohort strata with low statistical power by a combination of risk extrapolations from several

  15. Seroprevalence of feline immunodeficiency virus and feline leukaemia virus in Australia: risk factors for infection and geographical influences (2011–2013

    Directory of Open Access Journals (Sweden)

    Mark E Westman

    2016-05-01

    Full Text Available Objectives Our aim was to: (i determine the current seroprevalence of feline immunodeficiency virus (FIV and feline leukaemia virus (FeLV in three large cohorts of cats from Australia; and (ii investigate potential risk factors for retroviral infection. Methods Cohort 1 (n = 2151 for FIV, n = 2241 for FeLV consisted of cats surrendered to a shelter on the west coast of Australia (Perth, Western Australia [WA]. Cohort 2 (n = 2083 for FIV, n = 2032 for FeLV consisted of client-owned cats with outdoor access recruited from around Australia through participating veterinary clinics. Cohort 3 (n = 169 for FIV, n = 166 for FeLV consisted of cats presenting to Murdoch University Veterinary Hospital for a variety of reasons. Fresh whole blood was collected and tested using a commercially available point-of-care lateral flow ELISA kit that detects p27 FeLV antigen and antibodies to FIV antigens (p15 and p24 (cohorts 1 and 2, or one of two lateral flow immunochromatography kits that detect p27 antigen and antibodies to FIV antigen (p24 and/or gp40 (cohort 3. Data recorded for cats in cohort 2 included signalment, presenting complaint and postcode, allowing investigation of risk factors for FIV or FeLV infection, as well as potential geographical ‘hot spots’ for infection. Results The seroprevalence of FIV was 6% (cohort 1, 15% (cohort 2 and 14% (cohort 3, while the seroprevalence of FeLV was 1%, 2% and 4% in the same respective cohorts. Risk factors for FIV infection among cats in cohort 2 included age (>3 years, sex (male, neutering status (entire males and location (WA had a significantly higher FIV seroprevalence compared with the Australian Capital Territory, New South Wales and Victoria. Risk factors for FeLV infection among cats in cohort 2 included health status (‘sick’ and location (WA cats were approximately three times more likely to be FeLV-infected compared with the rest of Australia. No geographical hot spots of FIV infection were

  16. Seroprevalence of feline immunodeficiency virus and feline leukaemia virus in Australia: risk factors for infection and geographical influences (2011–2013)

    Science.gov (United States)

    Westman, Mark E; Paul, Amanda; Malik, Richard; McDonagh, Phillip; Ward, Michael P; Hall, Evelyn; Norris, Jacqueline M

    2016-01-01

    Objectives Our aim was to: (i) determine the current seroprevalence of feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) in three large cohorts of cats from Australia; and (ii) investigate potential risk factors for retroviral infection. Methods Cohort 1 (n = 2151 for FIV, n = 2241 for FeLV) consisted of cats surrendered to a shelter on the west coast of Australia (Perth, Western Australia [WA]). Cohort 2 (n = 2083 for FIV, n = 2032 for FeLV) consisted of client-owned cats with outdoor access recruited from around Australia through participating veterinary clinics. Cohort 3 (n = 169 for FIV, n = 166 for FeLV) consisted of cats presenting to Murdoch University Veterinary Hospital for a variety of reasons. Fresh whole blood was collected and tested using a commercially available point-of-care lateral flow ELISA kit that detects p27 FeLV antigen and antibodies to FIV antigens (p15 and p24) (cohorts 1 and 2), or one of two lateral flow immunochromatography kits that detect p27 antigen and antibodies to FIV antigen (p24 and/or gp40) (cohort 3). Data recorded for cats in cohort 2 included signalment, presenting complaint and postcode, allowing investigation of risk factors for FIV or FeLV infection, as well as potential geographical ‘hot spots’ for infection. Results The seroprevalence of FIV was 6% (cohort 1), 15% (cohort 2) and 14% (cohort 3), while the seroprevalence of FeLV was 1%, 2% and 4% in the same respective cohorts. Risk factors for FIV infection among cats in cohort 2 included age (>3 years), sex (male), neutering status (entire males) and location (WA had a significantly higher FIV seroprevalence compared with the Australian Capital Territory, New South Wales and Victoria). Risk factors for FeLV infection among cats in cohort 2 included health status (‘sick’) and location (WA cats were approximately three times more likely to be FeLV-infected compared with the rest of Australia). No geographical hot spots of FIV infection were

  17. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission.

    Science.gov (United States)

    Brunner, Andrew M; Li, Shuli; Fathi, Amir T; Wadleigh, Martha; Ho, Vincent T; Collier, Kerry; Connolly, Christine; Ballen, Karen K; Cutler, Corey S; Dey, Bimalangshu R; El-Jawahri, Areej; Nikiforow, Sarah; McAfee, Steven L; Koreth, John; Deangelo, Daniel J; Alyea, Edwin P; Antin, Joseph H; Spitzer, Thomas R; Stone, Richard M; Soiffer, Robert J; Chen, Yi-Bin

    2016-11-01

    We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow-up was 27·2 months post-HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post-HCT; 43 controls were alive without relapse at this cut-off. Sorafenib patients had improved 2-year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2-year PFS (82% vs. 53%, P = 0·0081) and lower 2-year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post-HCT sorafenib in FLT3-ITD AML, and support further evaluation of post-HCT FLT3 inhibition. © 2016 John Wiley & Sons Ltd.

  18. The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study

    Directory of Open Access Journals (Sweden)

    van Coeverden Silvia CCM

    2008-06-01

    Full Text Available Abstract Background To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL are nowadays mainly treated with intrathecal chemotherapy (ITC instead of central nervous system (CNS radiation therapy (CRT to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients. Methods Twenty young adult survivors of childhood ALL with reduced bone mineral density ( IQ and neuropsychological performance were assessed at pre-treatment (T1 and after one (T2 and two (T3 years. ANOVA was performed with assessment at T1, T2 and T3 as repeated measurements factor. Relations between test score changes and changes of IGF-I levels were determined by calculating the Pearson correlation coefficient. Results Scores on the cognitive tests were in the normal range. Verbal short- and long-term memory performance decreased between T1 and T2, and increased between T2 and T3. Performance at T3 was not significantly different from that at T1. Performance for sustained attention improved from T1 to T2 and from T1 to T3. Visual-spatial memory was improved after one year of GH treatment. A significant positive correlation was found for Δ IGF-I (T2-T1 with difference scores of visual-spatial memory (T2-T1 and T3-T1, indicating that IGF-I increase after one year of GH treatment is associated with increase in cognitive-perceptual performance at month 12 and 24. Conclusion Since the level of intellectual functioning of our patient cohort was in the normal range the present finding that GH treatment has negative effects on verbal memory and positive on attention and visual-spatial memory warrants similar studies in other groups of ALL survivors. Also, a lower dose of GH should be determined

  19. 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)

    DEFF Research Database (Denmark)

    Panagopoulos, Ioannis; Kerndrup, Gitte; Carlsen, Niels

    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...

  20. High-dose vincristine, fractionated total-body irradiation and cyclophosphamide as conditioning regimen in allogeneic and autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission: a 7-year Italian multicentre study

    Energy Technology Data Exchange (ETDEWEB)

    Uderzo, C. [Milan Univ. (Italy); Rondelli, R.; Dini, G. [Bologna Univ. (Italy)] [and others

    1995-04-01

    We investigated the feasibility and efficacy of high-dose vincristine (4 mg/m{sup 2} over 4 d) combined with fractionated total body irradiation (F-TBI) (200 cGy x 2 over 3 d) and cyclophosphamide (60 mg/kg for 2 d) as a preparative regimen in allogeneic (AlloBMT) and autologous (ABMT) bone marrow transplantation for 75 consecutive children (median age at transplant 8.5 years) with acute lymphoblastic leukaemia in second complete remission (CR). Median duration of first CR was 26 and 25 months in the AlloBMT and ABMT group, respectively. We conclude that the conditioning regimen with high-dose vincrostine combined with cyclophosphamide and F-TBI is feasible and promising although its therapeutic advantage should be tested in larger series of patients enrolled in randomized studies. (author).