Analysis of the clinical impact of NPM1 mutant allele burden in a large cohort of younger adult patients with acute myeloid leukaemia

Although an NPM1 mutation is generally considered to be a good prognostic marker in acute myeloid leukaemia, it has recently been suggested that a higher level of NPM1 mutant (NPM1MUT) alleles relative to wild‐type alleles is associated with poor clinical outcome. We therefore sought to confirm this finding in a larger study of 876 NPM1MUT cases entered into UK national trials. In univariate analysis, the higher NPM1MUT allele burden was associated with a lower complete remission (CR) rate, higher relapse rate and reduced overall survival, but this was largely attributable to the association of the higher NPM1MUT allele burden with other known poor risk factors, particularly the presence of a concomitant FLT3 internal tandem duplication. In multivariate analysis, there was no significant impact of the NPM1MUT allele burden on CR rates, and the impact on relapse and overall survival, whilst still significant, was greatly reduced. This impact was similar in patients who did or did not receive an allogeneic transplant in first CR. We conclude that the binary presence or absence of an NPM1 mutation, combined with minimal residual disease levels following induction therapy, should continue to be used in therapeutic management rather than stratification according to the NPM1MUT level

Therapy for isocitrate dehydrogenase 2 (IDH2)(R172)-mutant acute myeloid leukaemia

Although we earlier reported a very poor outcome for younger adult patients with isocitrate dehydrogenase 2 (IDH2)R172-mutated acute myeloid leukaemia (AML) entered into UK trials compared to IDH2WT and IDH2R140-mutated patients, this was not corroborated by a study from the German-Austrian AML Study Group. We have therefore investigated a later cohort of IDH2-mutated patients to identify any changes in outcome and whether this could inform the optimal treatment for IDH2R172 AML. We found an improved outcome for IDH2R172-mutated AML in the later trials and the data suggests that this may be due to the increased use of allogeneic transplantation to consolidate first remission

Additional impact of mutational genotype on prognostic determination in resistant and relapsed acute myeloid leukaemia

Outcome after failure of initial therapy in younger adult patients with acute myeloid leukaemia (AML) is highly variable. Cytogenetics, length of first remission (CR1) before relapse, and allogeneic transplantation are known prognostic factors, but the contribution of leukaemic genotype is less clear, particularly in resistant disease. Of 5,651 younger adult patients entered into UK MRC/NCRI AML trials between 1988 and 2014 with available FLT3ITD and NPM1 genotype, 326 (6%) had resistant disease and 2338 (41 %) relapsed after achieving CR1. Overall survival (OS) was significantly higher in relapsed compared to resistant disease (p = 0·03). Independent favourable prognostic factors for OS in resistant disease included lower blast cell percentage after two courses of induction therapy (p = 0.0006) and NPM1 mutant (NPM1MUT) (p = 0.04). In relapsed disease, longer CR1 was a favourable independent factor for attainment of CR2 (p < 0.0001) and OS from time of relapse (p < 0.0001), but CR2 rate and OS from relapse were significantly worse in those who had received an allograft in CR1 (respectively p < 0.05, p < 0·002). NPM1MUT was marginally beneficial for OS (p = 0.04). FLT3ITD and DNMT3AMUT were adverse factors for OS (respectively p < 0.0001, p = 0.02). Mutational analysis adds additional independent prognostic information to demographic features and previous therapy in patients with resistant and relapsed disease

Identifying Health Economic Considerations to Include in the Research Protocol of a Randomized Controlled Trial (the REDUCE-RISK Trial): Systematic Literature Review and Assessment.

BACKGROUND: The REDUCE-RISK trial was set up to compare the effectiveness of weekly subcutaneously administered methotrexate with daily oral azathioprine or 6-mercaptopurine in low-risk Crohn disease (CD) or subcutaneously administered adalimumab (ADA) in high-risk CD in a pediatric population (age 6-17 years). OBJECTIVE: The aim of this study is to perform a systematic review to provide input into the research protocol to gather the necessary information to improve the performance of an evidence-based economic evaluation when the trial is finished. METHODS: The Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database, websites of HTA institutes, CRD's National Health Service Economic Evaluation Database, MEDLINE (OVID), and Embase databases were consulted to retrieve (reviews of) relevant economic evaluations. Studies were eligible if they included a pediatric or adult population with inflammatory bowel diseases (CD and ulcerative colitis [UC]) treated with ADA (Humira). There were no restrictions on the comparator. Only economic evaluations expressing outcomes in life years gained or quality-adjusted life years gained were selected. RESULTS: A total of 12 primary studies were identified. None of these studies included a pediatric population because of a lack of supporting trials. The economic evaluations identified in our systematic review indicate that ADA is an appropriate intervention for inclusion in such a trial. From a health economic point of view, it is important to make an incremental analysis comparing such an intervention with standard care and not immediately versus another (expensive) biological treatment. Information on the impact of children's school attendance and parents' productivity is currently lacking in economic evaluations, and none of the underlying trials measured quality of life (QoL) using a generic utility instrument. CONCLUSIONS: The review of the economic literature on ADA for the treatment of patients with CD supports the performance of a trial with biologicals in pediatric patients, including making a distinction according to disease severity. Conducting an economic literature review enabled us to decide which variables should be added to the research protocol from an economic point of view. Measurements for children's and parents' QoL (EuroQol 5-Dimension questionnaires), children's school attendance, and parents' productivity (WPAI-CD-CG questionnaire) were added to the research protocol. This will provide support for the calculation of the cost-effectiveness of the interventions evaluated in the REDUCE-RISK trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694

Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?

The BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi-lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of 'hot spot' genome imbalances associated with BCR/ABL1 positive pre-B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the 'hot spot' regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML. © 2013 John Wiley & Sons Ltd and Crown

Multi-omics differentially classify disease state and treatment outcome in pediatric Crohn's disease

Background: Crohn's disease (CD) has an unclear etiology, but there is growing evidence of a direct link with a dysbiotic microbiome. Many gut microbes have previously been associated with CD, but these have mainly been confounded with patients' ongoing treatments. Additionally, most analyses of CD patients' microbiomes have focused on microbes in stool samples, which yield different insights than profiling biopsy samples. Results: We sequenced the 16S rRNA gene (16S) and carried out shotgun metagenomics (MGS) from the intestinal biopsies of 20 treatment-naïve CD and 20 control pediatric patients. We identified the abundances of microbial taxa and inferred functional categories within each dataset. We also identified known human genetic variants from the MGS data. We then used a machine learning approach to determine the classification accuracy when these datasets, collapsed to different hierarchical groupings, were used independently to classify patients by disease state and by CD patients' response to treatment. We found that 16S-identified microbes could classify patients with higher accuracy in both cases. Based on follow-ups with these patients, we identified which microbes and functions were best for predicting disease state and response to treatment, including several previously identified markers. By combining the top features from all significant models into a single model, we could compare the relative importance of these predictive features. We found that 16S-identified microbes are the best predictors of CD state whereas MGS-identified markers perform best for classifying treatment response. Conclusions: We demonstrate for the first time that useful predictors of CD treatment response can be produced from shotgun MGS sequencing of biopsy samples despite the complications related to large proportions of host DNA. The top predictive features that we identified in this study could be useful for building an improved classifier for CD and treatment response based on sufferers' microbiome in the future. The BISCUIT project is funded by a Clinical Academic Fellowship from the Chief Scientist Office (Scotland)-CAF/08/01

Multi-membership gene regulation in pathway based microarray analysis

This article is available through the Brunel Open Access Publishing Fund. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Gene expression analysis has been intensively researched for more than a decade. Recently, there has been elevated interest in the integration of microarray data analysis with other types of biological knowledge in a holistic analytical approach. We propose a methodology that can be facilitated for pathway based microarray data analysis, based on the observation that a substantial proportion of genes present in biochemical pathway databases are members of a number of distinct pathways. Our methodology aims towards establishing the state of individual pathways, by identifying those truly affected by the experimental conditions based on the behaviour of such genes. For that purpose it considers all the pathways in which a gene participates and the general census of gene expression per pathway. Results: We utilise hill climbing, simulated annealing and a genetic algorithm to analyse the consistency of the produced results, through the application of fuzzy adjusted rand indexes and hamming distance. All algorithms produce highly consistent genes to pathways allocations, revealing the contribution of genes to pathway functionality, in agreement with current pathway state visualisation techniques, with the simulated annealing search proving slightly superior in terms of efficiency. Conclusions: We show that the expression values of genes, which are members of a number of biochemical pathways or modules, are the net effect of the contribution of each gene to these biochemical processes. We show that by manipulating the pathway and module contribution of such genes to follow underlying trends we can interpret microarray results centred on the behaviour of these genes.The work was sponsored by the studentship scheme of the School of Information Systems, Computing and Mathematics, Brunel Universit

Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia

In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance. LSC in CD34+ and more mature CD34− AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (SPC) but may be differentiated by functional markers. We therefore investigated the oxidative/reactive oxygen species (ROS) profile, its relationship with cell-cycle/BCL2 for normal SPC, and whether altered in AML and myelodysplasia (MDS). In control BM (n = 24), ROS levels were highest in granulocyte-macrophage progenitors (GMP) and CD34− myeloid precursors but megakaryocyte-erythroid progenitors had equivalent levels to CD34+CD38low immature-SPC although they were ki67high. BCL2 upregulation was specific to GMPs. This profile was also observed for CD34+SPC in MDS-without-excess-blasts (MDS-noEB, n = 12). Erythroid CD34− precursors were, however, abnormally ROS-high in MDS-noEB, potentially linking oxidative stress to cell loss. In pre-treatment AML (n = 93) and MDS-with-excess-blasts (MDS-RAEB) (n = 14), immunophenotypic mature-SPC had similar ROS levels to co-existing immature-SPC. However ROS levels varied between AMLs; Flt3ITD+/NPM1wild-type CD34+SPC had higher ROS than NPM1mutated CD34+ or CD34− SPC. An aberrant ki67lowBCL2high immunophenotype was observed in CD34+AML (most prominent in Flt3ITD AMLs) but also in CD34− AMLs and MDS-RAEB, suggesting a shared redox/pro-survival adaptation. Some patients had BCL2 overexpression in CD34+ ROS-high as well as ROS-low fractions which may be indicative of poor early response to standard chemotherapy. Thus normal SPC subsets have distinct ROS, cell-cycle, BCL2 profiles that in AML /MDS-RAEB are decoupled from maturation. The combined profile of these functional properties in AML subpopulations may be relevant to differential treatment resistance

The impact of heavy-quark loops on LHC dark matter searches

If only tree-level processes are included in the analysis, LHC monojet searches give weak constraints on the dark matter-proton scattering cross section arising from the exchange of a new heavy scalar or pseudoscalar mediator with Yukawa-like couplings to quarks. In this letter we calculate the constraints on these interactions from the CMS 5.0/fb and ATLAS 4.7/fb searches for jets with missing energy including the effects of heavy-quark loops. We find that the inclusion of such contributions leads to a dramatic increase in the predicted cross section and therefore a significant improvement of the bounds from LHC searches.Comment: 12 pages, 1 table, 3 figures, v2: extended discussion and improved relic density calculation - matches published versio

Interpol and the Emergence of Global Policing

This chapter examines global policing as it takes shape through the work of Interpol, the International Criminal Police Organization. Global policing emerges in the legal, political and technological amalgam through which transnational police cooperation is carried out, and includes the police practices inflected and made possible by this phenomenon. Interpol’s role is predominantly in the circulation of information, through which it enters into relationships and provides services that affect aspects of governance, from the local to national, regional and global. The chapter describes this assemblage as a noteworthy experiment in developing what McKeon called a frame for common action. Drawing on Interpol publications, news stories, interviews with staff, and fieldwork at the General Secretariat in Lyon, France, the history, institutional structure, and daily practices are described. Three cases are analyzed, concerning Red Notices, national sovereignty, and terrorism, in order to explore some of the problems arising in Interpol’s political and technical operating arrangements. In conclusion, international and global policing are compared schematically, together with Interpol’s attempts to give institutional and procedural direction to the still-evolving form of global policing