Changing geographical patterns and trends in cancer incidence in children and adolescents in Europe, 1991-2010 (Automated Childhood Cancer Information System): a population-based study.

A deceleration in the increase in cancer incidence in children and adolescents has been reported in several national and regional studies in Europe. Based on a large database representing 1·3 billion person-years over the period 1991-2010, we provide a consolidated report on cancer incidence trends at ages 0-19 years. We invited all population-based cancer registries operating in European countries to participate in this population-based registry study. We requested a listing of individual records of cancer cases, including sex, age, date of birth, date of cancer diagnosis, tumour sequence number, primary site, morphology, behaviour, and the most valid basis of diagnosis. We also requested population counts in each calendar year by sex and age for the registration area, from official national sources, and specific information about the covered area and registration practices. An eligible registry could become a contributor if it provided quality data for all complete calendar years in the period 1991-2010. Incidence rates and the average annual percentage change with 95% CIs were reported for all cancers and major diagnostic groups, by region and overall, separately for children (age 0-14 years) and adolescents (age 15-19 years). We examined and quantified the stability of the trends with joinpoint analyses. For the years 1991-2010, 53 registries in 19 countries contributed a total of 180 335 unique cases. We excluded 15 162 (8·4%) of 180 335 cases due to differing practices of registration, and considered the quality indicators for the 165 173 cases included to be satisfactory. The average annual age-standardised incidence was 137·5 (95% CI 136·7-138·3) per million person-years and incidence increased significantly by 0·54% (0·44-0·65) per year in children (age 0-14 years) with no change in trend. In adolescents, the combined European incidence was 176·2 (174·4-178·0) per million person-years based on all 35 138 eligible cases and increased significantly by 0·96% (0·73-1·19) per year, although recent changes in rates among adolescents suggest a deceleration in this increasing trend. We observed temporal variations in trends by age group, geographical region, and diagnostic group. The combined age-standardised incidence of leukaemia based on 48 458 cases in children was 46·9 (46·5-47·3) per million person-years and increased significantly by 0·66% (0·48-0·84) per year. The average overall incidence of leukaemia in adolescents was 23·6 (22·9-24·3) per million person-years, based on 4702 cases, and the average annual change was 0·93% (0·49-1·37). We also observed increasing incidence of lymphoma in adolescents (average annual change 1·04% [0·65-1·44], malignant CNS tumours in children (average annual change 0·49% [0·20-0·77]), and other tumours in both children (average annual change 0·56 [0·40-0·72]) and adolescents (average annual change 1·17 [0·82-1·53]). Improvements in the diagnosis and registration of cancers over time could partly explain the observed increase in incidence, although some changes in underlying putative risk factors cannot be excluded. Cancer incidence trends in this young population require continued monitoring at an international level. Federal Ministry of Health of the Federal German Government, the European Union's Seventh Framework Programme, and International Agency for Research on Cancer

The Chiral Phase Transition in Dissipative Dynamics

Numerical simulations of the chiral phase transition in the (3+1)dimensional O(4)-model are presented. The evolutions of the chiral field follow purely dissipative dynamics, starting from random chirally symmetric initial configurations down to the true vacuum with spontaneously broken symmetry. The model stabilizes topological textures which are formed together with domains of disoriented chiral condensate (DCC) during the roll-down phase. The classically evolving field acts as source for the emission of pions and $\sigma$ mesons. The exponents of power laws for the growth of angular correlations and for emission rates are extracted. Fluctuations in the abundance ratios for neutral and charged pions are compared with those for uncorrelated sources as potential signature for the chiral phase transition after heavy-ion collisions. It is found that the presence of stabilizing textures (baryons and antibaryons) prevents sufficiently rapid growth of DCC-domain size, so observability of anomalous tails in the abundance ratios is unlikely. However, the transient formation of growing DCC domains causes sizable broadening of the distributions as compared to the statistical widths of generic sources.Comment: 28 pages, 8 figure

The nature of slow dynamics in a minimal model of frustration-limited domains

We present simulation results for the dynamics of a schematic model based on the frustration-limited domain picture of glass-forming liquids. These results are compared with approximate theoretical predictions analogous to those commonly used for supercooled liquid dynamics. Although model relaxation times increase by several orders of magnitude in a non-Arrhenius manner as a microphase separation transition is approached, the slow relaxation is in many ways dissimilar to that of a liquid. In particular, structural relaxation is nearly exponential in time at each wave vector, indicating that the mode coupling effects dominating liquid relaxation are comparatively weak within this model. Relaxation properties of the model are instead well reproduced by the simplest dynamical extension of a static Hartree approximation. This approach is qualitatively accurate even for temperatures at which the mode coupling approximation predicts loss of ergodicity. These results suggest that the thermodynamically disordered phase of such a minimal model poorly caricatures the slow dynamics of a liquid near its glass transition

Derivatization of estrogens enhances specificity and sensitivity of analysis of human plasma and serum by liquid chromatography tandem mass spectrometry

AbstractEstrogens circulate at concentrations less than 20pg/mL in men and postmenopausal women, presenting analytical challenges. Quantitation by immunoassay is unreliable at these low concentrations. Liquid chromatography tandem mass spectrometry (LC–MS/MS) offers greater specificity and sometimes greater sensitivity, but ionization of estrogens is inefficient. Introduction of charged moieties may enhance ionization, but many such derivatives of estrogens generate non-specific product ions originating from the “reagent” group. Therefore an approach generating derivatives with product ions specific to individual estrogens was sought.Estrogens were extracted from human plasma and serum using solid phase extraction and derivatized using 2-fluoro-1-methylpyridinium-p-toluenesulfonate (FMP-TS). Electrospray in positive mode with multiple reaction monitoring using a QTrap 5500 mass spectrometer was used to quantify “FMP” derivatives of estrogens, following LC separation.Transitions for the FMP derivatives of estrone (E1) and estradiol (E2) were compound specific (m/z 362→238 and m/z 364→128, respectively). The limits of detection and quantitation were 0.2pg on-column and the method was linear from 1–400pg/sample. Measures of intra- and inter-assay variability, precision and accuracy were acceptable (<20%). The derivatives were stable over 24h at 10°C (7–9% degradation). Using this approach, E1 and E2, respectively were detected in human plasma and serum: pre-menopausal female serum (0.5mL) 135–473, 193–722pmol/L; male plasma (1mL) 25–111, 60–180pmol/L and post-menopausal female plasma (2mL), 22–78, 29–50pmol/L.Thus FMP derivatization, in conjunction with LC–MS/MS, is suitable for quantitative analysis of estrogens in low abundance in plasma and serum, offering advantages in specificity over immunoassay and existing MS techniques

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML