Features of childhood cancer in primary care: a population-based nested case-control study.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: This study investigated the risk of cancer in children with alert symptoms identified in current UK guidance, or with increased consultation frequency in primary care. METHODS: A population-based, nested case-control study used data from the General Practice Research Database. In all, 1267 children age 0-14 years diagnosed with childhood cancer were matched to 15,318 controls. Likelihood ratios and positive predictive values (PPVs) were calculated to assess risk. RESULTS: Alert symptoms recorded in the 12 and 3 months before diagnosis were present in 33.7% and 27.0% of cases vs 5.4% and 1.4% of controls, respectively. The PPV of having cancer for any alert symptom in the 3 months before diagnosis was 0.55 per 1000 children. Cases consulted more frequently particularly in the 3 months before diagnosis (86% cases vs 41% controls). Of these, 36% of cases and 9% of controls had consulted 4 times or more. The PPV for cancer in a child consulting 4 times or more in 3 months was 0.13 per 1000 children. CONCLUSION: Alert symptoms and frequent consultations are associated with childhood cancer. However, individual symptoms and consultation patterns have very low PPVs for cancer in primary care (e.g., of 10,000 children with a recorded alert symptom, approximately 6 would be diagnosed with cancer within 3 months).RMD is funded by the National Institute for Health Research (NIHR). WH was part funded by a NIHR postdoctoral fellowship. This study is based on data from the Full Feature General Practice Research Database (GPRD) obtained under licence from the UK Medicines and Healthcare Products Regulatory Agency (MHRA). However, the interpretation and conclusions contained in this study are those of the author/s alone. Access to the GPRD was funded through the Medical Research Council (MRC) licence agreement with the UK Medicines and Healthcare Products Regulatory Agency

Features of cancer in teenagers and young adults in primary care: a population-based nested case-control study

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Teenagers and young adults (TYA, 15-24 years) diagnosed with cancer report repeated visits to primary care before referral. We investigated associations of symptoms and consultation frequency in primary care with TYA cancers. METHODS: Population-based, case-control study was carried out using data from the Clinical Practice Research Datalink (CPRD). A total of 1064 TYA diagnosed with cancer were matched to 13,206 controls. Symptoms independently associated with specific cancers were identified. Likelihood ratios (LRs) and positive predictive values (PPVs) were calculated. RESULTS: In the 3 months before diagnosis, 397 (42.9%) cases consulted > or =4 times vs 593(11.5%) controls (odds ratio (OR): 12.1; 95% CI: 9.7, 15.1), yielding a PPV for any cancer of 0.018%. The LR of lymphoma with a head/neck mass was 434 (95% CI: 60, 3158), with a PPV of 0.5%. Corresponding figures in other cancers included - LR of leukaemia with lymphadenopathy (any site): 29 (95% CI: 8, 112), PPV 0.015%; LR of CNS tumour with seizure: 56 (95% CI: 19, 163), PPV 0.024%; and LR of sarcoma with lump/mass/swelling: 79 (95% CI: 24, 264), PPV 0.042%. CONCLUSION: Teenagers and young adults with cancer consulted more frequently than controls in the 3 months before diagnosis. Primary care features of cancer match secondary care reports, but were of very low risk; nonetheless, some features increased the likelihood of cancer substantially and should be taken seriously when assessing TYA.RMD is funded by the National Institute for Health Research (NIHR). WH was, in part, funded by an NIHR postdoctoral fellowship. This study is based on data from the Full Feature Clinical Practice Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare Products Regulatory Agency (MHRA). Access to the CPRD was funded through the Medical Research Council (MRC) licence agreement with the UK Medicines and Healthcare Products Regulatory Agency. The conduct of this study was approved by the Independent Scientific Advisory Committee (ISAC) of the MHRS (Protocol 10_056A) and the University of Bristol (reference: 35515

Systematic review of fatty acid composition of human milk from mothers of preterm compared to full-term infants

Background: Fatty acid composition of human milk serves as guidance for the composition of infant formulae. The aim of the study was to systematically review data on the fatty acid composition of human milk of mothers of preterm compared to full-term infants. Methods: An electronic literature search was performed in English (Medline and Medscape) and German (SpringerLink) databases and via the Google utility. Fatty acid compositional data for preterm and fullterm human milk were converted to differences between means and 95% confidence intervals. Results: We identified five relevant studies publishing direct comparison of fatty acid composition of preterm versus full-term human milk. There were no significant differences between the values of the principal saturated and monounsaturated fatty acids. In three independent studies covering three different time points of lactation, however, docosahexaenoic acid (DHA) values were significantly higher in milk of mothers of preterm as compared to those of full-term infants, with an extent of difference considered nutritionally relevant. Conclusion: Higher DHA values in preterm than in full-term human milk underlines the importance of using own mother's milk for feeding preterm babies and raises the question whether DHA contents in preterm formulae should be higher than in formulae for full-term infants. Copyright (c) 2008 S. Karger AG, Basel

Association between chronic irritability and depressive symptoms in children and adolescents.

Association between chronic irritability and depressive symptoms in children and adolescents. Busto-Garrido, M.; Gutierrez-Castillo, D; Navas- Gonzalez, JR; Gutierrez-Bedmar, M; Gutierrez-Casares, JR; Martin-Lunar, MT; Rodríguez-Rosado, A; Pena-Andreu, JM. European Psychiatry 415(2017) 5221.Chronic irritability is the most frequently reported symptom in child and adolescent depression. The association of both has been linked with high rates of chronicity, comorbility and impairment. Objectives To study the association between chronic irritability and depressive symptoms in children and adolescents. Methods We have studied 857 participants recruited from the only Child and Adolescent Mental Health Clinic in a catchment area of 122968 people under 18 (2004-2010). A sample of 677 participants (57 controls and 620 patients) was included to carry out a cross-sectional study. Chronic irritability was measured by a Visual Analog Scale (VAS irritability) -scored from 0 to 10-, and depressive symptoms by the Children's Depression Inventory (CDI). The participants were categorized into controls and patients, and according to their chronic irritability (≤4 [I],5 [II] and ≥6 [III]). The mean of CDI score was calculated for each of the groups, adjusted by sex and age, and analyzed by ANCOVA. Results The following means were obtained from the controls: 13,71 (group I), 9,82 (group II) and 17,45 (group III). Regarding to the patients: 13,92 (group I), 11,54 (group II) and 15,64 (group III). A quadratic association (p <0,0015) was found between VAS irritability score and CDI score. Conclussions There is not a lineal association between chronic irritability and depressive symptoms in children and adolescent. High rates of depressive symptoms were associated both with high and low rates of irritability. Several questions remain unexplained about the status of irritability in psychiatry as Stringaris group has been pointed out. Disclosure statement I have no potential conflict of interest to discloseUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

On the mechanism of iodine oxide particle formation

The formation of atmospherically relevant iodine oxides IxO y (x = 1,...,3, y = 1,...,7) has been studied experimentally using time-of-flight mass spectrometry combined with a soft ionisation source, complemented with ab initio electronic structure calculations of ionisation potentials and bond energies at a high level of theory presented in detail in the accompanying paper (Galvez et al., 2013). For the first time, direct experimental evidence of the I2Oy (y = 1,...,5) molecules in the gas phase has been obtained. These chemical species are observed alongside their precursors (IO and OIO) in experiments where large amounts of aerosol are also generated. The measured relative concentrations of the I xOy molecules and their dependence on ozone concentration have been investigated by using chemical modelling and rate theory calculations. It is concluded that I2O4 is the most plausible candidate to initiate nucleation, while the contribution of I2O5 in the initial steps is likely to be marginal. The absence of large I 3Oy (y = 3,...,6) peaks in the mass spectra and the high stability of the I2O4-I2O4 dimer indicate that dimerisation of I2O4 is the key step in iodine oxide particle nucleation

The effect of transmucosal 0.2mg/kg Midazolam premedication on dental anxiety, anaesthetic induction and psychological morbidity in children undergoing general anaesthesia for tooth extraction

&lt;b&gt;Background:&lt;/b&gt; The project aims were to evaluate the benefit of transmucosal Midazolam 0.2mg/kg pre-medication on anxiety, induction behaviour and psychological morbidity in children undergoing general anaesthesia (GA) extractions. &lt;b&gt;Method:&lt;/b&gt; 179 children aged 5-10 years (mean 6.53 years) participated in this randomised, double blind, placebo controlled trial. Ninety children had Midazolam placed in the buccal pouch. Dental anxiety was recorded pre operatively and 48 hours later using a child reported MCDAS-FIS scale. Behaviour at anaesthetic induction was recorded and psychological morbidity was scored by the parent using the Rutter Scale pre-operatively and again one-week later. Subsequent dental attendance was recorded at one, three and six months after GA. &lt;b&gt;Results:&lt;/b&gt; Whilst levels of mental anxiety did not reduce overall, the most anxious patients demonstrated a reduction in anxiety after receiving midazolam premedicationmay (p=0.01). Neither induction behaviour nor psychological morbidity improved. Irrespective of group, parents reported less hyperactive (p= 0.002) and more prosocial behaviour (p=0.002) after the procedure:;, older children improved most (p=0.048), Post GA Dental attendance was poor and unrelated to after the procedure and unaffected by premedication. &lt;b&gt;Conclusion:&lt;/b&gt; 0.2mg/kg buccal Midazolam provided some evidence for reducing anxiety in the most dentally anxious patients. However, induction behaviour, psychological morbidity and subsequent dental attendance were not found to alter between the premedication groups

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

Retrospective cohort study evaluating clinical, biochemical and pharmacological prognostic factors for prostate cancer progression using primary care data

This is the final version. Available on open access from BMJ Publishing group via the DOI in this recordObjectives – To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation. Design – Retrospective cohort study, employing Cox proportional hazards regression controlling for age, PSA, and Gleason score, stratified by diagnostic stage. Setting – Primary care in England Participants – Males with localised prostate cancer diagnosed between 01/01/1987 and 31/12/2016 within the Clinical Practice Research Datalink database, with linked data from the National Cancer Registration and Analysis Service and Office for National Statistics. Primary and Secondary outcomes – Primary outcome measure was prostate cancer mortality. Secondary outcomes measures were all-cause mortality and commencing systematic therapy. Up13 staging after diagnosis was not used as a secondary outcome owing to significant missing data. Results 10,901 males (mean age 74.38 +/- 9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (+/- 6.36) years. 2,331 (21.38%) men underwent systemic therapy and 3,250 (31.65%) died, including 1,250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C-Reactive Protein; high ferritin; low haemoglobin; high blood glucose; and low albumin. Conclusions This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression.Can Test Collaborative/CRU

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Explaining the t tbar forward-backward asymmetry without dijet or flavor anomalies

We consider new physics explanations of the anomaly in the top quark forward-backward asymmetry measured at the Tevatron, in the context of flavor conserving models. The recently measured LHC dijet distributions strongly constrain many otherwise viable models. A new scalar particle in the antitriplet representation of flavor and color can fit the t tbar asymmetry and cross section data at the Tevatron and avoid both low- and high-energy bounds from flavor physics and the LHC. An s-channel resonance in uc to uc scattering at the LHC is predicted to be not far from the current sensitivity. This model also predicts rich top quark physics for the early LHC from decays of the new scalar particles. Single production gives t tbar j signatures with high transverse momentum jet, pair production leads to t tbar j j and 4 jet final states.Comment: 7 pages, 6 figures; v2: notation clarified, references adde