The Association Between Self-Reported Symptoms of Recent Airway Infection and CRP Values in a General Population: The Tromsø Study: Tromsø 6

C-reactive protein (CRP) is a much used biomarker for respiratory tract infection; however, the influence of airway infection on the CRP level in the general population has not been well described. The study aimed to evaluate the impact of recent symptoms of airway infection on the CRP level and how the predictive power of other known CRP predictors is influenced by taking respiratory symptoms into account. A total of 6,325 participants, aged 38–87 years, in the Tromsø Study, a repeated population-based survey, were examined with questionnaires, measurements of height and weight, spirometry, and high-sensitivity CRP analyses. The mean CRP value was 2.86 mg/L, and the geometric mean was 1.51 mg/L. Geometric means above 2.0 mg/L were found in the subgroups with the following characteristics: self-reported COPD, diabetes, recent symptoms of airway infection, forced expiratory volume in 1 s (FEV1) <80% predicted, body mass index (BMI) ≥30, and subjects treated with inhaled or oral corticosteroids. Among the subjects who reported recent airway infection, 10.5% had a CRP value of ≥10 mg/L, compared to 3.3% among the remaining participants. By multivariate analysis, BMI was the strongest independent predictor of the CRP level, followed by recent airway infection, FEV1% predicted, age, and current smoking. The study clearly demonstrates that a report of recent symptoms of airway infection strongly predicts the CRP level in the population. Such symptoms were shared rather equally between subgroups with increased CRP level, and the risk of being an important confounder in epidemiological studies is probably low. In the clinical setting, care should be taken when using the CRP level as a guide for medical prevention of chronic diseases

Using Basic Science to Design a Clinical Trial: Baseline Characteristics of Women Enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women’s Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD

Multilevel genomics of colorectal cancers with microsatellite instability—clinical impact of JAK1 mutations and consensus molecular subtype 1

Background Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. Methods A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling—including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration. Results Novel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10−5), but not with immune cell infiltration—this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05–0.9] and 0.4 [0.2–0.9], respectively, P = 0.03 and 0.02). Conclusions Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-

Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial

Contains fulltext : 110433.pdf (publisher's version ) (Open Access)BACKGROUND: To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density. METHODS/DESIGN: This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of >/=20%, aged 30-55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor. DISCUSSION: Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition. TRIAL REGISTRATION: Netherland Trial Register NTR2789