Topography of cancer-associated immune cells in human solid tumors.

Lymphoid and myeloid cells are abundant in the tumor microenvironment, can be quantified by immunohistochemistry and shape the disease course of human solid tumors. Yet, there is no comprehensive understanding of spatial immune infiltration patterns ('topography') across cancer entities and across various immune cell types. In this study, we systematically measure the topography of multiple immune cell types in 965 histological tissue slides from N = 177 patients in a pan-cancer cohort. We provide a definition of inflamed ('hot'), non-inflamed ('cold') and immune excluded patterns and investigate how these patterns differ between immune cell types and between cancer types. In an independent cohort of N = 287 colorectal cancer patients, we show that hot, cold and excluded topographies for effector lymphocytes (CD8) and tumor-associated macrophages (CD163) alone are not prognostic, but that a bivariate classification system can stratify patients. Our study adds evidence to consider immune topographies as biomarkers for patients with solid tumors.

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Comparative evaluation of methods approximating drug prescription durations in claims data: modeling, simulation, and application to real data.

PURPOSE: The purpose of this study was to compare the predictive accuracy of different methods suggested for approximation of drug prescription durations in claims data. METHODS: We expanded a well-established modeling and simulation framework to compare approximated drug prescription durations with 'true' (i.e., simulated) durations. Real claims data of persons aged ≥65 years insured by the German nationwide 'Statutory Health Insurance Fund' AOK between 2010 and 2012 provided empiric input parameters that were completed with missing information on actual dosing patterns from an observational cohort. The distinct approximation methods were based on crude measures (one tablet a day), population-averaged measures (defined daily doses), or individually-derived measures (longitudinal coverage approximation of the applied dose, COV). As a proof-of-principle, we assessed the methods' performance to predict the well-characterized bleeding risks of anticoagulant, antiplatelet, and/or non-steroidal anti-inflammatory drugs. RESULTS: When applied to modeling and simulation data sets, the closest, least biased, and thus most accurate approximation was observed using the COV approximation. In a real-data example, rather similar results to an external reference were obtained for all methods. However, some of the differences between methods were meaningful, and the most reasonable and consistent results were obtained with the COV approach. CONCLUSION: Based on theoretically most accurate approximations and practically reasonable estimates, the individual COV approach was preferable over the population-averaged defined daily dose technique, although the latter might be justified in certain situations. Advantages of the COV approach are expected to be even bigger for drug therapies with particularly large dosing heterogeneity. Copyright © 2016 John Wiley & Sons, Ltd.

Suitability of circulating miRNAs as potential prognostic markers in colorectal cancer.

miRNAs are crucial in cellular processes and have been shown to be abnormally expressed in cancer tissue and the circulation. Circulating miRNAs may serve as a novel class of minimally invasive biomarkers for prognosis. Within a first methodologic study, we evaluated the miRNA profile kinetics in the plasma of patients with colorectal cancer after surgical tumor removal to identify potential suitability as prognostic biomarkers. This pilot study is based on the ColoCare Study, a cohort study of newly diagnosed patients with stage I-IV colorectal cancer. Colorectal cancer pre- and postsurgical blood (2-7 days after surgery) and 6 months follow-up blood from 35 patients were examined and candidate miRNAs were investigated in the plasma. miRNA levels were measured by two-step qRT-PCR. Statistical analysis was performed using log-transformed normalized CT values using SAS 9.3. Comparing pre- and postsurgical miRNA levels revealed a statistically significant decrease of nine circulating miRNAs after surgery (miR92a, miR18a, miR320a, miR106a, miR16-2, miR20a, miR223, miR17, and miR143). Analyses of plasma levels over all three time points demonstrated a statistically significant decrease from presurgery to postsurgery and re-increase from postsurgery to the six months follow-up time point of four circulating miRNAs (miR92a, miR320a, miR106a, and miR18a). We were able to show for the first time that in plasma miRNA profiles change within days after colorectal cancer surgery. Our results underscore the role of the investigated miRNAs in colorectal cancer and their potential utility as prognostic biomarkers. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology."

The importance of social support for people with type 2 diabetes - a qualitative study with general practitioners, practice nurses and patients.

OBJECTIVE: Social support is an important element of family medicine within a primary care setting, delivered by general practitioners and practice nurses in addition to usual clinical care. The aim of the study was to explore general practitioner's, practice nurse's and people with type 2 diabetes' views, experiences and perspectives of the importance of social support in caring for people with type 2 diabetes and their role in providing social support. METHODS: Interviews with general practitioners (n=10) and focus groups with practice nurses (n=10) and people with diabetes (n=9). All data were audio-recorded, fully transcribed and thematically analysed using qualitative content analysis by Mayring. RESULTS: All participants emphasized the importance of the concept of social support and its impacts on well-being of people with type 2 diabetes. Social support is perceived helpful for people with diabetes in order to improve diabetes control and give support for changes in lifestyle habits (physical activity and dietary changes). General practitioners identified a lack of information about facilities in the community like sports or self-help groups. Practice nurses emphasized that they need more training, such as in dietary counselling. CONCLUSIONS: Social support given by general practitioners and practice nurses plays a crucial role for people with type 2 diabetes and is an additional component of social care. However there is a need for an increased awareness by general practitioners and practice nurses about the influence social support could have on the individual's diabetes management.