What implementation interventions increase cancer screening rates? a systematic review

<p>Abstract</p> <p>Background</p> <p>Appropriate screening may reduce the mortality and morbidity of colorectal, breast, and cervical cancers. However, effective implementation strategies are warranted if the full benefits of screening are to be realized. As part of a larger agenda to create an implementation guideline, we conducted a systematic review to evaluate interventions designed to increase the rate of breast, cervical, and colorectal cancer (CRC) screening. The interventions considered were: client reminders, client incentives, mass media, small media, group education, one-on-one education, reduction in structural barriers, reduction in out-of-pocket costs, provider assessment and feedback interventions, and provider incentives. Our primary outcome, screening completion, was calculated as the overall median post-intervention absolute percentage point (PP) change in completed screening tests.</p> <p>Methods</p> <p>Our first step was to conduct an iterative scoping review in the research area. This yielded three relevant high-quality systematic reviews. Serving as our evidentiary foundation, we conducted a formal update. Randomized controlled trials and cluster randomized controlled trials, published between 2004 and 2010, were searched in MEDLINE, EMBASE and PSYCHinfo.</p> <p>Results</p> <p>The update yielded 66 studies new eligible studies with 74 comparisons. The new studies ranged considerably in quality. Client reminders, small media, and provider audit and feedback appear to be effective interventions to increase the uptake of screening for three cancers. One-on-one education and reduction of structural barriers also appears effective, but their roles with CRC and cervical screening, respectively, are less established. More study is required to assess client incentives, mass media, group education, reduction of out-of-pocket costs, and provider incentive interventions.</p> <p>Conclusion</p> <p>The new evidence generally aligns with the evidence and conclusions from the original systematic reviews. This review served as the evidentiary foundation for an implementation guideline. Poor reporting, lack of precision and consistency in defining operational elements, and insufficient consideration of context and differences among populations are areas for additional research.</p

FUSIONS Definitional Framework for Food Waste

none21To develop reliable food waste estimates, which can be accurately repeated over time, it is necessary to produce data within a robust methodological framework. This must comprise a consistent definition of food waste and its components, and consistent system boundaries for the food supply chain. The absence of a framework for defining food waste to date has led to the production of datasets that are not always comparable or transparent as to which fractions are included. A common definitional framework will support policy-makers at both EU and Member State level, and stakeholders across the food supply chain, by enabling them to accurately track the rate of food waste reduction, and the effectiveness of their waste prevention strategies. The development of this framework for defining food waste signals a key step towards improving our understanding of the food waste challenge in Europe and its consistent use will help measure progress towards both resource efficiency and food security goals.openKarin Östergren; Jenny Gustavsson; Hilke Bos-Brouwers; Toine Timmermans; Ole-Jørgen Hansen; Hanne Møller; Gina Anderson; Clementine O’Connor; Han Soethoudt; Tom Quested; Sophie Easteal; Alessandro Politano; Cecilia Bellettato; Massimo Canali; Luca Falasconi; Silvia Gaiani; Matteo Vittuari; Felicitas Schneider; Graham Moates; Keith Waldron; Barbara RedlingshöferKarin Östergren; Jenny Gustavsson; Hilke Bos-Brouwers; Toine Timmermans; Ole-Jørgen Hansen; Hanne Møller; Gina Anderson; Clementine O’Connor; Han Soethoudt; Tom Quested; Sophie Easteal; Alessandro Politano; Cecilia Bellettato; Massimo Canali; Luca Falasconi; Silvia Gaiani; Matteo Vittuari; Felicitas Schneider; Graham Moates; Keith Waldron; Barbara Redlingshöfe

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 169

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: the REMOVAL trial

Aim: To determine whether metformin's effects on carotid artery intima‐media thickness (cIMT) in type 1 diabetes differ according to smoking status. Methods: Regression model effect estimates for the effect of metformin versus placebo (double‐blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. Results: In 428 randomized participants (227 never‐smokers, 201 ever‐smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.012 mm, 95% CI −0.021 to −0.002; p = .0137) but not in ever‐smokers (0.003 mm, 95% CI −0.008 to 0.014; p = .5767); and similarly in non‐current smokers (−0.008 mm, 95% CI −0.015 to −0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI −0.007 to 0.032; p = .1887). Three‐way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non‐current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.020 mm, 95% CI −0.034 to −0.006; p = .0067) but not in ever‐smokers (−0.006 mm, 95% CI −0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three‐way interaction term. Conclusions: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes

Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.MethodsAdult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. ResultsIn this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.ConclusionWhile independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Studie van de tumor biologie, en van het verouderend effect van een chemotherapeutische behandeling bij oudere patiënten met borstkanker

The main objective of this doctoral research was to expand the scientific knowledge on the interface between cancer and biological aging. Aging is a multifactorial process that is linked in a very complex way to cancer. Because this had never been done in tumors spontaneously occurring in human patients, we started by studying stromal characteristics of breast cancers arising in young respectively old patients. Based on the description of the SASP (senescence associated secretory profile) and AST (autophagy to senescence transition) in literature, two phenomena supposed to occur in senescent cells (e.g. fibroblasts), and the hypothesis that senescent cells accumulate in the body with aging, tumors arising in older patients could be expected to display a stromal compartment with different characteristics, which ultimately could lead to a different behavior of the tumor cells. By laser capturing the stromal compartments of breast cancers from young and old patients, and comparing the gene expression profiles, we confirmed for the first time in humans, the presence of both phenomena in the older breast cancer stromal samples. Moreover, we found that the older stromal compartment displays significant differences in gene expression compared to younger stroma, which concerned mainly genes responsible for proliferation, dedifferentiation and migration into the extracellular matrix. In a second part of the thesis, we investigated biological aging in the rest of the organism, and the impact from cancer treatment (by chemotherapy) on this process. The main purpose of this research was to provide more evidence-based knowledge, allowing incorporation of the concept ‘biological age’ into therapy decisions for older patients. To do this, it was important to study the value of several biological markers in reflecting the biological age of a patient, as there is no current gold standard for this. In a retrospective study investigating several biological and clinical parameters of aging in young and old breast cancer patients IL-6 showed to be a robust frailty marker. Other markers like Leukocyte Telomere Length, IGF-1 and MCP-1 showed correlations with chronological age but not with frailty level. During this study we also developed the Leuven Oncogeriatric Frailty Score, a tool that summarizes the clinical frailty level of a patient in a more subtle way than do the currently used tools like Balducci classification. Next, we performed a prospective study in early breast cancer patients either or not treated with adjuvant chemotherapy, and tested if the natural evolution of clinical and/or biological aging markers was influenced by chemotherapy. We did not find unexpected changes in the evolution of the most robust aging markers (Leukocyte Telomere Length and Interleukin-6) which means that we do not find convincing evidence that the chemotherapy we studied (Docetaxel-Cyclophosphamide) would accelerate biological aging in breast cancer patients. This is a reassuring finding for oncologists treating older patients. As a secondary endpoint, we checked if clinical or biological markers were correlated with short-term toxicity from chemotherapy, but neither of the aging parameters was useful in predicting grade II-III-IV toxicity, or unplanned hospital readmissions.List of Abbreviations 6 General introduction 7 Objectives of the research 25 Results - Chapter 1: The footprint of the aging stroma in older breast cancers patients 28 - Chapter 2: Biological aging and frailty markers in breast cancer patients 69 - Chapter 3: The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters 85 Concluding discussion and perspectives 105 Appendix 1: Example of a Geriatric Assessment 115 Abstract of the research 135 Nederlandse Samenvatting 136 Curriculum Vitae 138 Bibliography 142nrpages: 147status: publishe

p16(INK4a): A central player in cellular senescence and a promising aging biomarker in elderly cancer patients

The p16INK4a tumor suppressor protein functions as a cyclin-dependent kinase inhibitor, preventing phosphorylation of the retinoblastoma protein and consequently arresting the cell cycle in the G1-phase. Together with p53 and p21CIP1 it has an important function in inducing permanent cell cycle arrest, called senescence, in response to all sorts of cellular damage. Bypass of these senescence pathways has been shown to be associated with increased occurrence of multiple malignancies. In this review we focus on the role of p16INK4a in cellular senescence, its tumor suppression potential and its effect on aging. Also, the consequences of senescence in cancer therapy and its possible side-effects are considered. p16INK4a expression in peripheral blood T-lymphocytes is discussed as a promising candidate biomarker which could reflect biological age and could be used to guide individual optimal treatment in the elderly cancer population. © 2011 Elsevier Inc.status: publishe