Objectives To assess the impact of population-based mammographic screening on breast cancer mortality in Europe, considering different methodologies and limitations of the data. Methods We conducted a systematic literature review of European trend studies (n ¼ 17), incidencebased mortality (IBM) studies (n ¼ 20) and case-control (CC) studies (n ¼ 8). Estimates of the reduction in breast cancer mortality for women invited versus not invited and/or for women screened versus not screened were obtained. The results of IBM studies and CC studies were each pooled using a random effects meta-analysis. Results Twelve of the 17 trend studies quantified the impact of population-based screening on breast cancer mortality. The estimated breast cancer mortality reductions ranged from 1% to 9% per year in studies reporting an annual percentage change, and from 28% to 36% in those comparing post-and prescreening periods. In the IBM studies, the pooled mortality reduction was 25% (relative risk [RR] 0.75, 95% confidence interval [CI] 0.69 -0.81) among invited women and 38% (RR 0.62, 95% CI 0.56 -0.69) among those actually screened. The corresponding pooled estimates from the CC studies were 31% (odds ratio [OR] 0.69, 95% CI 0.57 -0.83), and 48% (OR 0.52, 95% CI 0.42 -0.65) adjusted for self-selection. Conclusions Valid observational designs are those where sufficient longitudinal individual data are available, directly linking a woman's screening history to her cause of death. From such studies, the best 'European' estimate of breast cancer mortality reduction is 25 -31% for women invited for screening, and 38 -48% for women actually screened. Much of the current controversy on breast cancer screening is due to the use of inappropriate methodological approaches that are unable to capture the true effect of mammographic screening.

Purpose Non-invasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early stage PDAC from healthy individuals (H). Experimental design Proteomes of 18 urine samples from healthy controls, chronic pancreatitis and PDAC patients (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated using ELISA assays using multiple logistic regression applied to a training dataset in a multicentre cohort comprising 488 urine samples. Results LYVE-1, REG1A and TFF1 were selected as candidate biomarkers. When comparing PDAC (n=192) to healthy (n=87) urines, the resulting areas under the receiver operating characteristic curves (AUCs) of the panel were 0.89 (95%CI 0.84-0.94) in the training (70% of the data), and 0.92 (95%CI 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n=71) to healthy urines, the panel achieved AUCs of 0.90 (95%CI 0.84-0.96) and 0.93 (95%CI 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9 the panel achieved a higher AUC of 0.97 (95%CI 0.94-0.99) than CA19.9 (AUC=0.88, 95%CI 0.81-0.95, p=0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95%CI 0.94-0.99) to 0.99 (95%CI 0.97-1.00, p=0.04) but did not improve the comparison of stage I-IIA PDAC (n=17) to healthy urine. Conclusion We have established a novel, three-protein biomarker panel that is able to detect patients with early stage pancreatic cancer in urine specimens.

Objective. Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique.Methods. The study included 16 patients with CMC OA and 17 matched controls. Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of two identical sessions. Voxelwise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether sessionwise rCBF differences were related to variability in perceived ongoing pain.Results. In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the periaqueductal gray/nucleus cuneiformis. Sessionwise rCBF differences in the OA group in the postcentral, rostral/ subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain. No significant sessionwise rCBF differences were observed in controls.Conclusion. This is the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA. Observed rCBF changes potentially indicate dysregulated CNS appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA. Understanding the neural basis of ongoing pain is likely to be important in developing novel treatment strategies.Persistent pain is a major health care problem. As many as 100 million people in Europe alone experience an intractable, ongoing malaise that affects quality of life, places an increasing burden on health care resources, and costs the economy in excess of €50 billion every year (1). While multidisciplinary pain management strategies help patients cope (2), there is a recognized, unmet need for the development of novel, more

Background: With changes in diagnosis, treatment, and management of breast cancer since the mammography screening trials, there is a need to evaluate contemporary breast screening programs. A case-control study was set up to assess the current impact of attendance in the English Breast Screening Program on breast cancer mortality.Methods: Cancer registry cases who died from primary breast cancer ages 47 to 89 years in London in 2008 to 2009 (869 women) were matched to 1 or 2 general population controls (1,642 women) with no diagnosis of breast cancer at the time of the case's diagnosis, who were alive at the case's death. Cases and controls were matched for date of birth and screening area, and had been invited to breast screening at least once prior to the case's diagnosis. ORs were estimated using conditional logistic regression. Self-selection bias was addressed using contemporaneous attendance at the cervical screening program.

Development of treatments for acute and chronic pain conditions remains a challenge, with an unmet need for improved sensitivity and reproducibility in measuring pain in patients. Here we used pulsed-continuous arterial spin-labelling [pCASL], a relatively novel perfusion magnetic-resonance imaging technique, in conjunction with a commonly-used post-surgical model, to measure changes in regional cerebral blood flow [rCBF] associated with the experience of being in ongoing pain. We demonstrate repeatable, reproducible assessment of ongoing pain that is independent of patient self-report. In a cross-over trial design, 16 participants requiring bilateral removal of lower-jaw third molars underwent pain-free pre-surgical pCASL scans. Following extraction of either left or right tooth, repeat scans were acquired during post-operative ongoing pain. When pain-free following surgical recovery, the pre/post-surgical scanning procedure was repeated for the remaining tooth. Voxelwise statistical comparison of pre and post-surgical scans was performed to reveal rCBF changes representing ongoing pain. In addition, rCBF values in predefined pain and control brain regions were obtained. rCBF increases (5–10%) representing post-surgical ongoing pain were identified bilaterally in a network including primary and secondary somatosensory, insula and cingulate cortices, thalamus, amygdala, hippocampus, midbrain and brainstem (including trigeminal ganglion and principal-sensory nucleus), but not in a control region in visual cortex. rCBF changes were reproducible, with no rCBF differences identified across scans within-session or between post-surgical pain sessions. This is the first report of the cerebral representation of ongoing post-surgical pain without the need for exogenous tracers. Regions of rCBF increases are plausibly associated with pain and the technique is reproducible, providing an attractive proposition for testing interventions for on-going pain that do not rely solely on patient self-report. Our findings have the potential to improve our understanding of the cerebral representation of persistent painful conditions, leading to improved identification of specific patient sub-types and implementation of mechanism-based treatments.