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Diagnostic performance of urine biomarkers in discriminating pancreatic adenocarcinoma all stages (A-C) and stage I-II (D-F) from chronic pancreatitis patients. A, ROC curves of PDAC (n=143) versus CP (n=62) patients for individual urine biomarkers in the training set (70% of the data). B, ROC curves of PDAC versus CP patients for the panel in the training set and in the independent validation set (30% of the data, PDAC n=49, CP n=30). C, Summary table. D, ROC curves of individual urine biomarkers in training dataset (70%, PDAC stage I-II n= 56, CP=66). E, ROC curves of the panel in training and validation (PDAC stage I-II n=15, CP n=26) dataset. F, Summary table. Cnorm, creatinine-normalised, creat, creatinine, AUC: area under the curve SN: sensitivity, SP: specificity with 95% Confidence Interval (CI). SN and SP in the validation set were derived for optimal cutpoint determined in the training dataset.

Expression of the protein biomarkers in pancreatic cancer tissues. A, Immunohistochemical analysis of REG1A: i) REG1A in poorly differentiated PDAC, ii) luminal REG1A in malignant glands. B, TFF1: i) heterogenous expression in cancer,, ii) luminal TFF1 in malignant gland. C, LYVE1 expression in the scattered lymphatic vessels i) in the muscle layer and ii) in the stroma surrounding malignant gland. D, The biomarker levels during monitoring of pancreatic adenocarcinoma patients: LYVE1, REG1A and TFF1 were measured using ELISA in urine samples collected before surgery and during the patient's follow up. Each point represents log-transformed ELISA values at a particular time point (x-axis).

Exploratory comparison of plasma CA19.9 and the urine biomarker panel in discriminating early pancreatic adenocarcinoma from chronic pancreatitis patients. A, ROC curves of the biomarker panel with corresponding plasma CA19.9 alone and in combination comparing CP urine (n=50), and urines from PDAC stages I-II (n=71) and, I-IIA (n=16) (B). C, Summary table. AUC: area under the curve, SN: sensitivity, SP: specificity with 95% Confidence Interval (CI). SN and SP in the validation set were derived for optimal cutpoint determined in the training dataset.

Supplementary Figure Legends from Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma

Urine biomarker concentrations in different tumours. Scatter dot plots of urine LYVE1, REG1A and plasma CA19.9 in different hepatobiliary pathologies and early stages of pancreatic adenocarcinoma (I-IIA, n=16) and I-II (n=71). The level of TFF1 protein was not measured in these samples due to substantial modifications made to the original ELISA assay by the source company at the moment of this analysis. IPMN (n=33): intraductal papillary mucinous neoplasm, AMP (n=26): ampullary cancer, NET (n=18): neuroendocrine tumour, CHL (n=24): cholangiocarcinoma, DuCA (n=16): duodenal cancer. Bars indicate median and IQR values. Upper bars: Kruskal-Wallis/Dunn's post test, *: p0.05 (no adjustment for multiplicity was made).

Correlation of the three urinary biomarkers and plasma CA19.9 (CA19.9p). A, Correlation plots (Navy blue: Healthy; Turquoise: chronic pancreatitis (CP); Purple: pancreatic adenocarcinoma (PDAC). B, Pearson correlation coefficients and corresponding significance (NS: non-significant, *: p

Expression of non-redundant proteins identified by GeLC-MS/MS from males and females in healthy controls, chronic pancreatitis and pancreatic adenocarcinoma patients.

Urine proteome analysis. A, schematic outline of the study. B, classification of total identified proteins according to sub-cellular localisation and C, functional activity determined by Ingenuity Pathway Analysis. H: healthy, CP: chronic pancreatitis, PDAC: pancreatic ductal adenocarcinoma, GeLC/MS/MS: SDS-PAGE-Liquid Chromatography-Tandem Mass Spectrometry.

Background The English national bowel cancer screening program offering a guaiac fecal occult blood test began in July 2006. In randomized controlled trials of guaiac fecal occult blood test screening, reductions in mortality were accompanied by reductions in advanced stage colorectal cancer (CRC). We aimed to evaluate the effect of participation in the national bowel cancer screening program on stage-specific CRC incidence as a likely precursor of a mortality effect. Methods In this population-based case-control study, cases were individuals diagnosed with CRC aged 60-79 years between January 1, 2012, and December 31, 2013. Two controls per case were matched on geographic region, gender, date of birth, and year of first screening invitation. Screening histories were extracted from the screening database. Conditional logistic regression with correction for self-selection bias was used to estimate odds ratios (odds ratios corrected for self-selection bias [cOR]) and 95% confidence intervals (CIs) by Duke stage, sex, and age. Results 14 636 individuals with CRC and 29 036 without were eligible for analysis. The odds of CRC (any stage) were increased within 30 days of a screening test and decreased thereafter. No reduction in CRC (any stage) among screened individuals compared with those not screened was observed (cOR = 1.00, 95% CI = 0.89 to 1.15). However, screened individuals had lower odds of Duke stage D CRC (cOR = 0.68, 95% CI = 0.50 to 0.93). We estimate 435 fewer Duke D CRC by age 80 years in 100 000 people screened biennially between ages 60 and 74 years compared with an unscreened cohort. Conclusion The impact of colorectal screening on advanced CRC incidence suggests that the program will meet its aim of reducing mortality.

Funder: Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, Funder: American Cancer Society NHPDCSGBR-GBRLONG Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, BACKGROUND: This study investigates whether quantitative breast density (BD) serves as an imaging biomarker for more intensive breast cancer screening by predicting interval, and node-positive cancers. METHODS: This case-control study of 1204 women aged 47-73 includes 599 cancer cases (302 screen-detected, 297 interval; 239 node-positive, 360 node-negative) and 605 controls. Automated BD software calculated fibroglandular volume (FGV), volumetric breast density (VBD) and density grade (DG). A radiologist assessed BD using a visual analogue scale (VAS) from 0 to 100. Logistic regression and area under the receiver operating characteristic curves (AUC) determined whether BD could predict mode of detection (screen-detected or interval); node-negative cancers; node-positive cancers, and all cancers vs. controls. RESULTS: FGV, VBD, VAS, and DG all discriminated interval cancers (all p < 0.01) from controls. Only FGV-quartile discriminated screen-detected cancers (p < 0.01). Based on AUC, FGV discriminated all cancer types better than VBD or VAS. FGV showed a significantly greater discrimination of interval cancers, AUC = 0.65, than of screen-detected cancers, AUC = 0.61 (p < 0.01) as did VBD (0.63 and 0.53, respectively, p < 0.001). CONCLUSION: FGV, VBD, VAS and DG discriminate interval cancers from controls, reflecting some masking risk. Only FGV discriminates screen-detected cancers perhaps adding a unique component of breast cancer risk.

Parkinson’s disease (PD) is a highly heterogeneous disease both with respect to arising symptoms and its progression over time. This hampers the design of disease modifying trials for PD as treatments which would potentially show efficacy in specific patient subgroups could be considered ineffective in a heterogeneous trial cohort. Establishing clusters of PD patients based on their progression patterns could help to entangle the exhibited heterogeneity, illuminate clinical differences among patient subgroups, and identify the biological pathways and molecular players which underlie the evident differences. Further, stratification of patients into clusters with distinct progression patterns could help to recruit more homogeneous trial cohorts. In the present work, we applied an artificial intelligence-based algorithm to model and cluster longitudinal PD progression trajectories from the Parkinson’s Progression Markers Initiative. Using a combination of six clinical outcome scores covering both motor and non-motor symptoms, we were able to identify specific clusters of PD that showed significantly different patterns of PD progression. The inclusion of genetic variants and biomarker data allowed us to associate the established progression clusters with distinct biological mechanisms, such as perturbations in vesicle transport or neuroprotection. Furthermore, we found that patients of identified progression clusters showed significant differences in their responsiveness to symptomatic treatment. Taken together, our work contributes to a better understanding of the heterogeneity encountered when examining and treating patients with PD, and points towards potential biological pathways and genes that could underlie those differences.

Background: There is uncertainty about overdiagnosis in mammography screening. Methods: We aimed to estimate the effect of screening on breast cancer incidence and overdiagnosis in the NHS Breast Screening Programme in England. The study included 57,493 cases and 105,653 controls, with cases defined as women diagnosed at ages 47–89 with primary breast cancer, invasive or ductal carcinoma in situ, in 2010 or 2011. Where possible, two controls were selected per case, matched on date of birth and screening area. Conditional logistic regression was used to estimate the effect of screening on breast cancer risk, with adjustment for potential self-selection bias. Results were combined with national incidence data to estimate absolute rates of overdiagnosis. Overdiagnosis was calculated as the cumulative excess of cancers diagnosed in the age group 50–77 in a woman attending three-yearly screening between ages 50 and 70 compared with a woman attending no screens. Results: The estimated number of cases overdiagnosed in women attending all screens in the programme was 679.3 per 100,000 without adjustment for self-selection bias and 261.2 per 100,000 with adjustment. These corresponded to an estimated 9.5% of screen-detected cancers overdiagnosed without adjustment and 3.7% with adjustment for self-selection. Conclusions: The NHS Breast Screening Programme in England confers at worst modest levels of overdiagnosis.

BackgroundOver the past 30 years since the implementation of the National Health Service Breast Screening Programme, improvements in diagnostic techniques and treatments have led to the need for an up-to-date evaluation of its benefit on risk of death from breast cancer. An initial pilot case-control study in London indicated that attending mammography screening led to a mortality reduction of 39%.MethodsBased on the same study protocol, an England-wide study was set up. Women aged 47–89 years who died of primary breast cancer in 2010 or 2011 were selected as cases (8288 cases). When possible, two controls were selected per case (15,202 controls) and were matched by date of birth and screening area.ResultsConditional logistic regressions showed a 38% reduction in breast cancer mortality after correcting for self-selection bias (OR 0.62, 95% CI 0.56–0.69) for women being screened at least once. Secondary analyses by age group, and time between last screen and breast cancer diagnosis were also performed.ConclusionsAccording to this England-wide case-control study, mammography screening still plays an important role in lowering the risk of dying from breast cancer. Women aged 65 or over see a stronger and longer lasting benefit of screening compared to younger women.

Background: In England, population mammographic screening has been offered to women for over 20 years. Overall decrease in breast cancer mortality rates and improvements in cancer awareness and organization of medical care over this period call for a more current evaluation of the mediators behind the better prognosis of screening-exposed breast cancers. Methods: A case–control study was conducted within the English National Breast Screening Program. Women who died from primary breast cancer in 2008 to 2009 were matched (by year of birth, screening invitation, and area) to controls that received a diagnosis of invasive breast cancer at the time of the case diagnosis but survived the case death. Data were analyzed by unconditional logistic regression with adjustment for matching factors. Results: The unadjusted OR for dying from breast cancer associated with ever having attended breast screening was 0.44 [95% confidence interval (CI), 0.33–0.58]. After adjustment for lead time, overdiagnosis, and self-selection, the OR increased to 0.69 (95% CI, 0.50–0.94). Adjusting for tumor size, lymph node status, stage, grade, histopathology, and laterality accounted for all the screening effect (OR, 1.00; 95% CI, 0.71–1.40). Further adjustment for treatment factors only had a minimal impact on the OR (OR, 1.02; 95% CI, 0.72–1.45). Conclusions: Our results suggest that earlier diagnosis, as reflected by tumor characteristics, remains the major mediator of the improvement in breast cancer survival due to participation in mammographic screening. Impact: Mammographic screening continues to prevent breast cancer–related deaths in the epoch of adjuvant systemic therapy. Cancer Epidemiol Biomarkers Prev; 25(3); 479–87. ©2015 AACR. See related article by Massat et al., p. 455

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. Sensitivity analyses were undertaken to assess the likely effect of lead time bias. Results: Attendance at breast screening resulted in a breast cancer mortality reduction of 39% [OR, 0.61; 95% confidence interval (CI), 0.44–0.85] after self-selection correction. Attendance in the last 3 years prior to diagnosis resulted in a 60% mortality reduction (OR, 0.40; 95% CI, 0.31–0.51). Lead time bias effects were negligible. Conclusion: Our results suggest that community breast screening programs provide their expected benefit in terms of reducing the risk of breast cancer death among women participating. Impact: Mammography is an important tool for reducing breast cancer mortality and its impact could be increased by encouraging regular attendance. Cancer Epidemiol Biomarkers Prev; 25(3); 455–62. ©2015 AACR. See related article by Massat et al., p. 479

BackgroundA lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. MethodsWe chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. ResultsWhen compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. ConclusionsFunctional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism.

Osteoarthritis (OA) is a major cause of long-term disability (1). Traditionally characterized by structural degradation of one or more synovial joints, OA is typically associated with pain, swelling, and stiffness (2). Reduced manual dexterity and inability to perform tasks due to symptoms affect quality of life and ability to function independently (3). Levels of pain and disability experienced by patients often do not correspond to the level of tissue damage observed in the affected joints (4), suggesting involvement of central nervous system mechanisms in the generation of OA-related pain (5). Given the prevalence of OA and an increasingly aging population, there is a pressing need for more effective treatments (6,7). Many commonly prescribed medications are ill suited for long-term use due to side effects including tolerance, dependency, and gastrointestinal complications (8,9). While pain is always a personal experience and subject to multiple psychosocial factors, there has long been a desire to complement subjective reports with reliable markers of pain perception and treatment effectiveness (10,11). Neuroimaging methodologies offer the potential to meet these desires (12). Functional magnetic resonance imaging (fMRI) provides a safe, noninvasive, repeatable indirect measure of neural activity suitable for use in crossover trial designs (12). Reports have suggested that fMRI could demonstrate analgesic effects in populations of patients with clinical pain, adding value to conventional behavioral end points and facilitating decision-making early in drug development, reducing risk, development times, and cost (12). Experimental fMRI studies have provided useful insights into the neural mechanisms of drug action (for review, see ref.(13)). In order to fulfill this potential, fMRI must depict the neural correlates of the response to analgesics in patients experiencing persistent pain. Preliminary studies in OA have shown promise in establishing neural correlates of response to analgesics (14,15), but to date these studies have been underpowered or lacked appropriate placebo control. In this study we investigated the potential of fMRI as a “fit-for-purpose” measurement technique in development of analgesics for persistent pain. We sought to determine the ability of fMRI to detect changes in brain functioning following a 1-week course of naproxen in individuals with OA of the first carpometacarpal (CMC) joint. Naproxen is an established, effective nonsteroidal antiinflammatory drug (NSAID) labeled for treatment of OA-related symptoms in the UK (http://www.emc.medicines.org.uk). We aimed to detect naproxen-induced changes in brain activity using a functionally relevant task that evoked pain. We hypothesized that task-evoked brain activity would be reduced following administration of naproxen, compared to placebo. In particular, we hypothesized that a network of brain regions previously associated with pain perception would display significant reductions in activity following naproxen administration, during the task load that induced the highest rating of pain intensity.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival.

Dr. Berrino raises the possibility of a healthy screenee bias in our estimates of the effect of being screened between 3 and 36 months before diagnosis and of ever being screened ([1, 2][1]). The argument for the presence of such bias hangs on the exclusion of the 3-month period before diagnosis and

Purpose: Noninvasive 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. Experimental design: Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. Results: LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (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) with healthy urine specimens, 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) with healthy urine. Conclusions: We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens. Clin Cancer Res; 21(15); 3512–21. ©2015 AACR.

Objectives: Reducing cancer screening inequalities in England is a major focus of the 2011 Department of Health cancer outcome strategy. Screening coverage requires regular monitoring in order to implement targeted interventions where coverage is low. This study aimed to characterise districts with atypical coverage levels for cervical or breast screening. Design: Observational study of district-level coverage in the English Cervical and Breast screening programmes in 2012. Setting: England, UK. Participants: All English women invited to participate in the cervical (age group 25-49 and 50-64) and breast (age group 50-64) screening programmes. Outcomes: Risk adjustment models for coverage were developed based on district-level characteristics. Funnel plots of adjusted coverage were constructed, and atypical districts examined by correlation analysis. Results: Variability in coverage was primarily explained by population factors, whereas general practice characteristics had little independent effect. Deprivation and ethnicity other than white, Asian, black or mixed were independently associated with poorer coverage in both screening programmes, with ethnicity having the strongest effect; by comparison, the influence of Asian, black or mixed ethnic minority was limited. Deprivation, ethnicity and urbanisation largely accounted for the lower cervical screening coverage in London. However, for breast screening, being located in London remained a strong negative predictor. A subset of districts was identified as having atypical coverage across programmes. Correlates of deprivation in districts with relatively low adjusted coverage were substantially different from overall correlates of deprivation. Discussion: These results inform the continuing drive to reduce avoidable cancer deaths in England, and encourage implementation of targeted interventions in communities residing in districts identified as having atypically low coverage. Sequential implementation to monitor the impact of local interventions would help accrue evidence on 'what works'.

Background Colorectal cancer is the third most common cause of cancer death in both males and females in England. A national bowel cancer screening programme was rolled out in England between 2006 and 2010. In the post-randomised controlled trials epoch, assessment of the impact of the programme using observational studies is needed. This study protocol was set up at the request of the UK Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis to evaluate the effect of the current bowel cancer screening programme on incidence of advanced primary colorectal cancer. Methods/Design All incident cases of primary colorectal cancer in England will be included. Cases will be matched to controls with respect to sex, age, area of registration and year of first invitation to screening. Each evaluation round will cover a 2-year period, starting from January 2012, and ongoing thereafter. In the first instance, a pilot will be carried out in a single region. Variables related to colorectal tumour pathology will be obtained to enable selection and matching of cases and controls, and to allow analyses stratification by anatomical subsite within the bowel. Cases at Duke’s stage B or worse will be considered as "advanced stage". The influence of sex will also be investigated. The incidence ratio observed in randomised controlled trials between controls (not invited) and non-attender invitees will be used to correct for self-selection bias overall. Screening participation at other national screening programmes (cervical, breast) will also be collected to derive a more contemporaneous adjustment factor for self-selection bias and assess consistency in self-selection correction in female patients. Full ethical approval was obtained from the Health Research Authority. Discussion The case–control design is potentially prone to a number of biases. The size of the planned study, the design specifications and the development of analytical strategies to cope with bias should enable us to obtain accurate estimates of reduction in incidence of advanced stage disease. The results of analyses by sex and anatomical subsite may highlight the potential need for sex-specific recommendations in the programme.

Background: From 2013, once-only flexible sigmoidoscopy (FS) at age 55 is being phased into the England National Health Service Bowel Cancer Screening Programme (NHSBCSP), augmenting biennial guaiac faecal occult blood testing (gFOBT) at ages 60–74. Here, we project the impact of this change on colorectal cancer (CRC) cases and deaths prevented in England by mid-2030. Methods: We simulated the life-course of English residents reaching age 55 from 2013 onwards. Model inputs included population numbers, invitation rates and CRC incidence and mortality rates. The impact of gFOBT and FS alone on CRC incidence and mortality were derived from published trials, assuming an uptake of 50% for FS and 57% for gFOBT. For FS plus gFOBT, we assumed the gFOBT effect to be 75% of the gFOBT alone impact. Results: By mid-2030, 8.5 million individuals will have been invited for once-only FS screening. Adding FS to gFOBT screening is estimated to prevent an extra 9627 (−10%) cases and 2207 (−12%) deaths by mid-2030. If FS uptake is 38% or 71%, respectively, an extra 7379 (−8%) or 13 689 (−15%) cases and 1691 (−9%) or 3154 (−17%) deaths will be prevented by mid-2030. Conclusions: Adding once-only FS at age 55 to the NHSBCSP will prevent ∼10 000 CRC cases and ∼2000 CRC deaths by mid-2030 if FS uptake is 50%. In 2030, one cancer was estimated to be prevented per 150 FS screening episodes, and one death prevented per 900 FS screening episodes. The actual reductions will depend on the FS invitation schedule and uptake rates.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

Background In England, a national breast screening programme (NHSBSP) has been in place since 1988, and assessment of its impact on breast cancer incidence and mortality is essential to ensure that the programme is indeed doing more good than harm. This article describes large observation studies designed to estimate the effects of the current programme in terms of the benefits on breast cancer incidence and mortality and detrimental effect in terms of overdiagnosis. The case-control design of the cervical screening programme evaluation was highly effective in informing policy on screening intervals and age ranges. We propose innovative selection of cases and controls and gathering of additional variables to address new outcomes of interest and develop new methodologies to control for potential sources of bias. Methods/Design Traditional case-control evaluation of breast screening uses women who have died from breast cancer as cases, and women known to be alive at the time of case death as controls. Breast screening histories prior to the cases’ date of first diagnosis are compared. If breast screening is preventing mortality from breast cancer, cases will be characterised by a lesser screening history than controls. All deaths and incident cases of primary breast cancer in England within each 2-year study period will be included in this ongoing evaluation. Cases will be age- and area-matched to controls and variables related to cancer treatment and breast tumour pathology will be obtained to investigate the interplay between screening and treatment, and the effect of screening on incidence of advanced stage disease. Screening attendance at other national screening programmes will also be collected to derive superior adjustment for self-selection bias. The study is registered and has received full ethics approval.

Background Colorectal cancer (CRC) is the second commonest cancer in England. Incidence rates for colorectal adenomas and advanced colorectal neoplasia are higher in men than in women of all age groups. The male-to-female ratio for CRC incidence rates differs for different parts of the large bowel. Objective To summarize the current evidence on colorectal screening and prevention, focussing on potential differences in benefits between sexes and colorectal sites. Methods (i), We reviewed the evidence from randomized controlled trials (RCTs) of the impact of different screening approaches on CRC incidence and mortality, overall, for each sex separately, and for subsites of the large bowel. (ii) We reviewed studies comparing detection parameters for faecal immunochemical tests for haemoglobin (FIT) with guaiac FOBt (gFOBt). (iii) The role of aspirin in CRC prevention in the general population was reviewed using evidence from RCTs, with specific emphasis on the differences observed between sexes and lesion site. Results (i) Our intention-to-treat random-effects meta-analysis showed that once-only flexible sigmoidoscopy (FS) screening performed on average-risk individuals aged 55 + decreased CRC incidence by 18% and mortality by 28%, but sex-specific results were lacking. (ii) Modern quantitative FIT were superior to qualitative gFOBt in average-risk population screening in their ability to discriminate between individuals with and without colorectal neoplasia. Some recent FIT studies suggest varying operating characteristics in men and women. (iii) Evidence of an effect of aspirin on the incidence of CRC (in particular, proximal disease) in both sexes aged 40 and over at average-risk of CRC is emerging. Conclusions We encourage researchers of CRC screening and prevention to publish their results by sex where possible. Pilot studies should be undertaken before implementation of quantitative FIT in a national screening programme to establish the appropriate threshold. Finally, individual risk assessment for CRC and non-CRC events, will be necessary to make an informed decision on whether a patient should receive aspirin chemoprevention.

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.

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.

• Preprocessing and voxelwise image analysis performed using FSL (http://www.fmrib.ox.ac.uk/fsl ) • Mean rCBF values derived for each subject in each session extracted from probabilistic ROI masks using fslview Magnetic Resonance Perfusion Imaging Demonstrates Cerebral Representation of Ongoing Pain Following Third Molar Extraction Kristina Krause 1,2, Matthew Howard 2, Nadine Khawaja3, Natalie Massat4, John Huggins, 4 Gunter Schumann 1, Steve Williams2, Tara Renton3

The online version of the original article can be found under doi: 10.1007/s10549-014-2931-9 .

Aim: Invasive breast cancer is the second most common cause of cancer death among UK women. Although community breast screening has been shown to reduce breast cancer mortality, the relative effects of attendance at breast screening and improved treatment remain unclear.1 The aim of the study is to assess these relative effects on fatality from invasive primary breast cancer. Methods: A matched case-control study within the English National Breast Screening Programme was set up in the London region.2 Cases of invasive primary breast cancer death in 2008-09 were matched 1:1 to controls with breast cancer diagnosed within 6 months prior to the case diagnosis (age 47-89), known to be alive at the case death, and matched for date of birth and area of residence. All had been invited to breast screening at least once prior to first diagnosis. Cases and controls were compared with respect to screening attendance by conditional logistic regression adjusted for pathology, and treatment within 6 months of diagnosis. Results: The odds ratio (OR) for breast cancer fatality in women who attended at least one routine screen compared to never attenders was 0.41 (95% CI 0.30 - 0.55, p Conclusions: In women diagnosed with breast cancer, attendance at breast screening remained a significant protective factor for fatality from the disease after accounting for pathology and treatment; adjusting for treatment had little impact on the estimate. Potential biases remain to be investigated. References: 1 Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M: The benefits and harms of breast cancer screening: an independent review. Br J Cancer 2013, 108(11):2205. 2 Massat N, Sasieni P, Parmar D, Duffy S: An ongoing case-control study to evaluate the NHS breast screening programme. BMC Cancer 2013, 13(1):596. 3 Lesaffre E, Marx BD: Collinearity in generalized linear regression. Communications in Statistics - Theory and Methods 1993, 22(7): 1933. Disclosure: All authors have declared no conflicts of interest.