Nathalie J. Massat

The impact of mammographic screening on breast cancer mortality in Europe: a review of observational studies

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 = 17), incidence-based mortality (IBM) studies (n = 20) and case-control (CC) studies (n = 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 womans 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.

Beyond Patient Reported Pain: Perfusion Magnetic Resonance Imaging Demonstrates Reproducible Cerebral Representation of Ongoing Post-Surgical Pain

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.

Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma

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.

Alterations in Resting-State Regional Cerebral Blood Flow Demonstrate Ongoing Pain in Osteoarthritis An Arterial Spin-Labeled Magnetic Resonance Imaging Study

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.

Screening and primary prevention of colorectal cancer: a review of sex-specific and site-specific differences.

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.

Impact of Screening on Breast Cancer Mortality: The UK Program 20 Years On

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 cases diagnosis, who were alive at the cases 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 cases 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

Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas

Background:Uptake of bowel cancer screening is lowest in London, in populations of lower socio-economic status, and in particular ethnic or religious groups.Methods:We report on the evaluation of two interventions to improve uptake in an area including populations of low socio-economic status and considerable ethnic diversity. The interventions were face-to-face health promotion on bowel cancer screening at invitees’ general practice and health promotion delivered by telephone only. Nine large general practices in East London were chosen at random to offer face-to-face health promotion, and nine other large practices to offer telephone health promotion, with 24 practices of similar size as comparators. Data at practice level were analysed by Mann–Whitney–Wilcoxon tests and grouped-logistic regression.Results:There were 2034 invitees in the telephone intervention practices, 1852 in the face-to-face intervention practices and 5227 in the comparison practices. Median gFOBt kit uptake in the target population (aged 59–70) was 46.7% in the telephone practices, 43.8% in the face-to-face practices and 39.1% in the comparison practices. Significant improvements in the odds of uptake were observed following telephone intervention in both males (OR=1.39, 95% CI=1.20–1.61, P<0.001) and females (OR=1.49, 95% CI=1.29–1.73, P<0.001), while the face-to-face intervention mainly impacted uptake in males (OR=1.23, 95% CI=1.10–1.36), P<0.001) but did not lead to a significant increase in females (OR=1.12, 95% CI=0.96–1.29, P=0.2).Conclusions:Personally delivered health promotion improved uptake of bowel cancer screening in areas of low socio-economic status and high ethnic diversity. The intervention by telephone appears to be the most effective method.

Likely effect of adding flexible sigmoidoscopy to the English NHS Bowel Cancer Screening Programme: impact on colorectal cancer cases and deaths

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.

Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double‐Blind Placebo‐Controlled Functional Magnetic Resonance Imaging Study Using Naproxen

In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.

Pharmacologic modulation of hand pain in osteoarthritis

In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.