Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Modeling cartilage pathology in mucopolysaccharidosis VI using iPSCs reveals early dysregulation of chondrogenic and metabolic gene expression.

Mucopolysaccharidosis type VI (MPS VI) is a metabolic disorder caused by disease-associated variants in the Arylsulfatase B (ARSB) gene, resulting in ARSB enzyme deficiency, lysosomal glycosaminoglycan accumulation, and cartilage and bone pathology. The molecular response to MPS VI that results in cartilage pathology in human patients is largely unknown. Here, we generated a disease model to study the early stages of cartilage pathology in MPS VI. We generated iPSCs from four patients and isogenic controls by inserting the ARSB cDNA in the AAVS1 safe harbor locus using CRISPR/Cas9. Using an optimized chondrogenic differentiation protocol, we found Periodic acid-Schiff positive inclusions in hiPSC-derived chondrogenic cells with MPS VI. Genome-wide mRNA expression analysis showed that hiPSC-derived chondrogenic cells with MPS VI downregulated expression of genes involved in TGF-ß/BMP signalling, and upregulated expression of inhibitors of the Wnt/ß-catenin signalling pathway. Expression of genes involved in apoptosis and growth was upregulated, while expression of genes involved in glycosaminoglycan metabolism was dysregulated in hiPSC-derived chondrogenic cells with MPS VI. These results suggest that human ARSB deficiency in MPS VI causes changes in the transcriptional program underlying the early stages of chondrogenic differentiation and metabolism.

Trends in delayed breast cancer diagnosis after recall at screening mammography.

OBJECTIVES: To determine the extent and characteristics of delay in breast cancer diagnosis in women recalled at screening mammography. METHODS: We included a consecutive series of 817,656 screens of women who received biennial screening mammography in a Dutch breast cancer screening region between 1997 and 2016. During at least 3.5 years follow-up, radiological reports and biopsy reports were collected of all recalled women. The inclusion period was divided into four cohorts of four years each. We determined the number of screen-detected cancers and their characteristics, and assessed the proportion of recalled women who experienced a diagnostic delay of at least 4 months in breast cancer confirmation. RESULTS: The proportion of recalled women who experienced diagnostic delay decreased from 7.5 % in 1997-2001 (47/623) to 3.0 % in 2012-2016 (67/2223, P < 0.001). The proportion of women with a delay of at least two years increased from 27.7 % (13/47) in 1997-2001 to 75.7 % (53/70) in 2012-2016 (P < 0.001). Cancers with a diagnostic delay > 2 years were more frequently invasive (P = 0.009) than cancers with a diagnostic delay of 4-24 months. The most frequent cause of diagnostic delays was incorrect radiological classifications by clinical radiologists (55.2 % overall) after recall. CONCLUSIONS: The proportion of recalled women with a delayed breast cancer diagnosis has more than halved during two decades of screening mammography. Delays in breast cancer diagnosis are characterized by longer delay intervals, although the proportion of these delays among all screen-detected cancers has not increased. Preventing longer delays in breast cancer confirmation may help improve breast cancer survival.

COVID-19 in critically ill patients in North Brabant, the Netherlands: Patient characteristics and outcomes.

PURPOSE: Since the SARS-CoV-2 pandemic, countries are overwhelmed by critically ill Coronavirus disease 2019 (COVID-19) patients. As ICU capacity becomes limited we characterized critically ill COVID-19 patients in the Netherlands. METHODS: In this case series, COVID-19 patients admitted to the ICU of the Jeroen Bosch Hospital were included from March 9 to April 7, 2020. COVID-19 was confirmed by a positive result by a RT-PCR of a specimen collected by nasopharyngeal swab. Clinical data were extracted from medical records. RESULTS: The mean age of the 50 consecutively included critically ill COVID-19 patients was 65 ± 10 years, the mean BMI was 29 ± 4.7 and 66% were men. Seventy-eight percent of patients had ≥1 comorbidity, 34% had hypertension. Ninety-six percent of patients required mechanical ventilation and 80% were ventilated in prone position. Venous thromboembolism was recognized in 36% of patients. Seventy-four percent of patients survived and were successfully discharged from the ICU, the remaining 26% died (median follow up 86 days). The length of invasive ventilation in survivors was 15 days (IQR 12-31). CONCLUSIONS: The survival rate of COVID-19 critically ill patients in our population is considerably better than previously reported. Thrombotic complications are commonly found and merit clinical attention. TRIAL REGISTRATION NUMBER: NL2020.07.04.01.

Towards evidence-based follow-up intervals for breast cancer survivors: Estimates of the preclinical detectable phase of contralateral second breast cancer.

PURPOSE: Follow-up schemes in breast cancer survivors are predominantly consensus-based. To determine evidence-based follow-up intervals, estimates of sensitivity of the screening test(s) and duration of the preclinical detectable phase (PCDP) are key. We estimated the sensitivity and the duration of the PCDP of clinical breast examination (CBE) and mammography for the detection of contralateral second breast cancers (CBC) in breast cancer survivors. METHODS: Women with a CBC (N = 589) diagnosed in Florence between 1980 and 2005 were included. Test sensitivity and the duration of PCDP were estimated using a simple exponential model of PCDP duration. Analyses were stratified by follow-up period (0-5 vs. >5 years after primary diagnosis) and age at CBC diagnosis (<50 vs. ≥50 years). RESULTS: For CBE, test sensitivity was 55% and the duration of the PCDP 16 months. Mammography sensitivity was 91% and duration of the PCDP 35 months. Stratified analyses showed a higher test sensitivity for CBE for women aged <50 (70% vs. 51%). No difference in the duration of PCDP of CBE was found. For mammography, test sensitivity and the duration of the PCDP were higher for women with longer follow-up and in older women. CONCLUSIONS: Poor test sensitivity for CBE with a shorter duration of the PCDP compared with mammography were observed. Mammography had high test sensitivity and the potential to detect CBCs early. The estimated duration of the PCDP (35 months) was considerably longer than the recommended follow-up interval (12 months). Future studies are needed to determine whether a longer follow-up interval is appropriate.

Can a channelized Hotelling observer assess image quality in acquired mammographic images of an anthropomorphic breast phantom including image processing?

PURPOSE: To study the feasibility of a channelized Hotelling observer (CHO) to predict human observer performance in detecting calcification-like signals in mammography images of an anthropomorphic breast phantom, as part of a quality control (QC) framework. METHODS: A prototype anthropomorphic breast phantom with inserted gold disks of 0.25 mm diameter was imaged with two different digital mammography x-ray systems at four different dose levels. Regions of interest (ROIs) were extracted from the acquired processed and unprocessed images, signal-present and signal-absent. The ROIs were evaluated by a CHO using four different formulations of the difference of Gaussian (DoG) channel sets. Three human observers scored the ROIs in a two-alternative forced-choice experiment. We compared the human and the CHO performance on the simple task to detect calcification-like disks in ROIs with and without postprocessing. The proportion of correct responses of the human reader (PCH ) and the CHO (PCCHO ) was calculated and the correlation between the two was analyzed using a mixed-effect regression model. To address the signal location uncertainty, the impact of shifting the DoG channel sets in all directions up to two pixels was evaluated. Correlation results including the goodness of fit (r2 ) of PCH and PCCHO for all different parameters were evaluated. RESULTS: Subanalysis by system yielded strong correlations between PCH and PCCHO , with r2 between PCH and PCCHO was found to be between 0.926 and 0.958 for the unshifted and between 0.759 and 0.938 for the shifted channel sets, respectively. However, the linear fit suggested a slight system dependence. PCCHO with shifted channel sets increased CHO performance but the correlation with humans was decreased. These correlations were not considerably affected by of the DoG channel set used. CONCLUSIONS: There is potential for the CHO to be used in QC for the evaluation of detectability of calcification-like signals. The CHO can predict the PC of humans in images of calcification-like signals of two different systems. However, a global model to be used for all systems requires further investigation.

The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

The importance of early detection of calcifications associated with breast cancer in screening.

PURPOSE: The aim of this study was to assess how often women with undetected calcifications in prior screening mammograms are subsequently diagnosed with invasive cancer. METHODS: From a screening cohort of 63,895 women, exams were collected from 59,690 women without any abnormalities, 744 women with a screen-detected cancer and a prior negative exam, 781 women with a false positive exam based on calcifications, and 413 women with an interval cancer. A radiologist identified cancer-related calcifications, selected by a computer-aided detection system, on mammograms taken prior to screen-detected or interval cancer diagnoses. Using this ground truth and the pathology reports, the sensitivity for calcification detection and the proportion of lesions with visible calcifications that developed into invasive cancer were determined. RESULTS: The screening sensitivity for calcifications was 45.5%, at a specificity of 99.5%. A total of 68.4% (n = 177) of cancer-related calcifications that could have been detected earlier were associated with invasive cancer when diagnosed. CONCLUSIONS: Screening sensitivity for detection of malignant calcifications is low. Improving the detection of these early signs of cancer is important, because the majority of lesions with detectable calcifications that are not recalled immediately but detected as interval cancer or in the next screening round are invasive at the time of diagnosis.

Can the channelized Hotelling observer including aspects of the human visual system predict human observer performance in mammography?

PURPOSE: In mammography, images are processed prior to display. Model observers (MO) are candidates to objectively evaluate processed images if they can predict human observer performance for detail detection. The aim of this study was to investigate if the channelized Hotelling observer (CHO) can be configured to predict human observer performance in mammography like images. METHODS: The performance correlation between human observers and CHO has been evaluated using different channel-sets and by including aspects of the human visual system (HVS). The correlation was investigated for the detection of disk-shaped details in simulated white noise (WN) and clustered lumpy backgrounds (CLB) images, representing respectively quantum noise limited and mammography like images. The images were scored by the MO and five human observers in 2-alternative forced choice experiments. RESULTS: For WN images the most useful formulation of the CHO to predict human observer performance was obtained using three difference of Gaussian channels without adding HVS aspects (RLR2=0.62). For CLB images the most useful formulation was the partial least square channel-set without adding HVS aspects (RLR2=0.71). The correlation was affected by detail size and background. CONCLUSIONS: This study has shown that the CHO can predict human observer performance. Due to object size and background dependency it is important that the range of object sizes and allowed variability in background are specified and validated carefully before the CHO can be implemented for objective image quality assessment.

Can the non-pre-whitening model observer, including aspects of the human visual system, predict human observer performance in mammography?

PURPOSE: In mammography, images are processed prior to display. Current methodologies based on physical image quality measurements are however not designed for the evaluation of processed images. Model observers (MO) might be suitable for this evaluation. The aim of this study was to investigate whether the non-pre-whitening (NPW) MO can be used to predict human observer performance in mammography-like images by including different aspects of the human visual system (HVS). METHODS: The correlation between human and NPW MO performance has been investigated for the detection of disk shaped objects in simulated white noise (WN) and clustered lumpy backgrounds (CLB), representing quantum noise limited and mammography-like images respectively. The images were scored by the MO and five human observers in a 2-alternative forced choice experiment. RESULTS: For WN images it was found that the log likelihood ratio (RLR2), which expresses the goodness of fit, was highest (0.44) for the NPW MO without addition of HVS aspects. For CLB the RLR2 improved from 0.46 to 0.65 with addition of HVS aspects. The correlation was affected by object size and background. CONCLUSIONS: This study shows that by including aspects of the HVS, the performance of the NPW MO can be improved to better predict human observer performance. This demonstrates that the NPW MO has potential for image quality assessment. However, due to the dependencies found in the correlation, the NPW MO can only be used for image quality assessment for a limited range of object sizes and background variability.

The distribution of ductal carcinoma in situ (DCIS) grade in 4232 women and its impact on overdiagnosis in breast cancer screening.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has rapidly increased over time. The malignant potential of DCIS is dependent on its differentiation grade. METHODS: Our aim is to determine the distribution of different grades of DCIS among women screened in the mass screening programme, and women not screened in the mass screening programme, and to estimate the amount of overdiagnosis by grade of DCIS. We retrospectively included a population-based sample of 4232 women with a diagnosis of DCIS in the years 2007-2009 from the Nationwide network and registry of histopathology and cytopathology in the Netherlands. Excluded were women with concurrent invasive breast cancer, lobular carcinoma in situ and no DCIS, women recently treated for invasive breast cancer, no grade mentioned in the record, inconclusive record on invasion, and prevalent DCIS. The screening status was obtained via the screening organisations. The distribution of grades was incorporated in the well-established and validated microsimulation model MISCAN. RESULTS: Overall, 17.7 % of DCIS were low grade, 31.4 % intermediate grade, and 50.9 % high grade. This distribution did not differ by screening status, but did vary by age. Older women were more likely to have low-grade DCIS than younger women. Overdiagnosis as a proportion of all cancers in women of the screening age was 61 % for low-grade, 57 % for intermediate-grade, 45 % for high-grade DCIS. For women age 50-60 years with a high-grade DCIS this overdiagnosis rate was 21-29 %, compared to 50-66 % in women age 60-75 years with high-grade DCIS. CONCLUSIONS: Amongst the rapidly increasing numbers of DCIS diagnosed each year is a significant number of overdiagnosed cases. Tailoring treatment to the probability of progression is the next step to preventing overtreatment. The basis of this tailoring could be DCIS grade and age.

Extrapolation of pre-screening trends: Impact of assumptions on overdiagnosis estimates by mammographic screening.

BACKGROUND: Overdiagnosis by mammographic screening is defined as the excess in breast cancer incidence in the presence of screening compared to the incidence in the absence of screening. The latter is often estimated by extrapolating the pre-screening incidence trend. The aim of this theoretical study is to investigate the impact of assumptions in extrapolating the pre-screening incidence trend of invasive breast cancer on the estimated percentage of overdiagnosis. METHODS: We extracted data on invasive breast cancer incidence and person-years by calendar year (1975-2009) and 5-year age groups (0-85 years) from Dutch databases. Different combinations of assumptions for extrapolating the pre-screening period were investigated, such as variations in the type of regression model, end of the pre-screening period, screened age range, post-screening age range and adjustment for a trend in women <45. This resulted in 69,120 estimates of the percentage of overdiagnosis, i.e. excess cancer incidence in the presence of screening as a proportion of the number of screen-detected and interval cancers. RESULTS: Most overdiagnosis percentages are overestimated because of inadequate adjustment for lead time. The overdiagnosis estimates range between -7.1% and 65.1%, with a median of 33.6%. The choice of pre-screening period has the largest influence on the estimated percentage of overdiagnosis: the median estimate is 17.1% for extrapolations using 1975-1986 as the pre-screening period and 44.7% for extrapolations using 1975-1988 as the pre-screening period. CONCLUSION: The results of this theoretical study most likely cover the true overdiagnosis estimate, which is unknown, and may not necessarily represent the median overdiagnosis estimate. This study shows that overdiagnosis estimates heavily depend on the assumptions made in extrapolating the incidence in the pre-screening period, especially on the choice of the pre-screening period. These limitations should be acknowledged when adopting this approach to estimate overdiagnosis.

Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT).

Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.

SIMULATING LOCAL DENSE AREAS USING PMMA TO ASSESS AUTOMATIC EXPOSURE CONTROL IN DIGITAL MAMMOGRAPHY.

Current digital mammography (DM) X-ray systems are equipped with advanced automatic exposure control (AEC) systems, which determine the exposure factors depending on breast composition. In the supplement of the European guidelines for quality assurance in breast cancer screening and diagnosis, a phantom-based test is included to evaluate the AEC response to local dense areas in terms of signal-to-noise ratio (SNR). This study evaluates the proposed test in terms of SNR and dose for four DM systems. The glandular fraction represented by the local dense area was assessed by analytic calculations. It was found that the proposed test simulates adipose to fully glandular breast compositions in attenuation. The doses associated with the phantoms were found to match well with the patient dose distribution. In conclusion, after some small adaptations, the test is valuable for the assessment of the AEC performance in terms of both SNR and dose.

Erratum: Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT).

[This corrects the article DOI: 10.1038/npjpcrm.2016.17.].

Average glandular dose in digital mammography and digital breast tomosynthesis: comparison of phantom and patient data.

For the evaluation of the average glandular dose (AGD) in digital mammography (DM) and digital breast tomosynthesis (DBT) phantoms simulating standard model breasts are used. These phantoms consist of slabs of polymethyl methacrylate (PMMA) or a combination of PMMA and polyethylene (PE). In the last decades the automatic exposure control (AEC) increased in complexity and became more sensitive to (local) differences in breast composition. The question is how well the AGD estimated using these simple dosimetry phantoms agrees with the average patient AGD. In this study the AGDs for both dosimetry phantoms and for patients have been evaluated for 5 different x-ray systems in DM and DBT modes. It was found that the ratios between patient and phantom AGD did not differ considerably using both dosimetry phantoms. These ratios averaged over all breast thicknesses were 1.14 and 1.15 for the PMMA and PMMA-PE dosimetry phantoms respectively in DM mode and 1.00 and 1.02 in the DBT mode. These ratios were deemed to be sufficiently close to unity to be suitable for dosimetry evaluation in quality control procedures. However care should be taken when comparing systems for DM and DBT since depending on the AEC operation, ratios for particular breast thicknesses may differ substantially (0.83-1.96). Although the predictions of both phantoms are similar we advise the use of PMMA + PE slabs for both DM and DBT to harmonize dosimetry protocols and avoid any potential issues with the use of spacers with the PMMA phantoms.

Arbitration of discrepant BI-RADS 0 recalls by a third reader at screening mammography lowers recall rate but not the cancer detection rate and sensitivity at blinded and non-blinded double reading.

PURPOSE: To evaluate the characteristics of low suspicion lesions (BI-RADS 0) at blinded and non-blinded double reading of screening mammograms and to determine the potential effect of arbitration of discrepant BI-RADS 0 recalls by a third reader on screening outcome. METHODS: We included a series of 84,927 consecutive digital screening mammograms, double read in a blinded (43,184 screens) or non-blinded (41,743 screens) fashion, between July 2009 and July 2011. Discrepant readings were routinely recalled for further evaluation. During 2 years of follow-up, radiology, surgical and pathology reports were collected of all recalled women. Arbitration of discrepant BI-RADS 0 recalls (only one radiologist assigning a BI-RADS 0 score) was retrospectively performed by a third screening radiologist. RESULTS: At blinded and non-blinded double reading, 32.0% and 32.5% of recalls were assigned BI-RADS 0 with a positive predictive value (PPV) of 7.2% and 6.8%, respectively. Compared to non-blinded double reading, BI-RADS 0 recalls at blinded double reading showed a higher discrepancy rate (9.0 versus 4.3 per 1000 screens, p < 0.001) and false positive recall rate (10.1 versus 8.4 per 1000 screens, p = 0.012). Arbitration of discrepant BI-RADS 0 recalls would have significantly lowered recall rate (from 3.4% to 2.8% at blinded double reading, p < 0.001, and from 2.8% to 2.5% at non-blinded double reading, p = 0.008), without a decrease in cancer detection rate (from 7.5‰ to 7.3‰, p = 0.751, and from 6.6‰ to 6.5‰, p = 0.832, respectively) and program sensitivity (from 83.2% to 81.2%, p = 0.453, and from 76.0% to 74.6%, p = 0.667, respectively). Arbitration would have significantly increased the PPV at blinded double reading (from 22.3% to 26.3%, p = 0.015). CONCLUSION: We advise arbitration of discrepant BI-RADS 0 recalls, at (non-)blinded double reading of screening mammograms, to reduce recall rates and improve the PPV of recall at blinded double reading.

Overdiagnosis by mammographic screening for breast cancer studied in birth cohorts in The Netherlands.

A drawback of early detection of breast cancer through mammographic screening is the diagnosis of breast cancers that would never have become clinically detected. This phenomenon, called overdiagnosis, is ideally quantified from the breast cancer incidence of screened and unscreened cohorts of women with follow-up until death. Such cohorts do not exist, requiring other methods to estimate overdiagnosis. We are the first to quantify overdiagnosis from invasive breast cancer and ductal carcinoma in situ (DCIS) in birth cohorts using an age-period-cohort -model (APC-model) including variables for the initial and subsequent screening rounds and a 5-year period after leaving screening. Data on the female population and breast cancer incidence were obtained from Statistics Netherlands, "Stichting Medische registratie" and the Dutch Cancer Registry for women aged 0-99 years. Data on screening participation was obtained from the five regional screening organizations. Overdiagnosis was calculated from the excess breast cancer incidence in the screened group divided by the breast cancer incidence in presence of screening for women aged 20-99 years (population perspective) and for women in the screened-age range (individual perspective). Overdiagnosis of invasive breast cancer was 11% from the population perspective and 17% from the invited women perspective in birth cohorts screened from age 49 to 74. For invasive breast cancer and DCIS together, overdiagnosis was 14% from population perspective and 22% from invited women perspective. A major strength of an APC-model including the different phases of screening is that it allows to estimate overdiagnosis in birth cohorts, thereby preventing overestimation.

The potential use of ultra-low radiation dose images in digital mammography--a clinical proof-of-concept study in craniocaudal views.

OBJECTIVE: To estimate the potential of low-dose images in digital mammography by analysing the effect of substantial dose reduction in craniocaudal (CC) views on clinical performance. METHODS: At routine mammography, additional CC views were obtained with about 10% of the standard dose. Five radiologists retrospectively read the standard [mediolateral oblique (MLO) + CC] and combination low-dose mammograms (standard MLO + low-dose CC). If present, lesion type, conspicuity and suggested work-up were recorded. Final diagnoses were made by histology or follow up. A t-test or χ(2) test was used to compare results. RESULTS: 421 cases were included, presenting 5 malignancies, 66 benign lesions and multiple non-specific radiologic features. Using MLO with low-dose CC, all lesions were detected by at least one reader, but altogether less often than with standard mammography (sensitivity, 73.9% vs 81.5%). Missed lesions concerned all types. Lesions detected with both protocols were described similarly (p = 0.084) with comparable work-up recommendations (p = 0.658). CONCLUSION: Mammography with ultra-low-dose CC images particularly influences detection. While sensitivity decreased, specificity was unaffected. In this proof-of-concept study a lower limit was to be determined that is not intended nor applicable for clinical practice. This should facilitate further research in optimization of a low-dose approach, which has potential in a relatively young and largely asymptomatic population. ADVANCES IN KNOWLEDGE: Tungsten/silver-acquired mammography images might facilitate substantial dose reduction. Ultra-low-dose CC images reduce sensitivity, but not specificity. Low-dose images have potential in a largely young and asymptomatic population; a baseline is set for further research in optimization of a low-dose approach.

Variations in screening outcome among pairs of screening radiologists at non-blinded double reading of screening mammograms: a population-based study.

OBJECTIVES: Substantial inter-observer variability in screening mammography interpretation has been reported at single reading. However, screening results of pairs of screening radiologists have not yet been published. We determined variations in screening performances among pairs of screening radiologists at non-blinded double reading. METHODS: We included pairs of screening radiologists with at least 7,500 screening examinations per pair, obtained between 1997 and 2011. During 2-year follow-up, breast imaging reports, surgical reports and pathology results were collected of all referred women and interval cancers. Referral rate, cancer detection rate, positive predictive value and sensitivity were calculated for each pair. RESULTS: A total of 310,906 screening mammograms, read by 26 pairs of screening radiologists, were included for analysis. The referral rate ranged from 1.0 % (95 % CI 0.8 %-1.2 %) to 1.5 % (95 % CI 1.3 %-1.8 %), the cancer detection rate from 4.0 (95 % CI 2.8-5.2) to 6.3 (95 % CI 4.5-8.0) per 1,000 screens. The programme sensitivity and positive predictive value of referral ranged from 55.1 % (95 % CI 45.1 %-65.1 %) to 81.5 % (95 % CI 73.4 %-89.6 %) and from 28.7 % (95 % CI 20.8 %-36.6 %) to 49.5 % (95 % CI 39.7 %-59.3 %), respectively. CONCLUSION: We found significant variations in screening outcomes among pairs of screening radiologists at non-blinded double reading. This stresses the importance of monitoring screening results on a local scale. KEY POINTS: • Substantial inter-observer variability in screening mammography interpretation is known at single reading • Population-based study showed significant variations in outcomes among pairs of screening radiologists • Local monitoring and regular feedback are important to optimise screening outcome.