Triplinones A-H: Anti-Inflammatory Arylalkenyl α,ß-Unsaturated-δ-Lactones Isolated from the Leaves of Australian Rainforest Plant Cryptocarya triplinervis (Lauraceae).

Our ongoing exploration of Australian rainforest plants for the biodiscovery of anti-inflammatory agents led to the isolation and structural elucidation of eight new arylalkenyl α,ß-unsaturated-δ-lactones, triplinones A-H (1-8), from the leaves of the Australian rainforest plant Cryptocarya triplinervis B. Hyland (Lauraceae). The chemical structures of these compounds were established by NMR spectroscopic data analysis, while their relative and absolute configurations were established using a combination of Mosher ester analysis utilizing both Riguera's and Kishi's methods, ECD experiments, and X-ray crystallography analysis. Compounds 1-8 exhibited good inhibitory activities toward nitric oxide (NO) production in lipopolysaccharide (LPS) and interferon (IFN)-γ induced RAW 264.7 macrophages, in particular compounds 1-3 and 5, with IC50 values of 7.3 ± 0.5, 6.0 ± 0.3, 5.6 ± 0.3, and 5.4 ± 2.5 µM, respectively.

Spin crossover of a Fe(II) mononuclear complex induced by intermolecular factors involving chloride and solvent ordering.

Two new salts of a mononuclear tripodal Fe(II) complex were prepared, using ClO4- and Cl-. The ClO4- sample (1) remained HS at low temperatures, similar to the previously reported BF4- analogue. Crystallising with the Cl- anion (2) led to a markedly different crystal packing arrangement, and engendered SCO activity. This has been correlated to the lower crystal packing density in 2 and the coordination complex conformational differences arising due to the packing motifs of 1 and 2. Further, solvent ordering effects have been proposed to facilitate spin transition behaviour in 2.

Fatigue and vigilance in medical experts detecting breast cancer.

An abundance of laboratory-based experiments has described a vigilance decrement of reducing accuracy to detect targets with time on task, but there are few real-world studies, none of which have previously controlled the environment to control for bias. We describe accuracy in clinical practice for 360 experts who examined >1 million women's mammograms for signs of cancer, whilst controlling for potential biases. The vigilance decrement pattern was not observed. Instead, test accuracy improved over time, through a reduction in false alarms and an increase in speed, with no significant change in sensitivity. The multiple-decision model explains why experts miss targets in low prevalence settings through a change in decision threshold and search quit threshold and propose it should be adapted to explain these observed patterns of accuracy with time on task. What is typically thought of as standard and robust research findings in controlled laboratory settings may not directly apply to real-world environments and instead large, controlled studies in relevant environments are needed.

Atypia detected during breast screening and subsequent development of cancer: observational analysis of the Sloane atypia prospective cohort in England.

OBJECTIVE: To explore how the number and type of breast cancers developed after screen detected atypia compare with the anticipated 11.3 cancers detected per 1000 women screened within one three year screening round in the United Kingdom. DESIGN: Observational analysis of the Sloane atypia prospective cohort in England. SETTING: Atypia diagnoses through the English NHS breast screening programme reported to the Sloane cohort study. This cohort is linked to the English Cancer Registry and the Mortality and Birth Information System for information on subsequent breast cancer and mortality. PARTICIPANTS: 3238 women diagnosed as having epithelial atypia between 1 April 2003 and 30 June 2018. MAIN OUTCOME MEASURES: Number and type of invasive breast cancers detected at one, three, and six years after atypia diagnosis by atypia type, age, and year of diagnosis. RESULTS: There was a fourfold increase in detection of atypia after the introduction of digital mammography between 2010 (n=119) and 2015 (n=502). During 19 088 person years of follow-up after atypia diagnosis (until December 2018), 141 women developed breast cancer. Cumulative incidence of cancer per 1000 women with atypia was 0.95 (95% confidence interval 0.28 to 2.69), 14.2 (10.3 to 19.1), and 45.0 (36.3 to 55.1) at one, three, and six years after atypia diagnosis, respectively. Women with atypia detected more recently have lower rates of subsequent cancers detected within three years (6.0 invasive cancers per 1000 women (95% confidence interval 3.1 to 10.9) in 2013-18 v 24.3 (13.7 to 40.1) in 2003-07, and 24.6 (14.9 to 38.3) in 2008-12). Grade, size, and nodal involvement of subsequent invasive cancers were similar to those of cancers detected in the general screening population, with equal numbers of ipsilateral and contralateral cancers. CONCLUSIONS: Many atypia could represent risk factors rather than precursors of invasive cancer requiring surgery in the short term. Women with atypia detected more recently have lower rates of subsequent cancers detected, which might be associated with changes to mammography and biopsy techniques identifying forms of atypia that are more likely to represent overdiagnosis. Annual mammography in the short term after atypia diagnosis might not be beneficial. More evidence is needed about longer term risks.

Development and quality appraisal of a new English breast screening linked data set as part of the age, test threshold, and frequency of mammography screening (ATHENA-M) study.

OBJECTIVES: To build a data set capturing the whole breast cancer screening journey from individual breast cancer screening records to outcomes and assess data quality. METHODS: Routine screening records (invitation, attendance, test results) from all 79 English NHS breast screening centres between January 1, 1988 and March 31, 2018 were linked to cancer registry (cancer characteristics and treatment) and national mortality data. Data quality was assessed using comparability, validity, timeliness, and completeness. RESULTS: Screening records were extracted from 76/79 English breast screening centres, 3/79 were not possible due to software issues. Data linkage was successful from 1997 after introduction of a universal identifier for women (NHS number). Prior to 1997 outcome data are incomplete due to linkage issues, reducing validity. Between January 1, 1997 and March 31, 2018, a total of 11 262 730 women were offered screening of whom 9 371 973 attended at least one appointment, with 139 million person-years of follow-up (a median of 12.4 person years for each woman included) with 73 810 breast cancer deaths and 1 111 139 any-cause deaths. Comparability to reference data sets and internal validity were demonstrated. Data completeness was high for core screening variables (>99%) and main cancer outcomes (>95%). CONCLUSIONS: The ATHENA-M project has created a large high-quality and representative data set of individual women's screening trajectories and outcomes in England from 1997 to 2018, data before 1997 are lower quality. ADVANCES IN KNOWLEDGE: This is the most complete data set of English breast screening records and outcomes constructed to date, which can be used to evaluate and optimize screening.

Assignment of the biological value of solid breast masses based on quantitative evaluations of spectral CT examinations using electron density mapping, Zeffective mapping and iodine mapping.

OBJECTIVE: We aimed to asses, in a clinical setting, whether the newly available quantitative evaluation of electron density (ED) in spectral CT examinations of the breast provide information on the biological identity of solid breast masses and whether ED maps yield added value to the diagnostic information of iodine maps and Zeff maps calculated from the same CT image datasets. METHODS: All patients at the University Breast Cancer Center who underwent a clinically indicated Dual Layer Computed Tomography (DLCT) examination for staging of invasive breast cancer from 2018 to 2020 were prospectively included. Iodine concentration maps, Zeff maps and ED maps were automatically reconstructed from the DLCT datasets. Region of interest (ROI) based evaluations in the breast target lesions and in the aorta were performed semi-automatically in identical anatomical positions using dedicated evaluation software. Case-by-case evaluations were carried independently by 2 of 4 radiologists for each examination, respectively. Statistical analysis derived from the ROIs was done by calculating ROC/AUC curves and Youden indices. RESULTS: The evaluations comprised 166 DLCT examinations. In the ED maps the measurements in the breast target lesions yielded Youden cutpoints of 104.0% (reader 1) and 103.8% (reader 2) resulting in AUCs of 0.63 and 0.67 at the empirical cutpoints. The variables "Zeff" and "iodine content" derived from the target lesions showed superior diagnostical results, with a Youden cutpoint of 8.0 mg/ml in the iodine maps and cutpoints of 1.1/1.2 in the Zeff maps the AUCs ranging from 0.84 to 0.85 (p = 0.023 to <0.000). The computational combination of Zeff and ED measurements in the target lesions yielded a slight AUC increase (readers 1: 0.85-0.87; readers 2: 0.84-0.94). The ratios of the measured values in the target lesions normalized to the values measured in the aorta showed comparable results. The AUCs of ED derived from the cutpoints showed inferior results to those derived from the Zeff maps and iodine maps (ED: 0.64 and 0.66 for reader 1 and 2; Zeff: 0.86 for both readers; iodine content: 0.89 and 0.86 for reader 1 and 2, respectively). The computational combination of the ED results and the Zeff measurements did not lead to a clinically relevant diagnostic gain with AUCs ranging from 0.86 to 0.88. CONCLUSIONS: Quantitative assessments of Zeff, iodine content and ED all targeting the physical and chemical aspects of iodine uptake in solid breast masses confirmed diagnostically robust cutpoints for the differentiation of benign and malignant findings (Zeff < 7.7, iodine content of <0.8 mg/ml). The evaluations of the ED did not indicate any added diagnostic value beyond the quantitative assessments of Zeff and iodine content. Further research is warranted to develop suitable clinical indications for the use of ED maps.

Evidence-informed recommendations on managing breast screening atypia: perspectives from an expert panel consensus meeting reviewing results from the Sloane atypia project.

Evidence-based clinical guidelines are essential to maximize patient benefit and to reduce clinical uncertainty and inconsistency in clinical practice. Gaps in the evidence base can be addressed by data acquired in routine practice. At present, there is no international consensus on management of women diagnosed with atypical lesions in breast screening programmes. Here, we describe how routine NHS breast screening data collected by the Sloane atypia project was used to inform a management pathway that maximizes early detection of cancer and minimizes over-investigation of lesions with uncertain malignant potential. A half-day consensus meeting with 11 clinical experts, 1 representative from Independent Cancer Patients' Voice, 6 representatives from NHS England (NHSE) including from Commissioning, and 2 researchers was held to facilitate discussions of findings from an analysis of the Sloane atypia project. Key considerations of the expert group in terms of the management of women with screen detected atypia were: (1) frequency and purpose of follow-up; (2) communication to patients; (3) generalizability of study results; and (4) workforce challenges. The group concurred that the new evidence does not support annual surveillance mammography for women with atypia, irrespective of type of lesion, or woman's age. Continued data collection is paramount to monitor and audit the change in recommendations.

Recruiting women with ductal carcinoma in situ to a randomised controlled trial: lessons from the LORIS study.

BACKGROUND: The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. METHODS: Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. RESULTS: Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. CONCLUSIONS: Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. TRIAL REGISTRATION: ISRCTN27544579, prospectively registered on 22 May 2014.

DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants.

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (KAT6A), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B (KAT6B). We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions.

Investigating the Conformations of a Family of [M2L3]4+ Helicates Using Single Crystal X-ray Diffraction.

We present five new dinuclear triple helicate compounds of types [Mn2L3](ClO4)4, [Co2L3](BF4)4, [Ni2L3](BF4)4, [Cu2L3](BF4)4, and [Zn2L3](BF4)4, where L is a previously reported semi-rigid ligand incorporating two α-diimine primary donor groups and two secondary 4-pyridyl donor groups. All complexes have been characterized in both solution and the solid state. Single crystal X-ray diffraction studies were used to probe the variation in the respective helical structures as the coordinated metal ion was altered, including the effect on the orientations of the secondary binding domains. The influence of the metal ion size, the spin state in the case of Fe(II), and the presence of Jahn-Teller distortions on the overall helical structure has been investigated. These results form a basis for the design and construction of new large metallosupramolecular architectures which manifest properties associated with the constituent helical metalloligand units.

Lessons learned from independent external validation of an AI tool to detect breast cancer using a representative UK data set.

OBJECTIVE: To pilot a process for the independent external validation of an artificial intelligence (AI) tool to detect breast cancer using data from the NHS breast screening programme (NHSBSP). METHODS: A representative data set of mammography images from 26,000 women attending 2 NHS screening centres, and an enriched data set of 2054 positive cases were used from the OPTIMAM image database. The use case of the AI tool was the replacement of the first or second human reader. The performance of the AI tool was compared to that of human readers in the NHSBSP. RESULTS: Recommendations for future external validations of AI tools to detect breast cancer are provided. The tool recalled different breast cancers to the human readers. This study showed the importance of testing AI tools on all types of cases (including non-standard) and the clarity of any warning messages. The acceptable difference in sensitivity and specificity between the AI tool and human readers should be determined. Any information vital for the clinical application should be a required output for the AI tool. It is recommended that the interaction of radiologists with the AI tool, and the effect of the AI tool on arbitration be investigated prior to clinical use. CONCLUSION: This pilot demonstrated several lessons for future independent external validation of AI tools for breast cancer detection. ADVANCES IN KNOWLEDGE: Knowledge has been gained towards best practice procedures for performing independent external validations of AI tools for the detection of breast cancer using data from the NHS Breast Screening Programme.

Spin Crossover Induced by Changing the Identity of the Secondary Metal Ion from PdII to NiII in a Face-Centered FeII 8 MII 6 Cubic Cage.

Discrete spin crossover (SCO) heteronuclear cages are a rare class of materials which have potential use in next-generation molecular transport and catalysis. Previous investigations of cubic cage [Fe8 Pd6 L8 ]28+ constructed using semi-rigid metalloligands, found that FeII centers of the cage did not undergo spin transition. In this work, substitution of the secondary metal center at the face of the cage resulted in SCO behavior, evidenced by magnetic susceptibility, Mössbauer spectroscopy and single crystal X-ray diffraction. Structural comparisons of these two cages shed light on the possible interplay of inter- and intramolecular interactions associated with SCO in the NiII analogue, 1 ([Fe8 Ni6 L8 (CH3 CN)12 ]28+ ). The distorted octahedral coordination environment, as well as the occupation of the CH3 CN in the NiII axial positions of 1, prevented close packing of cages observed in the PdII analogue. This led to offset, distant packing arrangements whereby important areas within the cage underwent dramatic structural changes with the exhibition of SCO.

Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia.

PURPOSE: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study. PARTICIPANTS: Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term. FINDINGS TO DATE: To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods. FUTURE PLANS: Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)-results from the UK Sloane Project.

BACKGROUND: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. METHODS: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. RESULTS: Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005). CONCLUSIONS: The higher breast cancer mortality with microinvasion indicates a more aggressive disease.

Tristaenone A: A New Anti-Inflammatory Compound Isolated from the Australian Indigenous Plant Tristaniopsis laurina.

Inspired by ethnopharmacological knowledge, we conducted a bioassay-guided fractionation of the leaves of Tristaniopsis laurina which led to the discovery of a new anti-inflammatory compound, tristaenone A (1). The structure was elucidated by detailed spectroscopic data analysis, and the absolute configuration was established using X-ray crystallography analysis. Tristaenone A (1) suppressed LPS and IFN-γ-induced NO, TNF-α and IL-6 production in RAW 264.7 cells with IC50 values of 37.58 ± 2.45 µM, 80.6 ± 5.82 µM and 125.65 ± 0.34 µM, respectively. It also inhibited NF-κB nuclear translocation by 52.93 ± 14.14% at a concentration of 31.85 µM.

Unresected screen-detected ductal carcinoma in situ: Outcomes of 311 women in the Forget-Me-Not 2 study.

BACKGROUND AND AIM: The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. METHODS: English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. RESULTS: Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4-21%), 39% (24-58%) and 36% (24-50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. CONCLUSION: The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment.

Prediction of Upstaging in Ductal Carcinoma in Situ Based on Mammographic Radiomic Features.

Background Improving diagnosis of ductal carcinoma in situ (DCIS) before surgery is important in choosing optimal patient management strategies. However, patients may harbor occult invasive disease not detected until definitive surgery. Purpose To assess the performance and clinical utility of mammographic radiomic features in the prediction of occult invasive cancer among women diagnosed with DCIS on the basis of core biopsy findings. Materials and Methods In this Health Insurance Portability and Accountability Act-compliant retrospective study, digital magnification mammographic images were collected from women who underwent breast core-needle biopsy for calcifications that was performed at a single institution between September 2008 and April 2017 and yielded a diagnosis of DCIS. The database query was directed at asymptomatic women with calcifications without a mass, architectural distortion, asymmetric density, or palpable disease. Logistic regression with regularization was used. Differences across training and internal test set by upstaging rate, age, lesion size, and estrogen and progesterone receptor status were assessed by using the Kruskal-Wallis or χ2 test. Results The study consisted of 700 women with DCIS (age range, 40-89 years; mean age, 59 years ± 10 [standard deviation]), including 114 with lesions (16.3%) upstaged to invasive cancer at subsequent surgery. The sample was split randomly into 400 women for the training set and 300 for the testing set (mean ages: training set, 59 years ± 10; test set, 59 years ± 10; P = .85). A total of 109 radiomic and four clinical features were extracted. The best model on the test set by using all radiomic and clinical features helped predict upstaging with an area under the receiver operating characteristic curve of 0.71 (95% CI: 0.62, 0.79). For a fixed high sensitivity (90%), the model yielded a specificity of 22%, a negative predictive value of 92%, and an odds ratio of 2.4 (95% CI: 1.8, 3.2). High specificity (90%) corresponded to a sensitivity of 37%, positive predictive value of 41%, and odds ratio of 5.0 (95% CI: 2.8, 9.0). Conclusion Machine learning models that use radiomic features applied to mammographic calcifications may help predict upstaging of ductal carcinoma in situ, which can refine clinical decision making and treatment planning. © RSNA, 2022.

Breast screening atypia and subsequent development of cancer: protocol for an observational analysis of the Sloane database in England (Sloane atypia cohort study).

INTRODUCTION: The National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would never have become symptomatic. As well as breast cancer, a spectrum of atypical epithelial proliferations (atypia) can also be detected as part of screening. This spectrum of changes, while not cancer, may mean that a woman is more likely to develop breast cancer in the future. Follow-up of atypia is not evidence based. We currently do not know which atypia should be detected to avoid future cancer. This study will explore how atypia develops into breast cancer in terms of number of women, time of cancer development, cancer type and severity, and whether this varies for different types of atypia. METHODS AND ANALYSIS: The Sloane cohort study began in April 2003 with ongoing data collection including atypia diagnosed through screening at screening units in the UK. The database for England has 3645 cases (24 September 2020) of epithelial atypia, with follow-up from 1 to 15 years. The outcomes include subsequent invasive breast cancer and the nature of subsequent cancer. Descriptive statistics will be produced. The observed rates of breast cancer at 1, 3 and 6 years for types of atypia will be reported with CIs, to enable comparison to women in the general population. Time to event methods will be used to describe the time to breast cancer diagnosis for the types of atypia, including flexible parametric modelling if appropriate. Patient representatives from Independent Cancer Patients' Voice are included at every stage of the research. ETHICS AND DISSEMINATION: The study has received research ethics approval from the University of Warwick Biomedical and Scientific Research Ethics Committee (BSREC 10/20-21, 8 October 2020), Public Health England office for data release approvals (ODR1718_313) and approval from the English Breast Research Advisory Committee (BSPRAC_031). The findings will be disseminated to breast screening clinicians (via journal publication and conference presentation), to the NHS Breast Screening Programme to update their guidelines on how women with atypia should be followed up, and to the general public.

Optimising breast cancer screening reading: blinding the second reader to the first reader's decisions.

OBJECTIVES: In breast cancer screening, two readers separately examine each woman's mammograms for signs of cancer. We examined whether preventing the two readers from seeing each other's decisions (blinding) affects behaviour and outcomes. METHODS: This cohort study used data from the CO-OPS breast-screening trial (1,119,191 women from 43 screening centres in England) where all discrepant readings were arbitrated. Multilevel models were fitted using Markov chain Monte Carlo to measure whether reader 2 conformed to the decisions of reader 1 when they were not blinded, and the effect of blinding on overall rates of recall for further tests and cancer detection. Differences in positive predictive value (PPV) were assessed using Pearson's chi-squared test. RESULTS: When reader 1 recalls, the probability of reader 2 also recalling was higher when not blinded than when blinded, suggesting readers may be influenced by the other's decision. Overall, women were less likely to be recalled when reader 2 was blinded (OR 0.923; 95% credible interval 0.864, 0.986), with no clear pattern in cancer detection rate (OR 1.029; 95% credible interval 0.970, 1.089; Bayesian p value 0.832). PPV was 22.1% for blinded versus 20.6% for not blinded (p < 0.001). CONCLUSIONS: Our results suggest that when not blinded, reader 2 is influenced by reader 1's decisions to recall (alliterative bias) which would result in bypassing arbitration and negate some of the benefits of double-reading. We found a relationship between blinding the second reader and slightly higher PPV of breast cancer screening, although this analysis may be confounded by other centre characteristics. KEY POINTS: • In Europe, it is recommended that breast screening mammograms are analysed by two readers but there is little evidence on the effect of 'blinding' the readers so they cannot see each other's decisions. • We found evidence that when the second reader is not blinded, they are more likely to agree with a recall decision from the first reader and less likely to make an independent judgement (alliterative error). This may reduce overall accuracy through bypassing arbitration. • This observational study suggests an association between blinding the second reader and higher positive predictive value of screening, but this may be confounded by centre characteristics.