Limited impact of adding digital breast tomosynthesis to full field digital mammography in an elevated breast cancer risk population.

PURPOSE: To investigate the impact of adding digital breast tomosynthesis (DBT) to full field digital mammography (FFDM) in screening asymptomatic women with an elevated breast cancer life time risk (BCLTR) but without known genetic mutation. METHODS: This IRB-approved single-institution multi-reader study on prospectively acquired FFDM + DBT images included 429 asymptomatic women (39-69y) with an elevated BC risk on their request form. The BCLTR was calculated for each patient using the IBISrisk calculator v8.0b. The screening protocol and reader study consisted of 4-view FFDM + DBT, which were read by four independent radiologists using the BI-RADS lexicon. Standard of care (SOC) included ultrasound (US) and magnetic resonance imaging (MRI) for women with > 30 % BCLTR. Breast cancer detection rate (BCDR), sensitivity and positive predictive value were assessed for FFDM and FFDM + DBT and detection outcomes were compared with McNemar-test. RESULTS: In total 7/429 women in this clinically elevated breast cancer risk group were diagnosed with BC using SOC (BCDR 16.3/1000) of which 4 were detected with FFDM. Supplemental DBT did not detect additional cancers and BCDR was the same for FFDM vs FFDM + DBT (9.3/1000, McNemar p = 1). Moderate inter-reader agreement for diagnostic BI-RADS score was found for both study arms (ICC for FFDM and FFDM + DBT was 0.43, resp. 0.46). CONCLUSION: In this single institution study, supplemental screening with DBT in addition to standard FFDM did not increase BCDR in this higher-than-average BC risk group, objectively documented using the IBISrisk calculator.

Optimized signal of calcifications in wide-angle digital breast tomosynthesis: a virtual imaging trial.

OBJECTIVES: Evaluate microcalcification detectability in digital breast tomosynthesis (DBT) and synthetic 2D mammography (SM) for different acquisition setups using a virtual imaging trial (VIT) approach. MATERIALS AND METHODS: Medio-lateral oblique (MLO) DBT acquisitions on eight patients were performed at twice the automatic exposure controlled (AEC) dose. The noise was added to the projections to simulate a given dose trajectory. Virtual microcalcification models were added to a given projection set using an in-house VIT framework. Three setups were evaluated: (1) standard acquisition with 25 projections at AEC dose, (2) 25 projections with a convex dose distribution, and (3) sparse setup with 13 projections, every second one over the angular range. The total scan dose and angular range remained constant. DBT volume reconstruction and synthetic mammography image generation were performed using a Siemens prototype algorithm. Lesion detectability was assessed through a Jackknife-alternative free-response receiver operating characteristic (JAFROC) study with six observers. RESULTS: For DBT, the area under the curve (AUC) was 0.97 ± 0.01 for the standard, 0.95 ± 0.02 for the convex, and 0.89 ± 0.03 for the sparse setup. There was no significant difference between standard and convex dose distributions (p = 0.309). Sparse projections significantly reduced detectability (p = 0.001). Synthetic images had a higher AUC with the convex setup, though not significantly (p = 0.435). DBT required four times more reading time than synthetic mammography. DISCUSSION: A convex setup did not significantly improve detectability in DBT compared to the standard setup. Synthetic images exhibited a non-significant increase in detectability with the convex setup. Sparse setup significantly reduced detectability in both DBT and synthetic mammography. CLINICAL RELEVANCE STATEMENT: This virtual imaging trial study allowed the design and efficient testing of different dose distribution trajectories with real mammography images, using a dose-neutral protocol. KEY POINTS: • In DBT, a convex dose distribution did not increase the detectability of microcalcifications compared to the current standard setup but increased detectability for the SM images. • A sparse setup decreased microcalcification detectability in both DBT and SM images compared to the convex and current clinical setups. • Optimal microcalcification cluster detection in the system studied was achieved using either the standard or convex dose setting, with the default number of projections.

The impact of (simulated) resolution on breast cancer diagnosis based on high-resolution 3D micro-CT microcalcification images.

BACKGROUND: Breast microcalcifications (MCs) are considered to be a robust marker of breast cancer. A machine learning model can provide breast cancer diagnosis based on properties of individual MCs - if their characteristics are captured at high resolution and in 3D. PURPOSE: The main purpose of the study was to explore the impact of image resolution (8 µm, 16 µm, 32 µm, 64 µm) when diagnosing breast cancer using radiomics features extracted from individual high resolution 3D micro-CT MC images. METHODS: Breast MCs extracted from 86 female patients were analyzed at four different spatial resolutions: 8 µm (original resolution) and 16 µm, 32 µm, 64 µm (simulated image resolutions). Radiomic features were extracted at each image resolution in an attempt, to find a compact feature signature allowing to distinguish benign and malignant MCs. Machine learning algorithms were used for classifying individual MCs and samples (i.e., patients). For sample diagnosis, a custom-based thresholding approach was used to combine individual MC results into sample results. We conducted classification experiments when using (a) the same MCs visible in 8 µm, 16 µm, 32 µm, and 64 µm resolution; (b) the same MCs visible in 8 µm, 16 µm, and 32 µm resolution; (c) the same MCs visible in 8 µm and 16 µm resolution; (d) all MCs visible in 8 µm, 16 µm, 32 µm, and 64 µm resolution. Accuracy, sensitivity, specificity, AUC, and F1 score were computed for each experiment. RESULTS: The individual MC results yielded an accuracy of 77.27%, AUC of 83.83%, F1 score of 77.25%, sensitivity of 80.86%, and specificity of 72.2% at 8 µm resolution. For the individual MC classifications we report for the F1 scores: a 2.29% drop when using 16 µm instead of 8 µm, a 4.01% drop when using 32 µm instead of 8 µm, a 10.69% drop when using 64 µm instead of 8 µm. The sample results yielded an accuracy and F1 score of 81.4%, sensitivity of 80.43%, and specificity value of 82.5% at 8 µm. For the sample classifications we report for F1 score values: a 6.3% drop when using 16 µm instead of 8 µm, a 4.91% drop when using 32 µm instead of 8 µm, and a 6.3% drop when using 64 µm instead of 8 µm. CONCLUSIONS: The highest classification results are obtained at the highest resolution (8 µm). If breast MCs characteristics could be visualized/captured in 3D at a higher resolution compared to what is used nowadays in digital mammograms (approximately 70 µm), breast cancer diagnosis will be improved.

The Upgrade Risk of B3 Lesions to (Pre)Invasive Breast Cancer After Diagnosis on Core Needle or Vacuum Assisted Biopsy. A Belgian National Cohort Study.

INTRODUCTION: Flat epithelial atypia (FEA), lobular neoplasia (LN), papillary lesions (PL), radial scar (RS) and atypical ductal hyperplasia (ADH) are lesions of uncertain malignant potential and classified as B3 lesions by the European guidelines for quality assurance in breast cancer screening and diagnosis. Current management is usually wide local excision (WE), surveillance may be sufficient for some. We investigated the upgrade rate of B3 lesions to breast malignancy in a subsequent resection specimen after diagnosis on core needle-or vacuum assisted biopsy (CNB-VAB) in a national population-based series. METHODS: Using data from the Belgian Cancer Registry (BCR) between January 1, 2013 and December 31, 2016, inclusion criteria were new diagnosis of a B3 lesion on CNB or VAB with subsequent histological assessment on a wider excision specimen. Histological agreement between first- and follow-up investigation was analyzed to determine the upgrade risk to ductal adenocarcinoma in situ (DCIS) or invasive breast cancer (IC) according to the type of B3 lesion. RESULTS: Of 1855 diagnosed B3 lesions, 812 were included in this study: 551 after CNB-261 after VAB. After diagnosis on CNB and VAB, we found 19.0% and 14.9% upgrade to malignancy respectively. Upgrade risks after CNB and VAB were: FEA 39.5% and 17.6%; LN 40.5% and 4.3%; PL 10.4% and 12.5%; RS 25.7%and 0.0%; ADH 29.5% and 20.0%. CONCLUSION: Based on the observed upgrade rate we propose three recommendations: first, resection of ADH, and FEA with WE; second, resection of RS and classical LN with therapeutic VAB and further surveillance when radio-pathological correlation is concordant; third, surveillance of PL.

Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.

BACKGROUND: Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Because magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound-based pediatric Leuven Imaging Classification to complement the MIC. METHODS: A prospective study cohort of 74 patients with genotyped ADPKD (37 female) was followed longitudinally with ultrasound, including 3D ultrasound, and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range [IQR]) at diagnosis of 3 (IQR, 0-9) years and at first 3D ultrasound evaluation of 10 (5-14) years. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type. RESULTS: PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and glucosidase IIα unit only once (1%). Over these 247 evaluations, the median height was 143 (IQR, 122-166) cm and total kidney volume was 236 (IQR, 144-344) ml, leading to an htTKV of 161 (IQR, 117-208) ml/m. Applying the adult Mayo classification in children younger than 15 years strongly underestimated ADPKD severity, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease used to establish the MIC. CONCLUSIONS: We proposed a five-level Leuven Imaging Classification ADPKD pediatric model as a novel classification tool on the basis of patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.

Retrospective Cohort Study of Practical Applications of Paramagnetic Seed Localisation in Breast Carcinoma and Other Malignancies.

(1) Background: Paramagnetic seeds are a safe alternative for the wire-guided localisation of non-palpable breast lesions, but can also be applied for non-breast lesions. This study presents the experience with a paramagnetic seed, MagSeed® (Endomagnetics Ltd., Cambridge, UK, CE-registered and FDA-cleared), in an academic and non-academic breast centre. (2) Methods: Multicentre, retrospective analysis of 374 consecutive patients who underwent surgery after paramagnetic seed localisation (MSL) between 2018 and 2020. Indications for localisation included non-palpable breast lesions (n = 356), lymph nodes (n = 15) or soft tissue lesions (n = 3). The primary outcome was feasibility and the rate of positive section margins. The secondary outcome was predictive factors for positive section margins. (3) Results: The accurate excision of high-risk breast lesions, lymph nodes and soft tissue lesions was seen in 91.07% (n = 56). Positive section margins were observed in 7.86% (n = 25) after breast conserving surgery for invasive or ductal carcinoma in situ (DCIS) (n = 318). Invasive breast cancer associated with DCIS (p = 0.043) and the size of DCIS (p < 0.001) were significantly correlated with the positive section margins. (4) Conclusion: This study confirms the feasibility of MSL, as well as the higher risk for positive margins in cases of breast carcinoma with associated DCIS. Soft tissue lesions and lymph nodes associated with other malignancies, e.g., melanoma, can also be localised with paramagnetic seeds. This offers perspectives for future applications, such as the de-escalation of axillary treatment in breast cancer.

Towards updated understanding of brain metastasis.

Brain metastasis (BM) is a common complication in cancer patients with advanced disease and attributes to treatment failure and final mortality. Currently there are several therapeutic options available; however these are only suitable for limited subpopulation: surgical resection or radiosurgery for cases with a limited number of lesions, targeted therapies for approximately 18% of patients, and immune checkpoint inhibitors with a response rate of 20-30%. Thus, there is a pressing need for development of novel diagnostic and therapeutic options. This overview article aims to provide research advances in disease model, targeted therapy, blood brain barrier (BBB) opening strategies, imaging and its incorporation with artificial intelligence, external radiotherapy, and internal targeted radionuclide theragnostics. Finally, a distinct type of BM, leptomeningeal metastasis is also covered.

Development and characterization of a chick embryo chorioallantoic membrane (CAM) based platform for evaluation of vasoactive medications.

Among various anti-cancer therapies, tumor vascular disrupting agents (VDAs) play a crucial role, for which their off-targeting effects on normal vessels need also to be investigated. The purpose of this study was to set up an in-ovo platform that combines a laser speckle contrast imaging (LSCI) modality with chick embryo chorioallantoic membrane (CAM) to real-time monitor vascular diameters and perfusion without and with intravascular injection. Two eggshell windows for both observation or measurement and injection were opened. Dynamic blood perfusion images and corresponding statistic graphs were acquired by using a LSCI unit on CAMs from embryo date (ED) 9 to ED15. A dedicated fine needle catheter was made for slow intravascular administration over 30 min with simultaneous LSCI acquisition. To verify the connectivity between CAM vessels and the embryonic circulations in the egg, contrast-enhanced 3D micro computed tomography (µCT), 2D angiography and histology were executed. This platform was successfully established to acquire, quantify and demonstrate vascular and hemodynamic information from the CAM. Chick embryos even with air cell opened remained alive from ED9 to ED15. Through collecting LSCI derived CAM vascular diameter and perfusion parameters, ED12 was determined as the best time window for vasoactive drug studies. A reverse correlation between CAM vessel diameter and blood perfusion rate was found (p < 0.002). Intravascular infusion and simultaneous LSCI acquisition for 30 min in ovo proved feasible. Contrast-enhanced angiography and histomorphology could characterize the connectivity between CAM vasculature and embryonic circulation. This LSCI-CAM platform was proved effective for investigating the in-ovo hemodynamics, which paves the road for further preclinical research on vasoactive medications including VDAs.

Heterogeneity of Synchronous Lung Metastasis Calls for Risk Stratification and Prognostic Classification: Evidence from a Population-Based Database.

The epidemiology and associated potential heterogeneity of synchronous lung metastasis (sLM) have not been reported at a population-based level. Cancer patients with valid information about sLM status in the Surveillance, Epidemiology, and End Results database were enrolled. The prevalence of sLM, with a 95% confidential interval, and median survival of sLM, with interquartile range, were calculated and compared by Chi-square analyses and log-rank tests by primary cancer type and clinicopathological factors. Furthermore, the risk factors of sLM development were identified by multivariate logistic regression. Among 1,672,265 enrolled cases, 3.3% cases were identified with sLM, with a median survival of 7 months. Heterogeneity in prevalence and prognosis in sLM was observed among different primary cancers, with the highest prevalence in main bronchus cancer and best survival in testis cancer. Higher prevalence and poorer prognosis were observed in the older population, male population, African American, patients with lower socioeconomic status, and cases with advanced T stage, N stage, or more malignant pathological characteristics. Race, age, T stage, N stage, metastasis to other sites, insurance status and marital status were associated with sLM development (p < 0.001). The current study highlights the heterogeneity of the prevalence and prognosis in patients with sLM.

Development and characterization of a rat brain metastatic tumor model by multiparametric magnetic resonance imaging and histomorphology.

To facilitate the development of new brain metastasis (BM) treatment, an easy-to-use and clinically relevant animal model with imaging platform is needed. Rhabdomyosarcoma BM was induced in WAG/Rij rats. Post-implantation surveillance and characterizations were systematically performed with multiparametric MRI including 3D T1 and T2 weighted imaging, diffusion-weighted imaging (DWI), T1 and T2 mapping, and perfusion-weighted imaging (PWI), which were validated by postmortem digital radiography (DR), µCT angiography and histopathology. The translational potential was exemplified by the application of a vascular disrupting agent (VDA). BM was successfully induced in most rats of both genders (18/20). Multiparametric MRI revealed significantly higher T2 value, pre-contrast-enhanced (preCE) T1 value, DWI-derived apparent diffusion coefficient (ADC) and CE ratio, but a lower post-contrast-enhanced (postCE) T1 value in BM lesions than in adjacent brain (p < 0.01). PWI showed the dynamic and higher contrast agent uptake in the BM compared with the adjacent brain. DR, µCT and histopathology characterized the BM as hypervascular tumors. After VDA treatment, the BM showed drug-related perfusion changes and partial necrosis as evidenced by anatomical, functional MRI parameters and postmortem findings. The present BM model and imaging modalities represent a feasible and translational platform for developing BM-targeting therapeutics.

Prevalence, progression and implications of breast artery calcification in patients with chronic kidney disease.

Breast arterial calcification (BAC) is increasingly recognized as a specific marker of medial calcification. The present retrospective observational cohort study aimed to define the prevalence, progression rate, risk factors and clinical implications of BAC in chronic kidney disease (CKD) patients across stages of disease. The presence and extent of BAC were determined on mammograms in 310 females (58.7 ± 10.8 years, Caucasian) with CKD across various stages of disease [CKD G2-5D n = 132; transplant (Tx) recipients n = 178]. In a subset of 88 patients, repeat mammography was performed, allowing us to calculate the annualized BAC rate. Overall, BAC was observed in 34.7% of the patients. BAC prevalence (P = 0.02) and BAC score (P = 0.05) increased along the progression of CKD. In the overall cohort, patients with BAC were characterized by older age, more cardiovascular disease, more inflammation, higher pulse pressure and borderline higher prevalence of diabetes and were more often treated with a vitamin K antagonist (VKA). The BAC progression rate was significantly lower in Tx patients as compared with CKD G5D. Progressors were characterized by more inflammation, worse kidney function, higher BAC score and higher serum phosphate level (Tx only) at baseline and were more often treated with a VKA. Major adverse cardiovascular event-free survival was significantly worse in Tx patients with BAC. In conclusion, BAC is common among CKD patients, progresses at a slower pace in Tx patients as compared with CKD 5D and associates with dismal cardiovascular outcomes. BAC score, kidney function, serum phosphate at baseline and VKA usage seem to be important determinants of progression.

Virtual clinical trial to compare cancer detection using combinations of 2D mammography, digital breast tomosynthesis and synthetic 2D imaging.

OBJECTIVES: This study was designed to compare the detection of subtle lesions (calcification clusters or masses) when using the combination of digital breast tomosynthesis (DBT) and synthetic mammography (SM) with digital mammography (DM) alone or combined with DBT. METHODS: A set of 166 cases without cancer was acquired on a DBT mammography system. Realistic subtle calcification clusters and masses in the DM images and DBT planes were digitally inserted into 104 of the acquired cases. Three study arms were created: DM alone, DM with DBT and SM with DBT. Five mammographic readers located the centre of any lesion within the images that should be recalled for further investigation and graded their suspiciousness. A JAFROC figure of merit (FoM) and lesion detection fraction (LDF) were calculated for each study arm. The visibility of the lesions in the DBT images was compared with SM and DM images. RESULTS: For calcification clusters, there were no significant differences (p > 0.075) in FoM or LDF. For masses, the FoM and LDF were significantly improved in the arms using DBT compared to DM alone (p < 0.001). On average, both calcification clusters and masses were more visible on DBT than on DM and SM images. CONCLUSIONS: This study demonstrated that masses were detected better with DBT than with DM alone and there was no significant difference (p = 0.075) in LDF between DM&DBT and SM&DBT for calcifications clusters. Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses. KEY POINTS: • The detection of masses was significantly better using DBT than with digital mammography alone. • The detection of calcification clusters was not significantly different between digital mammography and synthetic 2D images combined with tomosynthesis. • Our results support previous studies that it may be acceptable to not acquire digital mammography alongside tomosynthesis for subtle calcification clusters and ill-defined masses for the imaging technology used.

Comparing breast cancer imaging characteristics of CHEK2 with BRCA1 and BRCA2 gene mutation carriers.

PURPOSE: Breast cancer gene (BRCA) 1 and 2 mutations are frequently studied gene mutations (GM); the incidence of checkpoint kinase 2 (CHEK2) is increasing. We describe the imaging features of breast cancer (BC) in CHEK2 mutations, compared to BRCA 1 and 2 using mammography, ultrasound (US) and magnetic resonance imaging (MRI). METHOD: Inclusion criteria were primary BC in GM carriers, treated in the same hospital. Age at diagnosis, histology, hormone receptor and human epidermal growth factor receptor 2 (HER2) status were retrieved. Mammography descriptors were mass, asymmetry and suspicious microcalcifications. The enhancement pattern (MRI), shape and border, architectural distortion, the presence of a hyperechoic rim and cystic complex structure (US) were documented. Analyses were performed using SAS software (version 9.4). Fishers' exact test was used to test associations between two categorical variables. RESULTS: In 191 women, 233 malignant lesions were diagnosed (78 in BRCA1, 109 in BRCA2, 46 in CHEK2). In CHEK2 carriers, mammographically, suspicious microcalcifications (54%) were more prevalent (BRCA2 (48%) and BRCA1 carriers (33%)) (p-value = 0.057) compared to mass lesions (35%). On US, lesions were most frequently ill-defined (86%) (p = 0.579) and irregular (94.5%) (p = 0.098) compared to BRCA2 (77% and 80% resp.) and BRCA1 carriers (71% and 72% resp.). On MRI, mass lesions showed a type 3 curve in CHEK2 (67%) compared to BRCA1 (36%) and BRCA2 (50%) (p = 0.056). CONCLUSIONS: Malignant radiological characteristics of breast cancer, more specifically suspicious microcalcifications, were more frequently seen in CHEK2 and BRCA2 compared to BRCA1 mutation carriers (without a significant difference) indicating the importance of mammography in follow-up of CHEK2 carriers.

Getting Rid of Patient's Misconceptions About the Radiology Department Using Animated Video in the Waiting Room.

OBJECTIVES: Patients often confuse the role of the radiologist with that of the technician. The aim of this study is to explore patients' current perceptions about the radiology department and to evaluate how it's possible to get rid of misconceptions using informative animated video in the waiting room. MATERIALS AND METHODS: In this multi-centric study (UZ Leuven, ZNA Middelheim), 278 patients of all ages and education levels were surveyed in the radiology waiting room. 107 patients filled out the survey after watching an informative animated video (www.makeradiologyvisible.com). The remaining patients did not watch the video. RESULTS: Half of the patients (86/171) in the non-video group believe the radiologist "performs the scanning", compared to 19% (20/107) in the video group (p < 0.001). Patients who think their own physician will interpret the images is 36% (61/171) in the non-video group and 10% (11/107) in the video group (p < 0.001). In the non-video group, 32% (55/171) believe the technician performs the exam compared to 59% (63/107) in the video group (p < 0.001). After the video, 67% (72/107) of patients have more respect for the work of the radiologist, 52% (56/107) experience less anxiety and 65% (70/107) think the video is of added value to their visit. All items showed a better impact in high-educational subgroups. CONCLUSION: Animated informative videos help to increase patient knowledge about the radiology department. It moderates expectations, reduces anxiety, and ameliorates the overall experience. Although, the learning curve is steeper in highly educated patients, all educational levels benefit.

Validation of a candidate instrument to assess image quality in digital mammography using ROC analysis.

PURPOSE: To validate a candidate instrument, to be used by different professionals to assess image quality in digital mammography (DM), against detection performance results. METHODS: A receiver operating characteristics (ROC) study was conducted to assess the detection performance in DM images with four different image quality levels due to different quality issues. Fourteen expert breast radiologists from five countries assessed a set of 80 DM cases, containing 60 lesions (40 cancers, 20 benign findings) and 20 normal cases. A visual grading analysis (VGA) study using a previously-described candidate instrument was conducted to evaluate a subset of 25 of the images used in the ROC study. Eight radiologists that had participated in the ROC study, and seven expert breast-imaging physicists, evaluated this subset. The VGA score (VGAS) and the ROC and visual grading characteristics (VGC) areas under the curve (AUCROC and AUCVGC) were compared. RESULTS: No large differences in image quality among the four levels were detected by either ROC or VGA studies. However, the ranking of the four levels was consistent: level 1 (partial AUCROC: 0.070, VGAS: 6.77) performed better than levels 2 (0.066, 6.15), 3 (0.061, 5.82), and 4 (0.062, 5.37). Similarity between radiologists' and physicists' assessments was found (average VGAS difference of 10 %). CONCLUSIONS: The results from the candidate instrument were found to correlate with those from ROC analysis, when used by either observer group. Therefore, it may be used by different professionals, such as radiologists, radiographers, and physicists, to assess clinically-relevant image quality variations in DM.

Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

How does image quality affect radiologists' perceived ability for image interpretation and lesion detection in digital mammography?

OBJECTIVES: To study how radiologists' perceived ability to interpret digital mammography (DM) images is affected by decreases in image quality. METHODS: One view from 45 DM cases (including 30 cancers) was degraded to six levels each of two acquisition-related issues (lower spatial resolution and increased quantum noise) and three post-processing-related issues (lower and higher contrast and increased correlated noise) seen during clinical evaluation of DM systems. The images were shown to fifteen breast screening radiologists from five countries. Aware of lesion location, the radiologists selected the most-degraded mammogram (indexed from 1 (reference) to 7 (most degraded)) they still felt was acceptable for interpretation. The median selected index, per degradation type, was calculated separately for calcification and soft tissue (including normal) cases. Using the two-sided, non-parametric Mann-Whitney test, the median indices for each case and degradation type were compared. RESULTS: Radiologists were not tolerant to increases (medians: 1.5 (calcifications) and 2 (soft tissue)) or decreases (median: 2, for both types) in contrast, but were more tolerant to correlated noise (median: 3, for both types). Increases in quantum noise were tolerated more for calcifications than for soft tissue cases (medians: 3 vs. 4, p = 0.02). Spatial resolution losses were considered less acceptable for calcification detection than for soft tissue cases (medians: 3.5 vs. 5, p = 0.001). CONCLUSIONS: Perceived ability of radiologists for image interpretation in DM was affected not only by image acquisition-related issues but also by image post-processing issues, and some of those issues affected calcification cases more than soft tissue cases. KEY POINTS: • Lower spatial resolution and increased quantum noise affected the radiologists' perceived ability to interpret calcification cases more than soft tissue lesion or normal cases. • Post-acquisition image processing-related effects, not only image acquisition-related effects, also impact the perceived ability of radiologists to interpret images and detect lesions. • In addition to current practices, post-acquisition image processing-related effects need to also be considered during the testing and evaluation of digital mammography systems.

Development and content validity evaluation of a candidate instrument to assess image quality in digital mammography: A mixed-method study.

PURPOSE: To develop a candidate instrument to assess image quality in digital mammography, by identifying clinically relevant features in images that are affected by lower image quality. METHODS: Interviews with fifteen expert breast radiologists from five countries were conducted and analysed by using adapted directed content analysis. During these interviews, 45 mammographic cases, containing 44 lesions (30 cancers, 14 benign findings), and 5 normal cases, were shown with varying image quality. The interviews were performed to identify the structures from breast tissue and lesions relevant for image interpretation, and to investigate how image quality affected the visibility of those structures. The interview findings were used to develop tentative items, which were evaluated in terms of wording, understandability, and ambiguity with expert breast radiologists. The relevance of the tentative items was evaluated using the content validity index (CVI) and modified kappa index (k*). RESULTS: Twelve content areas, representing the content of image quality in digital mammography, emerged from the interviews and were converted into 29 tentative items. Fourteen of these items demonstrated excellent CVI ≥ 0.78 (k* > 0.74), one showed good CVI < 0.78 (0.60 ≤ k* ≤ 0.74), while fourteen were of fair or poor CVI < 0.78 (k* ≤ 0.59). In total, nine items were deleted and five were revised or combined resulting in 18 items. CONCLUSIONS: By following a mixed-method methodology, a candidate instrument was developed that may be used to characterise the clinically-relevant impact that image quality variations can have on digital mammography.

Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical features in invasive micropapillary breast carcinoma with long-term outcomes.

PURPOSE: We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features. METHODS: Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS). RESULTS: We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001). CONCLUSIONS: Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.

Cancer Surveillance in Healthy Carriers of Germline Pathogenic Variants in BRCA1/2: A Review of Secondary Prevention Guidelines.

Germline pathogenic alterations in the breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are the most prevalent causes of hereditary breast and ovarian cancer. The increasing trend in proportion of cancer patients undergoing genetic testing, followed by predictive testing in families of new index patients, results in a significant increase of healthy germline BRCA1/2 mutation carriers who are at increased risk for breast, ovarian, and other BRCA-related cancers. This review aims to give an overview of available screening guidelines for female and male carriers of pathogenic or likely pathogenic germline BRCA1/2 variants per cancer type, incorporating malignancies that are more or less recently well correlated with BRCA1/2. We selected guidelines from national/international organizations and/or professional associations that were published or updated between January 1, 2015, and February 1, 2020. In total, 12 guidelines were included. This review reveals several significant discordances between the different guidelines. Optimal surveillance strategies depend on accurate age-specific cancer risk estimates, which are not reliably available for all BRCA-related cancers. Up-to-date national or international consensus guidelines are of utmost importance to harmonize counseling and proposed surveillance strategies for BRCA1/2 carriers.