Addition of Contrast-enhanced Mammography to Tomosynthesis for Breast Cancer Detection in Women with a Personal History of Breast Cancer: Prospective TOCEM Trial Interim Analysis.

Background Digital breast tomosynthesis (DBT) is often inadequate for screening women with a personal history of breast cancer (PHBC). The ongoing prospective Tomosynthesis or Contrast-Enhanced Mammography, or TOCEM, trial includes three annual screenings with both DBT and contrast-enhanced mammography (CEM). Purpose To perform interim assessment of cancer yield, stage, and recall rate when CEM is added to DBT in women with PHBC. Materials and Methods From October 2019 to December 2022, two radiologists interpreted both examinations: Observer 1 reviewed DBT first and then CEM, and observer 2 reviewed CEM first and then DBT. Effects of adding CEM to DBT on incremental cancer detection rate (ICDR), cancer type and node status, recall rate, and other performance characteristics of the primary radiologist decisions were assessed. Results Among the participants (mean age at entry, 63.6 years ± 9.6 [SD]), 1273, 819, and 227 women with PHBC completed year 1, 2, and 3 screening, respectively. For observer 1, year 1 cancer yield was 20 of 1273 (15.7 per 1000 screenings) for DBT and 29 of 1273 (22.8 per 1000 screenings; ICDR, 7.1 per 1000 screenings [95% CI: 3.2, 13.4]) for DBT plus CEM (P < .001). Year 2 plus 3 cancer yield was four of 1046 (3.8 per 1000 screenings) for DBT and eight of 1046 (7.6 per 1000 screenings; ICDR, 3.8 per 1000 screenings [95% CI: 1.0, 7.6]) for DBT plus CEM (P = .001). Year 1 recall rate for observer 1 was 103 of 1273 (8.1%) for (incidence) DBT alone and 187 of 1273 (14.7%) for DBT plus CEM (difference = 84 of 1273, 6.6% [95% CI: 5.3, 8.1]; P < .001). Year 2 plus 3 recall rate was 40 of 1046 (3.8%) for DBT and 92 of 1046 (8.8%) for DBT plus CEM (difference = 52 of 1046, 5.0% [95% CI: 3.7, 6.3]; P < .001). In 18 breasts with cancer detected only at CEM after integration of both observers, 13 (72%) cancers were invasive (median tumor size, 0.6 cm) and eight of nine (88%) with staging were N0. Among 1883 screenings with adequate reference standard, there were three interval cancers (one at the scar, two in axillae). Conclusion CEM added to DBT increased early breast cancer detection each year in women with PHBC, with an accompanying approximately 5.0%-6.6% recall rate increase. Clinical trial registration no. NCT04085510 © RSNA, 2024 Supplemental material is available for this article.

Prospective Multicenter Diagnostic Performance of Technologist-Performed Screening Breast Ultrasound After Tomosynthesis in Women With Dense Breasts (the DBTUST).

PURPOSE: To assess diagnostic performance of digital breast tomosynthesis (DBT) alone or combined with technologist-performed handheld screening ultrasound (US) in women with dense breasts. METHODS: In an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant multicenter protocol in western Pennsylvania, 6,179 women consented to three rounds of annual screening, interpreted by two radiologist observers, and had appropriate follow-up. Primary analysis was based on first observer results. RESULTS: Mean participant age was 54.8 years (range, 40-75 years). Across 17,552 screens, there were 126 cancer events in 125 women (7.2/1,000; 95% CI, 5.9 to 8.4). In year 1, DBT-alone cancer yield was 5.0/1,000, and of DBT+US, 6.3/1,000, difference 1.3/1,000 (95% CI, 0.3 to 2.1; P = .005). In years 2 + 3, DBT cancer yield was 4.9/1,000, and of DBT+US, 5.9/1,000, difference 1.0/1,000 (95% CI, 0.4 to 1.5; P < .001). False-positive rate increased from 7.0% for DBT in year 1 to 11.5% for DBT+US and from 5.9% for DBT in year 2 + 3 to 9.7% for DBT+US (P < .001 for both). Nine cancers were seen only by double reading DBT and one by double reading US. Ten interval cancers (0.6/1,000 [95% CI, 0.2 to 0.9]) were identified. Despite reduction in specificity, addition of US improved receiver operating characteristic curves, with area under receiver operating characteristic curve increasing from 0.83 for DBT alone to 0.92 for DBT+US in year 1 (P = .01), with smaller improvements in subsequent years. Of 6,179 women, across all 3 years, 172/6,179 (2.8%) unique women had a false-positive biopsy because of DBT as did another 230/6,179 (3.7%) women because of US (P < .001). CONCLUSION: Overall added cancer detection rate of US screening after DBT was modest at 19/17,552 (1.1/1,000; CI, 0.5- to 1.6) screens but potentially overcomes substantial increases in false-positive recalls and benign biopsies.

Contrast-enhanced Mammography-guided Biopsy: Initial Trial and Experience.

OBJECTIVE: Evaluate lesion visibility and radiologist confidence during contrast-enhanced mammography (CEM)-guided biopsy. METHODS: Women with BI-RADS ≥4A enhancing breast lesions were prospectively recruited for 9-g vacuum-assisted CEM-guided biopsy. Breast density, background parenchymal enhancement (BPE), lesion characteristics (enhancement and conspicuity), radiologist confidence (scale 1-5), and acquisition times were collected. Signal intensities in specimens were analyzed. Patient surveys were collected. RESULTS: A cohort of 28 women aged 40-81 years (average 57) had 28 enhancing lesions (7/28, 25% malignant). Breast tissue was scattered (10/28, 36%) or heterogeneously dense (18/28, 64%) with minimal (12/28, 43%), mild (7/28, 25%), or moderate (9/28, 32%) BPE on CEM. Twelve non-mass enhancements, 11 masses, 3 architectural distortions, and 2 calcification groups demonstrated weak (12/28, 43%), moderate (14/28, 50%), or strong (2/28, 7%) enhancement. Specimen radiography demonstrated lesion enhancement in 27/28 (96%). Radiologists reported complete lesion removal on specimen radiography in 8/28 (29%). Average time from contrast injection to specimen radiography was 18 minutes (SD = 5) and, to post-procedure mammogram (PPM), 34 minutes (SD = 10). Contrast-enhanced mammography PPM was performed in 27/28 cases; 13/19 (68%) of incompletely removed lesions on specimen radiography showed residual enhancement; 6/19 (32%) did not. Across all time points, average confidence was 2.2 (SD = 1.2). Signal intensities of enhancing lesions were similar to iodine. Patients had an overall positive assessment. CONCLUSION: Lesion enhancement persisted through PPM and was visible on low energy specimen radiography, with an average "confident" score. Contrast-enhanced mammography-guided breast biopsy is easily implemented clinically. Its availability will encourage adoption of CEM.

Contrast Enhanced Digital Mammography (CEDM) Helps to Safely Reduce Benign Breast Biopsies for Low to Moderately Suspicious Soft Tissue Lesions.

RATIONALE AND OBJECTIVES: To preliminarily asses if Contrast Enhanced Digital Mammography (CEDM) can accurately reduce biopsy rates for soft tissue BI-RADS 4A or 4B lesions. MATERIALS AND METHODS: Eight radiologists retrospectively and independently reviewed 60 lesions in 54 consenting patients who underwent CEDM under Health Insurance Portability and Accountability Act compliant institutional review board-approved protocols. Readers provided Breast Imaging Reporting & Data System ratings sequentially for digital mammography/digital breast tomosynthesis (DM/DBT), then with ultrasound, then with CEDM for each lesion. Area under the curve (AUC), true positive rates and false positive rates, positive predictive values and negative predictive values were calculated. Statistical analysis accounting for correlation between lesion-examinations and between-reader variability was performed using OR/DBM (for SAS v.3.0), generalized linear mixed model for binary data (proc glimmix, SAS v.9.4, SAS Institute, Cary North Carolina), and bootstrap. RESULTS: The cohort included 49 benign, two high-risk and nine cancerous lesions in 54 women aged 34-74 (average 50) years. Reader-averaged AUC for CEDM was significantly higher than DM/DBT alone (0.85 versus 0.66, p < 0.001) or with US (0.85 versus 0.75, p = 0.001). CEDM increased true positive rates from 0.74 under DB/DBT, and 0.89 with US, to 0.90 with CEDM, (p = 0.019 DM/DBT versus CEDM, p = 0.78 DM/DBT + US versus CEDM) and decreased false positive rates from 0.47 using DM/DBT and 0.61 with US to 0.39 with CEDM (p = 0.017 DM/DBT versus CEDM, p = 0.001 DM/DBT+ US versus CEDM). For an expected cancer rate of 10%, CEDM positive predictive values was 20.5% (95% CI: 16%-27%) and negative predictive values 98.3% (95% CI: 96%-100%). CONCLUSION: Addition of CEDM for evaluation of low-moderate suspicion soft tissue breast lesions can substantially reduce biopsy of benign lesions without compromising cancer detection.

Diagnostic Performance of MRI, Molecular Breast Imaging, and Contrast-enhanced Mammography in Women with Newly Diagnosed Breast Cancer.

Background Staging newly diagnosed breast cancer by using dynamic contrast material-enhanced MRI is limited by access, high cost, and false-positive findings. The utility of contrast-enhanced mammography (CEM) and 99mTc sestamibi-based molecular breast imaging (MBI) in this setting is largely unknown. Purpose To compare extent-of-disease assessments by using MRI, CEM, and MBI versus pathology in women with breast cancer. Materials and Methods In this HIPAA-compliant prospective study, women with biopsy-proven breast cancer underwent MRI, CEM, and MBI between October 2014 and April 2018. Eight radiologists independently interpreted each examination result prospectively and were blinded to interpretations of findings with the other modalities. Visibility of index malignancies, lesion size, and additional suspicious lesions (malignant or benign) were compared during pathology review. Accuracy of index lesion sizing and detection of additional lesions in women without neoadjuvant chemotherapy were compared. Results A total of 102 women were enrolled and 99 completed the study protocol (mean age, 51 years ± 11 [standard deviation]; range, 32-77 years). Lumpectomy or mastectomy was performed in 71 women (79 index malignancies) without neoadjuvant chemotherapy and in 28 women (31 index malignancies) with neoadjuvant chemotherapy. Of the 110 index malignancies, MRI, CEM, and MBI depicted 102 (93%; 95% confidence interval [CI]: 86%, 97%), 100 (91%; 95% CI: 84%, 96%), and 101 (92%; 95% CI: 85%, 96%) malignancies, respectively. In patients without neoadjuvant chemotherapy, pathologic size of index malignancies was overestimated with all modalities (P = .02). MRI led to overestimation of 24% (17 of 72) of malignancies by more than 1.5 cm compared with 11% (eight of 70) with CEM and 15% (11 of 72) with MBI. MRI depicted more (P = .007) nonindex lesions, with sensitivity similar to that of CEM or MBI, resulting in lower positive predictive value of additional biopsies (13 of 46 [28%; 95% CI: 17%, 44%] for MRI; 14 of 27 [52%; 95% CI: 32%, 71%] for CEM; and 11 of 25 [44%; 95% CI: 24%, 65%] for MBI (overall P = .01). Conclusion Contrast-enhanced mammography, molecular breast imaging, and MRI showed similar detection of all malignancies. MRI depicted more nonindex suspicious benign lesions than did contrast-enhanced mammography or molecular breast imaging, leading to lower positive predictive value of additional biopsies. All three modalities led to overestimation of index tumor size, particularly MRI. © RSNA, 2019 Online supplemental material is available for this article.

Effect of the Availability of Prior Full-Field Digital Mammography and Digital Breast Tomosynthesis Images on the Interpretation of Mammograms.

PURPOSE: To assess the effect of and interaction between the availability of prior images and digital breast tomosynthesis (DBT) images in decisions to recall women during mammogram interpretation. MATERIALS AND METHODS: Verbal informed consent was obtained for this HIPAA-compliant institutional review board-approved protocol. Eight radiologists independently interpreted twice deidentified mammograms obtained in 153 women (age range, 37-83 years; mean age, 53.7 years ± 9.3 [standard deviation]) in a mode by reader by case-balanced fully crossed study. Each study consisted of current and prior full-field digital mammography (FFDM) images and DBT images that were acquired in our facility between June 2009 and January 2013. For one reading, sequential ratings were provided by using (a) current FFDM images only, (b) current FFDM and DBT images, and (c) current FFDM, DBT, and prior FFDM images. The other reading consisted of (a) current FFDM images only, (b) current and prior FFDM images, and (c) current FFDM, prior FFDM, and DBT images. Fifty verified cancer cases, 60 negative and benign cases (clinically not recalled), and 43 benign cases (clinically recalled) were included. Recall recommendations and interaction between the effect of prior FFDM and DBT images were assessed by using a generalized linear model accounting for case and reader variability. RESULTS: Average recall rates in noncancer cases were significantly reduced with the addition of prior FFDM images by 34% (145 of 421) and 32% (106 of 333) without and with DBT images, respectively (P < .001). However, this recall reduction was achieved at the cost of a corresponding 7% (23 of 345) and 4% (14 of 353) reduction in sensitivity (P = .006). In contrast, availability of DBT images resulted in a smaller reduction in recall rates (false-positive interpretations) of 19% (76 of 409) and 26% (71 of 276) without and with prior FFDM images, respectively (P = .001). Availability of DBT images resulted in 4% (15 of 338) and 8% (25 of 322) increases in sensitivity, respectively (P = .007). The effects of the availability of prior FFDM images or DBT images did not significantly change regardless of the sequence in presentation (P = .81 and P = .47 for specificity and sensitivity, respectively). CONCLUSION: The availability of prior FFDM or DBT images is a largely independent contributing factor in reducing recall recommendations during mammographic interpretation.

Ultrasound Guided Core Biopsy versus Fine Needle Aspiration for Evaluation of Axillary Lymphadenopathy in Patients with Breast Cancer.

Rationale and Objectives. To compare the sensitivities of ultrasound guided core biopsy and fine needle aspiration (FNA) for detection of axillary lymph node metastases in patients with a current diagnosis of ipsilateral breast cancer. Materials and Methods. From December 2008 to December 2010, 105 patients with breast cancer and abnormal appearing lymph nodes in the ipsilateral axilla consented to undergo FNA of an axillary node immediately followed by core biopsy of the same node, both with ultrasound guidance. Experienced pathologists evaluated the aspirate cytology without knowledge of the core histology. Cytology and core biopsy results were compared to sentinel node excision or axillary dissection pathology. Sensitivities were compared using McNemar's test. Results. Of 70 patients with axillary node metastases, FNA was positive in 55/70 (78.6%) and core was positive in 61/70 (87.1%) (P = 0.18). The FNA and core results were discordant in 14/70 (20%) patients. Ten cases were FNA negative/core positive. Four cases were FNA positive/core negative. Conclusion. Core biopsy detected six (8.6%) more cases of metastatic lymphadenopathy than FNA but the difference in sensitivities was not statistically significant. Core biopsy should be considered if the node is clearly imaged and readily accessible. FNA is a good alternative when a smaller needle is desired due to node location or other patient factors. This trial is registered with NCT01920139.

Comparison of two-dimensional synthesized mammograms versus original digital mammograms alone and in combination with tomosynthesis images.

PURPOSE: To assess interpretation performance and radiation dose when two-dimensional synthesized mammography (SM) images versus standard full-field digital mammography (FFDM) images are used alone or in combination with digital breast tomosynthesis images. MATERIALS AND METHODS: A fully crossed, mode-balanced multicase (n = 123), multireader (n = 8), retrospective observer performance study was performed by using deidentified images acquired between 2008 and 2011 with institutional review board approved, HIPAA-compliant protocols, during which each patient signed informed consent. The cohort included 36 cases of biopsy-proven cancer, 35 cases of biopsy-proven benign lesions, and 52 normal or benign cases (Breast Imaging Reporting and Data System [BI-RADS] score of 1 or 2) with negative 1-year follow-up results. Accuracy of sequentially reported probability of malignancy ratings and seven-category forced BI-RADS ratings was evaluated by using areas under the receiver operating characteristic curve (AUCs) in the random-reader analysis. RESULTS: Probability of malignancy-based mean AUCs for SM and FFDM images alone was 0.894 and 0.889, respectively (difference, -0.005; 95% confidence interval [CI]: -0.062, 0.054; P = .85). Mean AUC for SM with tomosynthesis and FFDM with tomosynthesis was 0.916 and 0.939, respectively (difference, 0.023; 95% CI: -0.011, 0.057; P = .19). In terms of the reader-specific AUCs, five readers performed better with SM alone versus FFDM alone, and all eight readers performed better with combined FFDM and tomosynthesis (absolute differences from 0.003 to 0.052). Similar results were obtained by using a nonparametric analysis of forced BI-RADS ratings. CONCLUSION: SM alone or in combination with tomosynthesis is comparable in performance to FFDM alone or in combination with tomosynthesis and may eliminate the need for FFDM as part of a routine clinical study.

Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development.

Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell proliferation and their effects on organ growth are complex and for many organs incompletely understood. In all vertebrate species, the cardiac natriuretic peptides (ANP and BNP) are produced by cardiomyocytes in the developing heart. However, their role during cardiogenesis is not defined. Using the embryonic zebrafish and neonatal mammalian cardiomyocytes we explored the natriuretic peptide signaling network during myocardial development. We observed that the cardiac natriuretic peptides ANP and BNP and the guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2 are functionally redundant during early cardiovascular development. In addition, we demonstrate that low levels of the natriuretic peptides preferentially activate Npr3, a receptor with Gi activator sequences, and increase cardiomyocyte proliferation through inhibition of adenylate cyclase. Conversely, high concentrations of natriuretic peptides reduce cardiomyocyte proliferation through activation of the particulate guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2, and activation of protein kinase G. These data link the cardiac natriuretic peptides in a complex hierarchy modulating cardiomyocyte numbers during development through opposing effects on cardiomyocyte proliferation mediated through distinct cyclic nucleotide signaling pathways.

Digital breast tomosynthesis versus supplemental diagnostic mammographic views for evaluation of noncalcified breast lesions.

PURPOSE: To compare the diagnostic performance of breast tomosynthesis versus supplemental mammography views in classification of masses, distortions, and asymmetries. MATERIALS AND METHODS: Eight radiologists who specialized in breast imaging retrospectively reviewed 217 consecutively accrued lesions by using protocols that were HIPAA compliant and institutional review board approved in 182 patients aged 31-60 years (mean, 50 years) who underwent diagnostic mammography and tomosynthesis. The lesions in the cohort included 33% (72 of 217) cancers and 67% (145 of 217) benign lesions. Eighty-four percent (182 of 217) of the lesions were masses, 11% (25 of 217) were asymmetries, and 5% (10 of 217) were distortions that were initially detected at clinical examination in 8% (17 of 217), at mammography in 80% (173 of 217), at ultrasonography (US) in 11% (25 of 217), or at magnetic resonance imaging in 1% (2 of 217). Histopathologic examination established truth in 191 lesions, US revealed a cyst in 12 lesions, and 14 lesions had a normal follow-up. Each lesion was interpreted once with tomosynthesis and once with supplemental mammographic views; both modes included the mediolateral oblique and craniocaudal views in a fully crossed and balanced design by using a five-category Breast Imaging Reporting and Data System (BI-RADS) assessment and a probability-of-malignancy score. Differences between modes were analyzed with a generalized linear mixed model for BI-RADS-based sensitivity and specificity and with modified Obuchowski-Rockette approach for probability-of-malignancy-based area under the receiver operating characteristic (ROC) curve. RESULTS: Average probability-of-malignancy-based area under the ROC curve was 0.87 for tomosynthesis versus 0.83 for supplemental views (P < .001). With tomosynthesis, the false-positive rate decreased from 85% (989 of 1160) to 74% (864 of 1160) (P < .01) for cases that were rated BI-RADS category 3 or higher and from 57% (663 of 1160) to 48% (559 of 1160) for cases rated BI-RADS category 4 or 5 (P < .01), without a meaningful change in sensitivity. With tomosynthesis, more cancers were classified as BI-RADS category 5 (39% [226 of 576] vs 33% [188 of 576]; P = .017) without a decrease in specificity. CONCLUSION: Tomosynthesis significantly improved diagnostic accuracy for noncalcified lesions compared with supplemental mammographic views.

Widespread iron-rich conditions in the mid-Proterozoic ocean.

The chemical composition of the ocean changed markedly with the oxidation of the Earth's surface, and this process has profoundly influenced the evolutionary and ecological history of life. The early Earth was characterized by a reducing ocean-atmosphere system, whereas the Phanerozoic eon (less than 542 million years ago) is known for a stable and oxygenated biosphere conducive to the radiation of animals. The redox characteristics of surface environments during Earth's middle age (1.8-1 billion years ago) are less well known, but it is generally assumed that the mid-Proterozoic was home to a globally sulphidic (euxinic) deep ocean. Here we present iron data from a suite of mid-Proterozoic marine mudstones. Contrary to the popular model, our results indicate that ferruginous (anoxic and Fe(2+)-rich) conditions were both spatially and temporally extensive across diverse palaeogeographic settings in the mid-Proterozoic ocean, inviting new models for the temporal distribution of iron formations and the availability of bioessential trace elements during a critical window for eukaryotic evolution.