An Artificial Intelligence-based Mammography Screening Protocol for Breast Cancer: Outcome and Radiologist Workload.

Background Developments in artificial intelligence (AI) systems to assist radiologists in reading mammograms could improve breast cancer screening efficiency. Purpose To investigate whether an AI system could detect normal, moderate-risk, and suspicious mammograms in a screening sample to safely reduce radiologist workload and evaluate across Breast Imaging Reporting and Data System (BI-RADS) densities. Materials and Methods This retrospective simulation study analyzed mammographic examination data consecutively collected from January 2014 to December 2015 in the Danish Capital Region breast cancer screening program. All mammograms were scored from 0 to 10, representing the risk of malignancy, using an AI tool. During simulation, normal mammograms (score < 5) would be excluded from radiologist reading and suspicious mammograms (score > recall threshold [RT]) would be recalled. Two radiologists read the remaining mammograms. The RT was fitted using another independent cohort (same institution) by matching to the radiologist sensitivity. This protocol was further applied to each BI-RADS density. Screening outcomes were measured using the sensitivity, specificity, workload, and false-positive rate. The AI-based screening was tested for noninferiority sensitivity compared with radiologist screening using the Farrington-Manning test. Specificities were compared using the McNemar test. Results The study sample comprised 114 421 screenings for breast cancer in 114 421 women, resulting in 791 screen-detected, 327 interval, and 1473 long-term cancers and 2107 false-positive screenings. The mean age of the women was 59 years ± 6 (SD). The AI-based screening sensitivity was 69.7% (779 of 1118; 95% CI: 66.9, 72.4) and was noninferior (P = .02) to the radiologist screening sensitivity of 70.8% (791 of 1118; 95% CI: 68.0, 73.5). The AI-based screening specificity was 98.6% (111 725 of 113 303; 95% CI: 98.5, 98.7), which was higher (P < .001) than the radiologist specificity of 98.1% (111 196 of 113 303; 95% CI: 98.1, 98.2). The radiologist workload was reduced by 62.6% (71 585 of 114 421), and 25.1% (529 of 2107) of false-positive screenings were avoided. Screening results were consistent across BI-RADS densities, although not significantly so for sensitivity. Conclusion Artificial intelligence (AI)-based screening could detect normal, moderate-risk, and suspicious mammograms in a breast cancer screening program, which may reduce the radiologist workload. AI-based screening performed consistently across breast densities. © RSNA, 2022 Online supplemental material is available for this article.

Stand-Alone Use of Artificial Intelligence for Digital Mammography and Digital Breast Tomosynthesis Screening: A Retrospective Evaluation.

Background Use of artificial intelligence (AI) as a stand-alone reader for digital mammography (DM) or digital breast tomosynthesis (DBT) breast screening could ease radiologists' workload while maintaining quality. Purpose To retrospectively evaluate the stand-alone performance of an AI system as an independent reader of DM and DBT screening examinations. Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired between January 2015 and December 2016 were retrospectively collected from the Tomosynthesis Cordoba Screening Trial. An AI system computed a cancer risk score (range, 1-100) for DM and DBT examinations independently. AI stand-alone performance was measured using the area under the receiver operating characteristic curve (AUC) and sensitivity and recall rate at different operating points selected to have noninferior sensitivity compared with the human readings (noninferiority margin, 5%). The recall rate of AI and the human readings were compared using a McNemar test. Results A total of 15 999 DM and DBT examinations (113 breast cancers, including 98 screen-detected and 15 interval cancers) from 15 998 women (mean age, 58 years ± 6 [standard deviation]) were evaluated. AI achieved an AUC of 0.93 (95% CI: 0.89, 0.96) for DM and 0.94 (95% CI: 0.91, 0.97) for DBT. For DM, AI achieved noninferior sensitivity as a single (58.4%; 66 of 113; 95% CI: 49.2, 67.1) or double (67.3%; 76 of 113; 95% CI: 58.2, 75.2) reader, with a reduction in recall rate (P < .001) of up to 2% (95% CI: -2.4, -1.6). For DBT, AI achieved noninferior sensitivity as a single (77%; 87 of 113; 95% CI: 68.4, 83.8) or double (81.4%; 92 of 113; 95% CI: 73.3, 87.5) reader, but with a higher recall rate (P < .001) of up to 12.3% (95% CI: 11.7, 12.9). Conclusion Artificial intelligence could replace radiologists' readings in breast screening, achieving a noninferior sensitivity, with a lower recall rate for digital mammography but a higher recall rate for digital breast tomosynthesis. Published under a CC BY 4.0 license. See also the editorial by Fuchsjäger and Adelsmayr in this issue.

Interval Cancer Detection Using a Neural Network and Breast Density in Women with Negative Screening Mammograms.

Background Inclusion of mammographic breast density (BD) in breast cancer risk models improves accuracy, but accuracy remains modest. Interval cancer (IC) risk prediction may be improved by combining assessments of BD and an artificial intelligence (AI) cancer detection system. Purpose To evaluate the performance of a neural network (NN)-based model that combines the assessments of BD and an AI system in the prediction of risk of developing IC among women with negative screening mammography results. Materials and Methods This retrospective nested case-control study performed with screening examinations included women who developed IC and women with normal follow-up findings (from January 2011 to January 2015). An AI cancer detection system analyzed all studies yielding a score of 1-10, representing increasing likelihood of malignancy. BD was automatically computed using publicly available software. An NN model was trained by combining the AI score and BD using 10-fold cross-validation. Bootstrap analysis was used to calculate the area under the receiver operating characteristic curve (AUC), sensitivity at 90% specificity, and 95% CIs of the AI, BD, and NN models. Results A total of 2222 women with IC and 4661 women in the control group were included (mean age, 61 years; age range, 49-76 years). AUC of the NN model was 0.79 (95% CI: 0.77,0.81), which was higher than AUC of the AI cancer detection system or BD alone (AUC, 0.73 [95% CI: 0.71, 0.76] and 0.69 [95% CI: 0.67, 0.71], respectively; P < .001 for both). At 90% specificity, the NN model had a sensitivity of 50.9% (339 of 666 women; 95% CI: 45.2, 56.3) for prediction of IC, which was higher than that of the AI system (37.5%; 250 of 666 women; 95% CI: 33.0, 43.7; P < .001) or BD percentage alone (22.4%; 149 of 666 women; 95% CI: 17.9, 28.5; P < .001). Conclusion The combined assessment of an artificial intelligence detection system and breast density measurements enabled identification of a larger proportion of women who would develop interval cancer compared with either method alone. Published under a CC BY 4.0 license.

The role of TNFRSF11B in development of osteoarthritic cartilage.

OBJECTIVES: OA is a complex genetic disease with different risk factors contributing to its development. One of the genes, TNFRSF11B, previously identified with gain-of-function mutation in a family with early-onset OA with chondrocalcinosis, is among the highest upregulated genes in lesioned OA cartilage (RAAK-study). Here, we determined the role of TNFRSF11B overexpression in development of OA. METHODS: Human primary articular chondrocytes (9 donors RAAK study) were transduced using lentiviral particles with or without TNFRSF11B. Cells were cultured for 1 week in a 3 D in-vitro chondrogenic model. TNFRSF11B overexpression was confirmed by RT-qPCR, immunohistochemistry and ELISA. Effects of TNFRSF11B overexpression on cartilage matrix deposition, matrix mineralization, and genes highly correlated to TNFRSF11B in RNA-sequencing dataset (r >0.75) were determined by RT-qPCR. Additionally, glycosaminoglycans and collagen deposition were visualized with Alcian blue staining and immunohistochemistry (COL1 and COL2). RESULTS: Overexpression of TNFRSF11B resulted in strong upregulation of MMP13, COL2A1 and COL1A1. Likewise, mineralization and osteoblast characteristic markers RUNX2, ASPN and OGN showed a consistent increase. Among 30 genes highly correlated to TNFRSF11B, expression of only eight changed significantly, with BMP6 showing the highest increase (9-fold) while expression of RANK and RANKL remained unchanged indicating previously unknown downstream pathways of TNFRSF11B in cartilage. CONCLUSION: Results of our 3D in vitro chondrogenesis model indicate that upregulation of TNFRSF11B in lesioned OA cartilage may act as a direct driving factor for chondrocyte to osteoblast transition observed in OA pathophysiology. This transition does not appear to act via the OPG/RANK/RANKL triad common in bone remodeling.

Mutation in the CCAL1 locus accounts for bidirectional process of human subchondral bone turnover and cartilage mineralization.

OBJECTIVES: To study the mechanism by which the readthrough mutation in TNFRSF11B, encoding osteoprotegerin (OPG) with additional 19 amino acids at its C-terminus (OPG-XL), causes the characteristic bidirectional phenotype of subchondral bone turnover accompanied by cartilage mineralization in chondrocalcinosis patients. METHODS: OPG-XL was studied by human induced pluripotent stem cells expressing OPG-XL and two isogenic CRISPR/Cas9-corrected controls in cartilage and bone organoids. Osteoclastogenesis was studied with monocytes from OPG-XL carriers and matched healthy controls followed by gene expression characterization. Dual energy X-ray absorptiometry scans and MRI analyses were used to characterize the phenotype of carriers and non-carriers of the mutation. RESULTS: Human OPG-XL carriers relative to sex- and age-matched controls showed, after an initial delay, large active osteoclasts with high number of nuclei. By employing hiPSCs expressing OPG-XL and isogenic CRISPR/Cas9-corrected controls to established cartilage and bone organoids, we demonstrated that expression of OPG-XL resulted in excessive fibrosis in cartilage and high mineralization in bone accompanied by marked downregulation of MGP, encoding matrix Gla protein, and upregulation of DIO2, encoding type 2 deiodinase, gene expression, respectively. CONCLUSIONS: The readthrough mutation at CCAL1 locus in TNFRSF11B identifies an unknown role for OPG-XL in subchondral bone turnover and cartilage mineralization in humans via DIO2 and MGP functions. Previously, OPG-XL was shown to affect binding between RANKL and heparan sulphate (HS) resulting in loss of immobilized OPG-XL. Therefore, effects may be triggered by deficiency in the immobilization of OPG-XL Since the characteristic bidirectional pathophysiology of articular cartilage calcification accompanied by low subchondral bone mineralization is also a hallmark of OA pathophysiology, our results are likely extrapolated to common arthropathies.

Using deep learning to assist readers during the arbitration process: a lesion-based retrospective evaluation of breast cancer screening performance.

OBJECTIVES: To evaluate if artificial intelligence (AI) can discriminate recalled benign from recalled malignant mammographic screening abnormalities to improve screening performance. METHODS: A total of 2257 full-field digital mammography screening examinations, obtained 2011-2013, of women aged 50-69 years which were recalled for further assessment of 295 malignant out of 305 truly malignant lesions and 2289 benign lesions after independent double-reading with arbitration, were included in this retrospective study. A deep learning AI system was used to obtain a score (0-95) for each recalled lesion, representing the likelihood of breast cancer. The sensitivity on the lesion level and the proportion of women without false-positive ratings (non-FPR) resulting under AI were estimated as a function of the classification cutoff and compared to that of human readers. RESULTS: Using a cutoff of 1, AI decreased the proportion of women with false-positives from 89.9 to 62.0%, non-FPR 11.1% vs. 38.0% (difference 26.9%, 95% confidence interval 25.1-28.8%; p < .001), preventing 30.1% of reader-induced false-positive recalls, while reducing sensitivity from 96.7 to 91.1% (5.6%, 3.1-8.0%) as compared to human reading. The positive predictive value of recall (PPV-1) increased from 12.8 to 16.5% (3.7%, 3.5-4.0%). In women with mass-related lesions (n = 900), the non-FPR was 14.2% for humans vs. 36.7% for AI (22.4%, 19.8-25.3%) at a sensitivity of 98.5% vs. 97.1% (1.5%, 0-3.5%). CONCLUSION: The application of AI during consensus conference might especially help readers to reduce false-positive recalls of masses at the expense of a small sensitivity reduction. Prospective studies are needed to further evaluate the screening benefit of AI in practice. KEY POINTS: • Integrating the use of artificial intelligence in the arbitration process reduces benign recalls and increases the positive predictive value of recall at the expense of some sensitivity loss. • Application of the artificial intelligence system to aid the decision to recall a woman seems particularly beneficial for masses, where the system reaches comparable sensitivity to that of the readers, but with considerably reduced false-positives. • About one-fourth of all recalled malignant lesions are not automatically marked by the system such that their evaluation (AI score) must be retrieved manually by the reader. A thorough reading of screening mammograms by readers to identify suspicious lesions therefore remains mandatory.

Impact of Artificial Intelligence Decision Support Using Deep Learning on Breast Cancer Screening Interpretation with Single-View Wide-Angle Digital Breast Tomosynthesis.

Background The high volume of data in digital breast tomosynthesis (DBT) and the lack of agreement on how to best implement it in screening programs makes its use challenging. Purpose To compare radiologist performance when reading single-view wide-angle DBT images with and without an artificial intelligence (AI) system for decision and navigation support. Materials and Methods A retrospective observer study was performed with bilateral mediolateral oblique examinations and corresponding synthetic two-dimensional images acquired between June 2016 and February 2018 with a wide-angle DBT system. Fourteen breast screening radiologists interpreted 190 DBT examinations (90 normal, 26 with benign findings, and 74 with malignant findings), with the reference standard being verified by using histopathologic analysis or at least 1 year of follow-up. Reading was performed in two sessions, separated by at least 4 weeks, with a random mix of examinations being read with and without AI decision and navigation support. Forced Breast Imaging Reporting and Data System (categories 1-5) and level of suspicion (1-100) scores were given per breast by each reader. The area under the receiver operating characteristic curve (AUC) and the sensitivity and specificity were compared between conditions by using the public-domain iMRMC software. The average reading times were compared by using the Wilcoxon signed rank test. Results The 190 women had a median age of 54 years (range, 48-63 years). The examination-based reader-averaged AUC was higher when interpreting results with AI support than when reading unaided (0.88 [95% CI: 0.84, 0.92] vs 0.85 [95% CI: 0.80, 0.89], respectively; P = .01). The average sensitivity increased with AI support (64 of 74, 86% [95% CI: 80%, 92%] vs 60 of 74, 81% [95% CI: 74%, 88%]; P = .006), whereas no differences in the specificity (85 of 116, 73.3% [95% CI: 65%, 81%] vs 83 of 116, 71.6% [95% CI: 65%, 78%]; P = .48) or reading time (48 seconds vs 45 seconds; P = .35) were detected. Conclusion Using a single-view digital breast tomosynthesis (DBT) and artificial intelligence setup could allow for a more effective screening program with higher performance, especially in terms of an increase in cancers detected, than using single-view DBT alone. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chan and Helvie in this issue.

AI-based Strategies to Reduce Workload in Breast Cancer Screening with Mammography and Tomosynthesis: A Retrospective Evaluation.

Background The workflow of breast cancer screening programs could be improved given the high workload and the high number of false-positive and false-negative assessments. Purpose To evaluate if using an artificial intelligence (AI) system could reduce workload without reducing cancer detection in breast cancer screening with digital mammography (DM) or digital breast tomosynthesis (DBT). Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired from January 2015 to December 2016 were retrospectively collected from the Córdoba Tomosynthesis Screening Trial. The original reading settings were single or double reading of DM or DBT images. An AI system computed a cancer risk score for DM and DBT examinations independently. Each original setting was compared with a simulated autonomous AI triaging strategy (the least suspicious examinations for AI are not human-read; the rest are read in the same setting as the original, and examinations not recalled by radiologists but graded as very suspicious by AI are recalled) in terms of workload, sensitivity, and recall rate. The McNemar test with Bonferroni correction was used for statistical analysis. Results A total of 15 987 DM and DBT examinations (which included 98 screening-detected and 15 interval cancers) from 15 986 women (mean age ± standard deviation, 58 years ± 6) were evaluated. In comparison with double reading of DBT images (568 hours needed, 92 of 113 cancers detected, 706 recalls in 15 987 examinations), AI with DBT would result in 72.5% less workload (P < .001, 156 hours needed), noninferior sensitivity (95 of 113 cancers detected, P = .38), and 16.7% lower recall rate (P < .001, 588 recalls in 15 987 examinations). Similar results were obtained for AI with DM. In comparison with the original double reading of DM images (222 hours needed, 76 of 113 cancers detected, 807 recalls in 15 987 examinations), AI with DBT would result in 29.7% less workload (P < .001), 25.0% higher sensitivity (P < .001), and 27.1% lower recall rate (P < .001). Conclusion Digital mammography and digital breast tomosynthesis screening strategies based on artificial intelligence systems could reduce workload up to 70%. Published under a CC BY 4.0 license.

Cartilage from human-induced pluripotent stem cells: comparison with neo-cartilage from chondrocytes and bone marrow mesenchymal stromal cells.

Cartilage has little intrinsic capacity for repair, so transplantation of exogenous cartilage cells is considered a realistic option for cartilage regeneration. We explored whether human-induced pluripotent stem cells (hiPSCs) could represent such unlimited cell sources for neo-cartilage comparable to human primary articular chondrocytes (hPACs) or human bone marrow-derived mesenchymal stromal cells (hBMSCs). For this, chondroprogenitor cells (hiCPCs) and hiPSC-derived mesenchymal stromal cells (hiMSCs) were generated from two independent hiPSC lines and characterized by morphology, flow cytometry, and differentiation potential. Chondrogenesis was compared to hBMSCs and hPACs by histology, immunohistochemistry, and RT-qPCR, while similarities were estimated based on Pearson correlations using a panel of 20 relevant genes. Our data show successful differentiations of hiPSC into hiMSCs and hiCPCs. Characteristic hBMSC markers were shared between hBMSCs and hiMSCs, with the exception of CD146 and CD45. However, neo-cartilage generated from hiMSCs showed low resemblances when compared to hBMSCs (53%) and hPACs (39%) characterized by lower collagen type 2 and higher collagen type 1 expression. Contrarily, hiCPC neo-cartilage generated neo-cartilage more similar to hPACs (65%), with stronger expression of matrix deposition markers. Our study shows that taking a stepwise approach to generate neo-cartilage from hiPSCs via chondroprogenitor cells results in strong similarities to neo-cartilage of hPACs within 3 weeks following chondrogenesis, making them a potential candidate for regenerative therapies. Contrarily, neo-cartilage deposited by hiMSCs seems more prone to hypertrophic characteristics compared to hPACs. We therefore compared chondrocytes derived from hiMSCs and hiCPCs with hPACs and hBMSCs to outline similarities and differences between their neo-cartilage and establish their potential suitability for regenerative medicine and disease modelling.

Can artificial intelligence reduce the interval cancer rate in mammography screening?

OBJECTIVES: To investigate whether artificial intelligence (AI) can reduce interval cancer in mammography screening. MATERIALS AND METHODS: Preceding screening mammograms of 429 consecutive women diagnosed with interval cancer in Southern Sweden between 2013 and 2017 were analysed with a deep learning-based AI system. The system assigns a risk score from 1 to 10. Two experienced breast radiologists reviewed and classified the cases in consensus as true negative, minimal signs or false negative and assessed whether the AI system correctly localised the cancer. The potential reduction of interval cancer was calculated at different risk score thresholds corresponding to approximately 10%, 4% and 1% recall rates. RESULTS: A statistically significant correlation between interval cancer classification groups and AI risk score was observed (p < .0001). AI scored one in three (143/429) interval cancer with risk score 10, of which 67% (96/143) were either classified as minimal signs or false negative. Of these, 58% (83/143) were correctly located by AI, and could therefore potentially be detected at screening with the aid of AI, resulting in a 19.3% (95% CI 15.9-23.4) reduction of interval cancer. At 4% and 1% recall thresholds, the reduction of interval cancer was 11.2% (95% CI 8.5-14.5) and 4.7% (95% CI 3.0-7.1). The corresponding reduction of interval cancer with grave outcome (women who died or with stage IV disease) at risk score 10 was 23% (8/35; 95% CI 12-39). CONCLUSION: The use of AI in screen reading has the potential to reduce the rate of interval cancer without supplementary screening modalities. KEY POINTS: • Retrospective study showed that AI detected 19% of interval cancer at the preceding screening exam that in addition showed at least minimal signs of malignancy. Importantly, these were correctly localised by AI, thus obviating supplementary screening modalities. • AI could potentially reduce a proportion of particularly aggressive interval cancers. • There was a correlation between AI risk score and interval cancer classified as true negative, minimal signs or false negative.

Impact of artificial intelligence support on accuracy and reading time in breast tomosynthesis image interpretation: a multi-reader multi-case study.

OBJECTIVES: Digital breast tomosynthesis (DBT) increases sensitivity of mammography and is increasingly implemented in breast cancer screening. However, the large volume of images increases the risk of reading errors and reading time. This study aims to investigate whether the accuracy of breast radiologists reading wide-angle DBT increases with the aid of an artificial intelligence (AI) support system. Also, the impact on reading time was assessed and the stand-alone performance of the AI system in the detection of malignancies was compared to the average radiologist. METHODS: A multi-reader multi-case study was performed with 240 bilateral DBT exams (71 breasts with cancer lesions, 70 breasts with benign findings, 339 normal breasts). Exams were interpreted by 18 radiologists, with and without AI support, providing cancer suspicion scores per breast. Using AI support, radiologists were shown examination-based and region-based cancer likelihood scores. Area under the receiver operating characteristic curve (AUC) and reading time per exam were compared between reading conditions using mixed-models analysis of variance. RESULTS: On average, the AUC was higher using AI support (0.863 vs 0.833; p = 0.0025). Using AI support, reading time per DBT exam was reduced (p < 0.001) from 41 (95% CI = 39-42 s) to 36 s (95% CI = 35- 37 s). The AUC of the stand-alone AI system was non-inferior to the AUC of the average radiologist (+0.007, p = 0.8115). CONCLUSIONS: Radiologists improved their cancer detection and reduced reading time when evaluating DBT examinations using an AI reading support system. KEY POINTS: • Radiologists improved their cancer detection accuracy in digital breast tomosynthesis (DBT) when using an AI system for support, while simultaneously reducing reading time. • The stand-alone breast cancer detection performance of an AI system is non-inferior to the average performance of radiologists for reading digital breast tomosynthesis exams. • The use of an AI support system could make advanced and more reliable imaging techniques more accessible and could allow for more cost-effective breast screening programs with DBT.

Detection of Breast Cancer with Mammography: Effect of an Artificial Intelligence Support System.

Purpose To compare breast cancer detection performance of radiologists reading mammographic examinations unaided versus supported by an artificial intelligence (AI) system. Materials and Methods An enriched retrospective, fully crossed, multireader, multicase, HIPAA-compliant study was performed. Screening digital mammographic examinations from 240 women (median age, 62 years; range, 39-89 years) performed between 2013 and 2017 were included. The 240 examinations (100 showing cancers, 40 leading to false-positive recalls, 100 normal) were interpreted by 14 Mammography Quality Standards Act-qualified radiologists, once with and once without AI support. The readers provided a Breast Imaging Reporting and Data System score and probability of malignancy. AI support provided radiologists with interactive decision support (clicking on a breast region yields a local cancer likelihood score), traditional lesion markers for computer-detected abnormalities, and an examination-based cancer likelihood score. The area under the receiver operating characteristic curve (AUC), specificity and sensitivity, and reading time were compared between conditions by using mixed-models analysis dof variance and generalized linear models for multiple repeated measurements. Results On average, the AUC was higher with AI support than with unaided reading (0.89 vs 0.87, respectively; P = .002). Sensitivity increased with AI support (86% [86 of 100] vs 83% [83 of 100]; P = .046), whereas specificity trended toward improvement (79% [111 of 140]) vs 77% [108 of 140]; P = .06). Reading time per case was similar (unaided, 146 seconds; supported by AI, 149 seconds; P = .15). The AUC with the AI system alone was similar to the average AUC of the radiologists (0.89 vs 0.87). Conclusion Radiologists improved their cancer detection at mammography when using an artificial intelligence system for support, without requiring additional reading time. Published under a CC BY 4.0 license. See also the editorial by Bahl in this issue.

RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage.

OBJECTIVE: To uncover the microRNA (miRNA) interactome of the osteoarthritis (OA) pathophysiological process in the cartilage. METHODS: We performed RNA sequencing in 130 samples (n=35 and n=30 pairs for messenger RNA (mRNA) and miRNA, respectively) on macroscopically preserved and lesioned OA cartilage from the same patient and performed differential expression (DE) analysis of miRNA and mRNAs. To build an OA-specific miRNA interactome, a prioritisation scheme was applied based on inverse Pearson's correlations and inverse DE of miRNAs and mRNAs. Subsequently, these were filtered by those present in predicted (TargetScan/microT-CDS) and/or experimentally validated (miRTarBase/TarBase) public databases. Pathway enrichment analysis was applied to elucidate OA-related pathways likely mediated by miRNA regulatory mechanisms. RESULTS: We found 142 miRNAs and 2387 mRNAs to be differentially expressed between lesioned and preserved OA articular cartilage. After applying prioritisation towards likely miRNA-mRNA targets, a regulatory network of 62 miRNAs targeting 238 mRNAs was created. Subsequent pathway enrichment analysis of these mRNAs (or genes) elucidated that genes within the 'nervous system development' are likely mediated by miRNA regulatory mechanisms (familywise error=8.4×10-5). Herein NTF3 encodes neurotrophin-3, which controls survival and differentiation of neurons and which is closely related to the nerve growth factor. CONCLUSIONS: By an integrated approach of miRNA and mRNA sequencing data of OA cartilage, an OA miRNA interactome and related pathways were elucidated. Our functional data demonstrated interacting levels at which miRNA affects expression of genes in the cartilage and exemplified the complexity of functionally validating a network of genes that may be targeted by multiple miRNAs.

Can we reduce the workload of mammographic screening by automatic identification of normal exams with artificial intelligence? A feasibility study.

PURPOSE: To study the feasibility of automatically identifying normal digital mammography (DM) exams with artificial intelligence (AI) to reduce the breast cancer screening reading workload. METHODS AND MATERIALS: A total of 2652 DM exams (653 cancer) and interpretations by 101 radiologists were gathered from nine previously performed multi-reader multi-case receiver operating characteristic (MRMC ROC) studies. An AI system was used to obtain a score between 1 and 10 for each exam, representing the likelihood of cancer present. Using all AI scores between 1 and 9 as possible thresholds, the exams were divided into groups of low- and high likelihood of cancer present. It was assumed that, under the pre-selection scenario, only the high-likelihood group would be read by radiologists, while all low-likelihood exams would be reported as normal. The area under the reader-averaged ROC curve (AUC) was calculated for the original evaluations and for the pre-selection scenarios and compared using a non-inferiority hypothesis. RESULTS: Setting the low/high-likelihood threshold at an AI score of 5 (high likelihood > 5) results in a trade-off of approximately halving (- 47%) the workload to be read by radiologists while excluding 7% of true-positive exams. Using an AI score of 2 as threshold yields a workload reduction of 17% while only excluding 1% of true-positive exams. Pre-selection did not change the average AUC of radiologists (inferior 95% CI > - 0.05) for any threshold except at the extreme AI score of 9. CONCLUSION: It is possible to automatically pre-select exams using AI to significantly reduce the breast cancer screening reading workload. KEY POINTS: • There is potential to use artificial intelligence to automatically reduce the breast cancer screening reading workload by excluding exams with a low likelihood of cancer. • The exclusion of exams with the lowest likelihood of cancer in screening might not change radiologists' breast cancer detection performance. • When excluding exams with the lowest likelihood of cancer, the decrease in true-positive recalls would be balanced by a simultaneous reduction in false-positive recalls.

One-view digital breast tomosynthesis as a stand-alone modality for breast cancer detection: do we need more?

PURPOSE: To compare the performance of one-view digital breast tomosynthesis (1v-DBT) to that of three other protocols combining DBT and mammography (DM) for breast cancer detection. MATERIALS AND METHODS: Six radiologists, three experienced with 1v-DBT in screening, retrospectively reviewed 181 cases (76 malignant, 50 benign, 55 normal) in two sessions. First, they scored sequentially: 1v-DBT (medio-lateral oblique, MLO), 1v-DBT (MLO) + 1v-DM (cranio-caudal, CC) and two-view DM + DBT (2v-DM+2v-DBT). The second session involved only 2v-DM. Lesions were scored using BI-RADS® and level of suspiciousness (1-10). Sensitivity, specificity, receiver operating characteristic (ROC) and jack-knife alternative free-response ROC (JAFROC) were computed. RESULTS: On average, 1v-DBT was non-inferior to any of the other protocols in terms of JAFROC figure-of-merit, area under ROC curve, sensitivity or specificity (p>0.391). While readers inexperienced with 1v-DBT screening improved their sensitivity when adding more images (69-79 %, p=0.019), experienced readers showed similar sensitivity (76 %) and specificity (70 %) between 1v-DBT and 2v-DM+2v-DBT (p=0.482). Subanalysis by lesion type and breast density showed no difference among modalities. CONCLUSION: Detection performance with 1v-DBT is not statistically inferior to 2v-DM or to 2v-DM+2v-DBT; its use as a stand-alone modality might be sufficient for readers experienced with this protocol. KEY POINTS: • One-view breast tomosynthesis is not inferior to two-view digital mammography. • One-view DBT is not inferior to 2-view DM plus 2-view DBT. • Training may lead to 1v-DBT being sufficient for screening.

New reconstruction algorithm for digital breast tomosynthesis: better image quality for humans and computers.

Background The image quality of digital breast tomosynthesis (DBT) volumes depends greatly on the reconstruction algorithm. Purpose To compare two DBT reconstruction algorithms used by the Siemens Mammomat Inspiration system, filtered back projection (FBP), and FBP with iterative optimizations (EMPIRE), using qualitative analysis by human readers and detection performance of machine learning algorithms. Material and Methods Visual grading analysis was performed by four readers specialized in breast imaging who scored 100 cases reconstructed with both algorithms (70 lesions). Scoring (5-point scale: 1 = poor to 5 = excellent quality) was performed on presence of noise and artifacts, visualization of skin-line and Cooper's ligaments, contrast, and image quality, and, when present, lesion visibility. In parallel, a three-dimensional deep-learning convolutional neural network (3D-CNN) was trained (n = 259 patients, 51 positives with BI-RADS 3, 4, or 5 calcifications) and tested (n = 46 patients, nine positives), separately with FBP and EMPIRE volumes, to discriminate between samples with and without calcifications. The partial area under the receiver operating characteristic curve (pAUC) of each 3D-CNN was used for comparison. Results EMPIRE reconstructions showed better contrast (3.23 vs. 3.10, P = 0.010), image quality (3.22 vs. 3.03, P < 0.001), visibility of calcifications (3.53 vs. 3.37, P = 0.053, significant for one reader), and fewer artifacts (3.26 vs. 2.97, P < 0.001). The 3D-CNN-EMPIRE had better performance than 3D-CNN-FBP (pAUC-EMPIRE = 0.880 vs. pAUC-FBP = 0.857; P < 0.001). Conclusion The new algorithm provides DBT volumes with better contrast and image quality, fewer artifacts, and improved visibility of calcifications for human observers, as well as improved detection performance with deep-learning algorithms.

Artificial Intelligence for breast cancer detection: Technology, challenges, and prospects.

PURPOSE: This review provides an overview of the current state of artificial intelligence (AI) technology for automated detection of breast cancer in digital mammography (DM) and digital breast tomosynthesis (DBT). It aims to discuss the technology, available AI systems, and the challenges faced by AI in breast cancer screening. METHODS: The review examines the development of AI technology in breast cancer detection, focusing on deep learning (DL) techniques and their differences from traditional computer-aided detection (CAD) systems. It discusses data pre-processing, learning paradigms, and the need for independent validation approaches. RESULTS: DL-based AI systems have shown significant improvements in breast cancer detection. They have the potential to enhance screening outcomes, reduce false negatives and positives, and detect subtle abnormalities missed by human observers. However, challenges like the lack of standardised datasets, potential bias in training data, and regulatory approval hinder their widespread adoption. CONCLUSIONS: AI technology has the potential to improve breast cancer screening by increasing accuracy and reducing radiologist workload. DL-based AI systems show promise in enhancing detection performance and eliminating variability among observers. Standardised guidelines and trustworthy AI practices are necessary to ensure fairness, traceability, and robustness. Further research and validation are needed to establish clinical trust in AI. Collaboration between researchers, clinicians, and regulatory bodies is crucial to address challenges and promote AI implementation in breast cancer screening.

Characterization of a Delivery System Based on a Hyaluronic Acid 3D Scaffold and Gelatin Microparticles.

The objective of this study was to develop and characterize a novel hyaluronic acid (HA) 3D scaffold integrated with gelatin microparticles for sustained-delivery applications. To achieve this goal, the delivery microparticles were synthesized and thoroughly characterized, focusing on their crosslinking mechanisms (vanillin and genipin), degradation profiles, and release kinetics. Additionally, the cytotoxicity of the system was assessed, and its impact on the cell adhesion and distribution using mouse fibroblasts was examined. The combination of both biomaterials offers a novel platform for the gradual release of various factors encapsulated within the microparticles while simultaneously providing cell protection, support, and controlled factor dispersion due to the HA 3D scaffold matrix. Hence, this system offers a platform for addressing injure repair by continuously releasing specific encapsulated factors for optimal tissue regeneration. Additionally, by leveraging the properties of HA conjugates with small drug molecules, we can enhance the solubility, targeting capabilities, and cellular absorption, as well as prolong the system stability and half-life. As a result, this integrated approach presents a versatile strategy for therapeutic interventions aimed at promoting tissue repair and regeneration.

Multi-vendor robustness analysis of a commercial artificial intelligence system for breast cancer detection.

Purpose: Population-based screening programs for the early detection of breast cancer have significantly reduced mortality in women, but they are resource intensive in terms of time, cost, and workload and still have limitations mainly due to the use of 2D imaging techniques, which may cause overlapping of tissues, and interobserver variability. Artificial intelligence (AI) systems may be a valuable tool to assist radiologist when reading and classifying mammograms based on the malignancy of the detected lesions. However, there are several factors that can influence the outcome of a mammogram and thus also the detection capability of an AI system. The aim of our work is to analyze the robustness of the diagnostic ability of an AI system designed for breast cancer detection. Approach: Mammograms from a population-based screening program were scored with the AI system. The sensitivity and specificity by means of the area under the receiver operating characteristic (ROC) curve were obtained as a function of the mammography unit manufacturer, demographic characteristics, and several factors that may affect the image quality (age, breast thickness and density, compression applied, beam quality, and delivered dose). Results: The area under the curve (AUC) from the scoring ROC curve was 0.92 (95% confidence interval = 0.89 - 0.95). It showed no dependence with any of the parameters considered, as the differences in the AUC for different interval values were not statistically significant. Conclusion: The results suggest that the AI system analyzed in our work has a robust diagnostic capability, and that its accuracy is independent of the studied parameters.

Multi-modal artificial intelligence for the combination of automated 3D breast ultrasound and mammograms in a population of women with predominantly dense breasts.

OBJECTIVES: To assess the stand-alone and combined performance of artificial intelligence (AI) detection systems for digital mammography (DM) and automated 3D breast ultrasound (ABUS) in detecting breast cancer in women with dense breasts. METHODS: 430 paired cases of DM and ABUS examinations from a Asian population with dense breasts were retrospectively collected. All cases were analyzed by two AI systems, one for DM exams and one for ABUS exams. A selected subset (n = 152) was read by four radiologists. The performance of AI systems was based on analysis of the area under the receiver operating characteristic curve (AUC). The maximum Youden's index and its associated sensitivity and specificity were also reported for each AI systems. Detection performance of human readers in the subcohort of the reader study was measured in terms of sensitivity and specificity. RESULTS: The performance of the AI systems in a multi-modal setting was significantly better when the weights of AI-DM and AI-ABUS were 0.25 and 0.75, respectively, than each system individually in a single-modal setting (AUC-AI-Multimodal = 0.865; AUC-AI-DM = 0.832, p = 0.026; AUC-AI-ABUS = 0.841, p = 0.041). The maximum Youden's index for AI-Multimodal was 0.707 (sensitivity = 79.4%, specificity = 91.2%). In the subcohort that underwent human reading, the panel of four readers achieved a sensitivity of 93.2% and specificity of 32.7%. AI-multimodal achieves superior or equal sensitivity as single human readers at the same specificity operating points on the ROC curve. CONCLUSION: Multimodal (ABUS + DM) AI systems for detecting breast cancer in women with dense breasts are a potential solution for breast screening in radiologist-scarce regions.