Screening in Patients With Dense Breasts: Comparison of Mammography, Artificial Intelligence, and Supplementary Ultrasound.

BACKGROUND. Screening mammography has decreased performance in patients with dense breasts. Supplementary screening ultrasound is a recommended option in such patients, although it has yielded mixed results in prior investigations. OBJECTIVE. The purpose of this article is to compare the performance characteristics of screening mammography alone, standalone artificial intelligence (AI), ultrasound alone, and mammography in combination with AI and/or ultrasound in patients with dense breasts. METHODS. This retrospective study included 1325 women (mean age, 53 years) with dense breasts who underwent both screening mammography and supplementary breast ultrasound within a 1-month interval from January 2017 to December 2017; prior mammography and prior ultrasound examinations were available for comparison in 91.2% and 91.8%, respectively. Mammography and ultrasound examinations were interpreted by one of 15 radiologists (five staff; 10 fellows); clinical reports were used for the present analysis. A commercial AI tool was used to retrospectively evaluate mammographic examinations for presence of cancer. Screening performances were compared among mammography, AI, ultrasound, and test combinations, using generalized estimating equations. Benign diagnoses required 24 months or longer of imaging stability. RESULTS. Twelve cancers (six invasive ductal carcinoma; six ductal carcinoma in situ) were diagnosed. Mammography, standalone AI, and ultrasound showed cancer detection rates (per 1000 patients) of 6.0, 6.8, and 6.0 (all p > .05); recall rates of 4.4%, 11.9%, and 9.2% (all p < .05); sensitivity of 66.7%, 75.0%, and 66.7% (all p > .05); specificity of 96.2%, 88.7%, and 91.3% (all p < .05); and accuracy of 95.9%, 88.5%, and 91.1% (all p < .05). Mammography with AI, mammography with ultrasound, and mammography with both ultrasound and AI showed cancer detection rates of 7.5, 9.1, and 9.1 (all p > .05); recall rates of 14.9, 11.7, and 21.4 (all p < .05); sensitivity of 83.3%, 100.0%, and 100.0% (all p > .05); specificity of 85.8%, 89.1%, and 79.4% (all p < .05); and accuracy of 85.7%, 89.2%, and 79.5% (all p < .05). CONCLUSION. Mammography with supplementary ultrasound showed higher accuracy, higher specificity, and lower recall rate in comparison with mammography with AI and in comparison with mammography with both ultrasound and AI. CLINICAL IMPACT. The findings fail to show benefit of AI with respect to screening mammography performed with supplementary breast ultrasound in patients with dense breasts.

Artificial intelligence assistance for women who had spot compression view: reducing recall rates for digital mammography.

BACKGROUND: Mammography yields inevitable recall for indeterminate findings that need to be confirmed with additional views. PURPOSE: To explore whether the artificial intelligence (AI) algorithm for mammography can reduce false-positive recall in patients who undergo the spot compression view. MATERIAL AND METHODS: From January to December 2017, 236 breasts from 225 women who underwent the spot compression view due to focal asymmetry, mass, or architectural distortion on standard digital mammography were included. Three readers who were blinded to the study purpose, patient information, previous mammograms, following spot compression views, and any clinical or pathologic reports retrospectively reviewed 236 standard mammograms and determined the necessity of patient recall and the probability of malignancy per breast, first without and then with AI assistance. The performances of AI and the readers were evaluated with the recall rate, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. RESULTS: Among 236 examinations, 8 (3.4%) were cancers and 228 (96.6%) were benign. The recall rates of all three readers significantly decreased with AI assistance (P < 0.05). The reader-averaged recall rates significantly decreased with AI assistance regardless of breast composition (fatty breasts: 32.7% to 24.1%m P = 0.002; dense breasts: 33.6% to 21.2%, P < 0.001). The reader-averaged AUC increased with AI assistance and was comparable to that of standalone AI (0.835 vs. 0.895; P = 0.234). The reader-averaged specificity (71.2% to 79.8%, P < 0.001) and accuracy (71.3% to 79.7%, P < 0.001) significantly improved with AI assistance. CONCLUSION: AI assistance significantly reduced false-positive recall without compromising cancer detection in women with focal asymmetry, mass, or architectural distortion on standard digital mammography regardless of mammographic breast density.

Rhodamine-Based Cyclic Hydroxamate as Fluorescent pH Probe for Imaging of Lysosomes.

Monitoring the microenvironment within specific cellular regions is crucial for a comprehensive understanding of life events. Fluorescent probes working in different ranges of pH regions have been developed for the local imaging of different pH environments. Especially, rhodamine-based fluorescent pH probes have been of great interest due to their ON/OFF fluorescence depending on the spirolactam ring's opening/closure. By introducing the N-alkyl-hydroxamic acid instead of the alkyl amines in the spirolactam of rhodamine, we were able to tune the pH range where the ring opening and closing of the spirolactam occurs. This six-membered cyclic hydroxamate spirolactam ring of rhodamine B proved to be highly fluorescent in acidic pH environments. In addition, we could monitor pH changes of lysosomes in live cells and zebrafish.

Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aß interaction and Aß fibrillation.

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer''s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aß peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aß17-24 region of Aß and promoted Aß fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aß pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aß and ultimately the slower rate of brain Aß deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

US, Mammography, and Histopathologic Evaluation to Identify Low Nuclear Grade Ductal Carcinoma in Situ.

Background Low nuclear grade ductal carcinoma in situ (DCIS) identified at biopsy can be upgraded to intermediate to high nuclear grade DCIS at surgery. Methods that confirm low nuclear grade are needed to consider nonsurgical approaches for these patients. Purpose To develop a preoperative model to identify low nuclear grade DCIS and to evaluate factors associated with low nuclear grade DCIS at biopsy that was not upgraded to intermediate to high nuclear grade DCIS at surgery. Materials and Methods In this retrospective study, 470 women (median age, 50 years; interquartile range, 44-58 years) with 477 pure DCIS lesions at surgical histopathologic evaluation were included (January 2010 to December 2015). Patients were divided into the training set (n = 330) or validation set (n = 147) to develop a preoperative model to identify low nuclear grade DCIS. Features at US (mass, nonmass) and at mammography (morphologic characteristics, distribution of microcalcification) were reviewed. The upgrade rate of low nuclear grade DCIS was calculated, and multivariable regression was used to evaluate factors for associations with low nuclear grade DCIS that was not upgraded later. Results A preoperative model that included lesions manifesting as a mass at US without microcalcification and no comedonecrosis at biopsy was used to identify low nuclear grade DCIS, with a high area under the receiver operating characteristic curve of 0.97 (95% CI: 0.94, 1.00) in the validation set. The upgrade rate of low nuclear grade DCIS at biopsy was 38.8% (50 of 129). Ki-67 positivity (odds ratio, 0.04; 95% CI: 0.0003, 0.43; P = .005) was inversely associated with constant low nuclear grade DCIS. Conclusion The upgrade rate of low nuclear grade ductal carcinoma in situ (DCIS) at biopsy to intermediate to high nuclear grade DCIS at surgery occurred in more than a third of patients; low nuclear grade DCIS at final histopathologic evaluation could be identified if the mass was viewed at US without microcalcifications and had no comedonecrosis at histopathologic evaluation of biopsy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Rahbar in this issue. An earlier incorrect version appeared online. This article was corrected on April 14, 2022.

Mammographic Surveillance After Breast-Conserving Therapy: Impact of Digital Breast Tomosynthesis and Artificial Intelligence-Based Computer-Aided Detection.

BACKGROUND. Postoperative mammograms present interpretive challenges due to postoperative distortion and hematomas. The application of digital breast tomosyn-thesis (DBT) and artificial intelligence-based computer-aided detection (AI-CAD) after breast-conserving therapy (BCT) has not been widely investigated. OBJECTIVE. The purpose of our study was to assess the impact of additional DBT or AI-CAD on recall rate and diagnostic performance in women undergoing mammographic surveillance after BCT. METHODS. This retrospective study included 314 women (mean age, 53.3 ± 10.6 [SD] years; four with bilateral breast cancer) who underwent BCT followed by DBT (mean interval from surgery to DBT, 15.2 ± 15.4 months). Three breast radiologists independently reviewed images in three sessions: digital mammography (DM), DM with DBT (DM plus DBT), and DM with AI-CAD (DM plus AI-CAD). Recall rates and diagnostic performance were compared between DM, DM plus DBT, and DM plus AI-CAD using the readers' mean results. RESULTS. Of the 314 women, six breast recurrences (three ipsilateral and three contralateral) had developed at the time of surveillance mammography. The ipsilateral breast recall rate was lower for DM plus AI-CAD (1.9%) than for DM (11.2%) or DM plus DBT (4.1%) (p < .001). The contralateral breast recall rate was significantly lower for DM plus AI-CAD (1.5%, p < .001) than for DM (6.6%) but for not DM plus DBT (2.7%, p = .08). In the ipsilateral breast, accuracy was higher for DM plus AI-CAD (97.0%) than for DM (88.5%) or DM plus DBT (94.8%) (p < .05); specificity was higher for DM plus AI-CAD (98.3%) than for DM (89.3%) or DM plus DBT (96.1%) (p < .05); sensitivity was significantly lower for DM plus AI-CAD (22.2%) than for DM (66.7%, p = .03) but not DM plus DBT (22.2%, p > .99). In the contralateral breast, accuracy was significantly higher for DM plus AI-CAD (97.1%) than for DM (92.5%, p < .001) but not DM plus DBT (96.1%, p = .25); specificity was significantly higher for DM plus AI-CAD (98.6%) than for DM (93.7%, p < .001) but not DM plus DBT (97.5%) (p = .09); sensitivity was not different between DM (33.3%), DM plus DBT (22.2%), and DM plus AI-CAD (11.1%) (p > .05). CONCLUSION. After BCT, adjunct DBT or AI-CAD reduced recall rates and improved accuracy in the ipsilateral and contralateral breasts compared with DM. In the ipsilateral breast, the addition of AI-CAD resulted in a lower recall rate and higher accuracy than the addition of DBT. CLINICAL IMPACT. AI-CAD may help address the challenges of interpreting post-BCT surveillance mammograms.

Mass Spectrometry-Based Disulfide Mapping of Lysyl Oxidase-like 2.

Lysyl oxidase-like 2 (LOXL2) catalyzes the oxidative deamination of peptidyl lysines and hydroxylysines to promote extracellular matrix remodeling. Aberrant activity of LOXL2 has been associated with organ fibrosis and tumor metastasis. The lysine tyrosylquinone (LTQ) cofactor is derived from Lys653 and Tyr689 in the amine oxidase domain via post-translational modification. Based on the similarity in hydrodynamic radius and radius of gyration, we recently proposed that the overall structures of the mature LOXL2 (containing LTQ) and the precursor LOXL2 (no LTQ) are very similar. In this study, we conducted a mass spectrometry-based disulfide mapping analysis of recombinant LOXL2 in three forms: a full-length LOXL2 (fl-LOXL2) containing a nearly stoichiometric amount of LTQ, Δ1-2SRCR-LOXL2 (SRCR1 and SRCR2 are truncated) in the precursor form, and Δ1-3SRCR-LOXL2 (SRCR1, SRCR2, SRCR3 are truncated) in a mixture of the precursor and the mature forms. We detected a set of five disulfide bonds that is conserved in both the precursor and the mature recombinant LOXL2s. In addition, we detected a set of four alternative disulfide bonds in low abundance that is not associated with the mature LOXL2. These results suggest that the major set of five disulfide bonds is retained post-LTQ formation.

Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2.

Lysyl oxidase-2 (LOXL2) is a Cu2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn2+-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu2+ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu2. We propose that LTQ resides within 2.9 Å of the active site of Cu2+ in the mature LOXL2, and both LTQ and Cu2+ are solvent-exposed.

Added Value of MRI for Invasive Breast Cancer including the Entire Axilla for Evaluation of High-Level or Advanced Axillary Lymph Node Metastasis in the Post-ACOSOG Z0011 Trial Era.

Background In the post-American College of Surgeons Oncology Group Z0011 trial era, radiologists have increasingly focused on excluding high-level or advanced axillary lymph node metastasis (ALNM) by using an additional MRI scan positioned higher than lower axillae; however, the value of these additional scans remains undetermined. Purpose To evaluate whether a standard MRI protocol is sufficient to exclude high-level or advanced ALNM in breast cancer or additional MRI of entire axilla is needed. Materials and Methods This retrospective study evaluated women with invasive breast cancer who underwent breast MRI from April 2015 to December 2016. Some underwent neoadjuvant chemotherapy (NAC) and others underwent upfront surgery. Standard (routine axial scans including the lower axillae) and combined (routine axial scans plus additional scans including the entire axilla) MRI protocols were compared for high-level or advanced ALNM detection. Clinical-pathologic characteristics were analyzed. Uni- and multivariable logistic regression was performed to identify predictors of high-level or advanced ALNM. Results A total of 435 women (mean age ± standard deviation, 52 years ± 11) were evaluated (65 in the NAC group, 370 in the non-NAC group). With the standard MRI protocol, predictors of high-level ALNM were peritumoral edema (odds ratio [OR], 12.3; 95% CI: 3.9, 39.4; P < .001) and positive axilla (OR, 5.9; 95% CI: 2.0, 15.2; P < .001). Only three of 289 women with negative axillae without peritumoral edema had high-level ALNM. Predictors of advanced ALNM were positive axillae (OR, 8.9; 95% CI: 3.7, 21.5; P < .001) and peritumoral edema (OR, 2.8; 95% CI: 1.1, 6.9; P = .03). Only six of 310 women who had negative axillae without peritumoral edema had advanced ALNM. Conclusion The performance of standard MRI was satisfactory in excluding high-level and advanced axillary lymph node metastasis in most patients with breast cancer. However, the presence of peritumoral edema or positive axillae in the MRI findings emphasizes the benefits of a combined MRI protocol. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Abe in this issue.

Chronological Trends of Breast Ductal Carcinoma In Situ: Clinical, Radiologic, and Pathologic Perspectives.

BACKGROUND: Because no prior studies have evaluated the chronological trends of ductal carcinoma in situ (DCIS) despite the increasing number of surgeries performed for DCIS, this study analyzed how the clinical, radiologic, and pathologic characteristics of DCIS changed during a 10-year period. METHODS: Of 7123 patients who underwent primary breast cancer surgery at a single institution from 2006 to 2015, 792 patients with pure DCIS were included in this study. The chronological trends of age, symptoms, method for detecting either mammography or ultrasonography, tumor size, nuclear grade, comedonecrosis, and molecular markers were calculated using Poisson regression for all patients and asymptomatic patients. RESULTS: During 10 years, DCIS surgery rates significantly increased (p < 0.001). Despite the high percentage of DCIS detected on mammography, the detection rate for DCIS by mammography significantly decreased (97.3% in 2006 to 67.6% in 2015; p = 0.025), whereas the detection rate by ultrasound significantly increased (2.7% to 31.0%; p < 0.001). Conservation surgery rates (odds ratio [OR], 1.058), low-to-intermediate nuclear grade rates (OR, 1.069), and the absence of comedonecrosis (OR, 1.104) significantly increased over time (all p < 0.05). Estrogen receptor (ER) negativity (OR, 0.935) and human epidermal growth factor receptor 2 (HER2) positivity rates (OR, 0.953) significantly decreased (all p < 0.05). The same trends were observed for the 613 asymptomatic patients. CONCLUSION: The rate of DCIS detected on ultrasound only significantly increased during 10 years. Low-to-intermediate nuclear grade rates significantly increased, whereas ER negativity and HER2 positivity rates significantly decreased during the same period. These findings suggest that DCIS detected on screening ultrasound is less aggressive than DCIS detected on mammography.

Comparison of diagnostic performance of the ACR and Kwak TIRADS applying the ACR TIRADS' size thresholds for FNA.

OBJECTIVE: To investigate the diagnostic performances and unnecessary fine-needle aspiration (FNA) rates of two point-scale based TIRADS and compare them with a modified version using the ACR TIRADS' size thresholds. METHODS: Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent. A total of 2106 thyroid nodules 10 mm or larger in size in 2084 patients with definitive cytopathologic findings were included. Ultrasonography categories were assigned according to each guideline. We applied the ACR TIRADS' size thresholds for FNA to the Kwak TIRADS and defined it as the modified Kwak TIRADS (mKwak TIRADS). Diagnostic performances and unnecessary FNA rates were evaluated for both the original and modified guidelines. RESULTS: Of the original guidelines, the ACR TIRADS had higher specificity, accuracy, and area under the receiver operating characteristic curve (AUC) (63.1%, 68.9%, and 0.748, respectively). When the size threshold of the ACR TIRADS was applied to the Kwak TIRADS, the resultant mKwak TIRADS had higher specificity, accuracy, and AUC (64.7%, 70.3%, and 0.765, respectively) than the ACR TIRADS. The mKwak TIRADS also had a lower unnecessary FNA rate than the ACR TIRADS (54.8% and 56.4%, respectively). The false-negative rate of the Kwak TIRADS was the lowest (1.9%) among all TIRADS. CONCLUSION: The modified Kwak TIRADS incorporating the size thresholds of the ACR TIRADS showed higher diagnostic performance and a lower unnecessary FNA rate than the original point-scale based TIRADS. KEY POINTS: • Of the original guidelines, the ACR TIRADS had the highest specificity, accuracy, and area under the receiver operating characteristic curve (AUC) (63.1%, 68.9%, and 0.748, respectively). • When the size threshold of the ACR TIRADS was applied to the Kwak TIRADS, the resultant modified version of Kwak TIRADS had higher specificity, accuracy, and AUC (64.7%, 70.3%, and 0.765, respectively) than the ACR TIRADS. • The false-negative rate of the Kwak TIRADS was the lowest (1.9%) among all TIRADS.

Combining radiomics with ultrasound-based risk stratification systems for thyroid nodules: an approach for improving performance.

OBJECTIVES: To develop a radiomics score using ultrasound images to predict thyroid malignancy and to investigate its potential as a complementary tool to improve the performance of risk stratification systems. METHODS: We retrospectively included consecutive patients who underwent fine-needle aspiration (FNA) for thyroid nodules that were cytopathologically diagnosed as benign or malignant. Nodules were randomly assigned to a training and test set (8:2 ratio). A radiomics score was developed from the training set, and cutoff values based on the maximum Youden index (Rad_maxY) and for 5%, 10%, and 20% predicted malignancy risk (Rad_5%, Rad_10%, Rad_20%, respectively) were applied to the test set. The performances of the American College of Radiology (ACR) and the American Thyroid Association (ATA) guidelines were compared with the combined performances of the guidelines and radiomics score with interpretations from expert and nonexpert readers. RESULTS: A total of 1624 thyroid nodules from 1609 patients (mean age, 50.1 years [range, 18-90 years]) were included. The radiomics score yielded an AUC of 0.85 (95% CI: 0.83, 0.87) in the training set and 0.75 (95% CI: 0.69, 0.81) in the test set (Rad_maxY). When the radiomics score was combined with the ACR or ATA guidelines (Rad_5%), all readers showed increased specificity, accuracy, and PPV and decreased unnecessary FNA rates (all p < .05), with no difference in sensitivity (p > .05). CONCLUSION: Radiomics help predict thyroid malignancy and improve specificity, accuracy, PPV, and unnecessary FNA rate while maintaining the sensitivity of the ACR and ATA guidelines for both expert and nonexpert readers. KEY POINTS: • The radiomics score yielded an AUC of 0.85 and 0.75 in the training and test set, respectively. • For all readers, combining a 5% predicted malignancy risk cutoff for the radiomics score with the ACR and ATA guidelines significantly increased specificity, accuracy, and PPV and decreased unnecessary FNA rates, with no decrease in sensitivity. • Radiomics can help predict malignancy in thyroid nodules in combination with risk stratification systems, by improving specificity, accuracy, and PPV and unnecessary FNA rates while maintaining sensitivity for both expert and nonexpert readers.

Factors Predicting Breast Cancer Development in Women During Surveillance After Surgery for Atypical Ductal Hyperplasia of the Breast: Analysis of Clinical, Radiologic, and Histopathologic Features.

BACKGROUND: This study aimed to evaluate the risk of breast cancer development for women under surveillance after surgery for atypical ductal hyperplasia (ADH), as well as the clinical and pathologic factors associated with breast cancer development. METHODS: From November 2003 to December 2014, the study included 205 women (mean age, 47.1 ± 11.2 years; range 18-73 years) with a pathologic diagnosis of ADH at surgical excision who had preoperative mammography and ultrasonography (US) images and pathology slides available for review. The patients were classified into three groups according to the detection method as follows: negative group (with ADH occult on imaging), mammography group (with ADH detected on mammography), and US group (with ADH detected on US only). Clinical, radiologic, and histopathologic factors associated with breast cancer development after ADH surgery were evaluated. RESULTS: Breast cancer developed in 15 patients (7.3%) during surveillance after ADH surgery (follow-up period, 63.9 ± 40.8 months). Palpable lesions had significantly higher rates of breast cancer development after ADH surgery (26.7% vs 6.8%; P = 0.045). Breast cancer development after ADH surgery did not differ according to the detection method (P = 0.654). Palpability was significantly associated with breast cancer development during surveillance after ADH surgery (hazard ratio, 3.579; 95% confidence interval 1.048-12.220; P = 0.042). CONCLUSION: The breast cancer development rate for women under surveillance after ADH surgery was 7.3%. Palpability at the time of ADH diagnosis was significantly associated with breast cancer development.

Comparing recall rates following implementation of digital breast tomosynthesis to synthetic 2D images and digital mammography on women with breast-conserving surgery.

OBJECTIVES: To evaluate the recall rates of digital mammography (DM) and synthetic images after adding digital breast tomosynthesis (DBT) in patients with breast-conserving surgery. METHODS: From November 2015 to April 2017, 229 women with breast-conserving surgery due to breast cancer who underwent DBT after surgery were included (mean interval, 12.9 ± 1.4 months). All women underwent combo-mode DBT examinations including full-field DM, tomosynthesis, and reconstructed synthetic 2D images. Three board-certified breast radiologists reviewed the images sequentially: synthetic 2D+DBT and, 1 month later, DM and then DM+DBT. Recall rates and the abnormality type causing the recall were calculated and compared for each mammographic modality and breast density. RESULTS: Of the 229 patients included, 230 mammography images were reviewed. One patient (0.4%) developed locoregional recurrences during follow-up (mean duration, 25.8 ± 4.5 months). Recall rates for synthetic 2D+DBT were significantly lower than for DM alone (4.1% (2.6-6.2) vs. 11.6% (9.2-14.5), respectively; p < 0.001). Recall rates did not differ between synthetic 2D+DBT and DM+DBT (4.1% (2.6-6.2) vs. 2.9% (1.9-4.5), respectively; p = 0.234). Recall rates of synthetic 2D+DBT and DM+DBT were significantly lower than those of DM alone, regardless of mammographic breast density (all p < 0.05, respectively). CONCLUSION: Adding DBT to synthetic 2D images or DM shows significant reduction in recall rates compared with DM alone for women who undergo breast-conserving surgery for breast cancer, regardless of mammographic density. KEY POINTS: • Recall rates for synthetic 2D+DBT were significantly lower than those of DM alone (4.1% (2.6-6.2) vs. 11.6% (9.2-14.5), respectively; p < 0.001). • No significant differences were seen in recall rates between synthetic 2D+DBT and DM+DBT (4.1 (2.6-6.2) vs. 2.9 (1.9-4.5), respectively; p = 0.234). • Reader-averaged recall rates after adding DBT to synthetic 2D or DM were significantly lower than those of DM alone, regardless of mammographic breast density (all p < 0.05, respectively).

Pattern-based vs. score-based guidelines using ultrasound features have different strengths in risk stratification of thyroid nodules.

OBJECTIVE: To evaluate and compare the diagnostic performances between recently published pattern-based and score-based TIRADS according to the experience level of the performer. METHODS: From July 2013 to January 2019, 8657 thyroid nodules in 8364 patients that had been cytopathologically diagnosed as benign or malignant were included (mean size, 22.0 mm ± 12.1). Thyroid nodules were categorized into US-based final assessment categories and US-FNA indications of five recently published TIRADS. Radiologists performing the US examinations were divided into the experienced vs. inexperienced group. Diagnostic performances and unnecessary biopsy rates were calculated and compared between the five TIRADS, also the experienced vs. inexperienced group. RESULTS: Of the 8657 thyroid nodules, 6706 (77.5%) were benign and 1951 (22.5%) were malignant. Diagnostic performances for US-based final assessment categories showed higher sensitivity and NPV for EU-TIRADS (92.7% and 96.5%), while Kwak-TIRADS had higher specificity, PPV, accuracy, and AUC (89.6%, 68.0%, 86.5%, and 0.878; all p < 0.05, respectively). Diagnostic performances for US-FNA indications showed higher sensitivity and NPV for KTA/KSThR TIRADS (98.5% and 97.0%), while Kwak-TIRADS had higher specificity, PPV, accuracy, and AUC (70.3%, 46.6%, 74.5%, and 0.797; all p < 0.05, respectively). Unnecessary biopsy rates were the lowest in Kwak-TIRADS for both US categories and US-FNA indications (32.0% and 53.4%, p < 0.001). Similar trends were seen in both the experienced and inexperienced group. CONCLUSION: The currently published score-based guidelines for thyroid nodules have significantly higher specificity, PPV, accuracy, and AUC and lower unnecessary biopsy rates, whereas pattern-based guidelines have higher sensitivity and NPV, regardless of the level of experience of the performer. KEY POINTS: • For US-based final assessment categories, EU-TIRADS had higher sensitivity and NPV, while Kwak-TIRADS had higher specificity, PPV, accuracy, and AUC. • For US-FNA indications, KTA/KSThR TIRADS had higher sensitivity and NPV, while Kwak-TIRADS had higher specificity, PPV, accuracy, and AUC. • Similar trends were seen in diagnostic performances for both experienced and inexperienced groups.

BI-RADS category 3, 4, and 5 lesions identified at preoperative breast MRI in patients with breast cancer: implications for management.

OBJECTIVES: To investigate outcomes and retrospectively evaluate characteristics of additional lesions initially assessed as BI-RADS category 3, 4, and 5 at preoperative MRI to determine appropriate follow-up management. METHODS: We retrospectively reviewed 429 lesions other than primary cancer initially assessed as BI-RADS category 3, 4, and 5 at preoperative MRI in 391 patients with breast cancer from March 2012 to December 2013. We investigated their malignancy rate and outcome according to BI-RADS category assessments. We also analyzed clinical and imaging characteristics of each lesion. Pathological results and imaging follow-up of at least 2 years were used as reference standards. RESULTS: Of 429 lesions in 391 patients (mean 48.1 years ± 9.4), the malignancy rate of BI-RADS 3, 4, and 5 lesions was 1.4% (3/213), 17.8% (38/214), and 50% (1/2), respectively. Of BI-RADS 3 lesions or BI-RADS 4 or 5 lesions that were followed up after benign-concordant biopsy (n = 114), two contralateral masses (2/306, 0.7%) were diagnosed as malignancy at 13.3 and 33.2 months after initial detection, within a median follow-up of 63.3 months. None of the NME or foci or lesions followed up after benign-concordant biopsy had a delayed diagnosis of malignancy. Of the 391 patients, 97.4% (381/391) received at least one type of adjuvant therapy. CONCLUSION: The incidence of delayed cancer diagnosis among additionally detected lesions other than primary cancer is very low and short-term follow-up is unnecessary. Contralateral masses which were not confirmed by biopsy may need annual follow-up. KEY POINTS: • 1.4% (3/213) of BI-RADS 3 lesions were malignant including 2 delayed diagnoses after 13.2 months and 33.2 months, and 17.8% (38/214) of BI-RADS 4 lesions and 50% (1/2) of BI-RADS 5 lesions were malignant. • The incidence of delayed diagnosis from additional MRI-detected lesions was very low (0.7%, 2/306) during follow-up, which were all T1N0 contralateral cancer. • Annual follow-up might be adequate for preoperative MRI-detected BI-RADS 3 lesions and BI-RADS 4 lesions followed up after benign-concordant biopsy.

Guideline Implementation on Fine-Needle Aspiration for Thyroid Nodules: Focusing on Micronodules.

OBJECTIVE: We investigated patients who were referred to our institution after fine-needle aspiration (FNA) was performed at outside clinics to evaluate how many nodules satisfied the FNA indications of the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and compare that to the number of thyroid nodules that satisfy the FNA indications of the American College of Radiology (ACR)-TIRADS and American Thyroid Association (ATA) guidelines. METHODS: Between January 2018 and December 2018, 2,628 patients were included in our study. The included patients were those referred for thyroid surgery after having a suspicious thyroid nodule. We retrospectively applied the three guidelines to each thyroid nodule and determined whether each nodule satisfied the FNA indications. We compared the proportion of nodules satisfying the FNA indications of each guideline using a generalized linear model and generalized estimating equation. RESULTS: The median size of the 2,628 thyroid nodules was 0.9 cm (range, 0.2 to 9.5 cm). We found that FNA was not indicated for 54.1%, 47.7%, and 19.1% of nodules and 87.3%, 99.0%, and 97.8% among them were micronodules (<1 cm) according to the ACR-TIRADS, ATA guideline, and K-TIRADS, respectively. The proportion of micronodules which satisfied the FNA indications was significantly higher for the K-TIRADS (65.1%) compared to the ACR TIRADS (12.1%) and ATA guideline (12.1%) (P<.001). CONCLUSION: Among patients referred for thyroid surgery to our institutions, about 35% of the micronodules underwent FNA despite not being appropriate for indications by the K-TIRADS. Systematic training for physicians as well as modifications to increase the sensitivity of the guideline may be needed to reduce the overdiagnosis of thyroid cancers, especially for micronodules.

Role of elastography for downgrading BI-RADS category 4a breast lesions according to risk factors.

BACKGROUND: Elastography has been introduced as an additional diagnostic tool to ultrasonography (US) which helps clinicians decide whether or not to perform biopsy on US-detected lesions. PURPOSE: To evaluate the role of strain elastography in downgrading Breast Imaging Reporting and Data System (BI-RADS) category 4a breast lesions according to personal risk factors for breast cancer in asymptomatic women. MATERIAL AND METHODS: Strain elastography features of a total of 255 asymptomatic category 4a lesions were classified as soft and not soft (intermediate and hard). Malignancy was confirmed by surgery or biopsy, and benignity was confirmed by surgery or biopsy with no change on US for at least six months. Malignancy rates of lesions with soft and not soft elastography were calculated according to the presence of risk factors. RESULTS: Of 255 lesions, 25 (9.8%) were malignant and 230 (90.2%) were benign. Of 195 lesions in average-risk women, the malignancy rate of lesions with soft elastography was 1.5% (1/68), which was significantly lower than the 14.2% (18/127) of lesions with not soft elastography ( P = 0.004). Of 60 lesions in increased-risk women, the malignancy rate of lesions with soft elastography was 15.0% (3/20), which was not significantly different from the 7.5% (3/40) of lesions with not soft elastography ( P = 0.390). CONCLUSION: In average-risk women, category 4a lesions with soft elastography could be followed up with US because of a low malignancy rate of 1.5%.

Extracellular Processing of Lysyl Oxidase-like 2 and Its Effect on Amine Oxidase Activity.

Overexpression of lysyl oxidase-like 2 (LOXL2) is associated with several hepatic and vascular fibrotic diseases and tumor progression in some aggressive cancers. Secreted LOXL2 promotes extracellular matrix cross-linking by catalyzing the oxidative deamination of peptidyl lysine. A great deal remains to be learned about the post-translational modifications of LOXL2, including whether such modifications modulate enzymatic and disease-promoting activities; such knowledge would inform the development of potential therapies. We discovered that upon secretion in cell culture, LOXL2 undergoes proteolytic processing of the first two of four scavenger receptor cysteine-rich domains at the N-terminus. A similar pattern of processing was also evident in tissue extracts from an invasive ductal carcinoma patient. Processing occurred at 314Arg-315Phe-316Arg-317Lys↓-318Ala-, implicating proprotein convertases. siRNA-mediated knockdown of proprotein convertases (furin, PACE4, and PC5/6), as well as incubation with their recombinant forms, showed that PACE4 is the major protease that acts on extracellular LOXL2. Unlike LOX, which requires cleavage of its propeptide for catalytic activation, cleavage of LOXL2 was not essential for tropoelastin oxidation or for cross-linking of collagen type IV in vitro. However, in the latter case, processing enhanced the extent of collagen cross-linking ∼2-fold at ≤10 nM LOXL2. These results demonstrate an important difference in the regulatory mechanisms for LOX and LOXL2 catalytic activity. Moreover, they pave the way for further studies of potential differential functions of LOXL2 isoforms in fibrosis and tumor progression.

Recombinant Human Lysyl Oxidase-like 2 Secreted from Human Embryonic Kidney Cells Displays Complex and Acidic Glycans at All Three N-Linked Glycosylation Sites.

Human lysyl oxidase-like 2 (hLOXL2), a glycoprotein implicated in tumor progression and organ fibrosis, is a molecular target for anticancer and antifibrosis treatment. This glycoprotein contains three predicted N-linked glycosylation sites; one is near the protein's active site, and at least one more is known to facilitate the protein's secretion. Because the glycosylation impacts the protein's biology, we sought to characterize the native, mammalian glycosylation profile and to determine how closely this profile is recapitulated when the protein is expressed in insect cells. All three glycosylation sites on the protein, expressed in human embryonic kidney (HEK) cells, were characterized individually using a mass spectrometry-based glycopeptide analysis workflow. These data were compared to the glycosylation profile of the same protein expressed in insect cells. We found that the producer cell type imparts a substantial influence on the glycosylation of this important protein. The more-relevant version, expressed in HEK cells, contains large, acidic glycoforms; these glycans are not generated in insect cells. The glycosylation differences likely have structural and functional consequences, and these data should be considered when generating protein for functional studies or for high-throughput screening campaigns.