Interlocked feedforward loops control cell-type-specific Rhodopsin expression in the Drosophila eye.

How complex networks of activators and repressors lead to exquisitely specific cell-type determination during development is poorly understood. In the Drosophila eye, expression patterns of Rhodopsins define at least eight functionally distinct though related subtypes of photoreceptors. Here, we describe a role for the transcription factor gene defective proventriculus (dve) as a critical node in the network regulating Rhodopsin expression. dve is a shared component of two opposing, interlocked feedforward loops (FFLs). Orthodenticle and Dve interact in an incoherent FFL to repress Rhodopsin expression throughout the eye. In R7 and R8 photoreceptors, a coherent FFL relieves repression by Dve while activating Rhodopsin expression. Therefore, this network uses repression to restrict and combinatorial activation to induce cell-type-specific expression. Furthermore, Dve levels are finely tuned to yield cell-type- and region-specific repression or activation outcomes. This interlocked FFL motif may be a general mechanism to control terminal cell-fate specification.

Abbreviated Breast MRI for Supplemental Screening in Patients With Dense Breasts: Comparison of Baseline Versus Subsequent-Round Examinations.

BACKGROUND. Abbreviated breast MRI (AB-MRI) achieves a higher cancer detection rate (CDR) than digital breast tomosynthesis when applied for baseline (i.e., first-round) supplemental screening of individuals with dense breasts. Limited literature has evaluated subsequent (i.e., sequential) AB-MRI screening rounds. OBJECTIVE. This study aimed to compare outcomes between baseline and subsequent rounds of screening AB-MRI in individuals with dense breasts who otherwise had an average risk for breast cancer. METHODS. This retrospective study included patients with dense breasts who otherwise had an average risk for breast cancer and underwent AB-MRI for supplemental screening between December 20, 2016, and May 10, 2023. The clinical interpretations and results of recommended biopsies for AB-MRI examinations were extracted from the EMR. Baseline and subsequent-round AB-MRI examinations were compared. RESULTS. The final sample included 2585 AB-MRI examinations (2007 baseline and 578 subsequent-round examinations) performed for supplemental screening of 2007 women (mean age, 57.1 years old) with dense breasts. Of 2007 baseline examinations, 1658 (82.6%) were assessed as BI-RADS category 1 or 2, 171 (8.5%) as BI-RADS category 3, and 178 (8.9%) as BI-RADS category 4 or 5. Of 578 subsequent-round examinations, 533 (92.2%) were assessed as BI-RADS category 1 or 2, 20 (3.5%) as BI-RADS category 3, and 25 (4.3%) as BI-RADS category 4 or 5 (p < .001). The abnormal interpretation rate (AIR) was 17.4% (349/2007) for baseline examinations versus 7.8% (45/578) for subsequent-round examinations (p < .001). For baseline examinations, PPV2 was 21.3% (38/178), PPV3 was 26.6% (38/143), and the CDR was 18.9 cancers per 1000 examinations (38/2007). For subsequent-round examinations, PPV2 was 28.0% (7/25) (p = .45), PPV3 was 29.2% (7/24) (p = .81), and the CDR was 12.1 cancers per 1000 examinations (7/578) (p = .37). All 45 cancers diagnosed by baseline or subsequent-round AB-MRI were stage 0 or 1. Seven cancers diagnosed by subsequent-round AB-MRI had a mean interval of 872 ± 373 (SD) days since prior AB-MRI and node-negative status at surgical axillary evaluation; six had an invasive component, all measuring 1.2 cm or less. CONCLUSION. Subsequent rounds of AB-MRI screening of individuals with dense breasts had lower AIR than baseline examinations while maintaining a high CDR. All cancers detected by subsequent-round examinations were early-stage node-negative cancers. CLINICAL IMPACT. The findings support sequential AB-MRI for supplemental screening in individuals with dense breasts. Further investigations are warranted to optimize the screening interval.

Mean Apparent Diffusion Coefficient Is a Sufficient Conventional Diffusion-weighted MRI Metric to Improve Breast MRI Diagnostic Performance: Results from the ECOG-ACRIN Cancer Research Group A6702 Diffusion Imaging Trial.

Background The Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Cancer Research Group A6702 multicenter trial helped confirm the potential of diffusion-weighted MRI for improving differential diagnosis of suspicious breast abnormalities and reducing unnecessary biopsies. A prespecified secondary objective was to explore the relative value of different approaches for quantitative assessment of lesions at diffusion-weighted MRI. Purpose To determine whether alternate calculations of apparent diffusion coefficient (ADC) can help further improve diagnostic performance versus mean ADC values alone for analysis of suspicious breast lesions at MRI. Materials and Methods This prospective trial (ClinicalTrials.gov identifier: NCT02022579) enrolled consecutive women (from March 2014 to April 2015) with a Breast Imaging Reporting and Data System category of 3, 4, or 5 at breast MRI. All study participants underwent standardized diffusion-weighted MRI (b = 0, 100, 600, and 800 sec/mm2). Centralized ADC measures were performed, including manually drawn whole-lesion and hotspot regions of interest, histogram metrics, normalized ADC, and variable b-value combinations. Diagnostic performance was estimated by using the area under the receiver operating characteristic curve (AUC). Reduction in biopsy rate (maintaining 100% sensitivity) was estimated according to thresholds for each ADC metric. Results Among 107 enrolled women, 81 lesions with outcomes (28 malignant and 53 benign) in 67 women (median age, 49 years; interquartile range, 41-60 years) were analyzed. Among ADC metrics tested, none improved diagnostic performance versus standard mean ADC (AUC, 0.59-0.79 vs AUC, 0.75; P = .02-.84), and maximum ADC had worse performance (AUC, 0.52; P < .001). The 25th-percentile ADC metric provided the best performance (AUC, 0.79; 95% CI: 0.70, 0.88), and a threshold using median ADC provided the greatest reduction in biopsy rate of 23.9% (95% CI: 14.8, 32.9; 16 of 67 BI-RADS category 4 and 5 lesions). Nonzero minimum b value (100, 600, and 800 sec/mm2) did not improve the AUC (0.74; P = .28), and several combinations of two b values (0 and 600, 100 and 600, 0 and 800, and 100 and 800 sec/mm2; AUC, 0.73-0.76) provided results similar to those seen with calculations of four b values (AUC, 0.75; P = .17-.87). Conclusion Mean apparent diffusion coefficient calculated with a two-b-value acquisition is a simple and sufficient diffusion-weighted MRI metric to augment diagnostic performance of breast MRI compared with more complex approaches to apparent diffusion coefficient measurement. © RSNA, 2020 Online supplemental material is available for this article.

Breast MRI during Neoadjuvant Chemotherapy: Lack of Background Parenchymal Enhancement Suppression and Inferior Treatment Response.

Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.

Breast MRI: False-Negative Results and Missed Opportunities.

Breast MRI is the most sensitive modality for the detection of breast cancer. However, false-negative cases may occur, in which the cancer is not visualized at MRI and is instead diagnosed with another imaging modality. The authors describe the causes of false-negative breast MRI results, which can be categorized broadly as secondary to perceptual errors or cognitive errors, or nonvisualization secondary to nonenhancement of the tumor. Tips and strategies to avoid these errors are discussed. Perceptual errors occur when an abnormality is not prospectively identified, yet the examination is technically adequate. Careful development of thorough search patterns is critical to avoid these errors. Cognitive errors occur when an abnormality is identified but misinterpreted or mischaracterized as benign. The radiologist may avoid these errors by utilizing all available prior examinations for comparison, viewing images in all planes to better assess the margins and shapes of abnormalities, and appropriately integrating all available information from the contrast-enhanced, T2-weighted, and T1-weighted images as well as the clinical history. Despite this, false-negative cases are inevitable, as certain subtypes of breast cancer, including ductal carcinoma in situ, invasive lobular carcinoma, and certain well-differentiated invasive cancers, may demonstrate little to no enhancement at MRI, owing to differences in angiogenesis and neovascularity. MRI is a valuable diagnostic tool in breast imaging. However, MRI should continue to be used as a complementary modality, with mammography and US, in the detection of breast cancer. ©RSNA, 2021.

Five Consecutive Years of Screening with Digital Breast Tomosynthesis: Outcomes by Screening Year and Round.

Background Limited data exist beyond prevalence rounds of digital breast tomosynthesis (DBT) screening. Purpose To compare DBT outcomes over multiple years and rounds to outcomes of digital mammography (DM) screening. Materials and Methods Retrospective analysis included 1 year of DM and 5 years of DBT screening (September 2011 to September 2016); 67 350 examinations were performed in 29 310 women. Recall rate (RR) percentage, cancer detection rate (CDR) per 1000 women screened, false-negative rate per 1000 women screened, positive predictive value of recall (PPV1) percentage, positive predictive value of biopsies performed percentage, sensitivity, and specificity were calculated. Cancers diagnosed within 1 year of screening were captured by means of linkage to state cancer registry, and biologic characteristics were grouped by prognostic factors. Performance trends across DBT rounds were compared with those from DM rounds by using logistic regression to account for examinations in the same woman. Analyses were adjusted for age, race, breast density, baseline examination, and reader. Results There were 56 839 DBT and 10 511 DM examinations. The mean patient age (± standard deviation) was 56 years ±11 for the entire cohort, 55 years ±11 for the DBT group, and 57 years ±11 for the DM group. RRs were significantly lower for the DBT group (8.0%, 4522 of 56 839; 95% confidence interval [CI]: 7.7, 8.2) than for the DM group (10.4%, 1094 of 10 511; 95% CI: 9.8, 11.0) (P < .001). CDRs were higher with DBT (6.0 per 1000 women screened; 95% CI: 5.4, 6.7 per 1000 women screened; 340 of 56 839) than with DM (5.1 per 1000 women screened; 95% CI: 3.9, 6.6 per 1000 women screened; 54 of 10 511) (P = .25), but this difference was not statistically significant. Both RR and CDR remained improved compared with DM for 5 years of DBT at the population level. False-negative rates were slightly lower for DBT (0.6 per 1000 women screened; 95% CI: 0.4, 0.8 per 1000 women screened; 33 of 56 839) than DM (0.9 per 1000 women screened; 0.4, 1.6 per 1000 women screened; nine of 10 511) overall (P = .30), but the difference was not statistically significant. In adjusted analyses, RR, biopsy recommendation rates, and PPV1 were improved for DBT versus DM (P ≤ .001). Compared with DM, a higher proportion of DBT-detected cancers were invasive (70% [238 of 340] vs 68.5% [37 of 54]) and had poor prognoses characteristics (32.6% [76 of 233] vs 25.0% [nine of 36]). Conclusion Favorable outcomes with digital breast tomosynthesis screening were sustained over multiple years and rounds. Digital breast tomosynthesis screening was associated with detection of a higher proportion of poor-prognosis cancers than was digital mammography. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Moy and Heller in this issue.

When is it Safe to Drive After Total Ankle Arthroplasty?

BACKGROUND: With the increase in the number of total ankle arthroplasties (TAA), guidelines on when physicians should begin to consider patients' return to driving are valuable. Further, due to sagittal motion strength, the ankle is the most important mover in braking motions over the knee and hip. QUESTIONS/PURPOSES: (1) Does brake-reaction time return to a safe value within 6 weeks of TAA? (2) Are there factors associated with a delay of return of brake-reaction time to safe values after TAA? METHODS: After obtaining institutional review board approval for the study, we prospectively recruited 60 patients undergoing right TAA. A large proportion of the patients undergoing TAA during the period were recruited. Patients who had extensive concomitant surgery, such as triple arthrodesis or tibial osteotomy, were excluded from the study. Patients were between 43 and 83 years old (median, 63 years), and 35 (59%) were men. Brake-reaction time was tested at 6 weeks postoperatively and repeated weekly until patients achieved a passing brake-reaction time. A control group of 20 volunteer participants matched for age and sex who did not have right lower-extremity pathology or pain were used to establish a passing brake-reaction time of 0.850 seconds. Patients were given a novel driver-readiness survey to complete; a score of 10 of 15 points or higher was considered a passing score. The following factors were explored for their association with brake-reaction time: age, American Orthopaedic Foot and Ankle Society (AOFAS)-Hindfoot assessment and VAS for pain via a patient-reported survey, and ankle plantarflexion and dorsiflexion via dedicated weightbearing lateral radiographs made with the ankle in maximum plantarflexion and dorsiflexion. RESULTS: At 6 weeks postoperatively, 92% of patients (54 of 59) achieved a passing brake-reaction time and were considered able to drive safely, and the mean brake-reaction time of the patients with a passing brake-reaction time was 0.626 seconds (± 0.111). At 9 weeks, all patients who completed the study achieved a passing brake-reaction time. Patients with a failed brake-reaction time at 6 weeks had greater median VAS scores for pain (3 [interquartile range 2 to 7] versus 1 [IQR 0 to 3]; p = 0.022) and diminished ankle plantarflexion (14° [± 5°] versus 24° [± 10°]; p = 0.037) compared with those with a passing brake-reaction time at that time point. All five patients with a failed brake-reaction time also had a failing score for the driver-readiness survey. CONCLUSIONS: More than 90% of patients in this series achieved a safe brake-reaction time within 6 weeks of TAA, and those who did not were more likely to have had more pain and a stiffer ankle. Surgeons might counsel patients with persistent pain and stiffness at 6 weeks to delay driving for an additional 3 weeks, since by 9 weeks after TAA, all patients in this series had a brake-reaction time comparable with patients who had not undergone surgery. Future studies might elucidate what key gaps in knowledge remain and determine a practical way to answer these questions. LEVEL OF EVIDENCE: Level II, therapeutic study.

How Does Perioperative Ketorolac Affect Opioid Consumption and Pain Management After Ankle Fracture Surgery?

BACKGROUND: The investigation of nonnarcotic drug regimens for postoperative pain management is important in addressing the opioid epidemic. NSAIDs can be a powerful adjunct in managing postoperative pain, but the possibility of delayed bone healing is a major concern for orthopaedic surgeons. Our recent retrospective study on ketorolac administration demonstrated that the NSAID is not associated with an increased risk of delayed union or nonunion after ankle fracture surgery. QUESTIONS/PURPOSES: To determine whether postoperative ketorolac (1) reduces opioid consumption, (2) improves VAS pain control, and (3) affects fracture healing after open reduction and internal fixation of ankle fractures. METHODS: Between August 2016 and December 2017, 128 patients undergoing open reduction and internal fixation of an acute ankle fracture were randomized before surgery via simple randomization to treatment with or without ketorolac. No patients changed treatment regimen groups or opted out of randomization. All other aspects of perioperative care were treated identically. A once-daily survey was distributed via email on postoperative Days 1 to 7. Unblinded participants were asked to report their daily opioid consumption, pain level, and sleep interference using the VAS, and pain frequency using a five-point Likert scale, and side effects with the VAS. For VAS pain, > 20 mm/100 mm on the VAS scale was required to be considered "improved." In all, 83% (106 of 128) patients completed all seven postoperative surveys with 14 in the control group and eight in the ketorolac group lost to follow-up. Fifty-six patients were administered ketorolac with opioid medication (treatment group) and 50 were administered opioids alone (control group). Participants were comprised of 42% men (44), and 58% women (62); mean age was 48 years. The treating surgeon assessed clinical healing based on the patient's ability to ambulate comfortably at 12 weeks postoperatively. Radiographic healing was assessed by two fellowship-trained orthopaedic foot and ankle surgeons blinded to the patient's name and time since surgery. The surgeons evaluated randomized standard ankle series (anteroposterior, mortise, and lateral) radiographs for resolution of each fracture line to determine fracture union, with delayed union being defined as fracture lines present on radiographs taken at 12-week postoperative visits. Intention-to-treat analysis was performed. RESULTS: Patients in the treatment group consumed a mean of 14 opioid pills, which was less than the mean of 19.3 opioids pills consumed by patients in the control group (p = 0.037). Patients with ketorolac had lower median VAS scores for pain (p < 0.035) postoperatively on postoperative Days 1 and 2 than did control patients. By contrast, patient-reported pain scores and scores for sleep did not convincingly show a benefit to the use of ketorolac. For patients whose ankle fractures healed at 12 weeks, there was no difference between the groups in terms of clinical healing (p = 0.575) and radiographic healing (p = 0.961). CONCLUSIONS: In this randomized study, adding ketorolac to the postoperative drug regimen decreased the use of opioid medication after open reduction and internal fixation of ankle fractures in the early postoperative period, and there were mixed, small effects on pain reduction. This NSAID is a valuable tool in helping patients manage postoperative pain with less use of narcotic analgesia. However, our study was underpowered to determine the true safety of this drug in terms of fracture healing and side effects and these questions warrant higher-powered randomized study investigation. LEVEL OF EVIDENCE: Level I, therapeutic study.

Effect of contrast dose on diagnostic performance in DCE-MR breast imaging.

OBJECTIVE: To assess the diagnostic performance of breast magnetic resonance (MR) imaging as a function of gadolinium contrast dose using a retrospective reader study. MATERIAL AND METHODS: IRB approval was obtained prior to the start of this study and was HIPAA compliant. One-hundred and fifty MR breast examinations were included that were acquired between January 2001 and December 2006. Seventy-five patients received contrast doses (gadopentetate dimeglumine) by weight of 0.10 mmol/kg and 75 patients were imaged using fixed volumes of 20 ml. The images were assessed by two radiologists with performance calculated for each reader as well as a combined assessment. Dose response was measured by comparing performance between cases binned by dose: <=0.10; >0.10; and >0.13 mmol/kg. Statistical significance was calculated using a one-sided Z-test for differences in proportions with interobserver agreement calculated using Cohen's kappa statistics. RESULTS: In the combined reader assessment with equivocal lesions classified as negative, sensitivity rose from 66% (19/29) to 92% (24/26, P < 0.01) and 95% (18/19, P < 0.01) with the specificity also increasing from 65% (32/49) to 87% (40/46, P < 0.01) and 86% (32/37, P = 0.01) corresponding to doses <=0.10, >0.10, >0.13 mmol/kg. With equivocal lesions classified as positive, sensitivity rose from 79% (23/29) to 92% (24/26, P < 0.10) and 95% (18/19, P < 0.10) Specificity also increased from 53% (26/49) to 72% (33/46, P < 0.05) and 70% (26/37, P = 0.05) with increasing dose. Interobserver agreement also improved at the higher doses.

Digital Breast Tomosynthesis: Concepts and Clinical Practice.

Digital breast tomosynthesis (DBT) is emerging as the standard of care for breast imaging based on improvements in both screening and diagnostic imaging outcomes. The additional information obtained from the tomosynthesis acquisition decreases the confounding effect of overlapping tissue, allowing for improved lesion detection, characterization, and localization. In addition, the quasi three-dimensional information obtained from the reconstructed DBT data set allows a more efficient imaging work-up than imaging with two-dimensional full-field digital mammography alone. Herein, the authors review the benefits of DBT imaging in screening and diagnostic breast imaging.

Breast Cancer Conspicuity on Simultaneously Acquired Digital Mammographic Images versus Digital Breast Tomosynthesis Images.

Background Digital breast tomosynthesis (DBT) has been shown to improve screening outcomes compared with digital mammography (DM) alone. However, little is known about differences in breast cancer conspicuity between DM and DBT or by mammographic view. Purpose To compare conspicuity of breast cancers at DM versus DBT and by mammographic view, craniocaudal (CC) versus mediolateral oblique (MLO). Materials and Methods Lesion conspicuity was graded by three readers by using a 0-5 numerical scale on both DM and DBT images from combined DM and DBT studies for 197 consecutive screening-detected cancers in women (mean age, 60.4 years ± 11.1 [standard deviation]) from October 1, 2011, through December 31, 2014. Intermodality (ie, DM vs DBT) and intramodality (ie, CC vs MLO) analyses were performed. For intramodality analyses, conspicuity was analyzed by view, CC versus MLO, within the same modality. Conspicuity grades were dichotomized into low (scores 0-3) and high (scores 4 and 5) conspicuity. This binary result was assessed by using a generalized linear mixed-effects model with logit link function, random-effect intercept for reader, and compound symmetry covariance structure for lesion. Results Cancers were more likely to be high conspicuity at DBT than at DM (odds ratio [OR], 2.4; 95% confidence interval [CI]: 1.9, 3.0; P < .01). At both DM and DBT, cancers were more likely to be high conspicuity at the CC than the MLO view (DM vs DBT OR, 1.6 [95% CI: 1.3, 1.9] vs 1.7 [95% CI: 1.3, 2.1], respectively; P < .01 for both). Cancers seen at one view only were more often detected at CC than MLO for both DM and DBT (DM vs DBT OR, 1.6 [95% CI: 1.2, 2.0] vs 3.6 [95% CI: 1.9, 7.0], respectively; P < .01.). Conclusion Cancers were more conspicuous at digital breast tomosynthesis than at digital mammography. Cancers may only be detected at one of two views, and they are more likely to be seen at the craniocaudal view. © RSNA, 2019.

Characterizing and eliminating errors in enhancement and subtraction artifacts in dynamic contrast-enhanced breast MRI: Chemical shift artifact of the third kind.

PURPOSE: To characterize errors in enhancement in breast dynamic contrast-enhanced (DCE) MRI studies as a function of echo time and determine the source of dark band artifacts in clinical subtraction images. METHODS: Computer simulations, oil and water substitute (methylene chloride), as well as an American College of Radiology quality control phantom were tested. Routine clinical DCE breast MRI study was bracketed with (accelerated) in-phase DCE acquisitions in five patients. RESULTS: Simulation results demonstrated up to -160% suppression of the expected enhancement caused by differential enhancement of fat and water. Two-dimensional gradient-recalled echo and fat-suppressed 3D GRE phantom imaging confirmed the simulation results and showed that fat suppression does not eliminate the artifact. In vivo in-phase DCE images showed increased enhancement consistent with predictions and also confirmed increased spatial blurring on in-phase 3D gradient-recalled echo images. Combined multi-dimensional partial Fourier and parallel imaging provided a time-equivalent in-phase DCE MRI acquisition. CONCLUSION: Errors in expected enhancement occur in DCE breast MRI subtraction images because of differential enhancement of fat and water and incomplete fat signal suppression. These errors can lead to artificial suppression of enhancement as well as dark band artifacts on subtraction images. These artifacts can be eliminated with a time-equivalent in-phase fat-suppressed 3D gradient-recalled echo sequence. Understanding chemical shift artifact of the third kind, a unique artifact of artificial enhancement suppression in the presence of intravoxel fat and water signal, will aid DCE breast MRI image interpretation. In-phase acquisitions (combined with simultaneous minimum echo time or opposed-phase echoes) may facilitate qualitative, quantitative and longitudinal analysis of contrast enhancement. Magn Reson Med 79:2277-2289, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The impact of preoperative magnetic resonance imaging and lumpectomy cavity shavings on re-excision rate in pure ductal carcinoma in situ-A single institution's experience.

BACKGROUND AND OBJECTIVES: The impact of preoperative magnetic resonance imaging (pMRI) and cavity shave margins (CSM) on re-excision rate (RR) in DCIS is unclear. We investigated whether either modality was associated with RR in DCIS. METHODS: This is a single-institution retrospective study of 295 women undergoing breast conservation surgery for pure DCIS (2010-2013). CSM were the systematic resection of 4-6 margins during lumpectomy whereas selective shave margins (SSM) were the selective resection of 1-3 margins. Patient demographics and clinical characteristics were abstracted. RR was analyzed according to the use of pMRI, SSM, or CSM with respect to three high-volume breast surgeons at our institution. RESULTS: RR was not associated with the use of pMRI (P = 0.87). Any shave margins (P = 0.05), DCIS size (P < 0.001), and DCIS grade (P = 0.14) associated with a lower RR. Of our high-volume surgeons, RR was lower for Surgeon A (P = 0.02). Multivariate analyses showed larger DCIS (OR 1.35, P = 0.005) and practices specific to surgeons B (OR 3.23, P = 0.04) and C (OR 3.57, P = 0.04) increased re-excision odds. CONCLUSIONS: SSM/CSM and pMRI use varied among surgeons. Our results suggested the routine use of CSM, not pMRI, could lower re-excision rate, which highlighted a quality improvement opportunity at our institution.

Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells.

The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation.

BI-RADS Category 3 Comparison: Probably Benign Category after Recall from Screening before and after Implementation of Digital Breast Tomosynthesis.

Purpose To evaluate Breast Imaging Reporting and Data System (BI-RADS) category 3 assessment at diagnostic examination after recall from screening in a large urban population after implementation of digital breast tomosynthesis (DBT) by focusing both on overall use and use stratified by recalled finding type and outcome at 2 years. Materials and Methods This was an intuitional review board-approved and HIPAA-compliant retrospective review of 10 728 digital mammography (DM) examinations from September 1, 2010, to August 30, 2011, and 15 571 screening DBT examinations from October 1, 2011, to February 28, 2013. The recall populations for DM and DBT were 1112 of 10 728 (10.4% of women screened) and 1366 of 15 571 (8.8% of women screened), respectively. Recall examinations were classified according to finding type: calcifications, asymmetry or focal asymmetry, mass, and architectural distortion. Differences between groups were compared by using the χ2 test. Results Although there was no significant change in the utilization rate of BI-RADS category 3 in those patients screened with DM compared with DBT (168 of 10 728, 1.6% for DM vs 206 of 15 571, 1.3% for DBT; P = .102), there was a mean overall reduction of 2.4 women per 1000 (95% confidence interval [CI]: -0.5, 5.4) recommended for short-term follow-up. Lesion types given a BI-RADS category 3 assessment after diagnostic work-up did not change. The distribution of recalled finding types significantly changed with DBT, with increased recall examinations for architectural distortion and mass (P < .001) and decreased recall examinations for asymmetries (P ≤ .001). There was no change in recall examinations for calcifications (P = .977). Conclusion Screening with DBT did not significantly change the utilization rate of BI-RADS category 3 classification; however, the overall number of patients recommended for short-interval follow-up decreased by a mean of 2.4 women per 1000 (95% CI: -0.5, 5.4). © RSNA, 2017 Online supplemental material is available for this article.

Agreement between Breast Percentage Density Estimations from Standard-Dose versus Synthetic Digital Mammograms: Results from a Large Screening Cohort Using Automated Measures.

Purpose To evaluate agreement between automated estimates of breast density made from standard-dose versus synthetic digital mammograms in a large cohort of women undergoing screening. Materials and Methods This study received institutional review board approval with waiver of consent. A total of 3668 negative (Breast Imaging Reporting and Data System category 1 or 2) digital breast tomosynthesis (DBT) screening examinations consecutively performed over a 4-month period at one institution for which both standard-dose and synthetic mammograms were available for analysis were retrospectively analyzed. All mammograms were acquired with a Selenia Dimensions system (Hologic, Bedford, Mass), and synthetic mammograms were generated by using the U.S. Food and Drug Administration-approved "C-View" software module. The "For Presentation" standard-dose mammograms and synthetic images were analyzed by using a fully automated algorithm. Agreement between density estimates was assessed by using Pearson correlation, linear regression, and Bland-Altman analysis. Differences were evaluated by using the paired Student t test. Results Breast percentage density (PD) estimates from synthetic and standard-dose mammograms were highly correlated (r = 0.92, P < .001), and the 95% Bland-Altman limits of agreement between PD estimates were -6.4% to 9.9%. Synthetic mammograms had PD estimates by an average of 1.7% higher than standard-dose mammograms (P < .001), with a larger disagreement by 1.56% in women with highly dense breast tissue (P < .0001). Conclusion Fully automated estimates of breast density made from synthetic mammograms are generally comparable to those made from standard-dose mammograms. This may be important, as standard two-dimensional mammographic images are increasingly being replaced by synthetic mammograms in DBT screening in an attempt to reduce radiation dose. © RSNA, 2017 Online supplemental material is available for this article.

Anti-HER2 CD4+ T-Helper Type 1 Immune Response is Superior to Breast MRI for Assessing Response to Neoadjuvant Therapy in Patients with HER2-Positive Breast Cancer.

BACKGROUND: In human epidermal growth factor 2-positive breast cancer (HER2+BC), neoadjuvant chemotherapy and anti-HER2-targeted therapy (nCT) achieves a complete pathologic response (pCR) in 40-67% of patients. Posttreatment magnetic resonance imaging (pMRI) is considered the gold standard, with high specificity but lower sensitivity for assessing response. The authors previously determined that anti-HER2Th1 immune response is associated with pathologic response after nCT in HER2+BC patients. This study contrasted pMRI with anti-HER2Th1 response for assessing pCR in HER2+BC. METHODS: A retrospective review of HER2+BC patients at the authors' institution was performed. Original pMRI reports were collected, and images were reviewed by a breast radiologist blinded to pCR and immune response. The post-nCT imaging-based tumor response was assessed by Response Evaluation Criteria in Solid Tumors. The anti-HER2Th1 response was determined by ex vivo stimulation of peripheral blood mononuclear cells with six major histocompatibility complex (MHC) class 2-derived HER2 peptides via enzyme-linked immunospot (ELISPOT). Posttreatment MRI and anti-HER2Th1 responses were cross-tabulated with pCR. Standard diagnostic metrics were computed. RESULTS: For 30 patients, pMRI and anti-HER2Th1 immune response were measured, with 13 patients (43.3%) achieving pCR. The mean anti-HER2Th1 response in pCR was 167 (range 53-418), and

Imaging With Synthesized 2D Mammography: Differences, Advantages, and Pitfalls Compared With Digital Mammography.

OBJECTIVE: Synthesized 2D (s2D) mammography is rapidly replacing digital mammography in breast imaging with digital breast tomosynthesis (DBT) to reduce radiation dose and maintain screening outcomes. We illustrate variations in the appearance of s2D and digital mammograms to aid in implementation of this technology. CONCLUSION: Despite subjective differences in the appearance of s2D and digital mammograms, early outcomes of screening using s2D mammography and DBT are not inferior to those achieved with digital mammography and DBT. Understanding these variations may aid in implementing this technique and improving patient outcomes.

Molecular Probes for Imaging the Sigma-2 Receptor: In Vitro and In Vivo Imaging Studies.

The sigma-2 (σ2) receptor has been validated as a biomarker of the proliferative status of solid tumors. Therefore, radiotracers having a high affinity and high selectivity for σ2 receptors have the potential to assess the proliferative status of human tumors using noninvasive imaging techniques such as Positron Emission Tomography (PET). Since the σ2 receptor has not been cloned, the current knowledge of this receptor has relied on receptor binding studies with the radiolabeled probes and investigation of the effects of the σ2 receptor ligands on tumor cells. The development of the σ2 selective fluorescent probes has proven to be useful for studying subcellular localization and biological functions of the σ2 receptor, for revealing pharmacological properties of the σ2 receptor ligands, and for imaging cell proliferation. Preliminary clinical imaging studies with [18F]ISO-1, a σ2 receptor probe, have shown promising results in cancer patients. However, the full utility of imaging the σ2 receptor status of solid tumors in the diagnosis and prediction of cancer therapeutic response will rely on elucidation of the functional role of this protein in normal and tumor cell biology.