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.

Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study.

BACKGROUND: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. METHODS: We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. RESULTS: At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. CONCLUSIONS: AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

Diffusion-weighted MRI Findings Predict Pathologic Response in Neoadjuvant Treatment of Breast Cancer: The ACRIN 6698 Multicenter Trial.

Purpose To determine if the change in tumor apparent diffusion coefficient (ADC) at diffusion-weighted (DW) MRI is predictive of pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer. Materials and Methods In this prospective multicenter study, 272 consecutive women with breast cancer were enrolled at 10 institutions (from August 2012 to January 2015) and were randomized to treatment with 12 weekly doses of paclitaxel (with or without an experimental agent), followed by 12 weeks of treatment with four cycles of anthracycline. Each woman underwent breast DW MRI before treatment, at early treatment (3 weeks), at midtreatment (12 weeks), and after treatment. Percentage change in tumor ADC from that before treatment (ΔADC) was measured at each time point. Performance for predicting pCR was assessed by using the area under the receiver operating characteristic curve (AUC) for the overall cohort and according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results The final analysis included 242 patients with evaluable serial imaging data, with a mean age of 48 years ± 10 (standard deviation); 99 patients had HR-positive (hereafter, HR+)/HER2-negative (hereafter, HER2-) disease, 77 patients had HR-/HER2- disease, 42 patients had HR+/HER2+ disease, and 24 patients had HR-/HER2+ disease. Eighty (33%) of 242 patients experienced pCR. Overall, ΔADC was moderately predictive of pCR at midtreatment/12 weeks (AUC = 0.60; 95% confidence interval [CI]: 0.52, 0.68; P = .017) and after treatment (AUC = 0.61; 95% CI: 0.52, 0.69; P = .013). Across the four disease subtypes, midtreatment ΔADC was predictive only for HR+/HER2- tumors (AUC = 0.76; 95% CI: 0.62, 0.89; P < .001). In a test subset, a model combining tumor subtype and midtreatment ΔADC improved predictive performance (AUC = 0.72; 95% CI: 0.61, 0.83) over ΔADC alone (AUC = 0.57; 95% CI: 0.44, 0.70; P = .032.). Conclusion After 12 weeks of therapy, change in breast tumor apparent diffusion coefficient at MRI predicts complete pathologic response to neoadjuvant chemotherapy. © RSNA, 2018 Online supplemental material is available for this article.

Exploring effects of presurgical weight loss among women with stage 0-II breast cancer: protocol for a randomised controlled feasibility trial.

INTRODUCTION: Obesity is a known risk factor for postmenopausal breast cancer and is associated with poorer prognosis for premenopausal and postmenopausal patients; however, the aetiological mechanisms are unknown. Preclinical studies support weight loss via caloric restriction and increased physical activity as a possible cancer control strategy, though few clinical studies have been conducted. We undertook a feasibility trial among women recently diagnosed with stage 0-II breast cancer hypothesising that presurgical weight loss would be feasible, safe and result in favourable changes in tumour markers and circulating biomarkers. METHODS AND ANALYSIS: A two-arm randomised controlled trial among 40 overweight or obese women, newly diagnosed with stage 0-II breast cancer and scheduled for surgery was planned. The attention control arm received upper body progressive resistance training and diet counselling to correct deficiencies in nutrient intake; the experimental arm received the same plus counselling on caloric restriction and aerobic exercise to achieve a weight loss of 0.68-0.919 kg/week. In addition to achieving feasibility benchmarks (accruing and retaining at least 80% of participants, and observing no serious adverse effects attributable to the intervention), we will explore the potential impact of an acute state of negative energy balance on tumour proliferation rates (Ki-67), as well as other tumour markers, serum biomarkers, gene expression, microbiome profiles and other clinical outcomes (eg, quality of life). Outcomes for the 2 study arms are compared using mixed models repeated-measures analyses. ETHICS AND DISSEMINATION: Ethics approval was received from the University of Alabama at Birmingham Institutional Review Board (Protocol number F130325009). Study findings will be disseminated through peer-reviewed publications. Given that this is one of the first studies to investigate the impact of negative energy balance directly on tumour biology in humans, larger trials will be pursued if results are favourable. TRIAL REGISTRATION NUMBER: NCT02224807; Pre-results.

Association between Preoperative Vascular Function and Postoperative Arteriovenous Fistula Development.

Arteriovenous fistula (AVF) maturation failure is the primary cause of dialysis vascular access dysfunction. To evaluate whether preoperative vascular functional properties predict postoperative AVF measurements, patients enrolled in the Hemodialysis Fistula Maturation Study underwent up to five preoperative vascular function tests (VFTs): flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), carotid-femoral pulse wave velocity, carotid-radial pulse wave velocity, and venous occlusion plethysmography. We used mixed effects multiple regression analyses to relate each preoperative VFT to ultrasound measurements of AVF blood flow rate and venous diameter at 1 day, 2 weeks, and 6 weeks after AVF placement. After controlling for AVF location, preoperative ultrasound measurements, and demographic factors (age, sex, race, and dialysis status), greater NMD associated with greater 6-week AVF blood flow rate and AVF diameter (per absolute 10% difference in NMD: change in blood flow rate =14.0%; 95% confidence interval [95% CI], 3.7% to 25.3%; P<0.01; change in diameter =0.45 mm; 95% CI, 0.25 to 0.65 mm; P<0.001). Greater FMD also associated with greater increases in 6-week AVF blood flow rate and AVF diameter (per absolute 10% difference in FMD: change in blood flow rate =11.6%; 95% CI, 0.6% to 23.9%; P=0.04; change in diameter =0.31 mm; 95% CI, 0.05 to 0.57 mm; P=0.02). None of the remaining VFT parameters exhibited consistent statistically significant relationships with both postoperative AVF blood flow rate and diameter. In conclusion, preoperative NMD and FMD positively associated with changes in 6-week AVF blood flow rate and diameter, suggesting that native functional arterial properties affect AVF development.

Arteriovenous Fistula Development in the First 6 Weeks after Creation.

PURPOSE: To assess the anatomic development of native arteriovenous fistula (AVF) during the first 6 weeks after creation by using ultrasonographic (US) measurements in a multicenter hemodialysis fistula maturation study. MATERIALS AND METHODS: Each institutional review board approved the prospective study protocol, and written informed consent was obtained. Six hundred and two participants (180 women and 422 men, 459 with upper-arm AVF and 143 with forearm AVF) from seven clinical centers underwent preoperative artery and vein US mapping. AVF draining vein diameter and blood flow rate were assessed postoperatively after 1 day, 2 weeks, and 6 weeks. Relationships among US measurements were summarized after using multiple imputation for missing measurements. RESULTS: In 55% of forearm AVFs (68 of 124) and 83% of upper-arm AVFs (341 of 411) in surviving patients without thrombosis or AVF intervention prior to 6 weeks, at least 50% of their 6-week blood flow rate measurement was achieved at 1 day. Among surviving patients without thrombosis or AVF intervention prior to week 2, 70% with upper-arm AVFs (302 of 433) and 77% with forearm AVFs (99 of 128) maintained at least 85% of their week 2 flow rate at week 6. Mean AVF diameters of at least 0.40 cm were seen in 85% (389 of 459), 91% (419 of 459), and 87% (401 of 459) of upper-arm AVFs and in 40% (58 of 143), 73% (104 of 143), and 77% (110 of 143) of forearm AVFs at 1 day, 2 weeks, and 6 weeks, respectively. One-day and 2-week AVF flow rates and diameters were used to predict 6-week levels, with 2-week prediction of 6-week measures more accurate than those of 1 day (flow rates, R(2) = 0.47 and 0.61, respectively; diameters, R(2) = 0.49 and 0.82, respectively). CONCLUSION: AVF blood flow rate at 1 day is usually more than 50% of the 6-week blood flow rate. Two-week measurements are more predictive of 6-week diameter and blood flow than those of 1 day. US measurements at 2 weeks may be of value in the early identification of fistulas that are unlikely to develop optimally.

Preoperative arterial microcalcification and clinical outcomes of arteriovenous fistulas for hemodialysis.

BACKGROUND: Arteriovenous fistulas (AVFs) often fail to mature, but the mechanism of AVF nonmaturation is poorly understood. Arterial microcalcification is common in patients with chronic kidney disease (CKD) and may limit vascular dilatation, thereby contributing to early postoperative juxta-anastomotic AVF stenosis and impaired AVF maturation. This study evaluated whether preexisting arterial microcalcification adversely affects AVF outcomes. STUDY DESIGN: Prospective study. SETTING & PARTICIPANTS: 127 patients with CKD undergoing AVF surgery at a large academic medical center. PREDICTORS: Preexisting arterial microcalcification (≥1% of media area) assessed independently by von Kossa stains of arterial specimens obtained during AVF surgery and by preoperative ultrasound. OUTCOMES: Juxta-anastomotic AVF stenosis (ascertained by ultrasound obtained 4-6 weeks postoperatively), AVF nonmaturation (inability to cannulate with 2 needles with dialysis blood flow ≥ 300mL/min for ≥6 sessions in 1 month within 6 months of AVF creation), and duration of primary unassisted AVF survival after successful use (time to first intervention). RESULTS: Arterial microcalcification was present by histologic evaluation in 40% of patients undergoing AVF surgery. The frequency of a postoperative juxta-anastomotic AVF stenosis was similar in patients with or without preexisting arterial microcalcification (32% vs 42%; OR, 0.65; 95% CI, 0.28-1.52; P=0.3). AVF nonmaturation was observed in 29%, 33%, 33%, and 33% of patients with <1%, 1% to 4.9%, 5% to 9.9%, and ≥10% arterial microcalcification, respectively (P=0.9). Sonographic arterial microcalcification was found in 39% of patients and was associated with histologic calcification (P=0.001), but did not predict AVF nonmaturation. Finally, among AVFs that matured, unassisted AVF maturation (time to first intervention) was similar for patients with and without preexisting arterial microcalcification (HR, 0.64; 95% CI, 0.35-1.21; P=0.2). LIMITATIONS: Single-center study. CONCLUSIONS: Arterial microcalcification is common in patients with advanced CKD, but does not explain postoperative AVF stenosis, AVF nonmaturation, or AVF failure after successful cannulation.

Combination therapy with anti-DR5 antibody and tamoxifen for triple negative breast cancer.

TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERß, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERß-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 µM and 38 µM, respectively. Synergy between TRA-8 (0-1000 ng/mL) and tamoxifen (20 µM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during therapy, but an antagonistic effect was observed when tamoxifen was combined. TRA-8 uptake into tumors was not changed by tamoxifen treatment. Histological analysis confirmed that caspase-3 activation induced by TRA-8 was significantly decreased when tamoxifen was used in combination. In conclusion, our findings suggest that the combined use of TRA-8 and tamoxifen may cause antagonistic effects for TNBC patients.

Antagonistic effects of anti-EMMPRIN antibody when combined with chemotherapy against hypovascular pancreatic cancers.

PURPOSE: To examine the antagonistic effects of anti-extracellular matrix metalloprotease inducer (anti-EMMPRIN) antibody when combined with chemotherapy using a hypovascular pancreatic tumor model. PROCEDURES: Severely compromised immunodeficient mice bearing orthotopic MIA PaCa-2 tumors were used (five to six animals per group). Dynamic contrast-enhanced magnetic resonance imaging was used to examine the relationship between tumor vascularity and size. Therapy was initiated when tumors were hypovascular. Treatments included: (1) gemcitabine alone, (2) anti-EMMPRIN antibody alone, and (3) combination, each for 2 weeks. Additionally, another treatment arm included ß-lapachone, an NAD(P)H/quinone 1 (NQO1) bioactivated agent. (18)F-fluoro-D-glucose-positron emission tomography/computed tomography imaging was used weekly to monitor therapeutic effects. RESULTS: Gemcitabine or anti-EMMPRIN monotherapy significantly delayed tumor growth, but the combination therapy showed an antagonistic effect. Similarly, tumor growth was significantly suppressed by ß-lapachone alone, and additive effects were noted when combined with gemcitabine, but the therapeutic efficacy was reduced when anti-EMMPRIN antibody was added. CONCLUSIONS: Anti-EMMPRIN antibody with chemotherapy in hypovascular tumors results in antagonistic effects.

Diffusion weighted imaging evaluated the early therapy effect of tamoxifen in an MNU-induced mammary cancer rat model.

PURPOSE: To assess the optimal time point of diffusion-weighted imaging (DWI) for early prognosis of breast cancer following tamoxifen therapy using a methylnitrosourea (MNU)-induced ER-positive breast-cancer model. METHODS: Two groups of Sprague-Dawley rats (n = 15 for group 1; n = 10 for group 2) were used. All animals (50 days old) were intravenously injected with MNU (50 mg/kg body weight) to induce ER-positive mammary tumors. When tumors were approximately 2 cm in diameter, DWI was performed on days 0, 3, and 7, and intratumoral apparent diffusion coefficient (ADC) values were measured. Therapy started on day 0 with tamoxifen (10 mg/kg diet) and continued for 4 weeks for group 1, but only 1 week for group 2, while tumor volume was measured by caliper twice weekly. All animals of group 2 were euthanized on day 7 after imaging, and Ki-67, TUNEL, ERα, and ERß staining were performed on tumor tissue. RESULTS: DW images of MNU-induced mammary tumors were successfully obtained with minimal motion artifact. For group 1, ADC change for 3 days after therapy initiation (ADC3D) was significantly correlated with tumor-volume change until day 11, but the significant correlation between ADC change for 7 days (ADC7D) and the tumor-volume change was observed until day 18. Similarly, for group 2, either ADC7D or ADC3D was significantly correlated with the tumor-volume change, but the higher significance was observed for ADC7D. Furthermore, ADC7D was significantly correlated with apoptotic (TUNEL stained), proliferative (Ki-67 stained), and ERß-positive cell densities, but ADC3D was not significantly correlated with any of those. CONCLUSIONS: ADC7D might be a more reliable surrogate imaging biomarker than ADC3D to assess effectiveness of tamoxifen therapy for ER-positive breast cancer, which may enable personalized treatment. The significant correlation between ADC7D and ERß-positive cell density suggests that ERß may play an important role as a therapeutic indicator of tamoxifen.

The ACR/Society of Breast Imaging Resident and Fellowship Training Curriculum for Breast Imaging, updated.

The education committees of the ACR Commission on Breast Imaging and the Society of Breast Imaging have revised the resident and fellowship training curriculum to reflect the current state of breast imaging in the United States. The original curriculum, created by the Society of Breast Imaging in 2000, had been updated only once before, in 2006. Since that time, a number of significant changes have occurred in the way mammography is acquired, how adjunctive breast imaging methods are used, and how pathology is assessed. This curricular update is meant to reflect these and other changes and to offer guidance to educators and trainees in preparing those interested in providing breast imaging services.

Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma.

The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models.

A triple-targeted ultrasound contrast agent provides improved localization to tumor vasculature.

OBJECTIVES: Actively targeting ultrasound contrast agents to tumor vasculature improves contrast-enhanced sonography of tumor angiogenesis. This report summarizes an evaluation of multitargeted microbubbles, comparing single-, dual-, and triple-targeted motifs. METHODS: Microbubbles were avidin-biotin linked to antibodies against mouse α(V)ß(3)-integrin, P-selectin, and vascular endothelial growth factor receptor 2. These receptors are constitutively overexpressed in tumor vasculature. Binding comparisons between targeted microbubble groups were evaluated on mouse SVR angiosarcoma endothelial cells. Levels of the targeted receptors were characterized with flow cytometry. Targeted microbubble groups were administered to human MDA-MB-231 breast cancer tumor-bearing mice (n = 3) followed by contrast-enhanced sonography in a microbubble-sensitive harmonic imaging mode implemented on an ultrasound scanner equipped with a linear array transducer (5 MHz transmit and 10 MHz receive) to evaluate differences in microbubble accumulation in the tumor vasculature. RESULTS: In vitro analysis showed a 50% increase (P < .001) in triple-targeted microbubble binding over dual-targeted microbubble groups in mouse SVR cells. Mice bearing MDA-MB-231 tumors showed a 40% increase in tumor image intensity after dosing with triple-targeted microbubbles compared with single- and dual-targeted microbubbles (P = .006). Histologic staining confirmed the presence of α(V)ß(3)-integrin, P-selectin, and vascular endothelial growth factor receptor 2 in the tumors. CONCLUSIONS: Microbubble accumulation in the tumor vasculature was improved using a triple-targeted microbubble approach.

Benign Renal Schwannoma: A Case Report and Literature Review.

Schwannomas are tumors arising from cells of the nerve sheath. While schwannomas are commonly found in peripheral nerves and cranial nerves, these tumors are rarely found within the kidney and may be difficult to differentiate from renal cell carcinoma. Few cases have been reported in the literature, and very little has been described regarding the imaging appearance of these rare renal tumors. We present a case of intrarenal schwannoma with sonographic, computed tomographic, and pathologic correlation.