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.

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

PURPOSE: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. PATIENTS AND METHODS: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. RESULTS: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen. CONCLUSIONS: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.

Test-retest repeatability and reproducibility of ADC measures by breast DWI: Results from the ACRIN 6698 trial.

BACKGROUND: Quantitative diffusion-weighted imaging (DWI) MRI is a promising technique for cancer characterization and treatment monitoring. Knowledge of the reproducibility of DWI metrics in breast tumors is necessary to apply DWI as a clinical biomarker. PURPOSE: To evaluate the repeatability and reproducibility of breast tumor apparent diffusion coefficient (ADC) in a multi-institution clinical trial setting, using standardized DWI protocols and quality assurance (QA) procedures. STUDY TYPE: Prospective. SUBJECTS: In all, 89 women from nine institutions undergoing neoadjuvant chemotherapy for invasive breast cancer. FIELD STRENGTH/SEQUENCE: DWI was acquired before and after patient repositioning using a four b-value, single-shot echo-planar sequence at 1.5T or 3.0T. ASSESSMENT: A QA procedure by trained operators assessed artifacts, fat suppression, and signal-to-noise ratio, and determine study analyzability. Mean tumor ADC was measured via manual segmentation of the multislice tumor region referencing DWI and contrast-enhanced images. Twenty cases were evaluated multiple times to assess intra- and interoperator variability. Segmentation similarity was assessed via the Sørenson-Dice similarity coefficient. STATISTICAL TESTS: Repeatability and reproducibility were evaluated using within-subject coefficient of variation (wCV), intraclass correlation coefficient (ICC), agreement index (AI), and repeatability coefficient (RC). Correlations were measured by Pearson's correlation coefficients. RESULTS: In all, 71 cases (80%) passed QA evaluation: 44 at 1.5T, 27 at 3.0T; 60 pretreatment, 11 after 3 weeks of taxane-based treatment. ADC repeatability was excellent: wCV = 4.8% (95% confidence interval [CI] 4.0, 5.7%), ICC = 0.97 (95% CI 0.95, 0.98), AI = 0.83 (95% CI 0.76, 0.87), and RC = 0.16 * 10-3 mm2 /sec (95% CI 0.13, 0.19). The results were similar across field strengths and timepoint subgroups. Reproducibility was excellent: interreader ICC = 0.92 (95% CI 0.80, 0.97) and intrareader ICC = 0.91 (95% CI 0.78, 0.96). DATA CONCLUSION: Breast tumor ADC can be measured with excellent repeatability and reproducibility in a multi-institution setting using a standardized protocol and QA procedure. Improvements to DWI image quality could reduce loss of data in clinical trials. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1617-1628.

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.

Ultrasound imaging of breast tumor perfusion and neovascular morphology.

A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic monitoring is currently undergoing profound changes. Novel imaging techniques that are sensitive to the unique biological conditions of each individual tumor represent valuable tools in the pursuit of personalized medicine.

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.

Ultrasound-stimulated drug delivery for treatment of residual disease after incomplete resection of head and neck cancer.

Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Luciferase-positive HNC squamous cell carcinoma (SCC) was implanted in the flanks of nude athymic mice (N = 24) that underwent various degrees of surgical tumor resection (0%, 50% or 100%). After surgery, animals received adjuvant therapy with cetuximab-IRDye alone, or cetuximab-IRDye in combination with US-stimulated drug delivery or saline injections (control) on days 4, 7 and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14 and 17 with an in vivo fluorescence imaging system, and tumor viability was evaluated at the same times with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for 24 d. Optical imaging revealed that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared with administration of drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups that received cetuximab-IRDye in combination with US-stimulated drug delivery, compared with the group that received only the drug. After various degrees of surgical resection, this novel study reports positive improvements in drug uptake in the residual cancer cells when drug delivery is stimulated with US.

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.

Early therapy assessment of combined anti-DR5 antibody and carboplatin in triple-negative breast cancer xenografts in mice using diffusion-weighted imaging and (1)H MR spectroscopy.

PURPOSE: To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and carboplatin therapy using DWI and MRS in 2LMP and SUM159 mouse models. MATERIALS AND METHODS: Four groups (n = 5/group) of each model were untreated or treated with carboplatin, TRA-8, and combination, respectively. DWI and MRS were applied on 0, 3, and 7 days after therapy initiation, and all tumors were collected thereafter for terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. The changes in intratumoral apparent diffusion coefficient (ADC) and fat-water ratios (FWRs) were compared with tumor volume changes and apoptotic cell densities. RESULTS: Mean ADC values of 2LMP and SUM159 tumors significantly increased 4 ± 4% and 37 ± 11% during 7 days of combination therapy, respectively, as compared to control groups (P < 0.05). Similarly, mean FWRs of 2LMP and SUM159 tumors significantly increased 102 ± 30% and 126 ± 52%, respectively, for 7 days of combined treatment (P < 0.05). The changes of the mean ADC values for 3 days (or FWRs for 7 days) were linearly proportional to either the mean volume changes or apoptotic cell densities in both models. CONCLUSION: DWI and MRS assessed the early tumor response to TRA-8 and carboplatin in TNBC mouse models.

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.

How do I screen patients for breast cancer?

Breast cancer is a complex, heterogeneous disease. Approximately 230,000 women are diagnosed with breast cancer in the United States each year and approximately 40,000 women die each year with breast cancer. Although prevention of the disease would be preferred, no real prospects are available in the near future that would be applicable to the majority of women who are at risk for breast cancer. Early detection remains an effective way to decrease mortality from breast cancer, treating it at an early stage when it is likely curable. Unfortunately, screening does have its limitations. Not all breast cancers can be identified with routine screening. Some breast cancers despite early detection still result in poor outcomes. Furthermore, false-positive results are not infrequently seen in women undergoing screening mammography. Most patients experience significant anxiety when called back for additional studies or a biopsy. Not to mention the additional cost and potential side effects and complications of invasive procedures. In addition, there are breast cancers that may be indolent and otherwise not a threat to patients. In fact, some studies show that up to one quarter of cancers detected by screening may represent overdiagnosis. Currently, however, there are no proven methods to discern with complete certainty the cancers that would progress to lethal disease from those that would not. Women should be counseled regarding the risks and benefits of screening. Women at average risk should initiate screening mammography annually at the age of 40 years. Women at significant increased risk for breast cancer should be screened earlier. MRI has been shown to increase detection of breast cancer in women at increased risk and should be used as an adjunct to mammography in this high-risk patient population.

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.