Diffusion Tensor Imaging for Characterizing Changes in Triple-Negative Breast Cancer During Neoadjuvant Systemic Therapy.

BACKGROUND: Assessment of treatment response in triple-negative breast cancer (TNBC) may guide individualized care for improved patient outcomes. Diffusion tensor imaging (DTI) measures tissue anisotropy and could be useful for characterizing changes in the tumors and adjacent fibroglandular tissue (FGT) of TNBC patients undergoing neoadjuvant systemic treatment (NAST). PURPOSE: To evaluate the potential of DTI parameters for prediction of treatment response in TNBC patients undergoing NAST. STUDY TYPE: Prospective. POPULATION: Eighty-six women (average age: 51 ± 11 years) with biopsy-proven clinical stage I-III TNBC who underwent NAST followed by definitive surgery. 47% of patients (40/86) had pathologic complete response (pCR). FIELD STRENGTH/SEQUENCE: 3.0 T/reduced field of view single-shot echo-planar DTI sequence. ASSESSMENT: Three MRI scans were acquired longitudinally (pre-treatment, after 2 cycles of NAST, and after 4 cycles of NAST). Eleven histogram features were extracted from DTI parameter maps of tumors, a peritumoral region (PTR), and FGT in the ipsilateral breast. DTI parameters included apparent diffusion coefficients and relative diffusion anisotropies. pCR status was determined at surgery. STATISTICAL TESTS: Longitudinal changes of DTI features were tested for discrimination of pCR using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC). A P value <0.05 was considered statistically significant. RESULTS: 47% of patients (40/86) had pCR. DTI parameters assessed after 2 and 4 cycles of NAST were significantly different between pCR and non-pCR patients when compared between tumors, PTRs, and FGTs. The median surface/average anisotropy of the PTR, measured after 2 and 4 cycles of NAST, increased in pCR patients and decreased in non-pCR patients (AUC: 0.78; 0.027 ± 0.043 vs. -0.017 ± 0.042 mm2 /s). DATA CONCLUSION: Quantitative DTI features from breast tumors and the peritumoral tissue may be useful for predicting the response to NAST in TNBC. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Quantitative Apparent Diffusion Coefficients From Peritumoral Regions as Early Predictors of Response to Neoadjuvant Systemic Therapy in Triple-Negative Breast Cancer.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC) is a strong predictor of patient survival. Edema in the peritumoral region (PTR) has been reported to be a negative prognostic factor in TNBC. PURPOSE: To determine whether quantitative apparent diffusion coefficient (ADC) features from PTRs on reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) predict the response to NAST in TNBC. STUDY TYPE: Prospective. POPULATION/SUBJECTS: A total of 108 patients with biopsy-proven TNBC who underwent NAST and definitive surgery during 2015-2020. FIELD STRENGTH/SEQUENCE: A 3.0 T/rFOV single-shot diffusion-weighted echo-planar imaging sequence (DWI). ASSESSMENT: Three scans were acquired longitudinally (pretreatment, after two cycles of NAST, and after four cycles of NAST). For each scan, 11 ADC histogram features (minimum, maximum, mean, median, standard deviation, kurtosis, skewness and 10th, 25th, 75th, and 90th percentiles) were extracted from tumors and from PTRs of 5 mm, 10 mm, 15 mm, and 20 mm in thickness with inclusion and exclusion of fat-dominant pixels. STATISTICAL TESTS: ADC features were tested for prediction of pCR, both individually using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC), and in combination in multivariable models with k-fold cross-validation. A P value < 0.05 was considered statistically significant. RESULTS: Fifty-one patients (47%) had pCR. Maximum ADC from PTR, measured after two and four cycles of NAST, was significantly higher in pCR patients (2.8 ± 0.69 vs 3.5 ± 0.94 mm2 /sec). The top-performing feature for prediction of pCR was the maximum ADC from the 5-mm fat-inclusive PTR after cycle 4 of NAST (AUC: 0.74; 95% confidence interval: 0.64, 0.84). Multivariable models of ADC features performed similarly for fat-inclusive and fat-exclusive PTRs, with AUCs ranging from 0.68 to 0.72 for the cycle 2 and cycle 4 scans. DATA CONCLUSION: Quantitative ADC features from PTRs may serve as early predictors of the response to NAST in TNBC. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Tumor necrosis by pretreatment breast MRI: association with neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC).

PURPOSE: To determine if tumor necrosis by pretreatment breast MRI and its quantitative imaging characteristics are associated with response to NAST in TNBC. METHODS: This retrospective study included 85 TNBC patients (mean age 51.8 ± 13 years) with MRI before NAST and definitive surgery during 2010-2018. Each MRI included T2-weighted, diffusion-weighted (DWI), and dynamic contrast-enhanced (DCE) imaging. For each index carcinoma, total tumor volume including necrosis (TTV), excluding necrosis (TV), and the necrosis-only volume (NV) were segmented on early-phase DCE subtractions and DWI images. NV and %NV were calculated. Percent enhancement on early and late phases of DCE and apparent diffusion coefficient were extracted from TTV, TV, and NV. Association between necrosis with pathological complete response (pCR) was assessed using odds ratio (OR). Multivariable analysis was used to evaluate the prognostic value of necrosis with T stage and nodal status at staging. Mann-Whitney U tests and area under the curve (AUC) were used to assess performance of imaging metrics for discriminating pCR vs non-pCR. RESULTS: Of 39 patients (46%) with necrosis, 17 had pCR and 22 did not. Necrosis was not associated with pCR (OR, 0.995; 95% confidence interval [CI] 0.4-2.3) and was not an independent prognostic factor when combined with T stage and nodal status at staging (P = 0.46). None of the imaging metrics differed significantly between pCR and non-pCR in patients with necrosis (AUC < 0.6 and P > 0.40). CONCLUSION: No significant association was found between necrosis by pretreatment MRI or the quantitative imaging characteristics of tumor necrosis and response to NAST in TNBC.

Functional Tumor Volume by Fast Dynamic Contrast-Enhanced MRI for Predicting Neoadjuvant Systemic Therapy Response in Triple-Negative Breast Cancer.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI is useful for diagnosis and assessment of treatment response in breast cancer. Fast DCE MRI offers a higher sampling rate of contrast enhancement curves in comparison to conventional DCE MRI, potentially characterizing tumor perfusion kinetics more accurately for measurement of functional tumor volume (FTV) as a predictor of treatment response. PURPOSE: To investigate FTV by fast DCE MRI as a predictor of neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC). STUDY TYPE: Prospective. POPULATION/SUBJECTS: Sixty patients with biopsy-confirmed TNBC between December 2016 and September 2020. FIELD STRENGTH/SEQUENCE: A 3.0 T/3D fast spoiled gradient echo-based DCE MRI ASSESSMENT: Patients underwent MRI at baseline and after four cycles (C4) of NAST, followed by definitive surgery. DCE subtraction images were analyzed in consensus by two breast radiologists with 5 (A.H.A.) and 2 (H.S.M.) years of experience. Tumor volumes (TV) were measured on early and late subtractions. Tumors were segmented on 1 and 2.5-minute early phases subtractions and FTV was determined using optimized signal enhancement thresholds. Interpolated enhancement curves from segmented voxels were used to determine optimal early phase timing. STATISTICAL TESTS: Tumor volumes were compared between patients who had a pathologic complete response (pCR) and those who did not using the area under the receiver operating curve (AUC) and Mann-Whitney U test. RESULTS: About 26 of 60 patients (43%) had pCR. FTV at 1 minute after injection at C4 provided the best discrimination between pCR and non-pCR, with AUC (95% confidence interval [CI]) = 0.85 (0.74,0.95) (P < 0.05). The 1-minute timing was optimal for FTV measurements at C4 and for the change between C4 and baseline. TV from the early phase at C4 also yielded a good AUC (95%CI) of 0.82 (0.71,0.93) (P < 0.05). DATA CONCLUSION: FTV and TV measured at 1 minute after injection can predict response to NAST in TNBC. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: 4.

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood.

Early life stress (ELS) is a risk for cardiovascular disease in adulthood although very little mechanistic insight is available. Because oxidative stress and endothelial dysfunction are major contributors to cardiovascular risk, we hypothesized that ELS induces endothelial dysfunction in adult male mice via increased superoxide production. Studies employed a mouse model of ELS, maternal separation with early weaning (MSEW), in which litters were separated from the dam for 4 h/day [postnatal days (PD) 2-5] and 8 h/day (PD6-16), and weaned at PD17. Control litters remained undisturbed until weaning at PD21. When compared with control mice, thoracic aortic rings from adult male MSEW mice displayed significant endothelial dysfunction that was reversed by the superoxide scavenger, polyethylene glycol-superoxide dismutase (PEG-SOD). PEG-SOD-inhibitable superoxide production by aortae from MSEW mice was significantly greater than observed in control aortae, although unaffected by nitric oxide synthase inhibition, suggesting that uncoupled nitric oxide synthase was not responsible for the accelerated superoxide production. Aortic SOD expression, plasma SOD activity, and total antioxidant activity were similar in MSEW and control mice, indicating unaltered antioxidant capacity in MSEW mice. Increased expression of the NADPH oxidase subunits, NOX2 and NOX4, was evident in the aortae of MSEW mice. Moreover, endothelial dysfunction and superoxide production in MSEW mice was reversed with the NADPH oxidase inhibitor, apocynin, indicating increased NADPH oxidase-dependent superoxide production and endothelial dysfunction. The finding that MSEW induces superoxide production and endothelial dysfunction in adult mice may provide a mechanistic link between ELS and adult cardiovascular disease risk.

Detection of diffusely abnormal white matter in multiple sclerosis on multiparametric brain MRI using semi-supervised deep learning.

In addition to focal lesions, diffusely abnormal white matter (DAWM) is seen on brain MRI of multiple sclerosis (MS) patients and may represent early or distinct disease processes. The role of MRI-observed DAWM is understudied due to a lack of automated assessment methods. Supervised deep learning (DL) methods are highly capable in this domain, but require large sets of labeled data. To overcome this challenge, a DL-based network (DAWM-Net) was trained using semi-supervised learning on a limited set of labeled data for segmentation of DAWM, focal lesions, and normal-appearing brain tissues on multiparametric MRI. DAWM-Net segmentation performance was compared to a previous intensity thresholding-based method on an independent test set from expert consensus (N = 25). Segmentation overlap by Dice Similarity Coefficient (DSC) and Spearman correlation of DAWM volumes were assessed. DAWM-Net showed DSC > 0.93 for normal-appearing brain tissues and DSC > 0.81 for focal lesions. For DAWM-Net, the DAWM DSC was 0.49 ± 0.12 with a moderate volume correlation (ρ = 0.52, p < 0.01). The previous method showed lower DAWM DSC of 0.26 ± 0.08 and lacked a significant volume correlation (ρ = 0.23, p = 0.27). These results demonstrate the feasibility of DL-based DAWM auto-segmentation with semi-supervised learning. This tool may facilitate future investigation of the role of DAWM in MS.

Deep Learning for Fully Automatic Tumor Segmentation on Serially Acquired Dynamic Contrast-Enhanced MRI Images of Triple-Negative Breast Cancer.

Accurate tumor segmentation is required for quantitative image analyses, which are increasingly used for evaluation of tumors. We developed a fully automated and high-performance segmentation model of triple-negative breast cancer using a self-configurable deep learning framework and a large set of dynamic contrast-enhanced MRI images acquired serially over the patients' treatment course. Among all models, the top-performing one that was trained with the images across different time points of a treatment course yielded a Dice similarity coefficient of 93% and a sensitivity of 96% on baseline images. The top-performing model also produced accurate tumor size measurements, which is valuable for practical clinical applications.

Assessment of Response to Neoadjuvant Systemic Treatment in Triple-Negative Breast Cancer Using Functional Tumor Volumes from Longitudinal Dynamic Contrast-Enhanced MRI.

Early assessment of neoadjuvant systemic therapy (NAST) response for triple-negative breast cancer (TNBC) is critical for patient care in order to avoid the unnecessary toxicity of an ineffective treatment. We assessed functional tumor volumes (FTVs) from dynamic contrast-enhanced (DCE) MRI after 2 cycles (C2) and 4 cycles (C4) of NAST as predictors of response in TNBC. A group of 100 patients with stage I-III TNBC who underwent DCE MRI at baseline, C2, and C4 were included in this study. Tumors were segmented on DCE images of 1 min and 2.5 min post-injection. FTVs were measured using the optimized percentage enhancement (PE) and signal enhancement ratio (SER) thresholds. The Mann-Whitney test was used to compare the performance of the FTVs at C2 and C4. Of the 100 patients, 49 (49%) had a pathologic complete response (pCR) and 51 (51%) had a non-pCR. The maximum area under the receiving operating characteristic curve (AUC) for predicting the treatment response was 0.84 (p < 0.001) for FTV at C4 followed by FTV at C2 (AUC = 0.82, p < 0.001). The FTV measured at baseline was not able to discriminate pCR from non-pCR. FTVs measured on DCE MRI at C2, as well as at C4, of NAST can potentially predict pCR and non-pCR in TNBC patients.

A Radiomics Model Based on Synthetic MRI Acquisition for Predicting Neoadjuvant Systemic Treatment Response in Triple-Negative Breast Cancer.

Purpose To determine if a radiomics model based on quantitative maps acquired with synthetic MRI (SyMRI) is useful for predicting neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC). Materials and Methods In this prospective study, 181 women diagnosed with stage I-III TNBC were scanned with a SyMRI sequence at baseline and at midtreatment (after four cycles of NAST), producing T1, T2, and proton density (PD) maps. Histopathologic analysis at surgery was used to determine pathologic complete response (pCR) or non-pCR status. From three-dimensional tumor contours drawn on the three maps, 310 histogram and textural features were extracted, resulting in 930 features per scan. Radiomic features were compared between pCR and non-pCR groups by using Wilcoxon rank sum test. To build a multivariable predictive model, logistic regression with elastic net regularization and cross-validation was performed for texture feature selection using 119 participants (median age, 52 years [range, 26-77 years]). An independent testing cohort of 62 participants (median age, 48 years [range, 23-74 years]) was used to evaluate and compare the models by area under the receiver operating characteristic curve (AUC). Results Univariable analysis identified 15 T1, 10 T2, and 12 PD radiomic features at midtreatment that predicted pCR with an AUC greater than 0.70 in both the training and testing cohorts. Multivariable radiomics models of maps acquired at midtreatment demonstrated superior performance over those acquired at baseline, achieving AUCs as high as 0.78 and 0.72 in the training and testing cohorts, respectively. Conclusion SyMRI-based radiomic features acquired at midtreatment are potentially useful for identifying early NAST responders in TNBC. Keywords: MR Imaging, Breast, Outcomes Analysis ClinicalTrials.gov registration no. NCT02276443 Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Houser and Rapelyea in this issue.

Assessment of Early Response to Neoadjuvant Systemic Therapy in Triple-Negative Breast Cancer Using Amide Proton Transfer-weighted Chemical Exchange Saturation Transfer MRI: A Pilot Study.

Purpose To determine if amide proton transfer-weighted chemical exchange saturation transfer (APTW CEST) MRI is useful in the early assessment of treatment response in persons with triple-negative breast cancer (TNBC). Materials and Methods In this prospective study, a total of 51 participants (mean age, 51 years [range, 26-79 years]) with TNBC were included who underwent APTW CEST MRI with 0.9- and 2.0-µT saturation power performed at baseline, after two cycles (C2), and after four cycles (C4) of neoadjuvant systemic therapy (NAST). Imaging was performed between January 31, 2019, and November 11, 2019, and was a part of a clinical trial (registry number NCT02744053). CEST MR images were analyzed using two methods-magnetic transfer ratio asymmetry (MTRasym) and Lorentzian line shape fitting. The APTW CEST signals at baseline, C2, and C4 were compared for 51 participants to evaluate the saturation power levels and analysis methods. The APTW CEST signals and their changes during NAST were then compared for the 26 participants with pathology reports for treatment response assessment. Results A significant APTW CEST signal decrease was observed during NAST when acquisition at 0.9-µT saturation power was paired with Lorentzian line shape fitting analysis and when the acquisition at 2.0 µT was paired with MTRasym analysis. Using 0.9-µT saturation power and Lorentzian line shape fitting, the APTW CEST signal at C2 was significantly different from baseline in participants with pathologic complete response (pCR) (3.19% vs 2.43%; P = .03) but not with non-pCR (2.76% vs 2.50%; P > .05). The APTW CEST signal change was not significant between pCR and non-pCR at all time points. Conclusion Quantitative APTW CEST MRI depended on optimizing acquisition saturation powers and analysis methods. APTW CEST MRI monitored treatment effects but did not differentiate participants with TNBC who had pCR from those with non-pCR. © RSNA, 2021 Clinical trial registration no. NCT02744053 Supplemental material is available for this article.Keywords Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, MR-Imaging, Breast, Technical Aspects, Tumor Response, Technology Assessment.

Preoperative Prediction of Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Cancer Using 18F-FDG PET/CT and DW-MRI: A Prospective Multicenter Study.

PURPOSE: Accurate preoperative prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal cancer could enable omission of esophagectomy in patients with a pathologic complete response (pCR). This study aimed to evaluate the individual and combined value of 18F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (18F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) during and after nCRT to predict pathologic response in patients with esophageal cancer. METHODS AND MATERIALS: In this multicenter prospective study, patients scheduled to receive nCRT followed by esophagectomy for esophageal cancer underwent 18F-FDG PET/CT and DW-MRI scanning before the start of nCRT, during nCRT, and before esophagectomy. Response to nCRT was based on histopathologic evaluation of the resection specimen. Relative changes in 18F-FDG PET/CT and DW-MRI parameters were compared between patients with pCR and non-pCR groups. Multivariable ridge regression analyses with bootstrapped c-indices were performed to evaluate the individual and combined value of 18F-FDG PET/CT and DW-MRI. RESULTS: pCR was found in 26.1% of 69 patients. Relative changes in 18F-FDG PET/CT parameters after nCRT (Δ standardized uptake value [SUV]mean,postP = .016, and Δ total lesion glycolysis postP = .024), as well as changes in DW-MRI parameters during nCRT (Δ apparent diffusion coefficient [ADC]duringP = .008) were significantly different between pCR and non-pCR. A c-statistic of 0.84 was obtained for a model with ΔADCduring, ΔSUVmean,post, and histology in classifying patients as pCR (versus 0.82 for ΔADCduring and 0.79 for ΔSUVmean,post alone). CONCLUSIONS: Changes on 18F-FDG PET/CT after nCRT and early changes on DW-MRI during nCRT can help identify pCR to nCRT in esophageal cancer. Moreover, 18F-FDG PET/CT and DW-MRI might be of complementary value in the assessment of pCR.

Multimodal Imaging of Pathologic Response to Chemoradiation in Esophageal Cancer.

PURPOSE: To examine the value of early changes in quantitative diffusion-weighted imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation in esophageal cancer. METHODS AND MATERIALS: Twenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent magnetic resonance imaging and FDG-PET/CT scans at baseline, interim (2 weeks after chemoradiation start), and first follow-up. On the basis of pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at baseline and relative changes at interim and follow-up scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics were evaluated for summary measures to characterize discrimination of pCR from non-pCR. RESULTS: Relative changes in tumor volume ADC (ΔADC) mean and 25th and 10th percentiles from baseline to interim were able to completely discriminate (area under the curve = 1, P < .0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high interreader reliability (95% limits of agreement of 1.001, 0.944, and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from baseline to interim was significantly different among pCR and non-pCR groups (P=.0117) and yielded an area under the curve of 0.947 (95% confidence interval 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, P=.027). CONCLUSIONS: Quantitative volume ΔADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of these data in larger, prospective, multicenter studies is essential.