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This study tested the hypothesis that a change in the apparent diffusion coefficient (ADC) measured in diffusion-weighted MRI (DWI) is an independent imaging marker, and ADC performs better than functional tumor volume (FTV) for assessing treatment response in patients with locally advanced breast cancer receiving neoadjuvant immunotherapy. A total of 249 patients were randomized to standard neoadjuvant chemotherapy with pembrolizumab (pembro) or without pembrolizumab (control). DCE-MRI and DWI, performed prior to and 3 weeks after the start of treatment, were analyzed. Percent changes of tumor ADC metrics (mean, 5th to 95th percentiles of ADC histogram) and FTV were evaluated for the prediction of pathologic complete response (pCR) using a logistic regression model. The area under the ROC curve (AUC) estimated for the percent change in mean ADC was higher in the pembro cohort (0.73, 95% confidence interval [CI]: 0.52 to 0.93) than in the control cohort (0.63, 95% CI: 0.43 to 0.83). In the control cohort, the percent change of the 95th percentile ADC achieved the highest AUC, 0.69 (95% CI: 0.52 to 0.85). In the pembro cohort, the percent change of the 25th percentile ADC achieved the highest AUC, 0.75 (95% CI: 0.55 to 0.95). AUCs estimated for percent change of FTV were 0.61 (95% CI: 0.39 to 0.83) and 0.66 (95% CI: 0.47 to 0.85) for the pembro and control cohorts, respectively. Tumor ADC may perform better than FTV to predict pCR at an early treatment time-point during neoadjuvant immunotherapy.

Background: The apparent diffusion coefficient (ADC) presents a biomarker that is sensitive to tumor cellularity. ADC maps can be calculated from non-contrast diffusion-weighted magnetic resonance imaging (DW-MRI) measurements. ACRIN 6698, a sub-study of clinical trial I-SPY 2, investigated mean ADC – averaged over the whole tumor – as a marker to predict pathologic complete response (pCR) [1]. This work compares a group of histogram-based ADC metrics in addition to mean ADC for early prediction of pCR in patients stratified by breast cancer subtype. Methods: We performed a retrospective analysis of DW-MRI, dynamic-contrast enhanced (DCE) MRI, and clinical outcome (i.e., pCR at surgery) in a cohort of 79 female patients who were diagnosed with high-risk, stage II/III breast cancer. Patients underwent neoadjuvant chemotherapy (NAC) with paclitaxel (12 weeks), followed by doxorubicin plus cyclophosphamide (12 weeks). The included population represents a subset of the I-SPY 2 cohort and comprises 48 patients with hormone receptor [HR]+/HER2-, and 31 patients with HR-/HER2-. DW- and DCE-MRI acquisitions were performed according to the I-SPY 2 protocol at pretreatment (T0) and after three weeks (T1) and were analyzed to find early treatment percentage (%) change (T0 to T1) in any metric M; where %-change = 100 × (M(T1) – M(T0))/M(T0). Histogram analysis provided nine region-of-interest (ROI)-based ADC metrics (Table 1). ROIs were manually delineated by expert observers in three-dimensional ADC maps, focusing on diffusion-restricted regions [2]. DCE-MRI was analyzed for the integral I-SPY 2 imaging marker of %-change in functional tumor volume (FTV) between T0 and T1. Statistical analysis compared the predictive power of ADC metrics and FTV, including: the receiver-operating-characteristic (ROC) curve from a logistic regression model to predict pCR as ‘positive’, area-under-the-curve (AUC) assessment, and rank-sum Wilcoxon test (p< 0.05: statistically significant). Results (Table 1): 16 out of 79 (20.3%) patients reached pCR at surgery, with 18.8% pCR among HR+/HER- and 22.6% among HR-/HER2- groups. For all nine computed ADC statistics (listed as median [Q1, Q3], across all patients), %-change was higher in patients who reached pCR than patients with non-pCR (highest value for metric ‘MIN’: 23.9% [-0.9%, 52.5] vs. 16.6% [0.4%, 27.6%], though without statistical significance: p=0.237). Likewise, %-change of FTV was also stronger in pCR patients than non-pCR patients (-58.8% [-80.6%, -22.5%] vs. -28.2% [54.2%, -2.7%], with statistical significance: p=0.036). For all patients combined (n=79), among the various reported ADC metrics, %-change in ‘PCTL_95’ (95th percentile of histogram) yielded the highest AUC (0.7; 95% CI = [0.56, 0.83]; p=0.012). %-change in FTV showed the second highest AUC (0.67; 95% CI = [0.52, 0.82]; p=0.036). By subtype, AUC was highest for %-change of ‘PCTL_95’ (0.69; 95% CI = [0.5, 0.87]; p=0.072) in the HR+/HER2- subgroup; and highest for both %-change of ‘MEAN’ (AUC = 0.73; 95% CI = [0.49, 0.94]; p=0.065) and ‘PCTL_75’ (AUC = 0.73; 95% CI = [0.49, 0.94]; p=0.073) triple negative (HR-/HER2-) subgroup. By comparison, %-change of FTV yielded AUCs of 0.64 (95% CI = [0.41, 0.85]; p=0.191) and 0.71 (95% CI = [0.51, 0.9]; p=0.098) in the HR+/HER2- and triple-negative subgroups, respectively. Conclusion: Various tumor ADC metrics from non-contrast DW-MRI demonstrate potential biomarkers for assessing responsiveness to NAC at an early treatment timepoint. ADC may have predictive performance that is comparable to FTV, depending on the breast cancer subtype. Observations for %-change in ‘MEAN’ ADC at T1 differed from previous reports [1], which may be explained by the small sample size and single (paclitaxel) drug arm. Additional studies are warranted to include patients of experimental arms and of HER2+ subtypes. [1] Partridge et al., Radiology 289(3):618-27 (2018) [2] Nu et al., Tomography 8: 1208-20 (2022) Results of statistical analysis of ADC-based and FTV markers for predicting treatment response at 3 weeks into NAC. Median [Q1, Q3] values represent the median and interquartile range over the respective patient population regarding the %-change of the respective ADC (FTV) metric from T0 to T1. T0: pretreatment, T1: 3-week timepoint, ADC: apparent diffusion coefficient, MRI: magnetic resonance imaging, DW: diffusion-weighted, DCE: dynamic-contrast enhanced, pCR: pathologic complete response, AUC: area under the ROC curve, 95% CI [LL, UL]: confidence interval lower and upper limit, PCTL_x: xth-percentile of tumor ADC histogram, MEAN: mean of ADC within ROI, MIN: minimum of ADC within ROI, MAX: maximum of ADC within ROI, FTV: functional tumor volume, **: statistically significant. Citation Format: Judith Zimmermann, Julia Carmona-Bozo, Nu N. Le, Natsuko Onishi, Lisa J. Wilmes, Jessica E. Gibbs, Jiachao Liang, David C. Newitt, Savannah Partridge, Patrick Bolan, Bonnie N. Joe, Elissa R. Price, Barbara LeStage, Nola M. Hylton, Wen Li. Diffusion-weighted magnetic resonance imaging for subtype-specific prediction of pathologic complete response in neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-33.

Breast magnetic resonance imaging (MRI) is recommended for the screening of women with a history of chest radiotherapy and consequent increased breast cancer risk. The purpose of this study was to evaluate the impact of prior chest radiotherapy on breast tissue background parenchymal enhancement (BPE) at screening breast MRI.A departmental database was reviewed to identify asymptomatic women with either a history of chest radiotherapy for Hodgkin's lymphoma or age-matched controls who underwent screening breast MRI between 2009 and 2013. MRI studies were analyzed on an automated breast MRI viewing platform to calculate breast BPE and breast density.A total of 61 cases (mean age 41.6 ± 6.75 years) and 61 controls (mean age 40.8 ± 6.99 years) were included. The age of patients at the time of chest radiotherapy was 22.6 ± 8.17 years. Screening MRI was performed 19.0 ± 7.43 years after chest radiotherapy. BPE was significantly higher in patients who received chest radiotherapy (50% vs. 37%, P 0.01). A weak to moderate positive correlation (r 0.3; P 0.03) was found between BPE and number of years post radiotherapy. There was a trend toward significant difference between the two groups in the correlation of BPE and age (P = 0.05). Breast density was not significantly different between the two groups.BPE is significantly greater in women who receive chest radiotherapy for childhood Hodgkin's lymphoma, and unexpectedly, it positively correlates with the number of years passed after radiation therapy. Long-term biological effects of radiation therapy on breast parenchyma need further research.

Diffusion weighted MRI has become ubiquitous in many areas of medicine, including cancer diagnosis and treatment response monitoring. Reproducibility of diffusion metrics is essential for their acceptance as quantitative biomarkers in these areas. We examined the variability in the apparent diffusion coefficient (ADC) obtained from both postprocessing software implementations utilized by the NCI Quantitative Imaging Network and online scan time-generated ADC maps. Phantom and in vivo breast studies were evaluated for two ([Formula: see text]) and four ([Formula: see text]) [Formula: see text]-value diffusion metrics. Concordance of the majority of implementations was excellent for both phantom ADC measures and in vivo [Formula: see text], with relative biases [Formula: see text] ([Formula: see text]) and [Formula: see text] (phantom [Formula: see text]) but with higher deviations in ADC at the lowest phantom ADC values. In vivo [Formula: see text] concordance was good, with typical biases of [Formula: see text] to 3% but higher for online maps. Multiple b-value ADC implementations were separated into two groups determined by the fitting algorithm. Intergroup mean ADC differences ranged from negligible for phantom data to 2.8% for [Formula: see text] in vivo data. Some higher deviations were found for individual implementations and online parametric maps. Despite generally good concordance, implementation biases in ADC measures are sometimes significant and may be large enough to be of concern in multisite studies.

Purpose Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. Patients and Methods In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. Results Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD ≥ 15 months, four patients had SD ≤ 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed. Conclusion Sorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.

Purpose: To compare the intraindividual differences of dynamic signal characteristics for 3 gadolinium chelates (gadopentetate dimeglumine GdDTPA, gadodiamide Gd-DTPA-BMA, and gadobenate dimeglumine GdBOPTA) using dynamic contrast enhanced magnetic resonance (MR) imaging (DCE-MRI) with a preclinical beagle model at 7 Tesla. Method and Materials: Seven beagles were scanned 3 times each with a 7-day interval between the scans on a 7T whole body MRI system (Achieva, Philips) using a T/R head coil. Three different Gd contrast agents including Gd-DTPA, Gd-DTPABMA, and Gd-BOPTA were injected in a randomized order with a power injector (Spectris, MedRad, Indianola, PA) using dose of 0.1 mmol/kg body weight and flow rate of 0.06 mL/s. During image acquisition and data analysis, the identity of the specific contrast agent used for each examination was blinded. A 3D RF-spoiled fast field echo sequence was used for dynamic scans with in-plane spatial resolution 0.47 0.47 mm 2 , temporal resolution of 9.5 seconds, and a total of 60 time points. Regions of interest were drawn within the carotid arteries and muscle tissue to determine semiquantitative parameters including maximum enhancement ratio, area under the signal enhancement curve over 90 seconds after contrast injection (AUC_90), time to maximum signal enhancement (Tmax), and washout_score. Additionally, quantitative pharmacokinetic parameters were measured in muscle tissues by applying 3 separate 2-compartment models; (1) artery input function (AIF) based Tofts model, (2) Brix model without AIF, and (3) AIF decomposed refined Brix model. Results: Gd-BOPTA produced higher signal to noise ratio on postcontrast T1- weighted images than the other 2 Gd based contrast agents at 7T. Quantitatively, Gd-BOPTA provided a significantly higher maximum enhancement ratio (P 0.01), AUC_90 (P 0.01) and washout_score (P 0.01) in beagle musculature and cranial vasculature compared with both Gd-DTPA and Gd-DTPA-BMA. Among all the quantitative pharmacokinetic parameters, only the exchange rate constants (kep) calculated from these 3 models did not show a significant difference among the various contrast agents. Conclusions: Gd chelate containing MR contrast agents can be used at 7T for DCEMRI. Gd-BOPTA demonstrates stronger signal enhancement than standard Gd chelates, in concordance with the results of studies at lower fields. The observed enhancement characteristics for the 3 contrast agents demonstrate that the pharmacokinetic parameter kep is more robust in various models using DCE-MRI than the other pharmacokinetic parameters. This information is important relative to multisite clinical trials and longterm clinical studies that often use several different contrast agents and different models.

Purpose Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC. Patients and Methods The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors). Results Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients. Conclusion Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.

To describe and determine the reproducibility of a simplified model to quantitatively measure heterogeneous intralesion contrast agent diffusion in colorectal liver metastases.This HIPAA-compliant retrospective study received institutional review board approval, and written informed consent was obtained from 14 patients (mean age, 61 years +/- 9 [standard deviation]; range, 41-78 years), including 10 men (mean age, 65 years +/- 8; range, 47-78 years) and four women (mean age, 54 years +/- 9; range, 41-59 years), with colorectal liver metastases. Magnetic resonance (MR) imaging was performed twice (first baseline MR image [B(1)] and second baseline MR image [B(2)]) in a single target lesion prior to therapy. Dynamic contrast material-enhanced MR imaging was performed by using a saturation-recovery fast gradient-echo sequence. A simplified contrast agent diffusion model was proposed, and a contrast agent diffusion coefficient (CDC) was calculated. The reproducibility of the CDC measurement was evaluated by using the Bland-Altman plot and a linear regression model.The mean CDC was 0.22 mm(2)/sec (range, 0.01-0.73 mm(2)/sec) on B(1) and 0.24 mm(2)/sec (range, 0.01-0.71 mm(2)/sec) on B(2), with an intraclass correlation coefficient of 0.91 (P.0001). Bland-Altman plot showed good agreement, with a mean difference in measurement pairs of 0.017 mm(2)/sec +/- 0.096. The slope from the linear regression model was 0.89 (95% confidence interval: 0.63, 1.15) and the intercept was 0.01 (95% confidence interval: -0.08, 0.09).The CDC enables a quantitative description of contrast enhancement heterogeneity in lesions. Given the high reproducibility of the CDC metric, CDC appears promising for further qualification as an imaging biomarker of change measurement in response assessment.http://radiology.rsnajnls.org/cgi/content/full/248/3/901/DC1.

One of the most powerful features of the dynamic contrast-enhanced (DCE) MRI technique is its capability to quantitatively measure the physiological or pathophysiological environments assessed by the passage of contrast agent by means of model-based pharmacokinetic analysis. The widely used two-compartment pharmacokinetic model developed by Brix and colleges fits tumor data well in most cases, but fails to explain the biexponential arterial input function. In this work, this problem has been attacked from a theoretical point of view, showing that this problem can be solved by adopting a more realistic model assumption when simplifying the general solutions of the two-compartment pharmacokinetic equations. Pharmacokinetic parameters derived from our model were demonstrated to have comparative tissue specificity to Ktrans from Larsson's model, better than those from Brix's model and the empirical area-under-the-curve (AUC). Tissue-type classifier constructed with the arterial input function–decomposed kep-kpe pair from our model was also demonstrated to have superior performance than any other classifier based on DCE-MRI pharmacokinetic parameters or empirical AUC. The feature that this classifier has a near-zero false-negative rate makes it a highly desirable tool for clinical diagnostic and response assessment applications. Magn Reson Med 59:1448–1456, 2008. © 2008 Wiley-Liss, Inc.

We assessed dynamic contrast enhanced magnetic resonance imaging as a biological marker of in vivo changes in microcirculation in the prostatic suburethral region.A total of 12 male beagle dogs with spontaneous benign prostatic hyperplasia were randomly allocated to 1 control group and 1 finasteride (Merck and Co., Whitehouse Station, New Jersey) treated group. Two baseline dynamic contrast enhanced magnetic resonance imaging examinations and 3 followups were performed to assess prostate microcirculation. Treatment duration was 3 months. The pharmacokinetic parameters evaluated in prostatic suburethral areas were the maximum enhancement ratio in AU, time to maximum signal enhancement in minutes, amplitude in AU and the exchange rate constant in minutes(-1).After completion of the therapeutic regimen time to maximum signal enhancement was significantly longer in the finasteride group than in controls (p0.01). Amplitude and the exchange rate constant decreased 39% and 34%, respectively, in the finasteride group at the end of treatment, which significantly differed from results in the control group (p0.05).Dynamic contrast enhanced magnetic resonance imaging is capable of noninvasively assessing the prostatic microcirculation changes induced by finasteride. Pharmacokinetic parameters show considerable promise to be biomarkers for the development of benign prostatic hyperplasia drugs such as 5alpha-reductase inhibitors by the in vivo monitoring of microvascular changes. A relevant clinical application could be the pretreatment assessment of finasteride effectiveness to decrease perioperative bleeding at transurethral prostate resection and in treatment for hematuria.

To establish the feasibility of chemical exchange saturation transfer (proteinCEST) MRI in the differentiation of osteoarthritis (OA) knee joints from non-OA joints by detecting mobile protein and peptide levels in synovial fluid by determining their relative distribution.A total of 25 knees in 11 men and 12 women with knee injuries were imaged using whole knee joint proteinCEST MRI sequence at 3 T. The joint synovial fluid was segmented and the asymmetric magnetization transfer ratio at 3.5 ppm MTR(asym) (3.5 ppm) was calculated to assess protein content in the synovial fluid. The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) distribution profile was compared using the independent Student's t test. The diagnostic performance of the 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in differentiating OA and non-OA knee joints was evaluated.The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in knee joints with OA was 8.6%±3.4% and significantly higher than that in the knee joints without OA (6.3%±1.4%, P.05). A knee joint with an 85th percentile of synovial fluid MTR(asym) (3.5 ppm) greater than 7.7% was considered to be an OA knee joint. With the threshold, the sensitivity, specificity and overall accuracy for differentiating knee joints with OA from the joints without OA were 54% (7/13), 92% (11/12) and 72% (18/25), respectively.proteinCEST MRI appears feasible as a quantitative methodology to determine mobile protein levels in synovial fluid and identify patterns characteristic for OA disease.