Assessment of early docetaxel response in an experimental model of human breast cancer using DCE‐MRI,ex vivo HR MAS,and in vivo 1H MRS

The purpose of this study was to evaluate the use of dynamic contrast‐enhanced (DCE) MRI, in vivo ¹H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF‐7) in mice. MCF‐7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE‐MRI and in vivo ¹H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two‐compartment model, yielding the vascular parameters K^trans and v_e. HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki‐67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel‐treated mice compared to the controls. The anti‐tumor effect led to an increase in K^trans and v_e values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki‐67 stained sections. In this study DCE‐MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra‐tumoral treatment effects. Copyright © 2009 John Wiley & Sons, Ltd.     

Cluster analysis of DCE‐MRI data identifies regional tracer‐kinetic changes after tumor treatment with high intensity focused ultrasound

Evaluation of high intensity focused ultrasound (HIFU) treatment with MRI is generally based on assessment of the non‐perfused volume from contrast‐enhanced T₁‐weighted images. However, the vascular status of tissue surrounding the non‐perfused volume has not been extensively investigated with MRI. In this study, cluster analysis of the transfer constant K^trans and extravascular extracellular volume fraction v_e, derived from dynamic contrast‐enhanced MRI (DCE‐MRI) data, was performed in tumor tissue surrounding the non‐perfused volume to identify tumor subregions with distinct contrast agent uptake kinetics. DCE‐MRI was performed in CT26.WT colon carcinoma‐bearing BALB/c mice before (n = 12), directly after (n = 12) and 3 days after (n = 6) partial tumor treatment with HIFU. In addition, a non‐treated control group (n = 6) was included. The non‐perfused volume was identified based on the level of contrast enhancement. Quantitative comparison between non‐perfused tumor fractions and non‐viable tumor fractions derived from NADH‐diaphorase histology showed a stronger agreement between these fractions 3 days after treatment (R² to line of identity = 0.91) compared with directly after treatment (R² = 0.74). Next, k‐means clustering with four clusters was applied to K^trans and v_e parameter values of all significantly enhanced pixels. The fraction of pixels within two clusters, characterized by a low K^trans and either a low or high v_e, significantly increased after HIFU. Changes in composition of these clusters were considered to be HIFU induced. Qualitative H&E histology showed that HIFU‐induced alterations in these clusters may be associated with hemorrhage and structural tissue disruption. Combined microvasculature and hypoxia staining suggested that these tissue changes may affect blood vessel functionality and thereby tumor oxygenation. In conclusion, it was demonstrated that, in addition to assessment of the non‐perfused tumor volume, the presented methodology gives further insight into HIFU‐induced effects on tumor vascular status. This method may aid in assessment of the consequences of vascular alterations for the fate of the tissue. Copyright © 2015 John Wiley & Sons, Ltd.     

Peritumoral tissue compression is predictive of exudate flux in a rat model of cerebral tumor: an MRI study in an embedded tumor

MRI estimates of extracellular volume and tumor exudate flux in peritumoral tissue are demonstrated in an experimental model of cerebral tumor. Peritumoral extracellular volume predicted the tumor exudate flux. Eighteen RNU athymic rats were inoculated intracerebrally with U251MG tumor cells and studied with dynamic contrast enhanced MRI (DCE‐MRI) approximately 18 days post implantation. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE‐MRI data, the distribution volume (i.e. tissue porosity) in the leaky rim of the tumor and that in the tissue external to the rim (the outer rim) were estimated, as was the tumor exudate flow from the inner rim of the tumor through the outer rim. Distribution volume in the outer rim was approximately half that of the inner adjacent region (p < 1 × 10^?4). The distribution volume of the outer ring was significantly correlated (R² = 0.9) with tumor exudate flow from the inner rim. Thus, peritumoral extracellular volume predicted the rate of tumor exudate flux. One explanation for these data is that perfusion, i.e. the delivery of blood to the tumor, was regulated by the compression of the mostly normal tissue of the tumor rim, and that the tumor exudate flow was limited by tumor perfusion. Copyright © 2015 John Wiley & Sons, Ltd.     

Assessment of tumor necrotic fraction by dynamic contrast‐enhanced MRI: a preclinical study of human tumor xenografts with histopathologic correlation

Contrary to the common notion that tumor necrotic regions are non‐enhancing after contrast administration, recent evidence has shown that necrotic regions exhibit delayed and slow uptake of gadolinium tracer on dynamic contrast‐enhanced MRI (DCE MRI). The purpose of this study is to explore whether the mapping of tumor voxels with delayed and slow enhancement on DCE MRI can be used to derive estimates of tumor necrotic fraction. Patient‐derived tumor xenograft lines of seven human cancers were implanted in 26 mice which were subjected to DCE MRI performed using a spoiled gradient recalled sequence. Gadolinium tracer concentration was estimated using the variable flip angle technique. To identify tumor voxels exhibiting delayed and slow uptake of contrast medium, clustering analysis was performed using a k‐means clustering algorithm that classified tumor voxels according to their contrast enhancement patterns. Comparison of the percentage of tumor voxels exhibiting delayed and slow enhancement with the tumor necrotic fraction estimated on histology showed a strong correlation (r = 0.962, p < 0.001). The mapping of tumor regions with delayed and slow contrast uptake on DCE MRI correlated strongly with tumor necrotic fraction, and can potentially serve as a non‐invasive imaging surrogate for the in vivo assessment of necrotic fraction. Copyright © 2014 John Wiley & Sons, Ltd.     

Relationship between diffusion parameters derived from intravoxel incoherent motion MRI and perfusion measured by dynamic contrast‐enhanced MRI of soft tissue tumors

Our aim was to evaluate the link between diffusion parameters measured by intravoxel incoherent motion (IVIM) diffusion‐weighted imaging (DWI) and the perfusion metrics obtained with dynamic contrast‐enhanced (DCE) MRI in soft tissue tumors (STTs). Twenty‐eight patients affected by histopathologically confirmed STT were included in a prospective study. All patients underwent both DCE MRI and IVIM DWI. The perfusion fraction f, diffusion coefficient D and perfusion‐related diffusion coefficient D* were estimated using a bi‐exponential function to fit the DWI data. DCE MRI was acquired with a temporal resolution of 3–5 s. Maps of the initial area under the gadolinium concentration curve (IAUGC), time to peak (TTP) and maximum slope of increase (MSI) were derived using commercial software. The relationships between the DCE MRI and IVIM DWI measurements were assessed by Spearman's test. To exclude false positive results under multiple testing, the false discovery rate (FDR) procedure was applied. The Mann–Whitney test was used to evaluate the differences between all variables in patients with non‐myxoid and myxoid STT. No significant relationship was found between IVIM parameters and any DCE MRI parameters. Higher f and D*f values were found in non‐myxoid tumors compared with myxoid tumors (p = 0.004 and p = 0.003, respectively). MSI was significantly higher in non‐myxoid tumors than in myxoid tumors (p = 0.029). From the visual assessments of single clinical cases, both f and D*f maps were in satisfactory agreement with DCE maps in the extreme cases of an avascular mass and a highly vascularized mass, whereas, for tumors with slight vascularity or with a highly heterogeneous perfusion pattern, this association was not straightforward. Although IVIM DWI was demonstrated to be feasible in STT, our data did not support evident relationships between perfusion‐related IVIM parameters and perfusion measured by DCE MRI. Copyright © 2015 John Wiley & Sons, Ltd.     

Quantification of microcirculatory parameters by joint analysis of flow‐compensated and non‐flow‐compensated intravoxel incoherent motion (IVIM) data

The aim of this study was to improve the accuracy and precision of perfusion fraction and blood velocity dispersion estimates in intravoxel incoherent motion (IVIM) imaging, using joint analysis of flow‐compensated and non‐flow‐compensated motion‐encoded MRI data. A double diffusion encoding sequence capable of switching between flow‐compensated and non‐flow‐compensated encoding modes was implemented. In vivo brain data were collected in eight healthy volunteers and processed using the joint analysis. Simulations were used to compare the performance of the proposed analysis method with conventional IVIM analysis. With flow compensation, strong rephasing was observed for the in vivo data, approximately cancelling the IVIM effect. The joint analysis yielded physiologically reasonable perfusion fraction maps. Estimated perfusion fractions were 2.43 ± 0.81% in gray matter, 1.81 ± 0.90% in deep gray matter, and 1.64 ± 0.72% in white matter (mean ± SD, n = 8). Simulations showed improved accuracy and precision when using joint analysis of flow‐compensated and non‐flow‐compensated data, compared with conventional IVIM analysis. Double diffusion encoding with flow compensation was feasible for in vivo imaging of the perfusion fraction in the brain. The strong rephasing implied that blood flowing through the cerebral microvascular system was closer to the ballistic limit than the diffusive limit. © 2016 The Authors NMR in Biomedicine published by John Wiley & Sons Ltd.     

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple‐negative breast cancer

Breast cancer is the second most commonly diagnosed malignancy among women globally. Past MRI studies have linked a high animal fat diet (HAFD) to increased mammary cancer risk in the SV40Tag mouse model of triple‐negative breast cancer. Here, serial MRI examines tumor progression and measures the arterial blood volume feeding mammary glands in low fat diet (LFD) or HAFD fed mice. Virgin female C3(1)SV40Tag mice (n = 8), weaned at 3 weeks old, were assigned to an LFD (n = 4, 3.7 kcal/g, 17.2% kcal from vegetable oil) or an HAFD (n = 4, 5.3 kcal/g, 60% kcal from lard) group. From ages 8 to 12 weeks, weekly fast spin echo MR images and time‐of‐flight (TOF) MR angiography of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed. Inguinal mammary glands were excised and fixed for ex vivo MRI and histology. Tumor, blood, and mammary gland volumes for each time point were measured from manually traced regions of interest; tumors were classified as invasive by histopathology‐blinded observers. Our analysis confirmed a strong correlation between total tumor volume and blood volume in the mammary gland. Tumor growth rates from weeks 8‐12 were twice as high in HAFD‐fed mice (0.42 ± 0.14/week) as in LFD‐fed mice (0.21 ± 0.03/week), p < 0.004. Mammary gland blood volume growth rate was 2.2 times higher in HAFD mice (0.29 ± 0.11/week) compared with LFD mice (0.13 ± 0.06/week), p < 0.02. The mammary gland growth rate of HAFD‐fed mice (0.071 ± 0.011/week) was 2.7 times larger than that of LFD‐fed mice (0.026 ± 0.009/week), p < 0.01. This is the first non‐invasive, in vivo MRI study to demonstrate a strong correlation between an HAFD and increased cancer burden and blood volume in mammary cancer without using contrast agents, strengthening the evidence supporting the adverse effects of an HAFD on mammary cancer. These results support the potential future use of TOF angiography to evaluate vasculature of suspicious lesions.     

Optimization of saturation‐recovery dynamic contrast‐enhanced MRI acquisition protocol: monte carlo simulation approach demonstrated with gadolinium MR renography

Dynamic contrast‐enhanced (DCE) MRI is widely used for the measurement of tissue perfusion and to assess organ function. MR renography, which is acquired using a DCE sequence, can measure renal perfusion, filtration and concentrating ability. Optimization of the DCE acquisition protocol is important for the minimization of the error propagation from the acquired signals to the estimated parameters, thus improving the precision of the parameters. Critical to the optimization of contrast‐enhanced T₁‐weighted protocols is the balance of the T₁‐shortening effect across the range of gadolinium (Gd) contrast concentration in the tissue of interest. In this study, we demonstrate a Monte Carlo simulation approach for the optimization of DCE MRI, in which a saturation‐recovery T₁‐weighted gradient echo sequence is simulated and the impact of injected dose (D) and time delay (TD, for saturation recovery) is tested. The results show that high D and/or high TD cause saturation of the peak arterial signals and lead to an overestimation of renal plasma flow (RPF) and glomerular filtration rate (GFR). However, the use of low TD (e.g. 100 ms) and low D leads to similar errors in RPF and GFR, because of the Rician bias in the pre‐contrast arterial signals. Our patient study including 22 human subjects compared TD values of 100 and 300 ms after the injection of 4 mL of Gd contrast for MR renography. At TD = 100 ms, we computed an RPF value of 157.2 ± 51.7 mL/min and a GFR of 33.3 ± 11.6 mL/min. These results were all significantly higher than the parameter estimates at TD = 300 ms: RPF = 143.4 ± 48.8 mL/min (p = 0.0006) and GFR = 30.2 ± 11.5 mL/min (p = 0.0015). In conclusion, appropriate optimization of the DCE MRI protocol using simulation can effectively improve the precision and, potentially, the accuracy of the measured parameters. Copyright © 2016 John Wiley & Sons, Ltd.     

High‐temporospatial‐resolution dynamic contrast‐enhanced (DCE) wrist MRI with variable‐density pseudo‐random circular Cartesian undersampling (CIRCUS) acquisition: evaluation of perfusion in rheumatoid arthritis patients

This study is to evaluate highly accelerated three‐dimensional (3D) dynamic contrast‐enhanced (DCE) wrist MRI for assessment of perfusion in rheumatoid arthritis (RA) patients. A pseudo‐random variable‐density undersampling strategy, circular Cartesian undersampling (CIRCUS), was combined with k–t SPARSE‐SENSE reconstruction to achieve a highly accelerated 3D DCE wrist MRI. Two healthy volunteers and 10 RA patients were studied. Two patients were on methotrexate (MTX) only (Group I) and the other eight were treated with a combination therapy of MTX and anti‐tumor necrosis factor (TNF) therapy (Group II). Patients were scanned at baseline and 3 month follow‐up. DCE MR images were used to evaluate perfusion in synovitis and bone marrow edema pattern in the RA wrist joints. A series of perfusion parameters was derived and compared with clinical disease activity scores of 28 joints (DAS28). 3D DCE wrist MR images were obtained with a spatial resolution of 0.3 × 0.3 × 1.5 mm³ and temporal resolution of 5 s (with an acceleration factor of 20). The derived perfusion parameters, most notably transition time (dT) of synovitis, showed significant negative correlations with DAS28‐ESR (r = ?0.80, p < 0.05) and DAS28‐CRP (r = ?0.87, p < 0.05) at baseline and also correlated significantly with treatment responses evaluated by clinical score changes between baseline and 3 month follow‐up (with DAS28‐ESR r = ?0.79, p < 0.05, and DAS28‐CRP r = ?0.82, p < 0.05). Highly accelerated 3D DCE wrist MRI with improved temporospatial resolution has been achieved in RA patients and provides accurate assessment of neovascularization and perfusion in RA joints, showing promise as a potential tool for evaluating treatment responses. Copyright © 2015 John Wiley & Sons, Ltd.     

Arterial spin labeling‐fast imaging with steady‐state free precession (ASL‐FISP): a rapid and quantitative perfusion technique for high‐field MRI

Arterial spin labeling (ASL) is a valuable non‐contrast perfusion MRI technique with numerous clinical applications. Many previous ASL MRI studies have utilized either echo‐planar imaging (EPI) or true fast imaging with steady‐state free precession (true FISP) readouts, which are prone to off‐resonance artifacts on high‐field MRI scanners. We have developed a rapid ASL‐FISP MRI acquisition for high‐field preclinical MRI scanners providing perfusion‐weighted images with little or no artifacts in less than 2 s. In this initial implementation, a flow‐sensitive alternating inversion recovery (FAIR) ASL preparation was combined with a rapid, centrically encoded FISP readout. Validation studies on healthy C57/BL6 mice provided consistent estimation of in vivo mouse brain perfusion at 7 and 9.4 T (249 ± 38 and 241 ± 17 mL/min/100 g, respectively). The utility of this method was further demonstrated in the detection of significant perfusion deficits in a C57/BL6 mouse model of ischemic stroke. Reasonable kidney perfusion estimates were also obtained for a healthy C57/BL6 mouse exhibiting differential perfusion in the renal cortex and medulla. Overall, the ASL‐FISP technique provides a rapid and quantitative in vivo assessment of tissue perfusion for high‐field MRI scanners with minimal image artifacts. Copyright © 2014 John Wiley & Sons, Ltd.     

In vivo detection of the effects of preconditioning on LNCaP tumors by a TNF‐α nanoparticle construct using MRI

The outcome of systemic and local therapies (e.g. chemotherapy, radiotherapy, surgery, focal ablation) for prostate cancer can be significantly improved by using tumor‐specific adjuvants prior to treatment (“preconditioning”). We propose to use dynamic contrast enhanced magnetic resonance imaging (DCE‐MRI) to monitor the in vivo response of a mouse model of prostate cancer treated with a vascular disruptive agent, TNF‐α, delivered on a gold nanoparticle (NP‐TNF). Six male nude mice bearing 4–5 week old LNCaP tumors were scanned at 9.4 T. DCE‐MRI was performed two days before and 4–5 h after treatment with NP‐TNF. An intraperitoneal (i.p.) bolus of gadolinium‐DTPA (Gd) was administered and contrast enhancement was measured for 90 min. Concentration–time curves of Gd were calculated and the area under the Gd curve (AUGC) was determined pre‐ and post‐treatment. NP‐TNF treatment caused an increase in contrast uptake in tumors. Interestingly, the early concentration (10 min post Gd bolus i.p.) was similar in both untreated and treated conditions; however, 90 min after injection, [Gd] was 3.4 times higher than before treatment. AUGC doubled from (11 ± 6) [Gd] × min before treatment to (22 ± 9) [Gd] × min after treatment. An increase in signal enhancement was also observed in the muscle but to a lesser degree. We also evaluated the kinetics of intravenous Gd administration in mice bearing a jugular vein catheter to mimic the delivery method used in clinical trials. The overall treatment effects were independent of the delivery pathway of the contrast agent. In conclusion, we show that DCE‐MRI is suitable to detect changes associated with a vascular disruptive agent in a mouse model of prostate cancer. The ability to characterize the effects of nanoparticle therapy in vivo with non‐destructive methods is important, as such compounds, in combination with treatment strategies, are progressing towards clinical trials. Copyright © 2014 John Wiley & Sons, Ltd.     

Dynamic contrast‐enhanced MRI in mouse tumors at 11.7 T: comparison of three contrast agents with different molecular weights to assess the early effects of combretastatin A4

Dynamic contrast‐enhanced (DCE)‐MRI is useful to assess the early effects of drugs acting on tumor vasculature, namely anti‐angiogenic and vascular disrupting agents. Ultra‐high‐field MRI allows higher‐resolution scanning for DCE‐MRI while maintaining an adequate signal‐to‐noise ratio. However, increases in susceptibility effects, combined with decreases in longitudinal relaxivity of gadolinium‐based contrast agents (GdCAs), make DCE‐MRI more challenging at high field. The aim of this work was to explore the feasibility of using DCE‐MRI at 11.7 T to assess the tumor hemodynamics of mice. Three GdCAs possessing different molecular weights (gadoterate: 560 Da, 0.29 mmol Gd/kg; p846: 3.5 kDa, 0.10 mmol Gd/kg; and p792: 6.47 kDa, 0.15 mmol Gd/kg) were compared to see the influence of the molecular weight in the highlight of the biologic effects induced by combretastatin A4 (CA4). Mice bearing transplantable liver tumor (TLT) hepatocarcinoma were divided into two groups (n = 5–6 per group and per GdCA): a treated group receiving 100 mg/kg CA4, and a control group receiving vehicle. The mice were imaged at 11.7 T with a T₁‐weighted FLASH sequence 2 h after the treatment. Individual arterial input functions (AIFs) were computed using phase imaging. These AIFs were used in the Extended Tofts Model to determine K^trans and v_p values. A separate immunohistochemistry study was performed to assess the vascular perfusion and the vascular density. Phase imaging was used successfully to measure the AIF for the three GdCAs. In control groups, an inverse relationship between the molecular weight of the GdCA and K^trans and v_p values was observed. K^trans was significantly decreased in the treated group compared with the control group for each GdCA. DCE‐MRI at 11.7 T is feasible to assess tumor hemodynamics in mice. With K^trans, the three GdCAs were able to track the early vascular effects induced by CA4 treatment. Copyright © 2014 John Wiley & Sons, Ltd.     

Optimization of arterial spin labeling MRI for quantitative tumor perfusion in a mouse xenograft model

Perfusion is an important biomarker of tissue function and has been associated with tumor pathophysiology such as angiogenesis and hypoxia. Arterial spin labeling (ASL) MRI allows noninvasive and quantitative imaging of perfusion; however, the application in mouse xenograft tumor models has been challenging due to the low sensitivity and high perfusion heterogeneity. In this study, flow‐sensitive alternating inversion recovery (FAIR) ASL was optimized for a mouse xenograft tumor. To assess the sensitivity and reliability for measuring low perfusion, the lumbar muscle was used as a reference region. By optimizing the number of averages and inversion times, muscle perfusion as low as 32.4 ± 4.8 (mean ± standard deviation) ml/100 g/min could be measured in 20 min at 7 T with a quantification error of 14.4 ± 9.1%. Applying the optimized protocol, heterogeneous perfusion ranging from 49.5 to 211.2 ml/100 g/min in a renal carcinoma was observed. To understand the relationship with tumor pathology, global and regional tumor perfusion was compared with histological staining of blood vessels (CD34), hypoxia (CAIX) and apoptosis (TUNEL). No correlation was observed when the global tumor perfusion was compared with these pathological parameters. Regional analysis shows that areas of high perfusion had low microvessel density, which was due to larger vessel area compared with areas of low perfusion. Nonetheless, these were not correlated with hypoxia or apoptosis. The results suggest that tumor perfusion may reflect certain aspect of angiogenesis, but its relationship with other pathologies needs further investigation. Copyright © 2015 John Wiley & Sons, Ltd.     

Multiparametric MRI analysis for the evaluation of MR‐guided high intensity focused ultrasound tumor treatment

For the clinical application of high intensity focused ultrasound (HIFU) for thermal ablation of malignant tumors, accurate treatment evaluation is of key importance. In this study, we have employed a multiparametric MRI protocol, consisting of quantitative T₁, T₂, ADC, amide proton transfer (APT), T_1ρ and DCE‐MRI measurements, to evaluate MR‐guided HIFU treatment of subcutaneous tumors in rats. K‐means clustering using all different combinations of the endogenous contrast MRI parameters (feature vectors) was performed to segment the multiparametric data into tissue populations with similar MR parameter values. The optimal feature vector for identification of the extent of non‐viable tumor tissue after HIFU treatment was determined by quantitative comparison between clustering‐derived and histology‐derived non‐viable tumor fractions. The highest one‐to‐one correspondence between these clustering‐based and histology‐based non‐viable tumor fractions was observed for the feature vector {ADC, APT‐weighted signal} (R² to line of identity (R²_y=x) = 0.92) and the strongest agreement was seen 3 days after HIFU (R²_y=x = 0.97). To compare the multiparametric MRI analysis results with conventional HIFU monitoring and evaluation methods, the histology‐derived non‐viable tumor fractions were also quantitatively compared with non‐perfused tumor fractions (derived from the level of contrast enhancement in the DCE‐MRI measurements) and 240 CEM tumor fractions (i.e. thermal dose > 240 cumulative equivalent minutes at 43 °C). The correlation between histology‐derived non‐viable tumor fractions directly after HIFU and the 240 CEM fractions was high, but not significant. The non‐perfused fractions overestimated the extent of non‐viable tumor tissue directly after HIFU, whereas an underestimation was observed 3 days after HIFU. In conclusion, we have shown that a multiparametric MR analysis, especially based on the ADC and the APT‐weighted signal, can potentially be used to determine the extent of non‐viable tumor tissue 3 days after HIFU treatment. We expect that this method can be incorporated in the current clinical workflow of MR–HIFU ablation therapies. Copyright © 2015 John Wiley & Sons, Ltd.     

Simultaneous measurement of T1/B1 and pharmacokinetic model parameters using active contrast encoding (ACE)‐MRI

The aim of this study was to assess the feasibility of combining dynamic contrast enhanced‐magnetic resonance imaging (DCE‐MRI) with the measurement of the radiofrequency (RF) transmit field B ₁ and pre‐contrast longitudinal relaxation time T ₁₀. A novel approach has been proposed to simultaneously estimate B ₁ and T ₁₀ from a modified DCE‐MRI scan that actively encodes the washout phase of the curve with different amounts of T ₁ and B ₁ weighting using multiple flip angles and repetition times, hence referred to as active contrast encoding (ACE)‐MRI. ACE‐MRI aims to simultaneously measure B ₁ and T ₁₀, together with contrast kinetic parameters, such as the transfer constant K ^trans, interstitial space volume fraction v _e and vascular space volume fraction v _p. The proposed method was tested using numerical simulations and in vivo studies with mouse models of breast cancer implanted in the flank and mammary fat pad, and glioma in the brain. In the numerical simulation study with a signal‐to‐noise ratio of 10, both B ₁ and T ₁₀ were estimated accurately with errors of 5.1 ± 3.5% and 12.3 ± 8.8% and coefficients of variation (CV) of 14.9 ± 8.6% and 15.0 ± 5.0%, respectively. Using the same ACE‐MRI data, the kinetic parameters K ^trans, v _e and v _p were also estimated with errors of 14.2 ± 8.3% (CV = 13.5 ± 4.6%), 14.7 ± 9.9% (CV = 13.3 ± 4.5%) and 14.0 ± 9.3% (CV = 14.0 ± 4.5%), respectively. For the in vivo tumor data from 11 mice, voxel‐wise comparisons between ACE‐MRI and DCE‐MRI methods showed that the mean differences for the five parameters were as follows: ΔK ^trans = 0.006 (/min), Δv _e = 0.016, Δv _p = 0.000, ΔB ₁ = ?0.014 and ΔT ₁ = ?0.085 (s), which suggests a good agreement between the two methods. When compared with separately measured B ₁ and T ₁₀, and DCE‐MRI estimated kinetic parameters as a reference, the mean relative errors of ACE‐MRI estimation were B ₁ = ?0.3%, T ₁₀ = ?8.5%, K ^trans = 11.4%, v _e = 14.5% and v _p = 4.5%. This proof‐of‐concept study demonstrates that the proposed ACE‐MRI method can be used to estimate B ₁ and T ₁₀, together with contrast kinetic model parameters.     

Assessing high‐intensity focused ultrasound treatment of prostate cancer with hyperpolarized 13C dual‐agent imaging of metabolism and perfusion

The goal of the study was to establish early hyperpolarized (HP) ¹³C MRI metabolic and perfusion changes that predict effective high‐intensity focused ultrasound (HIFU) ablation and lead to improved adjuvant treatment of partially treated regions. To accomplish this a combined HP dual‐agent (¹³C pyruvate and ¹³C urea) ¹³C MRI/multiparametric ¹H MRI approach was used to measure prostate cancer metabolism and perfusion 3–4 h, 1 d, and 5 d after exposure to ablative and sub‐lethal doses of HIFU within adenocarcinoma of mouse prostate tumors using a focused ultrasound applicator designed for murine studies. Pathologic and immunohistochemical analysis of the ablated tumor demonstrated fragmented, non‐viable cells and vasculature consistent with coagulative necrosis, and a mixture of destroyed tissue and highly proliferative, poorly differentiated tumor cells in tumor tissues exposed to sub‐lethal heat doses in the ablative margin. In ablated regions, the intensity of HP ¹³C lactate or HP ¹³C urea and dynamic contrast‐enhanced (DCE) MRI area under the curve images were reduced to the level of background noise by 3–4 h after treatment with no recovery by the 5 d time point in either case. In the tissues that received sub‐lethal heat dose, there was a significant 60% ± 12.4% drop in HP ¹³C lactate production and a significant 30 ± 13.7% drop in urea perfusion 3–4 h after treatment, followed by recovery to baseline by 5 d after treatment. DCE MRI K^trans showed a similar trend to HP ¹³C urea, demonstrating a complete loss of perfusion with no recovery in the ablated region, while having a 40%–50% decrease 3–4 h after treatment followed by recovery to baseline values by 5 d in the margin region. The utility of the HP ¹³C MR measures of perfusion and metabolism in optimizing focal HIFU, either alone or in combination with adjuvant therapy, deserves further testing in future studies.     

Three‐dimensional dynamic contrast‐enhanced MRI for the accurate,extensive quantification of microvascular permeability in atherosclerotic plaques

Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast‐enhanced MRI (DCE‐MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE‐MRI studies of atherosclerosis have been limited to two‐dimensional (2D) multi‐slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three‐dimensional (3D), high‐resolution, DCE‐MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion‐sensitized‐driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE‐MRI to be superior to 3D TSE DCE‐MRI in terms of temporal stability metrics. Both sequences show good intra‐ and inter‐observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near‐infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE‐MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under‐sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE‐MRI by up to four‐fold. We anticipate that the development of high‐spatial‐resolution 3D DCE‐MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease. Copyright © 2015 John Wiley & Sons, Ltd.     

A comprehensive non‐invasive framework for automated evaluation of acute renal transplant rejection using DCE‐MRI

The objective was to develop a novel and automated comprehensive framework for the non‐invasive identification and classification of kidney non‐rejection and acute rejection transplants using 2D dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). The proposed approach consists of four steps. First, kidney objects are segmented from the surrounding structures with a geometric deformable model. Second, a non‐rigid registration approach is employed to account for any local kidney deformation. In the third step, the cortex of the kidney is extracted in order to determine dynamic agent delivery, since it is the cortex that is primarily affected by the perfusion deficits that underlie the pathophysiology of acute rejection. Finally, we use an analytical function‐based model to fit the dynamic contrast agent kinetic curves in order to determine possible rejection candidates. Five features that map the data from the original data space to the feature space are chosen with a k‐nearest‐neighbor (KNN) classifier to distinguish between acute rejection and non‐rejection transplants. Our study includes 50 transplant patients divided into two groups: 27 patients with stable kidney function and the remainder with impaired kidney function. All of the patients underwent DCE‐MRI, while the patients in the impaired group also underwent ultrasound‐guided fine needle biopsy. We extracted the kidney objects and the renal cortex from DCE‐MRI for accurate medical evaluation with an accuracy of 0.97 ± 0.02 and 0.90 ± 0.03, respectively, using the Dice similarity metric. In a cohort of 50 participants, our framework classified all cases correctly (100%) as rejection or non‐rejection transplant candidates, which is comparable to the gold standard of biopsy but without the associated deleterious side‐effects. Both the 95% confidence interval (CI) statistic and the receiver operating characteristic (ROC) analysis document the ability to separate rejection and non‐rejection groups. The average plateau (AP) signal magnitude and the gamma‐variate model functional parameter α have the best individual discriminating characteristics. Copyright © 2013 John Wiley & Sons, Ltd.     

Diffusion‐weighted MRI monitoring of pancreatic cancer response to radiofrequency heat‐enhanced intratumor chemotherapy

The aim of this study was to evaluate the feasibility of using diffusion‐weighted MRI to monitor the early response of pancreatic cancers to radiofrequency heat (RFH)‐enhanced chemotherapy. Human pancreatic carcinoma cells (PANC‐1) in different groups and 24 mice with pancreatic cancer xenografts in four groups were treated with phosphate‐buffered saline (PBS) as a control, RFH at 42 °C, gemcitabine and gemcitabine plus RFH at 42 °C. One day before and 1, 7 and 14 days after treatment, diffusion‐weighted MRI and T₂‐weighted imaging were applied to monitor the apparent diffusion coefficients (ADCs) of tumors and tumor growth. MRI findings were correlated with the results of tumor apoptosis analysis. In the in vitro experiments, the quantitative viability assay showed lower relative cell viabilities for treatment with gemcitabine plus RFH at 42 °C relative to treatment with RFH only and gemcitabine only (37 ± 5% versus 65 ± 4% and 58 ± 8%, respectively, p < 0.05). In the in vivo experiments, the combination therapy resulted in smaller relative tumor volumes than RFH only and chemotherapy only (0.82 ± 0.17 versus 2.23 ± 0.90 and 1.64 ± 0.44, respectively, p = 0.003). In vivo, 14‐T MRI demonstrated a remarkable decrease in ADCs at day 1 and increased ADCs at days 7 and 14 in the combination therapy group. The apoptosis index in the combination therapy group was significantly higher than those in the chemotherapy‐only, RFH‐only and PBS treatment groups (37 ± 6% versus 20 ± 5%, 8 ± 2% and 3 ± 1%, respectively, p < 0.05). This study confirms that it is feasible to use MRI to monitor RFH‐enhanced chemotherapy in pancreatic cancers, which may present new options for the efficient treatment of pancreatic malignancies using MRI/RFH‐integrated local chemotherapy. Copyright © 2013 John Wiley & Sons, Ltd.     

Response of HT29 colorectal xenograft model to cediranib assessed with 18F‐fluoromisonidazole positron emission tomography,dynamic contrast‐enhanced and diffusion‐weighted MRI

Cediranib is a small‐molecule pan‐vascular endothelial growth factor receptor inhibitor. The tumor response to short‐term cediranib treatment was studied using dynamic contrast‐enhanced and diffusion‐weighted MRI at 7 T, as well as ¹⁸F‐fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline; they then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow‐up imaging performed 2 h after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and tumor necrosis. Dynamic contrast‐enhanced MRI‐derived parameters decreased significantly in cediranib‐treated tumors relative to pretreatment values [the muscle‐normalized initial area under the gadolinium concentration curve decreased by 48% (p = 0.002), the enhancing fraction by 43% (p = 0.003) and K^trans by 57% (p = 0.003)], but remained unchanged in controls. No change between the pre‐ and post‐treatment tumor apparent diffusion coefficients in either the cediranib‐ or vehicle‐treated group was observed over the course of this study. The ¹⁸F‐fluoromisonidazole mean standardized uptake value decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31‐positive vessels (59 per mm²), the fraction of smooth muscle actin‐positive vessels (80–87%) and the intercapillary distance (0.17 mm) were similar in cediranib‐ and vehicle‐treated groups. The fraction of perfused blood vessels in cediranib‐treated tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p = 0.02). The necrotic fraction was slightly higher in cediranib‐treated rats (34 ± 12%) than in controls (26 ± 10%, p = 0.23). These findings suggest that short‐term treatment with cediranib causes a decrease in tumor perfusion/permeability across the tumor cross‐section, but changes in vascular morphology, vessel density or tumor cellularity are not manifested at this early time point. Copyright © 2012 John Wiley & Sons, Ltd.