Gaussian mixture model‐based classification of dynamic contrast enhanced MRI data for identifying diverse tumor microenvironments: preliminary results

Tumor hypoxia develops heterogeneously, affects radiation sensitivity and the development of metastases. Prognostic information derived from the in vivo characterization of the spatial distribution of hypoxic areas in solid tumors can be of value for radiation therapy planning and for monitoring the early treatment response. Tumor hypoxia is caused by an imbalance between the supply and consumption of oxygen. The tumor oxygen supply is inherently linked to its vasculature and perfusion which can be evaluated by dynamic contrast enhanced (DCE‐) MRI using the contrast agent Gd‐DTPA. Thus, we hypothesize that DCE‐MRI data may provide surrogate information regarding tumor hypoxia. In this study, DCE‐MRI data from a rat prostate tumor model were analysed with a Gaussian mixture model (GMM)‐based classification to identify perfused, hypoxic and necrotic areas for a total of ten tumor slices from six rats, of which one slice was used as training data for GMM classifications. The results of pattern recognition analyzes were validated by comparison to corresponding Ak_ep maps defining the perfused area (0.84 ± 0.09 overlap), hematoxylin and eosin (H&E)‐stained tissue sections defining necrosis (0.64 ± 0.15 overlap) and pimonidazole‐stained sections defining hypoxia (0.72 ± 0.17 overlap), respectively. Our preliminary data indicate the feasibility of a GMM‐based classification to identify tumor hypoxia, necrosis and perfusion/permeability from non‐invasively acquired, in vivo DCE‐MRI data alone, possibly obviating the need for invasive procedures, such as biopsies, or exposure to radioactivity, such as positron emission tomography (PET) exams. Copyright © 2013 John Wiley & Sons, Ltd.     

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.     

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.     

Assessment of the need for DCE MRI in the detection of dominant lesions in the whole gland: Correlation between histology and MRI of prostate cancer

The purpose of this study was to evaluate the utility of dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI) in the detection of dominant prostate tumors with multi‐parametric MRI of the whole gland. Combined diffusion tensor imaging (DTI) and DCE MRI from 16 patients with biopsy‐proven prostate cancer and no previous treatment were acquired with a 3.0‐T MRI scanner prior to radical prostatectomy, and used to identify dominant tumors. MRI results were validated by whole‐mount histology. Paired t‐test and Wilcoxon test, logistic generalized linear mixed effect models and receiver operating characteristic (ROC) analyses were used for the estimation of the statistical significance of the results. In the peripheral zone (PZ), the areas under the ROC curve (ROC‐AUC) were 0.98 (sensitivity, 96%; specificity, 98%) for DTI, 0.96 (sensitivity, 92%; specificity, 97%) for DCE and 0.99 (sensitivity, 98%; specificity, 98%) for DTI + DCE. In the entire prostate, the ROC‐AUC values were 0.96 (sensitivity, 84%; specificity, 95%) for DTI, 0.87 (sensitivity, 45%; specificity, 94%) for DCE and 0.96 (sensitivity, 88%; specificity, 98%) for DTI + DCE. The increase in ROC‐AUC by the addition of DCE was not statistically significant in either PZ or the entire prostate. The results of this study have shown that DTI identified dominant tumors with high accuracy in both PZ and the entire prostate, whereas the inclusion of DCE MRI had no significant impact on the identification of either PZ or entire prostate dominant lesions. Our results suggest that the inclusion of DCE MRI may not increase the accuracy of dominant lesion detection, allowing for faster, better tolerated imaging studies.     

Difference in the intratumoral distributions of extracellular‐fluid and intravascular MR contrast agents in glioblastoma growth

Contrast enhancement by an extracellular‐fluid contrast agent (CA) (Gd‐DOTA) depends primarily on the blood–brain‐barrier permeability (bp ), and transverse‐relaxation change caused by intravascular T₂ CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single‐CA‐using dynamic contrast‐enhanced MRI (DCE‐MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd‐DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2 mL). bp was quantified according to the non‐PK parameters of Gd‐DOTA‐using DCE‐MRI (wash‐in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION‐induced ΔR₂* and ΔR₂. With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual‐contrast MRI demonstrated a different region‐oriented distribution between Gd‐DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR₂ and ΔR₂) as the tumor increased in size; (d) the tumor center showed greater bp ‐indicating parameters, i.e. wash‐in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI–histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate–dextran signals and up‐regulated immunoreactivity of CD31–VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular‐fluid Gd chelates and intravascular SPION.     

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.     

MRI and quantitative autoradiographic studies following bolus injections of unlabeled and (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants

In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast‐enhanced (DCE)‐MRI, and blood‐to‐brain influx rate constants (K_i) were calculated from Patlak plots of the data in areas with blood–brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE‐MRI study, radiolabeled sucrose or α‐aminoisobutyric acid was injected intravenously, and the brain disposition and K_i values were calculated by quantitative autoradiography (QAR) assay employing the single‐time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd‐DTPA, Gd‐[¹⁴C]DTPA, and K_i was calculated from both sets of data by the single‐time equation. The protocol included 3 h of middle cerebral artery occlusion and 2.5 h of reperfusion in male Wistar rats (n = 15) preceding the DCE‐MRI Gd‐DTPA and QAR Gd‐[¹⁴C]DTPA measurements. In addition to K_i, the tissue‐to‐blood concentration ratios, or volumes of distribution (V_R), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, V_R was nearly identical for Gd‐DTPA and Gd‐[¹⁴C]DTPA, and K_i was slightly, but not significantly, higher for Gd‐DTPA than for Gd‐[¹⁴C]DTPA. The K_i values were well correlated (r = 0.67; p = 0.001). When the arterial concentration–time curve of Gd‐DTPA was adjusted to match that of Gd‐[¹⁴C]DTPA, the two sets of K_i values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model‐dependent, approach) of the same data (p = 0.2–0.5). These findings demonstrate that this DCE‐MRI technique accurately measures the Gd‐DTPA concentration in blood and brain, and that K_i estimates based on such data are good quantitative indicators of BBB injury. Copyright © 2010 John Wiley & Sons, Ltd.     

A comparison of arterial spin labeling perfusion MRI and DCE‐MRI in human prostate cancer

Perfusion MRI has the potential to provide pathophysiological biomarkers for the evaluating, staging and therapy monitoring of prostate cancer. The objective of this study was to explore the feasibility of noninvasive arterial spin labeling (ASL) to detect prostate cancer in the peripheral zone and to investigate the correlation between the blood flow (BF) measured by ASL and the pharmacokinetic parameters K^trans (forward volume transfer constant), k_ep (reverse reflux rate constant between extracellular space and plasma) and v_e (the fractional volume of extracellular space per unit volume of tissue) measured by dynamic contrast‐enhanced (DCE) MRI in patients with prostate cancer. Forty‐three consecutive patients (ages ranging from 49 to 86 years, with a median age of 74 years) with pathologically confirmed prostate cancer were recruited. An ASL scan with four different inversion times (TI = 1000, 1200, 1400 and 1600 ms) and a DCE‐MRI scan were performed on a clinical 3.0 T GE scanner. BF, K^trans, k_ep and v_e maps were calculated. In order to determine whether the BF values in the cancerous area were statistically different from those in the noncancerous area, an independent t‐test was performed. Spearman's bivariate correlation was used to assess the relationship between BF and the pharmacokinetic parameters K^trans, k_ep and v_e. The mean BF values in the cancerous areas (97.1 ± 30.7, 114.7 ± 28.7, 102.3 ± 22.5, 91.2 ± 24.2 ml/100 g/min, respectively, for TI = 1000, 1200, 1400, 1600 ms) were significantly higher (p < 0.01 for all cases) than those in the noncancerous regions (35.8 ± 12.5, 42.2 ± 13.7, 53.5 ± 19.1, 48.5 ± 13.5 ml/100 g/min, respectively). Significant positive correlations (p < 0.01 for all cases) between BF and the pharmacokinetic parameters K^trans, k_ep and v_e were also observed for all four TI values (r = 0.671, 0.407, 0.666 for TI = 1000 ms; 0.713, 0.424, 0.698 for TI = 1200 ms; 0.604, 0.402, 0.595 for TI = 1400 ms; 0.605, 0.422, 0.548 for TI = 1600 ms). It can be seen that the quantitative ASL measurements show significant differences between cancerous and benign tissues, and exhibit strong to moderate correlations with the parameters obtained using DCE‐MRI. These results show the promise of ASL as a noninvasive alternative to DCE‐MRI. Copyright © 2014 John Wiley & Sons, Ltd.     

Comparing diagnostic accuracy of luminal water imaging with diffusion‐weighted and dynamic contrast‐enhanced MRI in prostate cancer: A quantitative MRI study

Luminal water imaging (LWI) is a new MRI T₂ mapping technique that has been developed with the aim of diagnosis of prostate carcinoma (PCa). This technique measures the fractional amount of luminal water in prostate tissue, and has shown promising preliminary results in detection of PCa. To include LWI in clinical settings, further investigation on the accuracy of this technique is required. In this study, we compare the diagnostic accuracy of LWI with those of diffusion‐weighted imaging (DWI) and dynamic contrast‐enhanced (DCE) MRI in detection and grading of PCa. Fifteen patients with biopsy‐proven PCa consented to participate in this ethics‐board‐approved prospective study. Patients were examined with LWI, DWI, and DCE sequences at 3 T prior to radical prostatectomy. Maps of MRI parameters were generated and registered to whole‐mount histology. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic accuracy of individual and combined MR parameters. Correlation with Gleason score (GS) was evaluated using Spearman's rank correlation test. The results show that area under the ROC curve (AUC) obtained from LWI was equal to or higher than the AUC obtained from DWI, DCE, or their combination, in peripheral zone (0.98 versus 0.90, 0.89, and 0.91 respectively), transition zone (0.99 versus 0.98, n/a, and 0.98), and the entire prostate (0.85 versus 0.81, 0.75, and 0.84). The strongest correlation with GS was achieved from LWI (ρ = ?0.81 ± 0.09, P < 0.001). Results of this pilot study show that LWI performs equally well as, or better than, DWI and DCE in detection of PCa. LWI provides significantly higher correlation with GS than DWI and DCE. This technique can potentially be included in clinical MRI protocols to improve characterization of tumors. However, considering the small size of the patient population in this study, a further study with a larger cohort of patients and broader range of GS is required to confirm the findings and draw a firm conclusion on the applicability of LWI in clinical settings.     

Dynamic contrast‐enhanced MRI texture analysis for pretreatment prediction of clinical and pathological response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

The aim of this study was to investigate the potential of texture analysis, applied to dynamic contrast‐enhanced MRI (DCE‐MRI), to predict the clinical and pathological response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) before NAC is started. Fifty‐eight patients with LABC were classified on the basis of their clinical response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines after four cycles of NAC, and according to their pathological response after surgery. T₁‐weighted DCE‐MRI with a temporal resolution of 1 min was acquired on a 3‐T Siemens Trio scanner using a dedicated four‐channel breast coil before the onset of treatment. Each lesion was segmented semi‐automatically using the 2‐min post‐contrast subtracted image. Sixteen texture features were obtained at each non‐subtracted post‐contrast time point using a gray level co‐occurrence matrix. Appropriate statistical analyses were performed and false discovery rate‐based q values were reported to correct for multiple comparisons. Statistically significant results were found at 1–3 min post‐contrast for various texture features for the prediction of both the clinical and pathological response. In particular, eight texture features were found to be statistically significant at 2 min post‐contrast, the most significant feature yielding an area under the curve (AUC) of 0.77 for response prediction for stable disease versus complete responders after four cycles of NAC. In addition, four texture features were found to be significant at the same time point, with an AUC of 0.69 for response prediction using the most significant feature for classification based on the pathological response. Our results suggest that texture analysis could provide clinicians with additional information to increase the accuracy of prediction of an individual response before NAC is started. Copyright © 2014 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.     

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.     

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.     

Classification of breast lesions pre‐contrast injection using water resonance lineshape analysis

Inhomogeneously broadened, non‐Lorentzian water resonances have been observed in small image voxels of breast tissue. The non‐Lorentzian components of the water resonance are probably produced by bulk magnetic susceptibility shifts caused by dense, deoxygenated tumor blood vessels (the ‘blood oxygenation level‐dependent’ effect), but can also be produced by other characteristics of local anatomy and physiology, including calcifications and interfaces between different types of tissue. Here, we tested the hypothesis that the detection of non‐Lorentzian components of the water resonance with high spectral and spatial resolution (HiSS) MRI allows the classification of breast lesions without the need to inject contrast agent. Eighteen malignant lesions and nine benign lesions were imaged with HiSS MRI at 1.5 T. A new algorithm was developed to detect non‐Lorentzian (or off‐peak) components of the water resonance. After a Lorentzian fit had been subtracted from the data, the largest peak in the residual spectrum in each voxel was identified as the major off‐peak component of the water resonance. The difference in frequency between these off‐peak components and the main water peaks, and their amplitudes, were measured in malignant lesions, benign lesions and breast fibroglandular tissue. Off‐peak component frequencies were significantly different between malignant and benign lesions (p < 0.001). Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of HiSS off‐peak component analysis compared with dynamic contrast‐enhanced (DCE) MRI parameters. The areas under the ROC curves for the ‘DCE rapid uptake fraction’, ‘DCE washout fraction’, ‘off‐peak component amplitude’ and ‘off‐peak component frequency’ were 0.75, 0.83, 0.50 and 0.86, respectively. These results suggest that water resonance lineshape analysis performs well in the classification of breast lesions without contrast injection and could improve the diagnostic accuracy of clinical breast MR examinations. In addition, this approach may provide an alternative to DCE MRI in women who are at risk for adverse reactions to contrast media. Copyright © 2012 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.     

Dual assessment of kidney perfusion and pH by exploiting a dynamic CEST‐MRI approach in an acute kidney ischemia–reperfusion injury murine model

Several factors can lead to acute kidney injury, but damage following ischemia and reperfusion injuries is the main risk factor and usually develops into chronic disease. MRI has often been proposed as a method with which to assess renal function. It does so by measuring the renal perfusion of an injected Gd‐based contrast agent. The use of pH‐responsive agents as part of the CEST (chemical exchange saturation transfer)‐MRI technique has recently shown that pH homeostasis is also an important indicator of kidney functionality. However, there is still a need for methods that can provide more than one type of information following the injection of a single contrast agent for the characterization of renal function. Herein we propose, for the first time, dynamic CEST acquisition following iopamidol injection to quantify renal function by assessing both perfusion and pH homeostasis. The aim of this study is to assess renal functionality in a murine unilateral ischemia–reperfusion injury model at two time points (3 and 7 days) after acute kidney injury. The renal‐perfusion estimates measured with iopamidol were compared with those obtained with a gadolinium‐based agent, via a dynamic contrast enhanced (DCE)‐MRI approach, to validate the proposed method. Compared with the contralateral kidneys, the clamped ones showed a significant decrease in renal perfusion, as measured using the DCE‐MRI approach, which is consistent with reduced filtration capability. Dynamic CEST‐MRI findings provided similar results, indicating that the clamped kidneys displayed significantly reduced renal filtration that persisted up to 7 days after the damage. In addition, CEST‐MRI pH imaging showed that the clamped kidneys displayed significantly increased pH values, reflecting the disturbance to pH homeostasis. Our results demonstrate that a single CEST‐MRI contrast agent can provide multiple types of information related to renal function and can discern healthy kidneys from pathological ones by combining perfusion measurements with renal pH mapping.     

Rapid simultaneous acquisition of T1 and T2 mapping images using multishot double spin‐echo EPI and automated variations of TR and TE (ms‐DSEPI‐T12)

A rapid method of simultaneous T₁ and T₂ measurement is presented which uses a segmented echo‐planar readout with varying repetition times (TR) and echo times (TE). This method is useful in T₁ mapping for analysis of dynamic contrast enhanced MRI (DCE‐MRI), where T₁ can be used to estimate contrast agent concentration. In the application of this method to dynamic imaging, the equilibrium magnetization is measured on pre‐contrast images and incorporated into post‐contrast T₁ calculations for improved accuracy. Simultaneous T₂ measurement allows correction of T₂ effects in the T₁ map which may occur at high contrast agent concentrations, and is performed without significant imaging time penalty. Phantom and in vivo results show the usefulness of this technique for analysis of contrast enhancement kinetics. Accurate rapid contrast agent concentration measurement may be useful for analyzing the distribution and kinetics of contrast agents or labeled pharmaceuticals. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume

The susceptibility differences at the gas–liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd‐DTPA (rCBV_Gd) and the MB‐induced susceptibility effect (ΔR₂*_MB) by conventional dynamic susceptibility contrast MRI (DSC‐MRI). Custom‐made MBs had a mean diameter of 0.92 µm and were capable of inducing 4.68 ± 3.02% of the maximum signal change (MSC). The MB‐associated ΔR₂*_MB was compared with rCBV_Gd in 16 rats on 4.7‐T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between ΔR₂*_MB and rCBV_Gd, and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC‐MRI, and emphasize the critical effect of TTP on MB‐based contrast MRI. Copyright © 2013 John Wiley & Sons, Ltd.