An In Silico Modelling Approach to Predict Hemodynamic Outcomes in Diabetic and Hypertensive Kidney Disease.

Early diagnosis of kidney disease remains an unmet clinical challenge, preventing timely and effective intervention. Diabetes and hypertension are two main causes of kidney disease, can often appear together, and can only be distinguished by invasive biopsy. In this study, we developed a modelling approach to simulate blood velocity, volumetric flow rate, and pressure wave propagation in arterial networks of ageing, diabetic, and hypertensive virtual populations. The model was validated by comparing our predictions for pressure, volumetric flow rate and waveform-derived indexes with in vivo data on ageing populations from the literature. The model simulated the effects of kidney disease, and was calibrated to align quantitatively with in vivo data on diabetic and hypertensive nephropathy from the literature. Our study identified some potential biomarkers extracted from renal blood flow rate and flow pulsatility. For typical patient age groups, resistive index values were 0.69 (SD 0.05) and 0.74 (SD 0.02) in the early and severe stages of diabetic nephropathy, respectively. Similar trends were observed in the same stages of hypertensive nephropathy, with a range from 0.65 (SD 0.07) to 0.73 (SD 0.05), respectively. Mean renal blood flow rate through a single diseased kidney ranged from 329 (SD 40, early) to 317 (SD 38, severe) ml/min in diabetic nephropathy and 443 (SD 54, early) to 388 (SD 47, severe) ml/min in hypertensive nephropathy, showing potential as a biomarker for early diagnosis of kidney disease. This modelling approach demonstrated its potential application in informing biomarker identification and facilitating the setup of clinical trials.

Genome-wide mRNA profiling in urinary extracellular vesicles reveals stress gene signature for diabetic kidney disease.

Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional "stress score" that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.

Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats.

Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97-98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.

Simultaneous evaluation of perfusion and morphology using GRASP MRI in hepatic fibrosis.

OBJECTIVES: To determine if golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced (DCE)-MRI allows simultaneous evaluation of perfusion and morphology in liver fibrosis. METHODS: Participants who were scheduled for liver biopsy or resection were enrolled (NCT02480972). Images were reconstructed at 12-s temporal resolution for morphologic assessment and at 3.3-s temporal resolution for quantitative evaluation. The image quality of the morphologic images was assessed on a four-point scale, and the Liver Imaging Reporting and Data System score was recorded for hepatic observations. Comparisons were made between quantitative parameters of DCE-MRI for the different fibrosis stages, and for hepatocellular carcinoma (HCCs) with different LR features. RESULTS: DCE-MRI of 64 participants (male = 48) were analyzed. The overall image quality consistently stood at 3.5 ± 0.4 to 3.7 ± 0.4 throughout the exam. Portal blood flow significantly decreased in participants with F2-F3 (n = 18, 175 ± 110 mL/100 mL/min) and F4 (n = 12, 98 ± 47 mL/100 mL/min) compared with those in participants with F0-F1 (n = 34, 283 ± 178 mL/100 mL/min, p < 0.05 for all). In participants with F4, the arterial fraction and extracellular volume were significantly higher than those in participants with F0-F1 and F2-F3 (p < 0.05). Compared with HCCs showing non-LR-M features (n = 16), HCCs with LR-M (n = 5) had a significantly prolonged mean transit time and lower arterial blood flow (p < 0.05). CONCLUSIONS: Liver MRI using GRASP obtains both sufficient spatial resolution for confident diagnosis and high temporal resolution for pharmacokinetic modeling. Significant differences were found between the MRI-derived portal blood flow at different hepatic fibrosis stages. KEY POINTS: A single MRI examination is able to provide both images with sufficient spatial resolution for anatomic evaluation and those with high temporal resolution for pharmacokinetic modeling. Portal blood flow was significantly lower in clinically significant hepatic fibrosis and mean transit time and extracellular volume increased in cirrhosis, compared with those in no or mild hepatic fibrosis. HCCs with different LR features showed different quantitative parameters of DCE-MRI: longer mean transit time and lower arterial flow were observed in HCCs with LR-M features.

Hepatectomy risk assessment with functional magnetic resonance imaging (HEPARIM).

BACKGROUND: Post hepatectomy liver failure (PHLF) remains a significant risk in patients undergoing curative liver resection for cancer, however currently available PHLF risk prediction investigations are not sufficiently accurate. The Hepatectomy risk assessment with functional magnetic resonance imaging trial (HEPARIM) aims to establish if quantitative MRI biomarkers of liver function & perfusion can be used to more accurately predict PHLF risk and FLR function, measured against indocyanine green (ICG) liver function test. METHODS: HEPARIM is an observational cohort study recruiting patients undergoing liver resection of 2 segments or more, prior to surgery patients will have both Dynamic Gadoxetate-enhanced (DGE) liver MRI and ICG testing. Day one post op ICG testing is repeated and R15 compared to the Gadoxetate Clearance (GC) of the future liver remnant (FLR-GC) as measure by preoperative DGE- MRI which is the primary outcome, and preoperative ICG R15 compared to GC of whole liver (WL-GC) as a secondary outcome. Data will be collected from medical records, biochemistry, pathology and radiology reports and used in a multi-variate analysis to the value of functional MRI and derive multivariant prediction models for future validation. DISCUSSION: If successful, this test will potentially provide an efficient means to quantitatively assess FLR function and PHLF risk enabling surgeons to push boundaries of liver surgery further while maintaining safe practice and thereby offering chance of cure to patients who would previously been deemed inoperable. MRI has the added benefit of already being part of the routine diagnostic pathway and as such would have limited additional burden on patients time or cost to health care systems. (Hepatectomy Risk Assessment With Functional Magnetic Resonance Imaging - Full Text View - ClinicalTrials.gov , n.d.) TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov NCT04705194 - Registered 12th January 2021 - Retrospectively registered.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (Km,u) of gadoxetate was 106 µM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T.

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 µmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol-1 s-1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.

Validation study of perfusion parameter in hypervascular hepatocellular carcinoma and focal nodular hyperplasia using dynamic susceptibility magnetic resonance imaging with super-paramagnetic iron oxide: comparison with single level dynamic CT arteriography.

BACKGROUND: Dynamic susceptibility contrast MR imaging (DSC-MRI) offers direct evaluation of neo-vascularity. Ferucarbotran does not accumulate in the interstitial space, instead remaining in the intravascular space during early phase imaging. We investigate tracer kinetic analysis with DSC-MRI with ferucarbotran and single level CT during hepatic arteriography (SL-CTHA) in assessment of hypervascular hepatocellular lesions and evaluate the usefulness of DSC-MRI with ferucarbotran. METHODS: Six patients having hypervascular hepatocellular carcinoma (HCC) and 3 patients having focal nodular hyperplasia (FNH) were included in the study. SL-CTHA was performed with the infusion of 3 mL of contrast media at a rate of 1 mL/s and scanned at a rate of 0.8 second per rotation. DSC-MRI was acquired with the echo-planar method at 1.5T system. A total dose of 1.4 mL (0.5 mol Fe/L) of ferucarbotran was used. Ferucarbotran was injected at a rate of 2 mL/s with 40 mL of physiological saline. Imaging was obtained at a temporal resolution of 1.2 or 0.46 seconds in 5 and 4 patients, respectively. For both CT and MRI modalities, a model-free analysis method was used to derive region of interest-based perfusion parameters. Plasma flow, distribution volume (DV) of contrast agent and estimated mean transit time (EMTT) were estimated. RESULTS: A strong correlation was obtained with plasma flow (r=0.8231, P=0.0064) between DSC-MRI and SL-CTHA. No significant correlation was obtained for DV and EMTT between DSC-MRI and SL-CTHA. All perfusion parameters showed no significant difference between SL-CTHA and DSC-MRI in FNH. On the other hand, in HCC, DV and EMTT showed significant differences (P=0.046 and 0.046), and plasma flow showed no significant difference between DSC-MRI and SL-CTHA. CONCLUSIONS: This pilot study demonstrates the possibility of quantitative analysis of liver tumor using superparamagnetic iron oxide (SPIO)-based agent and highlights the potential for SPIO-based agent in more precisely assessing the perfusion characteristic of hypervascular liver tumors than by using extracellular contrast media.

DCE-MRI for Early Prediction of Response in Hepatocellular Carcinoma after TACE and Sorafenib Therapy: A Pilot Study.

OBJECTIVE: Dynamic contrast-enhanced MRI (DCE-MRI) can measure the changes in tumor blood flow, vascular permeability and interstitial and intravascular volume. The objective was to evaluate the efficacy of DCE-MRI in prediction of Barcelona Clinic Liver Cancer (BCLC) staging B or C hepatocellular carcinoma (HCC) response after treatment with transcatheter arterial chemoembolization (TACE) followed by sorafenib therapy. METHODS: Sorafenib was administered four days after TACE of BCLC staging B or C HCC in 11 patients (21 lesions). DCE-MRI was performed with Gd-EOB-DTPA contrast before TACE and three and 10 days after TACE. DCE-MRI acquisitions were taken pre-contrast, hepatic arterial-dominant phase and 60, 120, 180, 240, 330, 420, 510 and 600 seconds post-contrast. Distribution volume of contrast agent (DV) and transfer constant Ktrans were calculated. Patients were grouped by mRECIST after one month or more post-TACE into responders (complete response, partial response) and non-responders (stable disease, progressive disease). RESULTS: DV was reduced in responders at three and 10 days post-TACE (p = 0.008 and p = 0.008 respectively). DV fell in non-responders at three days (p = 0.025) but was not significantly changed from pre-TACE values after sorafenib. Sensitivity and specificity for DV 10 days post-TACE were 88% and 77% respectively. CONCLUSION: DV may be a useful biomarker for early prediction of therapeutic outcome in intermediate HCC.

Renal Cell Carcinoma Perfusion before and after Radiofrequency Ablation Measured with Dynamic Contrast Enhanced MRI: A Pilot Study.

AIM: To investigate if the early treatment effects of radiofrequency ablation (RFA) on renal cell carcinoma (RCC) can be detected with dynamic contrast enhanced (DCE)-MRI and to correlate RCC perfusion with RFA treatment time. MATERIALS AND METHODS: 20 patients undergoing RFA of their 21 RCCs were evaluated with DCE-MRI before and at one month after RFA treatment. Perfusion was estimated using the maximum slope technique at two independent sittings. Total RCC blood flow was correlated with total RFA treatment time, tumour location, size and histology. RESULTS: DCE-MRI examinations were successfully evaluated for 21 RCCs (size from 1.3 to 4 cm). Perfusion of the RCCs decreased significantly (p < 0.0001) from a mean of 203 (±80) mL/min/100 mL before RFA to 8.1 (±3.1) mL/min/100 mL after RFA with low intra-observer variability (r ≥ 0.99, p < 0.0001). There was an excellent correlation (r = 0.95) between time to complete ablation and pre-treatment total RCC blood flow. Tumours with an exophytic location exhibit the lowest mean RFA treatment time. CONCLUSION: DCE-MRI can detect early treatment effects by measuring RCC perfusion before and after RFA. Perfusion significantly decreases in the zone of ablation, suggesting that it may be useful for the assessment of treatment efficacy. Pre-RFA RCC blood flow may be used to predict RFA treatment time.

Dynamic contrast-enhanced MRI measurement of renal function in healthy participants.

Background High repeatability, accuracy, and precision for renal function measurements need to be achieved to establish renal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a clinically useful diagnostic tool. Purpose To investigate the repeatability, accuracy, and precision of DCE-MRI measured renal perfusion and glomerular filtration rate (GFR) using iohexol-GFR as the reference method. Material and Methods Twenty healthy non-smoking volunteers underwent repeated DCE-MRI and an iohexol-GFR within a period of 10 days. Single-kidney (SK) MRI measurements of perfusion (blood flow, Fb) and filtration (GFR) were derived from parenchymal intensity time curves fitted to a two-compartment filtration model. The repeatability of the SK-MRI measurements was assessed using coefficient of variation (CV). Using iohexol-GFR as reference method, the accuracy of total MR-GFR was determined by mean difference (MD) and precision by limits of agreement (LoA). Results SK-Fb (MR1, 345 ± 84; MR2, 371 ± 103 mL/100 mL/min) and SK-GFR (MR1, 52 ± 14; MR2, 54 ± 10 mL/min/1.73 m2) measurements achieved a repeatability (CV) in the range of 15-22%. With reference to iohexol-GFR, MR-GFR was determined with a low mean difference but high LoA (MR1, MD 1.5 mL/min/1.73 m2, LoA [-42, 45]; MR2, MD 6.1 mL/min/1.73 m2, LoA [-26, 38]). Eighty percent and 90% of MR-GFR measurements were determined within ± 30% of the iohexol-GFR for MR1 and MR2, respectively. Conclusion Good repeatability of SK-MRI measurements and good agreement between MR-GFR and iohexol-GFR provide a high clinical potential of DCE-MRI for renal function assessment. A moderate precision in MR-derived estimates indicates that the method cannot yet be used in clinical routine.

Comparison of linear and nonlinear implementation of the compartmental tissue uptake model for dynamic contrast-enhanced MRI.

PURPOSE: Fitting tracer kinetic models using linear methods is much faster than using their nonlinear counterparts, although this comes often at the expense of reduced accuracy and precision. The aim of this study was to derive and compare the performance of the linear compartmental tissue uptake (CTU) model with its nonlinear version with respect to their percentage error and precision. THEORY AND METHODS: The linear and nonlinear CTU models were initially compared using simulations with varying noise and temporal sampling. Subsequently, the clinical applicability of the linear model was demonstrated on 14 patients with locally advanced cervical cancer examined with dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Simulations revealed equal percentage error and precision when noise was within clinical achievable ranges (contrast-to-noise ratio >10). The linear method was significantly faster than the nonlinear method, with a minimum speedup of around 230 across all tested sampling rates. Clinical analysis revealed that parameters estimated using the linear and nonlinear CTU model were highly correlated (ρ ≥ 0.95). CONCLUSION: The linear CTU model is computationally more efficient and more stable against temporal downsampling, whereas the nonlinear method is more robust to variations in noise. The two methods may be used interchangeably within clinical achievable ranges of temporal sampling and noise. Magn Reson Med 77:2414-2423, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

An open source software for analysis of dynamic contrast enhanced magnetic resonance images: UMMPerfusion revisited.

BACKGROUND: Perfusion imaging has become an important image based tool to derive the physiological information in various applications, like tumor diagnostics and therapy, stroke, (cardio-) vascular diseases, or functional assessment of organs. However, even after 20 years of intense research in this field, perfusion imaging still remains a research tool without a broad clinical usage. One problem is the lack of standardization in technical aspects which have to be considered for successful quantitative evaluation; the second problem is a lack of tools that allow a direct integration into the diagnostic workflow in radiology. RESULTS: Five compartment models, namely, a one compartment model (1CP), a two compartment exchange (2CXM), a two compartment uptake model (2CUM), a two compartment filtration model (2FM) and eventually the extended Toft's model (ETM) were implemented as plugin for the DICOM workstation OsiriX. Moreover, the plugin has a clean graphical user interface and provides means for quality management during the perfusion data analysis. Based on reference test data, the implementation was validated against a reference implementation. No differences were found in the calculated parameters. CONCLUSION: We developed open source software to analyse DCE-MRI perfusion data. The software is designed as plugin for the DICOM Workstation OsiriX. It features a clean GUI and provides a simple workflow for data analysis while it could also be seen as a toolbox providing an implementation of several recent compartment models to be applied in research tasks. Integration into the infrastructure of a radiology department is given via OsiriX. Results can be saved automatically and reports generated automatically during data analysis ensure certain quality control.

Factors associated with false-negative cardiovascular magnetic resonance perfusion studies: A Clinical evaluation of magnetic resonance imaging in coronary artery disease (CE-MARC) substudy.

PURPOSE: To examine factors associated with false-negative cardiovascular magnetic resonance (MR) perfusion studies within the large prospective Clinical Evaluation of MR imaging in Coronary artery disease (CE-MARC) study population. Myocardial perfusion MR has excellent diagnostic accuracy to detect coronary heart disease (CHD). However, causes of false-negative MR perfusion studies are not well understood. MATERIALS AND METHODS: CE-MARC prospectively recruited patients with suspected CHD and mandated MR, myocardial perfusion scintigraphy, and invasive angiography. This subanalysis identified all patients with significant coronary stenosis by quantitative coronary angiography (QCA) and MR perfusion (1.5T, T1 -weighted gradient echo), using the original blinded image read. We explored patient and imaging characteristics related to false-negative or true-positive MR perfusion results, with reference to QCA. Multivariate regression analysis assessed the likelihood of false-negative MR perfusion according to four characteristics: poor image quality, triple-vessel disease, inadequate hemodynamic response to adenosine, and Duke jeopardy score (angiographic myocardium-at-risk score). RESULTS: In all, 265 (39%) patients had significant angiographic disease (mean age 62, 79% male). Thirty-five (5%) had false-negative and 230 (34%) true-positive MR perfusion. Poor MR perfusion image quality, triple-vessel disease, and inadequate hemodynamic response were similar between false-negative and true-positive groups (odds ratio, OR [95% confidence interval, CI]: 4.1 (0.82-21.0), P = 0.09; 1.2 (0.20-7.1), P = 0.85, and 1.6 (0.65-3.8), P = 0.31, respectively). Mean Duke jeopardy score was significantly lower in the false-negative group (2.6 ± 1.7 vs. 5.4 ± 3.0, OR 0.34 (0.21-0.53), P < 0.0001). CONCLUSION: False-negative cardiovascular MR perfusion studies are uncommon, and more common in patients with lower angiographic myocardium-at-risk. In CE-MARC, poor image quality, triple-vessel disease, and inadequate hemodynamic response were not significantly associated with false-negative MR perfusion.

Physiological Background of Differences in Quantitative Diffusion-Weighted Magnetic Resonance Imaging Between Acute Malignant and Benign Vertebral Body Fractures: Correlation of Apparent Diffusion Coefficient With Quantitative Perfusion Magnetic Resonance Imaging Using the 2-Compartment Exchange Model.

OBJECTIVE: To test the hypothesis that apparent diffusion coefficient (ADC) in vertebral bone marrow of benign and malignant fractures is related to the volume of the interstitial space, determined with dynamic contrast-enhanced (DCE) magnetic resonance imaging. METHODS: Patients with acute benign (n = 24) and malignant (n = 19) vertebral body fractures were examined at 1.5 T. A diffusion-weighted single-shot turbo-spin-echo sequence (b = 100 to 600 s/mm) and DCE turbo-FLASH sequence were evaluated. Regions of interest were manually selected for each fracture. Apparent diffusion coefficient was determined with a monoexponential decay model. The DCE magnetic resonance imaging concentration-time curves were analyzed using a 2-compartment tracer-kinetic model. RESULTS: Apparent diffusion coefficient showed a significant positive correlation with interstitial volume in the whole study population (Pearson r = 0.66, P < 0.001), as well as in the malignant (Pearson r = 0.64, P = 0.004) and benign (Pearson r = 0.52, P = 0.01) subgroup. A significant correlation between ADC and the permeability-surface area product could be observed when analyzing the whole study population (Spearman rs = 0.40, P = 0.008), but not when separately examining the subgroups. Plasma flow showed a significant correlation with ADC in benign fractures (Pearson r = 0.23, P = 0.03). Plasma volume did not show significant correlations with ADC. CONCLUSIONS: The results support the hypothesis that the ADC of a lesion is inversely correlated to its cellularity. This explains previous observations that ADC is reduced in more malignant lesions.

Fifty Years of Technological Innovation: Potential and Limitations of Current Technologies in Abdominal Magnetic Resonance Imaging and Computed Tomography.

Magnetic resonance imaging (MRI) has become an important modality for the diagnosis of intra-abdominal pathology. Hardware and pulse sequence developments have made it possible to derive not only morphologic but also functional information related to organ perfusion (dynamic contrast-enhanced MRI), oxygen saturation (blood oxygen level dependent), tissue cellularity (diffusion-weighted imaging), and tissue composition (spectroscopy). These techniques enable a more specific assessment of pathologic lesions and organ functionality. Magnetic resonance imaging has thus transitioned from a purely morphologic examination to a modality from which image-based disease biomarkers can be derived. This fits well with several emerging trends in radiology, such as the need to accurately assess response to costly treatment strategies and the need to improve lesion characterization to potentially avoid biopsy. Meanwhile, the cost-effectiveness, availability, and robustness of computed tomography (CT) ensure its place as the current workhorse for clinical imaging. Although the lower soft tissue contrast of CT relative to MRI is a long-standing limitation, other disadvantages such as ionizing radiation exposure have become a matter of public concern. Nevertheless, recent technical developments such as dual-energy CT or dynamic volume perfusion CT also provide more functional imaging beyond morphology.The aim of this article was to review and discuss the most important recent technical developments in abdominal MRI and state-of-the-art CT, with an eye toward the future, providing examples of their clinical utility for the evaluation of hepatic and renal pathologies.

Alterations in anatomic and functional imaging parameters with repeated FDG PET-CT and MRI during radiotherapy for head and neck cancer: a pilot study.

BACKGROUND: The use of imaging to implement on-treatment adaptation of radiotherapy is a promising paradigm but current data on imaging changes during radiotherapy is limited. This is a hypothesis-generating pilot study to examine the changes on multi-modality anatomic and functional imaging during (chemo)radiotherapy treatment for head and neck squamous cell carcinoma (HNSCC). METHODS: Eight patients with locally advanced HNSCC underwent imaging including computed tomography (CT), Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT and magnetic resonance imaging (MRI) (including diffusion weighted (DW) and dynamic contrast enhanced (DCE)) at baseline and during (chemo)radiotherapy treatment (after fractions 11 and 21). Regions of interest (ROI) were drawn around the primary tumour at baseline and during treatment. Imaging parameters included gross tumour volume (GTV) assessment, SUVmax, mean ADC value and DCE-MRI parameters including Plasma Flow (PF). On treatment changes and correlations between these parameters were analysed using a Wilcoxon rank sum test and Pearson's linear correlation coefficient respectively. A p-value <0.05 was considered statistically significant. RESULTS: Statistically significant reductions in GTV-CT, GTV-MRI and GTV-DW were observed between all imaging timepoints during radiotherapy. Changes in GTV-PET during radiotherapy were heterogeneous and non-significant. Significant changes in SUVmax, mean ADC value, Plasma Flow and Plasma Volume were observed between the baseline and the fraction 11 timepoint, whilst only changes in SUVmax between baseline and the fraction 21 timepoint were statistically significant. Significant correlations were observed between multiple imaging parameters, both anatomical and functional; 20 correlations between baseline to the fraction 11 timepoint; 12 correlations between baseline and the fraction 21 timepoints; and 4 correlations between the fraction 11 and fraction 21 timepoints. CONCLUSIONS: Multi-modality imaging during radiotherapy treatment demonstrates early changes (by fraction 11) in both anatomic and functional imaging parameters. All functional imaging modalities are potentially complementary and should be considered in combination to provide multi-parametric tumour assessment, to guide potential treatment adaptation strategies. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015.

Comparison of the Diagnostic Performance of Four Quantitative Myocardial Perfusion Estimation Methods Used in Cardiac MR Imaging: CE-MARC Substudy.

PURPOSE: To compare the diagnostic performance of four tracer kinetic analysis methods to quantify myocardial perfusion from magnetic resonance (MR) imaging cardiac perfusion data sets in terms of their ability to lead to the diagnosis of myocardial ischemia. MATERIALS AND METHODS: The study was approved by the regional ethics committee, and all patients gave written consent. A representative sample of 50 patients with suspected ischemic heart disease was retrospectively selected from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease trial data set. Quantitative myocardial blood flow (MBF) was estimated from rest and adenosine stress MR imaging perfusion data sets by using four established methods. A matching diagnosis of both an inducible defect as assessed with single photon emission computed tomography and a luminal stenosis of 70% or more as assessed with quantitative x-ray angiography was used as the reference standard for the presence of myocardial ischemia. Diagnostic performance was evaluated with receiver operating characteristic (ROC) curve analysis for each method, with stress MBF and myocardial perfusion reserve (MPR) serving as continuous measures. RESULTS: Area under the ROC curve with stress MBF and MPR as the outcome measures, respectively, was 0.86 and 0.92 for the Fermi model, 0.85 and 0.87 for the uptake model, 0.85 and 0.80 for the one-compartment model, and 0.87 and 0.87 for model-independent deconvolution. There was no significant difference between any of the models or between MBF and MPR, except that the Fermi model outperformed the one-compartment model if MPR was used as the outcome measure (P = .02). CONCLUSION: Diagnostic performance of quantitative myocardial perfusion estimates is not affected by the tracer kinetic analysis method used.

Quantitative three-dimensional cardiovascular magnetic resonance myocardial perfusion imaging in systole and diastole.

BACKGROUND: Two-dimensional (2D) perfusion cardiovascular magnetic resonance (CMR) remains limited by a lack of complete myocardial coverage. Three-dimensional (3D) perfusion CMR addresses this limitation and has recently been shown to be clinically feasible. However, the feasibility and potential clinical utility of quantitative 3D perfusion measurements, as already shown with 2D-perfusion CMR and positron emission tomography, has yet to be evaluated. The influence of systolic or diastolic acquisition on myocardial blood flow (MBF) estimates, diagnostic accuracy and image quality is also unknown for 3D-perfusion CMR. The purpose of this study was to establish the feasibility of quantitative 3D-perfusion CMR for the detection of coronary artery disease (CAD) and to compare systolic and diastolic estimates of MBF. METHODS: Thirty-five patients underwent 3D-perfusion CMR with data acquired at both end-systole and mid-diastole. MBF and myocardial perfusion reserve (MPR) were estimated on a per patient and per territory basis by Fermi-constrained deconvolution. Significant CAD was defined as stenosis ≥70% on quantitative coronary angiography. RESULTS: Twenty patients had significant CAD (involving 38 out of 105 territories). Stress MBF and MPR had a high diagnostic accuracy for the detection of CAD in both systole (area under curve [AUC]: 0.95 and 0.92, respectively) and diastole (AUC: 0.95 and 0.94). There were no significant differences in the AUCs between systole and diastole (p values >0.05). At stress, diastolic MBF estimates were significantly greater than systolic estimates (no CAD: 3.21 ± 0.50 vs. 2.75 ± 0.42 ml/g/min, p < 0.0001; CAD: 2.13 ± 0.45 vs. 1.98 ± 0.41 ml/g/min, p < 0.0001); but at rest, there were no significant differences (p values >0.05). Image quality was higher in systole than diastole (median score 3 vs. 2, p = 0.002). CONCLUSIONS: Quantitative 3D-perfusion CMR is feasible. Estimates of MBF are significantly different for systole and diastole at stress but diagnostic accuracy to detect CAD is high for both cardiac phases. Better image quality suggests that systolic data acquisition may be preferable.