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Abstract The complexity of CT perfusion (CTP) acquisition protocols may limit the availability of target mismatch assessment at resource-limited hospitals. We compared CTP mismatch with a mismatch surrogate generated from a simplified dynamic imaging sequence comprising widely available non-contrast CT (NCCT) and multiphase CT angiography (mCTA). Consecutive patients with anterior circulation acute ischemic stroke who received NCCT, mCTA, and CTP were retrospectively included in this study. An mCTA-perfusion (mCTA-P) dynamic series was formed by co-registering NCCT and mCTA. We simulated an ideal mCTA-P study by down-sampling CTP (dCTP) dynamic images according to mCTA timing. Ischemic core and penumbra volumes were estimated by cerebral blood flow and Tmax thresholding, respectively, on perfusion maps calculated independently for CTP, dCTP, and mCTA-P by deconvolution. Concordance in target mismatch (core

Abstract CTP is an important diagnostic tool in managing patients with acute ischemic stroke, but challenges persist in the agreement of stroke lesion volumes and ischemic core-penumbra mismatch profiles determined with different CTP post-processing software. We investigated a systematic method of calibrating CTP stroke lesion thresholds between deconvolution algorithms using a digital perfusion phantom to improve inter-software agreement of mismatch profiles. Deconvolution-estimated cerebral blood flow (CBF) and Tmax was compared to the phantom ground truth via linear regression for one model-independent and two model-based deconvolution algorithms. Using the clinical standard of model-independent CBF 6 s as reference thresholds for ischemic core and penumbra, respectively, we determined that model-based CBF 6 s were the corresponding calibrated thresholds after accounting for quantitative differences revealed at linear regression. Calibrated thresholds were then validated in 63 patients with large vessel stroke by evaluating agreement (concordance and Cohen’s kappa, κ) between the two model-based and model-independent deconvolution methods in determining mismatch profiles used for clinical decision-making. Both model-based deconvolution methods achieved 95% concordance with model-independent assessment and Cohen’s kappa was excellent (κ = 0.87; 95% confidence interval [CI] 0.72–1.00 and κ = 0.86; 95% CI 0.70–1.00). Our systematic method of calibrating CTP stroke lesion thresholds may help harmonize mismatch profiles determined by different software.

CT perfusion (CTP)-derived quantitative maps of hemodynamic parameters have found important clinical applications in stroke, cancer, and cardiovascular disease. Blood flow, blood volume, transit time, and other perfusion parameters are sensitive markers of pathophysiology with impaired perfusion. This review summarizes the basic principles of CTP including image acquisition, tracer kinetic modeling, deconvolution algorithms, and diagnostic interpretation. The focus is on practical and theoretical considerations for accurate quantitative parametric imaging. Recommended CTP scan parameters to maintain CT number accuracy and optimize radiation dose versus image noise are first reviewed. Tracer kinetic models, which describe how injected contrast material is distributed between blood and the tissue microenvironment by perfusion and bidirectional passive exchange, are then derived. Deconvolution algorithms to solve for hemodynamic parameters of kinetic models are discussed and their quantitative accuracy benchmarked. The applications and diagnostic interpretation of CTP in stroke, cancer, and cardiovascular disease are summarized. Finally, we conclude with a discussion of future directions for CTP research, including radiation dose reduction, new opportunities with novel CT hardware, and emerging diagnostic applications.

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a “harmonized” alongside a “standard” dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

Purpose: The aortic time-enhancement curve obtained from dynamic CT myocardial perfusion imaging can be used to derive the cardiac output (CO) index based on the indicator dilution principle. The objective of this study was to investigate the effect of cardiac phase at which CT myocardial perfusion imaging is triggered on the CO index measurement with this approach. Methods: Electrocardiogram (ECG) gated myocardial perfusion imaging was performed on farm pigs with consecutive cardiac axial scans using a large-coverage CT scanner (Revolution, GE Healthcare) after intravenous contrast administration. Multiple sets of dynamic contrast-enhanced (DCE) cardiac images were reconstructed retrospectively from 30% to 80% R-R intervals with a 5% phase increment. The time-enhancement curve sampled from above the aortic orifice in each DCE image set was fitted with a modified gamma variate function (MGVF). The fitted curve was then normalized to the baseline data point unaffected by the streak artifact emanating from the contrast solution in the right heart chamber. The Stewart–Hamilton equation was used to calculate the CO index based on the integral of the fitted normalized aortic curve, and the results were compared among different cardiac phases. Results: The aortic time-enhancement curves sampled at different cardiac phases were different from each other, especially in the baseline portion of the curve where the effect of streak artifact was prominent. After properly normalizing and denoising with a MGVF, the integrals of the aortic curve were minimally different among cardiac phases (0.228 ± 0.001 Hounsfield Unit × second). The corresponding mean CO index was 4.031 ± 0.028 L/min. There were no statistical differences in either the integral of the aortic curve or CO index among different cardiac phases (p > 0.05 for all phases).

Abstract Purpose Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [18F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images. Methods Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [18F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance. Results [18F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUVLate and a model combining Ki and k4 of [18F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of

Abstract Purpose Identification of the dominant intraprostatic lesion(s) (DILs) can facilitate diagnosis and treatment by targeting biologically significant intra-prostatic foci. A PSMA ligand, [18F]DCFPyL (2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid), is better than choline-based [18F]FCH (fluorocholine) in detecting and localizing DIL because of higher tumour contrast, particularly when imaging is delayed to 1 h post-injection. The goal of this study was to investigate whether the different imaging performance of [18F]FCH and [18F]DCFPyL can be explained by their kinetic behaviour in prostate cancer (PCa) and to evaluate whether DIL can be accurately detected and localized using a short duration dynamic positron emission tomography (PET). Methods 19 and 23 PCa patients were evaluated with dynamic [18F]DCFPyL and [18F]FCH PET, respectively. The dynamic imaging protocol with each tracer had a total imaging time of 22 min and consisted of multiple frames with acquisition times from 10 to 180 s. Tumour and benign tissue regions identified by sextant biopsy were compared using standardized uptake value (SUV) and tracer kinetic parameters from kinetic analysis of time-activity curves. Results For [18F]DCFPyL, logistic regression identified K i and k 4 as the optimal model to discriminate tumour from benign tissue (84.2% sensitivity and 94.7% specificity), while only SUV was predictive for [18F]FCH (82.6% sensitivity and 87.0% specificity). The higher k 3 (binding) of [18F]FCH than [18F]DCFPyL explains why [18F]FCH SUV can differentiate tumour from benign tissue within minutes of injection. Superior [18F]DCFPyL tumour contrast was due to the higher k 4/k 3 (more rapid washout) in benign tissue compared to tumour tissue. Conclusions DIL was detected with good sensitivity and specificity using 22-min dynamic [18F]DCFPyL PET and avoids the need for delayed post-injection imaging timepoints. The dissimilar in vivo kinetic behaviour of [18F]DCFPyL and [18F]FCH could explain their different SUV images. Clinical Trial Registration NCT04009174 (ClinicalTrials.gov).

Abstract Background Stereotactic ablative radiation therapy (SABR) is effective in treating inoperable stage I non-small cell lung cancer (NSCLC), but imaging assessment of response after SABR is difficult. This prospective study aimed to develop a predictive model for true pathologic complete response (pCR) to SABR using imaging-based biomarkers from dynamic [18F]FDG-PET and CT Perfusion (CTP). Methods Twenty-six patients with early-stage NSCLC treated with SABR followed by surgical resection were included, as a pre-specified secondary analysis of a larger study. Dynamic [18F]FDG-PET and CTP were performed pre-SABR and 8-week post. Dynamic [18F]FDG-PET provided maximum and mean standardized uptake value (SUV) and kinetic parameters estimated using a previously developed flow-modified two-tissue compartment model while CTP measured blood flow, blood volume and vessel permeability surface product. Recursive partitioning analysis (RPA) was used to establish a predictive model with the measured PET and CTP imaging biomarkers for predicting pCR. The model was compared to current RECIST (Response Evaluation Criteria in Solid Tumours version 1.1) and PERCIST (PET Response Criteria in Solid Tumours version 1.0) criteria. Results RPA identified three response groups based on tumour blood volume before SABR (BVpre-SABR) and change in SUVmax (ΔSUVmax), the thresholds being BVpre-SABR = 9.3 mL/100 g and ΔSUVmax = − 48.9%. The highest true pCR rate of 92% was observed in the group with BVpre-SABR

Abstract Quantitative measurement of lung perfusion is a promising tool to evaluate lung pathophysiology as well as to assess disease severity and monitor treatment. However, this novel technique has not been adopted clinically due to various technical and physiological challenges; and it is still in the early developmental phase where the correlation between lung pathophysiology and perfusion maps is being explored. The purpose of this research work is to quantify the impact of pulmonary artery occlusion on lung perfusion indices using lung dynamic perfusion CT (DPCT). We performed Lung DPCT in ten anesthetized, mechanically ventilated juvenile pigs (18.6–20.2 kg) with a range of reversible pulmonary artery occlusions (0%, 40–59%, 60–79%, 80–99%, and 100%) created with a balloon catheter. For each arterial occlusion, DPCT data was analyzed using first-pass kinetics to derive blood flow (BF), blood volume (BV) and mean transit time (MTT) perfusion maps. Two radiologists qualitatively assessed perfusion maps for the presence or absence of perfusion defects. Perfusion maps were also analyzed quantitatively using a linear segmented mixed model to determine the thresholds of arterial occlusion associated with perfusion derangement. Inter-observer agreement was assessed using Kappa statistics. Correlation between arterial occlusion and perfusion indices was evaluated using the Spearman-rank correlation coefficient. Our results determined that perfusion defects were detected qualitatively in BF, BV and MTT perfusion maps for occlusions larger than 55%, 80% and 55% respectively. Inter-observer agreement was very good with Kappa scores > 0.92. Quantitative analysis of the perfusion maps determined the arterial occlusion threshold for perfusion defects was 50%, 76% and 44% for BF, BV and MTT respectively. Spearman-rank correlation coefficients between arterial occlusion and normalized perfusion values were strong (− 0.92, − 0.72, and 0.78 for BF, BV and MTT, respectively) and were statically significant (p

ImportanceAccurate monitoring of core body temperature is integral to targeted temperature management (TTM) following cardiac arrest. However, there are no reliable non-invasive methods for monitoring temperature during TTM.ObjectivesWe compared the accuracy and precision of a novel non-invasive Zero-Heat-Flux Thermometer (SpotOn™) to a standard invasive esophageal probe in a cohort of patients undergoing TTM post-cardiac arrest.Design, Setting, and ParticipantsWe prospectively enrolled 20 patients undergoing post-cardiac arrest care in the intensive care units at the London Health Sciences Centre in London, Canada. A SpotOn™ probe was applied on each patient's forehead, while an esophageal temperature probe was inserted, and both temperature readings were recorded at 1-min intervals for the duration of TTM.Main outcomes and MeasuresWe compared the SpotOn™ and esophageal monitors using the Bland–Altman analysis and the Pearson correlation, with accuracy set as a primary outcome. Secondary outcomes included precision and correlation. Bias exceeding 0.1°C and limits of agreement exceeding 0.5°C were considered clinically important.ResultsSixteen (80%) of patients had complete data used in the final analysis. The median (interquartile range) duration of recording was 38 (12–56) h. Compared to the esophageal probe, SpotOn™ had a bias of 0.06 ± 0.45°C and 95% limits of agreement of −0.83 to 0.95°C. The Pearson correlation coefficient was 0.97 (95% confidence interval 0.9663–0.9678), with a two-tailed p < 0.0001.Conclusion and RelevanceThe SpotOn™ is an accurate method that may enable non-invasive monitoring of core body temperature during TTM, although its precision is slightly worse than the predefined 0.5°C when compared to invasive esophageal probe.

Advances in imaging have changed prostate radiotherapy through improved biochemical control from focal boost and improved detection of recurrence. These advances are reviewed in the context of prostate stereotactic body radiation therapy (SBRT) and the ARGOS/CLIMBER trial protocol. ARGOS/CLIMBER will evaluate 1) the safety and feasibility of SBRT with focal boost guided by multiparametric MRI (mpMRI) and 18F-PSMA-1007 PET and 2) imaging and laboratory biomarkers for response to SBRT. To date, response to prostate SBRT is most commonly evaluated using the Phoenix Criteria for biochemical failure. The drawbacks of this approach include lack of lesion identification, a high false-positive rate, and delay in identifying treatment failure. Patients in ARGOS/CLIMBER will receive dynamic 18F-PSMA-1007 PET and mpMRI prior to SBRT for treatment planning and at 6 and 24 months after SBRT to assess response. Imaging findings will be correlated with prostate-specific antigen (PSA) and biopsy results, with the goal of early, non-invasive, and accurate identification of treatment failure.

Introduction: Selective brain cooling can minimize systemic complications associated with whole body cooling but maximize neuroprotection. Recently, we developed a non-invasive, portable and inexpensive system for selectively cooling the brain rapidly and demonstrated its safety and efficacy in porcine models. However, the widespread application of this technique in the clinical setting requires a reliable, non-invasive and accurate method for measuring local brain temperature so that cooling and rewarming rates can be controlled during targeted temperature management. In this study, we evaluate the ability of a zero-heat-flux SpotOn sensor, mounted on three different locations, to measure brain temperature during selective brain cooling in a pig model. Computed Tomography (CT) was used to determine the position of the SpotOn patches relative to the brain at different placement locations. Methods and Results: Experiments were conducted on two juvenile pigs. Body temperature was measured using a rectal temperature probe while brain temperature with an intraparenchymal thermocouple probe. A SpotOn patch was taped to the pig’s head at three different locations: 1-2 cm posterior (Location #1, n=1), central forehead (Location #2, n=1); and 1-2 cm anterior and lateral to the bregma i.e., above the eye on the forehead (Location #3, n=1). This cooling system was able to rapidly cool the brain temperature to 33.7 ± 0.2°C within 15 minutes, and maintain the brain temperature within 33-34°C for 4-6 hours before slowly rewarming to 34.8 ± 1.1°C from 33.7 ± 0.2°C, while maintaining the core body temperature (as per rectal temperature probe) above 36°C. We measured a mean bias of -1.1°C, -0.2°C and 0.7°C during rapid cooling in induction phase, maintenance and rewarming phase, respectively. Amongst the three locations, location #2 had the highest correlation (R2 = 0.8) between the SpotOn sensor and the thermocouple probe. Conclusions: This SBC method is able to tightly control the rewarming rate within 0.52 ± 0.20°C/h. The SpotOn sensor placed on the center of the forehead provides a good measurement of brain temperature in comparison to the invasive needle probe.

Background. The treatment of coronary stenosis is decided by performing high risk invasive surgery to generate the fractional flow reserve diagnostics index, a ratio of distal to proximal pressures in respect of coronary atherosclerotic plaques. Non-invasive methods are a need of the times that necessitate the use of mathematical models of coronary hemodynamic physiology. This study proposes an extensible mathematical description of the coronary vasculature that provides an estimate of coronary fractional flow reserve. Methods. By adapting an existing computational model of human coronary blood flow, the effects of large vessel stenosis and microvascular disease on fractional flow reserve were quantified. Several simulations generated flow and pressure information, which was used to compute fractional flow reserve under several conditions including focal stenosis, diffuse stenosis, and microvascular disease. Sensitivity analysis was used to uncover the influence of model parameters on fractional flow reserve. The model was simulated as coupled non-linear ordinary differential equations and numerically solved using our implicit higher order method. Results. Large vessel stenosis affected fractional flow reserve. The model predicts that the presence, rather than severity, of microvascular disease affects coronary flow deleteriously. Conclusions. The model provides a computationally inexpensive instrument for future in silico coronary blood flow investigations as well as clinical-imaging decision making. A combination of focal and diffuse stenosis appears to be essential to limit coronary flow. In addition to pressure measurements in the large epicardial vessels, diagnosis of microvascular disease is essential. The independence of the index with respect to heart rate suggests that computationally inexpensive steady state simulations may provide sufficient information to reliably compute the index.

Abstract Background Selective brain cooling (SBC) methods could alleviate the complications associated with systemic hypothermia. The authors (MFB, LK, and T-YL) have developed a simple and an effective nasopharyngeal SBC method using a vortex tube. The primary focus of the study is to evaluate the effectiveness of this approach on rabbits and compare it with our previous published finding on piglets, which are mammals without and with a carotid rete, respectively. Methods Experiments were conducted on six rabbits. Body temperature was measured continuously using an esophageal temperature probe while brain temperature was measured with an implanted thermometer. Two successive experiments were performed on each animal. In the first experiment, brain cooling was initiated by blowing room temperature air from the hospital medical air outlet, at a flow rate of 14–15 L/min into both nostrils for 60 min. The second series of measurements and brain cooling was performed in the same manner as the first one but blowing cold air (− 7 °C) at the same flow rate. Results One hour post cooling with room temperature air at a flow rate of 14–15 L/min, the brain temperature was 34.2 ± 1.2 °C which resulted in mean brain cooling rates of 3.7 ± 0.9 °C/h. Brain temperature could be reduced more rapidly at mean rates of 5.2 ± 1.9 °C/h, while the body temperature as measured by the esophageal temperature probe was maintained above 36 °C during cooling and maintaining period. Conclusions We have demonstrated that using the vortex tube allows initial rapid and SBC in rabbits. Moreover, comparing results between piglets and rabbits demonstrates clearly that the lack of a carotid rete does not prevent specific cooling of the brain by means of the nasopharyngeal method.

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.

Abstract The blood-brain barrier (BBB) is integral to maintaining a suitable microenvironment for neurons to function properly. Despite its importance, there are no bedside methods of assessing BBB disruption to help guide management of critical-care patients. The aim of this study was to demonstrate that dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) can quantify the permeability surface-area product (PS) of the BBB. Experiments were conducted in rats in which the BBB was opened by image-guided focused ultrasound. DCE-NIRS data were acquired with two dyes of different molecular weight, indocyanine green (ICG, 67 kDa) and 800CW carboxylate (IRDye, 1166 Da), and PS maps were generated by DCE computer tomography (CT) for comparison. Both dyes showed a strong correlation between measured PS values and sonication power (R2 = 0.95 and 0.92 for ICG and IRDye respectively), and the PS values for IRDye were in good agreement with CT values obtained with a contrast agent of similar molecular weight. These proof-of-principle experiments demonstrate that DCE NIRS can quantify BBB permeability. The next step in translating this method to critical care practice will be to adapt depth sensitive methods to minimize the effects of scalp contamination on NIRS PS values.

Objective: We evaluated the diagnostic accuracy of myocardial blood flow (MBF) and perfusion reserve (MPR) measured from low-dose dynamic contrast-enhanced (DCE) imaging with a whole-heart coverage CT scanner for detecting functionally significant coronary artery disease (CAD). Methods: Twenty one patients with suspected or known CAD had rest and dipyridamole stress MBF measurements with CT and SPECT myocardial perfusion imaging (MPI), and lumen narrowing assessment with coronary angiography (catheter and/or CT based) within 6 weeks. SPECT MBF measurements and coronary angiography were used together as reference to determine the functional significance of coronary artery stenosis. In each CT MPI study, DCE images of the whole heart were acquired with breath-hold using a low-dose acquisition protocol to generate MBF maps. Binomial logistic regression analysis was used to determine the diagnostic accuracy of CT-measured MBF and MPR (ratio of stress to rest MBF) for assessing functionally significant coronary stenosis. Results: Mean stress MBF and MPR in ischemic segments were lower than those in non-ischemic segments (1.37 ± 0.34 vs. 2.14 ± 0.64 ml/min/g; 1.56 ± 0.41 vs. 2.53 ± 0.70; p

Aberrations in brain microcirculation and the associated increase in blood-brain-barrier (BBB) permeability in addition to neuroinflammation and Aβ deposition observed in Alzheimer’s disease (AD) and ischemia have gained considerable attention recently. However, the role of microvascular homeostasis as a pathogenic substrate to disturbed microperfusion as well as an overlapping etiologic mechanism between AD and ischemia has not been thoroughly explored. In this study, we employ temporal histopathology of cerebral vasculature in a rat model of β-amyloid (Aβ) toxicity and endothelin-1 induced-ischemia (ET1) to investigate the panorama of cerebral pathology and the protein expression on d1, d7, and d28 post-injury. The combination of Aβ and ET1 pathological states leads to an alteration in microvascular anatomy, texture, diameter, density, and protein expression, in addition to disturbed vessel-matrix-connections, inter-compartmental water exchange and basement membrane profile within the lesion epicenter localized in the striatum of Aβ+ET1 brains compared to Aβ and ET1 rats. We conclude that the neural microvascular network, in addition to the neural tissue, is not only sensitive to structural deterioration but also serves as an underlying vascular etiology between ischemia and AD pathologies. Such investigation can provide prospects to appreciate the interrelationships between structure and responses of cerebral microvasculature and to provide a venue for vascular remodeling as a new treatment strategy.

Dialysis prolongs life but augments cardiovascular mortality. Imaging data suggests that dialysis increases myocardial blood flow (BF) heterogeneity, but its causes remain poorly understood. A biophysical model of human coronary vasculature was used to explain the imaging observations, and highlight causes of coronary BF heterogeneity. Post-dialysis CT images from patients under control, pharmacological stress (adenosine), therapy (cooled dialysate), and adenosine and cooled dialysate conditions were obtained. The data presented disparate phenotypes. To dissect vascular mechanisms, a 3D human vasculature model based on known experimental coronary morphometry and a space filling algorithm was implemented. Steady state simulations were performed to investigate the effects of altered aortic pressure and blood vessel diameters on myocardial BF heterogeneity. Imaging showed that stress and therapy potentially increased mean and total BF, while reducing heterogeneity. BF histograms of one patient showed multi-modality. Using the model, it was found that total coronary BF increased as coronary perfusion pressure was increased. BF heterogeneity was differentially affected by large or small vessel blocking. BF heterogeneity was found to be inversely related to small blood vessel diameters. Simulation of large artery stenosis indicates that BF became heterogeneous (increase relative dispersion) and gave multi-modal histograms. The total transmural BF as well as transmural BF heterogeneity reduced due to large artery stenosis, generating large patches of very low BF regions downstream. Blocking of arteries at various orders showed that blocking larger arteries results in multi-modal BF histograms and large patches of low BF, whereas smaller artery blocking results in augmented relative dispersion and fractal dimension. Transmural heterogeneity was also affected. Finally, the effects of augmented aortic pressure in the presence of blood vessel blocking shows differential effects on BF heterogeneity as well as transmural BF. Improved aortic blood pressure may improve total BF. Stress and therapy may be effective if they dilate small vessels. A potential cause for the observed complex BF distributions (multi-modal BF histograms) may indicate existing large vessel stenosis. The intuitive BF heterogeneity methods used can be readily used in clinical studies. Further development of the model and methods will permit personalized assessment of patient BF status.

We investigate thermal effects of pulmonary cooling which was induced by cold air through an endotracheal tube via a ventilator on newborn piglets. A mathematical model was initially employed to compare the thermal impact of two different gas mixtures, O2-medical air (1:2) and O2-Xe (1:2), across the respiratory tract and within the brain. Following mathematical simulations, we examined the theoretical predictions with O2-medical air condition on nine anesthetized piglets which were randomized to two treatment groups: 1) control group (n = 4) and 2) pulmonary cooling group (n = 5). Numerical and experimental results using O2-medical air mixture show that brain temperature fell from 38.5 °C and 38.3 °C ± 0.3 °C to 35.7 °C ± 0.9 °C and 36.5 °C ± 0.6 °C during 3 h cooling which corresponded to a mean cooling rate of 0.9 °C/h ± 0.2 °C/h and 0.6 °C/h ± 0.1 °C/h, respectively. According to the numerical results, decreasing the metabolic rate and increasing air velocity are helpful to maximize the cooling effect. We demonstrated that pulmonary cooling by cooling of inhalation gases immediately before they enter the trachea can slowly reduce brain and core body temperature of newborn piglets. Numerical simulations show no significant differences between two different inhaled conditions, i.e., O2-medical air (1:2) and O2-Xe (1:2) with respect to cooling rate.

Hypoxia in solid tumors occurs when metabolic demands in tumor cells surpass the delivery of oxygenated blood. We hypothesize that the 18F-fluorodeoxyglucose (18F-FDG) metabolism and tumor blood flow mismatch would correlate with tumor hypoxia.Liver perfusion computed tomography (CT) and 18F-FDG positron emission tomography (PET) imaging were performed in twelve rabbit livers implanted with VX2 carcinoma. Under CT guidance, a fiber optic probe was inserted into the tumor to measure the partial pressure of oxygen (pO2). Tumor blood flow (BF) and standardized uptake value (SUV) were measured to calculate flow-metabolism ratio (FMR). Tumor hypoxia was further identified using pimonidazole immunohistochemical staining. Pearson correlation analysis was performed to determine the correlation between the imaging parameters and pO2 and pimonidazole staining.Weak correlations were found between blood volume (BV) and pO2 level (r = 0.425, P = 0.004), SUV and pO2 (r = -0.394, P = 0.007), FMR and pimonidazole staining score (r = -0.388, P = 0.031). However, there was stronger correlation between tumor FMR and pO2 level (r = 0.557, P < 0.001).FMR correlated with tumor oxygenation and pimonidazole staining suggesting it may be a potential hypoxic imaging marker in liver tumor.

Vascular endothelial growth factor (VEGF) and other pro-angiogenic growth factors have been investigated to enhance muscle tissue perfusion and repair in Duchenne muscular dystrophy (DMD). Current understanding is limited by a lack of functional data following in vivo delivery of these growth factors. We previously used dynamic contrast-enhanced computed tomography to monitor disease progression in murine models of DMD, but no study to date has utilized this imaging technique to assess vascular therapy in a preclinical model of DMD. In the current study, we locally delivered VEGF and ANG1 alone or in combination to dystrophic hind limb skeletal muscle. Using functional imaging, we found the combination treatment as well as ANG1 alone prevented decline in muscle perfusion whereas VEGF alone had no effect compared to controls. These findings were validated histologically as demonstrated by increased alpha-smooth muscle actin-positive vessels in muscles that received either VEGF+ANG1 or ANG1 alone compared to the sham group. We further show that ANG1 alone slows progression of fibrosis compared to either sham or VEGF treatment. The findings from this study shed new light on the functional effects of vascular therapy and suggest that ANG1 alone may be a candidate therapy in the treatment of DMD.

Purpose: In diabetes, pancreatic beta cell mass declines significantly prior to onset of fasting hyperglycemia. This decline may be due to endoplasmic reticulum (ER) stress, and the system L amino acid transporter LAT1 may be a biomarker of this process. In this study, we used 5-(2-18F-fluoroethoxy)-L-tryptophan (18F-L-FEHTP) to target LAT1 as a potential biomarker of beta cell function in diabetes. Procedures: Uptake of 18F-L-FEHTP was determined in wild-type C57BL/6 mice by ex vivo biodistribution. Both dynamic and static positron emission tomography (PET) images were acquired in wild-type and Akita mice, a model of ER stress-induced diabetes, as well as in mice treated with streptozotocin (STZ). LAT1 expression in both groups of mice was evaluated by immunofluorescence microscopy. Results: Uptake of 18F-L-FEHTP was highest in the pancreas, and static PET images showed highly specific pancreatic signal. Time-activity curves showed significantly reduced 18F-L-FEHTP uptake in Akita mice, and LAT1 expression was also reduced. However, mice treated with STZ, in which beta cell mass was reduced by 62%, showed no differences in 18F-L-FEHTP uptake in the pancreas, and there was no significant correlation of 18F-L-FEHTP uptake with beta cell mass. Conclusions: 18F-L-FEHTP is highly specific for the pancreas with little background uptake in kidney or liver. We were able to detect changes in LAT1 in a mouse model of diabetes, but these changes did not correlate with beta cell function or mass. Therefore, 18F-L-FEHTP PET is not a suitable method for the noninvasive imaging of changes in beta cell function during the progression of diabetes.

INTRODUCTION:The capability of CT perfusion (CTP) Alberta Stroke Program Early CT Score (ASPECTS) to predict outcome and identify ischemia severity in acute ischemic stroke (AIS) patients is still questioned. METHODS:62 patients with AIS were imaged within 8 hours of symptom onset by non-contrast CT, CT angiography and CTP scans at admission and 24 hours. CTP ASPECTS was calculated on the affected hemisphere using cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps by subtracting 1 point for any abnormalities visually detected or measured within multiple cortical circular regions of interest according to previously established thresholds. MTT-CBV ASPECTS was considered as CTP ASPECTS mismatch. Hemorrhagic transformation (HT), recanalization status and reperfusion grade at 24 hours, final infarct volume at 7 days and modified Rankin scale (mRS) at 3 months after onset were recorded. RESULTS:Semi-quantitative and quantitative CTP ASPECTS were highly correlated (p

BACKGROUND:Tumor hypoxia is associated with treatment resistance to cancer therapies. Hypoxia can be investigated by immunohistopathologic methods but such procedure is invasive. A non-invasive method to interrogate tumor hypoxia is an attractive option as such method can provide information before, during, and after treatment for personalized therapies. Our study evaluated the correlations between computed tomography (CT) perfusion parameters and immunohistopathologic measurement of tumor hypoxia. METHODS:Wistar rats, 18 controls and 19 treated with stereotactic radiosurgery (SRS), implanted with the C6 glioma tumor were imaged using CT perfusion on average every five days to monitor tumor growth. A final CT perfusion scan and the brain were obtained on average 14 days (8-22 days) after tumor implantation. Tumor hypoxia was detected immunohistopathologically with pimonidazole. The tumor, necrotic, and pimonidazole-positive areas on histology samples were measured. Percent necrotic area and percent hypoxic areas were calculated. Tumor volume (TV), blood flow (BF), blood volume (BV), and permeability-surface area product (PS) were obtained from the CT perfusion studies. Correlations between CT perfusion parameters and histological parameters were assessed by Spearman's ρ correlation. A Bonferroni-corrected P value < 0.05 was considered significant. RESULTS:BF and BV showed significant correlations with percent hypoxic area ρ = -0.88, P < 0.001 and ρ = -0.81, P < 0.001, respectively, for control animals and ρ = -0.7, P < 0.001 and ρ = -0.6, P = 0.003, respectively, for all animals, while TV and BV were correlated (ρ = -0.64, P = 0.01 and ρ = -0.43, P = 0.043, respectively) with percent necrotic area. PS was not correlated with either percent necrotic or percent hypoxic areas. CONCLUSIONS:Percent hypoxic area provided significant correlations with BF and BV, suggesting that CT perfusion parameters are potential non-invasive imaging biomarkers of tumor hypoxia.

CT Perfusion (CTP) derived cerebral blood flow (CBF) thresholds have been proposed as the optimal parameter for distinguishing the infarct core prior to reperfusion. Previous threshold-derivation studies have been limited by uncertainties introduced by infarct expansion between the acute phase of stroke and follow-up imaging, or DWI lesion reversibility. In this study a model is proposed for determining infarction CBF thresholds at 3hr ischemia time by comparing contemporaneously acquired CTP derived CBF maps to 18F-FFMZ-PET imaging, with the objective of deriving a CBF threshold for infarction after 3 hours of ischemia. Endothelin-1 (ET-1) was injected into the brain of Duroc-Cross pigs (n = 11) through a burr hole in the skull. CTP images were acquired 10 and 30 minutes post ET-1 injection and then every 30 minutes for 150 minutes. 370 MBq of 18F-FFMZ was injected ~120 minutes post ET-1 injection and PET images were acquired for 25 minutes starting ~155-180 minutes post ET-1 injection. CBF maps from each CTP acquisition were co-registered and converted into a median CBF map. The median CBF map was co-registered to blood volume maps for vessel exclusion, an average CT image for grey/white matter segmentation, and 18F-FFMZ-PET images for infarct delineation. Logistic regression and ROC analysis were performed on infarcted and non-infarcted pixel CBF values for each animal that developed infarct. Six of the eleven animals developed infarction. The mean CBF value corresponding to the optimal operating point of the ROC curves for the 6 animals was 12.6 ± 2.8 mL·min-1·100g-1 for infarction after 3 hours of ischemia. The porcine ET-1 model of cerebral ischemia is easier to implement then other large animal models of stroke, and performs similarly as long as CBF is monitored using CTP to prevent reperfusion.

Tumor size is not a reliable marker for the assessment of early antivascular effects of antiangiogenics. In the present study, we used 200-µm in-plane high-resolution dynamic contrast-enhanced computed tomography (DCE-CT) to noninvasively assess the immediate antivascular effects of vandetanib in a subcutaneous human colon cancer (LoVo) xenograft model in nude rats and to investigate correlation between changes in CT perfusion parameters and tumor volume or immunohistochemical end points. At 3 to 4 weeks after LoVo cell implantation, the animal was gavaged with either vandetanib (50 mg/kg) or vehicle twice (22 hours apart) and scanned with a preclinical DCE-CT scanner before (0 hour) and after treatment (24 hours). Quantitative maps of blood flow (BF) and volume (BV) of the tumor were calculated from the acquired DCE-CT images. The rats were divided into nonhypovascular, hypovascular, and combined (regardless of vascularity) groups. In the nonhypovascular group, significant decreases in both tumor BF and BV were observed in the vandetanib-treated rats compared with increases in the vehicle-treated rats. A significant decrease in BV was detected in the vandetanib-treated rats in the combined group as well. No differences in tumor growth, vascular endothelial growth factor expression, microvessel density, or apoptosis were observed between vandetanib- and vehicle-treated rats in all three groups. These results demonstrate that BF and BV imaging biomarkers from DCE-CT imaging can be used for rapid monitoring of immediate (24 hours after) antimicrovascular effects of vandetanib on tumors, even in the absence of significant changes of tumor volume or clinically relevant immunohistochemical end points.

A fluorescein-GLP-1 (7-37) analog was generated to determine GLP-1R distribution in various cell types of the pancreas in both strains of mice and receptor-specific uptake was confirmed by blocking with exendin-4. Biodistribution studies were carried out using 68 Ga-labeled GLP-1 (7-37) peptides in CD1 and C57BL/6 mice. In addition, immunocompromised mice bearing GLP-1R-expressing insulinomas were evaluated by positron emission tomography (PET) imaging and ex vivo biodistribution studies. The optical GLP-1 probe strongly colocalized with immunofluorescence for insulin and glucagon, and more weakly with amylase (exocrine pancreas) and cytokeratin 19 (ductal cells), confirming its application for in situ GLP-1R imaging in various pancreatic cell types. Insulinomas were clearly visualized by in vivo PET. Reducing the peptide positive charge decreased renal retention as well as tumor uptake. Results demonstrate the application of the developed GLP-1 peptide analogues for in situ (optical) and in vivo (PET) imaging of GLP-1R expression.

The therapeutic efficacy of stereotactic radiosurgery for glioblastoma is not well understood, and there needs to be an effective biomarker to identify patients who might benefit from this treatment. This study investigated the efficacy of computed tomography (CT) perfusion imaging as an early imaging biomarker of response to stereotactic radiosurgery in a malignant rat glioma model.Rats with orthotopic C6 glioma tumors received either mock irradiation (controls, N = 8) or stereotactic radiosurgery (N = 25, 12 Gy in one fraction) delivered by Helical Tomotherapy. Twelve irradiated animals were sacrificed four days after stereotactic radiosurgery to assess acute CT perfusion and histological changes, and 13 irradiated animals were used to study survival. Irradiated animals with survival >15 days were designated as responders while those with survival ≤15 days were non-responders. Longitudinal CT perfusion imaging was performed at baseline and regularly for eight weeks post-baseline.Early signs of radiation-induced injury were observed on histology. There was an overall survival benefit following stereotactic radiosurgery when compared to the controls (log-rank P

Uteroplacental insufficiency (UPI)-induced intrauterine growth restriction (IUGR) predisposes individuals to adult visceral obesity. We postulated that low birth weight (LBW) offspring, from UPI-induced IUGR pregnancies, would display a visceral adipose lipogenic molecular signature involving altered gene expression, phosphorylation status of proteins of the lipid synthesis pathway and microRNA (miR) expression profile, occurring in association with increased visceral adiposity. Normal birth weight (NBW) and LBW (obtained by uterine artery ablation) male guinea pig pups were fed a control diet from weaning to 145 days and sacrificed. Despite being lighter at birth, LBW pups displayed body weights similar to NBW offspring at 145 days. At this age, which represents young adulthood, the relative weights of LBW epididymal white adipose tissue (EWAT) and lipid content were increased; which was consistent with adipocyte hypertrophy in the LBW offspring. Additionally, the mRNA expression of lipid synthesis-related genes including acetyl-CoA carboxylase 1 (ACC1), diglyceride acyltransferase 2 (DGAT2) and peroxisome proliferator-activated receptor gamma 1 (PPARγ1), was increased in LBW EWAT. Further, LBW EWAT displayed decreased phospho-ACC (Ser79) and phospho-PPARγ (Ser273) proteins. Moreover, the mRNA expression of hormone-sensitive lipase (HSL) and fatty acid binding protein 4 (FABP4), both involved in promoting adipose lipid storage, was increased in LBW EWAT. Finally, miR-24 and miR-103-2, miRs related to adipocyte development, were both increased in LBW EWAT. These findings indicate that, following an adverse in utero environment, lipid synthesis-related genes and miR expression, along with phosphorylation status of key regulators of lipid synthesis, appear to be chronically altered and occur in association with increased visceral adiposity in young adult IUGR male offspring.