Vascular Volume Fraction Research Articles

Homogenization of cortical bone reveals that the organization and shape of pores marginally affect elasticity.

With ageing and various diseases, the vascular pore volume fraction (porosity) in cortical bone increases, and the morphology of the pore network is altered. Cortical bone elasticity is known to decrease with increasing porosity, but the effect of the microstructure is largely unknown, while it has been thoroughly studied for trabecular bone. Also, popular micromechanical models have disregarded several micro-architectural features, idealizing pores as cylinders aligned with the axis of the diaphysis. The aim of this paper is to quantify the relative effects on cortical bone anisotropic elasticity of porosity and other descriptors of the pore network micro-architecture associated with pore number, size and shape. The five stiffness constants of bone assumed to be a transversely isotropic material were measured with resonant ultrasound spectroscopy in 55 specimens from the femoral diaphysis of 29 donors. The pore network, imaged with synchrotron radiation X-ray micro-computed tomography, was used to derive the pore descriptors and to build a homogenization model using the fast Fourier transform (FFT) method. The model was calibrated using experimental elasticity. A detailed analysis of the computed effective elasticity revealed in particular that porosity explains most of the variations of the five stiffness constants and that the effects of other micro-architectural features are small compared to usual experimental errors. We also have evidence that modelling the pore network as an ensemble of cylinders yields biased elasticity values compared to predictions based on the real micro-architecture. The FFT homogenization method is shown to be particularly efficient to model cortical bone.

Measurement of the perfusion fraction in brain tumors with intravoxel incoherent motion MR imaging: validation with histopathological vascular density in meningiomas.

To evaluate the quantification performance of the perfusion fraction (f) measured with intravoxel incoherent motion (IVIM) MR imaging in a comparison with the histological vascular density in meningiomas. 29 consecutive patients with meningioma (59.0 ± 16.8 years old, 8 males and 21 females) who underwent a subsequent surgical resection were examined with both IVIM imaging and a histopathological analysis. IVIM imaging was conducted using a single-shot SE-EPI sequence with 13 b-factors (0, 10, 20, 30, 50, 80, 100, 200, 300, 400, 600, 800, 1000 s mm-2) at 3T. The perfusion fraction (f) was calculated by fitting the IVIM bi-exponential model. The 90-percentile f-value in the tumor region-of-interest (ROI) was defined as the maximum f-value (f-max). Histopathological vascular density (%Vessel) was measured on CD31-immunostainted histopathological specimens. The correlation and agreement between the f-values and %Vessel was assessed. The f-max (15.5 ± 5.5%) showed excellent agreement [intraclass correlation coefficient (ICC) = 0.754] and a significant correlation (r = 0.69, p < 0.0001) with the %Vessel (12.9 ± 9.4%) of the tumors. The Bland-Altman plot analysis showed excellent agreement between the f-max and %Vessel (bias, -2.6%; 95% limits of agreement, from -16.0 to 10.8%). The f-max was not significantly different among the histological subtypes of meningioma. An excellent agreement and a significant correlation were observed between the f-values and %Vessel. The f-value can be used as a noninvasive quantitative imaging measure to directly assess the vascular volume fraction in brain tumors. Advances in knowledge: The f-value measured by IVIM imaging showed a significant correlation and an excellent agreement with the histological vascular density in the meningiomas. The f-value can be used as a noninvasive and quantitative imaging measure to directly assess the volume fraction of capillaries in brain tumors.

Deficiency of α Calcitonin-gene-related peptide impairs peri-implant angiogenesis and osseointegration via suppressive vasodilative activity

Blood supply is essential for the bone healing process to obtain successful osseointegration. α Calcitonin gene-related peptide (αCGRP) is osteoanabolic and is the most potent microvascular vasodilator currently known with validated angiogenic effect in vitro. We previously demonstrated that lentiviral αCGRP overexpression vector system could express the gene effectively to enhance titanium implant osseointegration. In this study, we investigated the effect of αCGRP on peri-implant angiogenesis during healing process in vivo. Based on investigation of blood vessel alteration in the peri-implant region of wild-type mice, we found a reduced angiogenesis alongside a decline in bone-implant contact percentage and bone mass in αCGRP −/− mice. Overexpression of αCGRP could partly rescue the impairment. Alterations were also detected in three-dimensional vascular structural parameters and expression of bone and vessel related genes. The results showed αCGRP increased vascular volume fraction and mean vessel size, as well as spatially relocated vessels approximate to the region of bone formation. And angiogenic and osteogenic genes were significantly upregulated in the transfection and αCGRP+/+ group. These results suggested that αCGRP played a synergic role in angiogenesis and osseointegration, partly as a consequence of its vasodilative activity.

The effects of intravoxel contrast agent diffusion on the analysis of DCE-MRI data in realistic tissue domains.

Quantitative evaluation of dynamic contrast enhanced MRI (DCE-MRI) allows for estimating perfusion, vessel permeability, and tissue volume fractions by fitting signal intensity curves to pharmacokinetic models. These compart mental models assume rapid equilibration of contrast agent within each voxel. However, there is increasing evidence that this assumption is violated for small molecular weight gadolinium chelates. To evaluate the error introduced by this invalid assumption, we simulated DCE-MRI experiments with volume fractions computed from entire histological tumor cross-sections obtained from murine studies. A 2D finite element model of a diffusion-compensated Tofts-Kety model was developed to simulate dynamic T1 signal intensity data. Digitized histology slices were segmented into vascular (vp ), cellular and extravascular extracellular (ve ) volume fractions. Within this domain, Ktrans (the volume transfer constant) was assigned values from 0 to 0.5 min-1 . A representative signal enhancement curve was then calculated for each imaging voxel and the resulting simulated DCE-MRI data analyzed by the extended Tofts-Kety model. Results indicated parameterization errors of -19.1% ± 10.6% in Ktrans , -4.92% ± 3.86% in ve , and 79.5% ± 16.8% in vp for use of Gd-DTPA over 4 tumor domains. These results indicate a need for revising the standard model of DCE-MRI to incorporate a correction for slow diffusion of contrast agent. Magn Reson Med 80:330-340, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Influence of parameter accuracy on pharmacokinetic analysis of hyperpolarized pyruvate.

To explore the effects of noise and error on kinetic analyses of tumor metabolism using hyperpolarized [1-13 C] pyruvate. Numerical simulations were performed to systematically investigate the effects of noise, the number of unknowns, and error in kinetic parameter estimates on kinetic analysis of the apparent rate of chemical conversion from hyperpolarized pyruvate to lactate (kPL ). A pharmacokinetic model with two physical and two chemical pools of hyperpolarized spins was used to generate and analyze the synthetic data. The reproducibility of kPL estimates worsened quickly when peak signal-to-noise ratio for hyperpolarized pyruvate was below approximately 20. The accuracy of kPL estimates was most sensitive to errors in high excitation angles, the vascular blood volume fraction (vb ), and the rate of pyruvate extravasation (kve ), and was least sensitive to errors in the T1 of pyruvate. When vb and/or kve were fit as additional unknowns, the accuracy of kPL estimates suffered, and when the vascular input function of pyruvate was also fit, the reproducibility of kPL estimates worsened. The accuracy and precision of kPL estimates improve substantially for peak signal-to-noise ratio above approximately 20. Accurate estimates of perfusion parameters (combinations of vb , kve , and the pyruvate vascular input function) and transmit calibration at high excitation angles have the greatest effect on the accuracy of kinetic analyses. Magn Reson Med 79:3239-3248, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The vascularization pattern of acellular nerve allografts after nerve repair in Sprague-Dawley rats

Objective: We have demonstrated that angiogenesis in acellular nerve allografts (ANAs) can promote neuroregeneration. The present study aimed to investigate the microvascular regeneration pattern of ANAs in Sprague-Dawley (SD) rats. Methods: Sixty male SD rats were randomly divided into an autologous group and a rat acellular nerve allograft group (rANA), and 10-mm sciatic nerve defects were induced in these rats. On the 7th, 14th and 21st days after surgery, systemic perfusion with Evans Blue (EB) or lead oxide was performed on the rats through carotid intubation. Samples were then collected for gross observation, and the microvessels in the nerves were reconstructed through microscopic CT scans using MIMICS software. The vascular volume fraction (VF, %) and microvessel growth rate (V, mm/d) in both groups were then measured, and 1 month after surgery, NF-200 staining was performed to observe and compare the growth condition of the axons. Results: Early post-operative perfusion with gelatin/EB showed EB permeation around the acellular nerve. Perfusion with gelatin/lead oxide showed that the blood vessels had grown into the allograft from both ends 7 days after the operation. Fourteen days after the operation, the microvessel growth rate of the autologous group was faster than that of the rANA group (0.39 ± 0.17 mm/d vs. 0.26 ± 0.14 mm/d, p < 0.05), and the vascular VF was also higher than that of the rANA group (8.92% ± 1.54% vs. 6.31% ± 1.21%, p < 0.05). Twenty-one days after the operation, the blood vessels at both ends of the allograft had connected to form a microvessel network. The growth rate was not significantly different between the two groups; however, the vascular VF of the autologous group was higher than that of the rANA group (12.18% ± 2.27% vs. 9.92% ± 0.84%, p < 0.05). One month after the operation, the NF-200 fluorescence (IOD) in the autologous group significantly increased compared with that of the rANA group (540,278 ± 17,424 vs. 473,310 ± 14,636, respectively, p < 0.05), suggesting that the results of the repair after nerve injury were significantly better in the autologous group than in the rANA group. Conclusion: Both the autologous nerve and ANAs rely on the permeation of tissue fluids to supply nutrients during the early stage, and microvessel growth mainly starts at both ends of the graft and enters the graft along the long axis. Compared to ANAs, the growth speed of revascularization in autologous nerve grafts was faster, leading to a better outcome in the autologous nerve group.

Effect of low-intensity whole-body vibration on bone defect repair and associated vascularization in mice

Low-intensity whole-body vibration (LIWBV) may stimulate bone healing, but the involvement of vascular ingrowth, which is essential for bone regeneration, has not been well examined. We thus investigated the LIWBV effect on vascularization during early-stage bone healing. Mice aged 13weeks were subjected to cortical drilling on tibial bone. Two days after surgery (day 0), mice were exposed daily to sine-wave LIWBV at 30Hz and 0.1g peak-to-peak acceleration for 20min/day (Vib) or were sham-treated (sham). Following vascular casting with a zirconium-based contrast agent on days 6, 9, or 12 and sacrifice, vascular and bone images were obtained by K-edge subtraction micro-CT using synchrotron lights. Bone regeneration advanced more in the Vib group from days 9 to 12. The vascular volume fraction decreased from days 6 to 9 in both groups; however, from days 9 to 12, it was increased in shams, while it stabilized in the Vib group. The vascular volume fraction tended to be or was smaller in the Vib group on days 6 and 12. The vessel number density was higher on day 9 but lower on day 12 in the Vib group. These results suggest that the LIWBV-promoted bone repair is associated with the modulation of vascularization, but additional studies are needed to determine the causality of this association.

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

The aim of this study was to assess the feasibility of combining dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) with the measurement of the radiofrequency (RF) transmit field B1 and pre-contrast longitudinal relaxation time T10 . A novel approach has been proposed to simultaneously estimate B1 and T10 from a modified DCE-MRI scan that actively encodes the washout phase of the curve with different amounts of T1 and B1 weighting using multiple flip angles and repetition times, hence referred to as active contrast encoding (ACE)-MRI. ACE-MRI aims to simultaneously measure B1 and T10 , together with contrast kinetic parameters, such as the transfer constant Ktrans , interstitial space volume fraction ve and vascular space volume fraction vp . The proposed method was tested using numerical simulations and in vivo studies with mouse models of breast cancer implanted in the flank and mammary fat pad, and glioma in the brain. In the numerical simulation study with a signal-to-noise ratio of 10, both B1 and T10 were estimated accurately with errors of 5.1±3.5% and 12.3±8.8% and coefficients of variation (CV) of 14.9±8.6% and 15.0±5.0%, respectively. Using the same ACE-MRI data, the kinetic parameters Ktrans , ve and vp were also estimated with errors of 14.2±8.3% (CV=13.5±4.6%), 14.7±9.9% (CV=13.3±4.5%) and 14.0±9.3% (CV=14.0±4.5%), respectively. For the in vivo tumor data from 11 mice, voxel-wise comparisons between ACE-MRI and DCE-MRI methods showed that the mean differences for the five parameters were as follows: ΔKtrans =0.006 (/min), Δve =0.016, Δvp =0.000, ΔB1 =-0.014 and ΔT1 =-0.085 (s), which suggests a good agreement between the two methods. When compared with separately measured B1 and T10 , and DCE-MRI estimated kinetic parameters as a reference, the mean relative errors of ACE-MRI estimation were B1 =-0.3%, T10 =-8.5%, Ktrans =11.4%, ve =14.5% and vp =4.5%. This proof-of-concept study demonstrates that the proposed ACE-MRI method can be used to estimate B1 and T10 , together with contrast kinetic model parameters.

Assessment of nonarteritic anterior ischemic optic neuropathy with intravoxel incoherent motion diffusion‐weighted imaging using readout‐segmented echo‐planar imaging, parallel imaging, and 2D navigator‐based reacquisition

To determine the feasibility of intravoxel incoherent motion (IVIM) for characterizing perfusion properties and its potential diagnostic utility for nonarteritic anterior ischemic optic neuropathy (NAION). IVIM diffusion-weighted imaging is a promising technique that can measure perfusion and diffusion characteristics simultaneously in a noninvasive manner. Orbital IVIM in a 3.0T scanner was performed on 33 patients with NAION and 15 controls using readout-segmented echo-planar imaging, parallel imaging, and 2D navigator-based reacquisition (RESOLVE-IVIM). Both visual field (VF) and visual acuity (VA) examinations were performed in 19 of the patients. The vascular volume fraction (f), diffusion coefficient (D), and pseudodiffusion coefficient (D*) were calculated for quantitative analysis. Additionally, correlation analyses of IVIM parameters with visual function were also performed. Affected optic nerves showed significantly lower f values than both unaffected contralateral nerves of the patients and nerves of the controls (P < 0.0001), and no significant difference for f was found between unaffected contralateral nerves and nerves of the controls (P = 0.1602). In addition, D and D* values showed no significant differences among the three groups (P = 0.0979, 0.0600, 0.6136 for D and 0.1779, 0.6253, 0.4743 for D*). Correlation analysis only demonstrated significant correlations between f values and the mean deviation of the visual field (r = 0.576, P = 0.0051). RESOLVE-IVIM measurement may reflect the perfusion abnormality and visual function impairment in NAION patients, demonstrating its potential application for the diagnosis and clinical evaluation of NAION. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1760-1766.

Abstract A23: A finite element model of perfusion and diffusion within tumors based on dynamic contrast enhanced magnetic resonance imaging

Abstract Quantitative analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data provides estimates of physiological parameters that characterize tissue volume fractions, blood flow, and vascular permeability. While it provides a reasonable description of well-vascularized tissue, the standard models do not include the effects of intra-voxel diffusion, which is hypothesized to play a significant role in distributing contrast agent in poorly vascularized voxels1. This mechanism has been studied in silico using simulated tissue regions, but the results have yet to be tested with experimental data. We hypothesize that explicit incorporation of the contrast agent diffusion into the standard models is required to accurately model delivery and retention of the contrast agent within poorly vascularized regions. To investigate the effect of the diffusion of contrast agent within a tumor, nude athymic mice are subcutaneously implanted with BT474 cancer cells, and tumors develop for 4-6 weeks prior to performing DCE-MRI. Following imaging, the tumors are extracted, sectioned, and stained for vascularity (CD31) and viability/cellularity (H&amp;E). Stained central slice sections were digitized in high resolution, segmented in MATLAB (Natick, MA), and a finite element model (FEM) was developed. A population arterial input function (AIF)2 serves as the source of contrast agent delivery into the FEM at the vascular boundaries, while the diffusion equation distributes the contrast agent through the extracellular space. The distribution of contrast agent over time within an imaging voxel is converted from concentration to MR signal intensity, and fit to the extended Tofts model3, providing estimates of vascular permeability and perfusion (Ktrans), extravascular extracellular volume fraction (ve), and vascular volume fraction (vp). These values are then compared to the true tissue volume fractions, determined by tissue segmentation, and an assigned (reasonable) set of Ktrans values. In order to verify the accuracy of the histologically segmented FEM, the simulated DCE-MRI signal is compared to in vivo experimental DCE-MRI scans of the same tumor. Comparison is completed by registering DCE-MRI voxels to simulated voxel domains, and directly measuring the difference between simulated and experimental signal intensities. Using a Ktrans of 0.4 min-1 and a diffusion constant of 3 x 10-5 mm2/s, the extended Tofts model poorly predicts tissue properties, with predicted Ktrans errors ranging from -95% to 68%, ve errors ranging -80% to 13%, and vp errors ranging 32% to 381%. Notably, necrotic regions of the tumor are subject to the highest level of error in the Tofts approximation of these parameters. Each of the maximum absolute prediction errors listed above occur in voxels with a vp value below 0.5% and ve above 80%. In contrast, the Tofts model can more accurately predict vp when the true value is above 5%, and most accurately predicts ve when its true value is below 70%. These results indicate that the lack of a diffusion term in the extended Tofts model can lead to significant errors in the estimates of physiological properties of tumor tissue in vivo. This is especially notable in regions with both a low vp and high ve, where the tissue is necrotic and poorly perfused. These results call for the inclusion of a diffusive term in the analysis of DCE-MRI in order to accurately model and understand contrast agent perfusion in a tumor. By including such a term, the diagnostic and predictive power of Ktrans ¸ vp, and ve, could be further improved. Our ongoing efforts for this research include further refining histology segmentation and model validation by comparing both simulated and measured DCE-MRI signal intensities. 1. Barnes, et al. PLoS One . 2014;9:e108726 2. Loveless, et al. Magn Reson Med . 2012; 67:226-236. 3. Tofts &amp; Kermode. Magn Reson Med . 1991;17:357-367. Citation Format: Ryan T. Woodall, Stephanie L. Eldridge, Anna G. Sorace, Thomas E. Yankeelov. A finite element model of perfusion and diffusion within tumors based on dynamic contrast enhanced magnetic resonance imaging. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A23.

Assessing tumor vascularization as a potential biomarker of imatinib resistance in gastrointestinal stromal tumors by dynamic contrast-enhanced magnetic resonance imaging

BackgroundMost metastatic gastrointestinal stromal tumors (GISTs) develop resistance to the first-line imatinib treatment. Recently, increased vessel density and angiogenic markers were reported in GISTs with a poor prognosis, suggesting that angiogenesis is implicated in GIST tumor progression and resistance. The purpose of this study was to investigate the relationship between tumor vasculature and imatinib resistance in different GIST mouse models using a noninvasive magnetic resonance imaging (MRI) functional approach.MethodsImmunodeficient mice (n = 8 for each cell line) were grafted with imatinib-sensitive (GIST882 and GIST-T1) and imatinib-resistant (GIST430) human cell lines. Dynamic contrast-enhanced MRI (DCE-MRI) was performed on GIST xenografts to quantify tumor vessel permeability (Ktrans) and vascular volume fraction (vp). Microvessel density (MVD), permeability (mean dextran density, MDD), and angiogenic markers were evaluated by immunofluorescence and western blot assays.ResultsDynamic contrast-enhanced magnetic resonance imaging showed significantly increased vessel density (P < 0.0001) and permeability (P = 0.0002) in imatinib-resistant tumors compared to imatinib-sensitive ones. Strong positive correlations were observed between MRI estimates, Ktrans and vp, and their related ex vivo values, MVD (r = 0.78 for Ktrans and r = 0.82 for vp) and MDD (r = 0.77 for Ktrans and r = 0.94 for vp). In addition, higher expression of vascular endothelial growth factor receptors (VEGFR2 and VEFGR3) was seen in GIST430.ConclusionsDynamic contrast-enhanced magnetic resonance imaging highlighted marked differences in tumor vasculature and microenvironment properties between imatinib-resistant and imatinib-sensitive GISTs, as also confirmed by ex vivo assays. These results provide new insights into the role that DCE-MRI could play in GIST characterization and response to GIST treatment. Validation studies are needed to confirm these findings.

Three Dimensional Quantification of Microarchitecture and Vessel Regeneration by Synchrotron Radiation Microcomputed Tomography in a Rat Model of Spinal Cord Injury.

A full understanding of the mechanisms behind spinal cord injury (SCI) processes requires reliable three-dimensional (3D) imaging tools for a thorough analysis of changes in angiospatial architecture. We aimed to use synchrotron radiation μCT (SRμCT) to characterize 3D temporal-spatial changes in microvasculature post-SCI. Morphometrical measurements revealed a significant decrease in vascular volume fraction, vascular bifurcation density, vascular segment density, and vascular connectivity density 1 day post-injury, followed by a gradual increase at 3, 7, and 14 days. At 1 day post-injury, SRμCT revealed an increase in vascular tortuosity (VT), which reached a plateau after 7 days and decreased slightly during the healing process. In addition, SRμCT images showed that vessels were largely concentrated in the gray matter 1 day post-injury. The maximal endothelial cell proliferation rate was detected at 7 days post-injury. The 3D morphology of the cavity appears in the spinal cord at 28 days post-injury. We describe a methodology for 3D analysis of vascular repair in SCI and reveal that endogenous revascularization occurs during the healing process. The spinal cord microvasculature configuration undergoes 3D remodeling and modification during the post-injury repair process. Examination of these processes might contribute to a full understanding of the compensatory vascular mechanisms after injury and aid in the development of novel and effective treatment for SCI.

Nogo-A regulates vascular network architecture in the postnatal brain

Recently, we discovered a new role for the well-known axonal growth inhibitory molecule Nogo-A as a negative regulator of angiogenesis in the developing central nervous system. However, how Nogo-A affected the three-dimensional (3D) central nervous system (CNS) vascular network architecture remained unknown. Here, using vascular corrosion casting, hierarchical, synchrotron radiation μCT-based network imaging and computer-aided network analysis, we found that genetic ablation of Nogo-A significantly increased the three-dimensional vascular volume fraction in the postnatal day 10 (P10) mouse brain. More detailed analysis of the cerebral cortex revealed that this effect was mainly due to an increased number of capillaries and capillary branchpoints. Interestingly, other vascular parameters such as vessel diameter, -length, -tortuosity, and -volume were comparable between both genotypes for non-capillary vessels and capillaries. Taken together, our three-dimensional data showing more vessel segments and branchpoints at unchanged vessel morphology suggest that stimulated angiogenesis upon Nogo-A gene deletion results in the insertion of complete capillary micro-networks and not just single vessels into existing vascular networks. These findings significantly enhance our understanding of how angiogenesis, vascular remodeling, and three-dimensional vessel network architecture are regulated during central nervous system development. Nogo-A may therefore be a potential novel target for angiogenesis-dependent central nervous system pathologies such as brain tumors or stroke.

Prognostic value of preoperative dynamic contrast-enhanced MRI perfusion parameters for high-grade glioma patients.

IntroductionThe prognostic value of the dynamic contrast-enhanced (DCE) MRI perfusion and its histogram analysis-derived metrics is not well established for high-grade glioma (HGG) patients. The aim of this prospective study was to investigate DCE perfusion transfer coefficient (Ktrans), vascular plasma volume fraction (vp), extracellular volume fraction (ve), reverse transfer constant (kep), and initial area under gadolinium concentration time curve (IAUGC) as predictors of progression-free (PFS) and overall survival (OS) in HGG patients.MethodsSixty-nine patients with suspected anaplastic astrocytoma or glioblastoma underwent preoperative DCE-MRI scans. DCE perfusion whole tumor region histogram parameters, clinical details, and PFS and OS data were obtained. Univariate, multivariate, and Kaplan–Meier survival analyses were conducted. Receiver operating characteristic (ROC) curve analysis was employed to identify perfusion parameters with the best differentiation performance.ResultsOn univariate analysis, ve and skewness of vp had significant negative impacts, while kep had significant positive impact on OS (P < 0.05). ve was also a negative predictor of PFS (P < 0.05). Patients with lower ve and IAUGC had longer median PFS and OS on Kaplan–Meier analysis (P < 0.05). Ktrans and ve could also differentiate grade III from IV gliomas (area under the curve 0.819 and 0.791, respectively).ConclusionsHigh ve is a consistent predictor of worse PFS and OS in HGG glioma patients. vp skewness and kep are also predictive for OS. Ktrans and ve demonstrated the best diagnostic performance for differentiating grade III from IV gliomas.

Separation of benign and malignant breast lesions using dynamic contrast enhanced MRI in a biopsy cohort.

To assess the diagnostic utility of contrast kinetic analysis for breast lesions and background parenchyma of women undergoing MRI-guided biopsies, for whom standard clinical analysis had failed to separate benign and malignant lesions. This study included 115 women who had indeterminate lesions based on routine diagnostic breast MRI exams and underwent an MRI (3 Tesla) -guided biopsy of one or more lesions suspicious for breast cancer. Breast dynamic contrast-enhanced (DCE)-MRI was performed using a radial stack-of-stars three-dimensional spoiled gradient echo pulse sequence and modified k-space weighted image contrast image reconstruction. Contrast kinetic model analysis was conducted to characterize the contrast enhancement patterns measured in lesions and background parenchyma (BP). The transfer rate (Ktrans ), interstitial volume fraction (ve ), and vascular volume fraction (vp ) estimated from the lesion and BP were used to separate malignant from benign lesions. The patients with malignant lesions had significantly (P < 0.05) higher median lesion-Ktrans (0.081 min-1 ), higher median BP-Ktrans (0.032 min-1 ), and BP-vp (0.020) than those without malignant lesions (0.056 min-1 , 0.017 min-1 and 0.012, respectively). The area under the receiver operating characteristic curve (AUC) of the BP-Ktrans (0.687) was highest among the single parameters and higher than that of the lesion-Ktrans (0.664). The combined logistic regression model of lesion-Ktrans , lesion-ve , BP-Ktrans , BP-ve , and BP-vp had the highest AUC of 0.730. Our results suggest that the contrast kinetic analysis of DCE-MRI data can be used to differentiate the malignant lesions from the benign and high-risk lesions among the indeterminate breast lesions recommended for MRI-guided biopsy exams. 3 J. MAGN. RESON. IMAGING 2017;45:1385-1393.

Quantification of Hepatic Vascular and Parenchymal Regeneration in Mice.

BackgroundLiver regeneration consists of cellular proliferation leading to parenchymal and vascular growth. This study complements previous studies on cellular proliferation and weight recovery by (1) quantitatively describing parenchymal and vascular regeneration, and (2) determining their relationship. Both together are needed to (3) characterize the underlying growth pattern.MethodsSpecimens were created by injecting a polymerizing contrast agent in either portal or hepatic vein in normal or regenerating livers after 70% partial hepatectomy. 3D image data were obtained through micro-CT scanning. Parenchymal growth was assessed by determining weight and volume of the regenerating liver. Vascular growth was described by manually determined circumscribed parameters (maximal vessel length and radius of right inferior portal/hepatic vein), automatically determined cumulative parameters (total edge length and total vascular volume), and parameters describing vascular density (total edge length/volume, vascular volume fraction). The growth pattern was explored by comparing the relative increase of these parameters to the increase expected in case of isotropic expansion.ResultsLiver volume recovery paralleled weight recovery and reached 90% of the original liver volume within 7 days. Comparing radius-related vascular parameters immediately after surgical resection and after virtual resection in-silico revealed a slight increase, possibly reflecting the effect of resection-induced portal hyperperfusion. Comparing length-related parameters between post-operative day 7 and after virtual resection showed similar vascular growth in both vascular systems investigated. In contrast, radius-related parameters increased slightly more in the portal vein. Despite the seemingly homogeneous 3D growth, the observed vascular parameters were not compatible with the hypothesis of isotropic expansion of liver parenchyma and vascular structures.ConclusionWe present an approach for the quantitative analysis of the vascular systems of regenerating mouse livers. We applied this technique for assessing the hepatic growth pattern. Prospectively, this approach can be used to investigate hepatic vascular regeneration under different conditions.

Functional imaging of the angiogenic switch in a transgenic mouse model of human breast cancer by dynamic contrast enhanced magnetic resonance imaging.

Tumour progression depends on several sequential events that include the microenvironment remodelling processes and the switch to the angiogenic phenotype, leading to new blood vessels recruitment. Non-invasive imaging techniques allow the monitoring of functional alterations in tumour vascularity and cellularity. The aim of this work was to detect functional changes in vascularisation and cellularity through Dynamic Contrast Enhanced (DCE) and Diffusion Weighted (DW) Magnetic Resonance Imaging (MRI) modalities during breast cancer initiation and progression of a transgenic mouse model (BALB-neuT mice). Histological examination showed that BALB-neuT mammary glands undergo a slow neoplastic progression from simple hyperplasia to invasive carcinoma, still preserving normal parts of mammary glands. DCE-MRI results highlighted marked functional changes in terms of vessel permeability (K(trans) , volume transfer constant) and vascularisation (vp , vascular volume fraction) in BALB-neuT hyperplastic mammary glands if compared to BALB/c ones. When breast tissue progressed from simple to atypical hyperplasia, a strong increase in DCE-MRI biomarkers was observed in BALB-neuT in comparison to BALB/c mice (K(trans) = 5.3 ± 0.7E-4 and 3.1 ± 0.5E-4; vp = 7.4 ± 0.8E-2 and 4.7 ± 0.6E-2 for BALB-neuT and BALB/c, respectively) that remained constant during the successive steps of the neoplastic transformation. Consistent with DCE-MRI observations, microvessel counting revealed a significant increase in tumour vessels. Our study showed that DCE-MRI estimates can accurately detect the angiogenic switch at early step of breast cancer carcinogenesis. These results support the view that this imaging approach is an excellent tool to characterize microvasculature changes, despite only small portions of the mammary glands developed neoplastic lesions in a transgenic mouse model.

Stroke assessment with intravoxel incoherent motion diffusion-weighted MRI.

Intravoxel incoherent motion (IVIM) diffusion-weighted MRI can simultaneously measure diffusion and perfusion characteristics in a non-invasive way. This study aimed to determine the potential utility of IVIM in characterizing brain diffusion and perfusion properties for clinical stroke. The multi-b-value diffusion-weighted images of 101 patients diagnosed with acute/subacute ischemic stroke were retrospectively evaluated. The diffusion coefficient D, representing the water apparent diffusivity, was obtained by fitting the diffusion data with increasing high b-values to a simple mono-exponential model. The IVIM-derived perfusion parameters, pseudodiffusion coefficient D*, vascular volume fraction f and blood flow-related parameter fD*, were calculated with the bi-exponential model. Additionally, the apparent diffusion coefficient (ADC) was fitted according to the mono-exponential model using all b-values. The diffusion parameters for the ischemic lesion and normal contralateral region were measured in each patient. Statistical analysis was performed using the paired Student t-test and Pearson correlation test. Diffusion data in both the ischemic lesion and normal contralateral region followed the IVIM bi-exponential behavior, and the IVIM model showed better goodness of fit than the mono-exponential model with lower Akaike information criterion values. The paired Student t-test revealed significant differences for all diffusion parameters (all P < 0.001) except D* (P = 0.218) between ischemic and normal areas. For all patients in both ischemic and normal regions, ADC was significantly positively correlated with D (both r = 1, both P < 0.001) and f (r = 0.541, P < 0.001; r = 0.262, P = 0.008); significant correlation was also found between ADC and fD* in the ischemic region (r = 0.254, P = 0.010). For all pixels within the region of interest from a representative subject in both ischemic and normal regions, ADC was significantly positively correlated with D (both r = 1, both P < 0.001), f (r = 0.823, P < 0.001; r = 0.652, P < 0.001) and fD* (r = 0.294, P < 0.001; r = 0.340, P < 0.001). These findings may have clinical implications for the use of IVIM imaging in the assessment and management of acute/subacute stroke patients. Copyright © 2016 John Wiley & Sons, Ltd.

Abstract B51: Metabolic imaging with hyperpolarized [1-13C]-pyruvate and DCE-MRI

Abstract Purpose: To improve the quality and specificity of metabolic imaging with hyperpolarized pyruvate using prior information from dynamic contrast-enhanced MRI (DCE-MRI). Background: Dynamic nuclear polarization (DNP) and MR spectroscopic imaging of [1-13C]-pyruvate shows tremendous promise for imaging aerobic glycolysis with sensitivity, specificity, and resolution that was previously impossible. Exogeneous, enriched hyperpolarized (HP) pyruvate is injected as a bolus and traverses multiple biological barriers before it is exposed to intracellular enzymes that mediate its fate. Preservation of the spin label through chemical reaction allows visualization of pyruvate and its chemical endpoints (lactate, alanine, and carbon dioxide/bicarbonate). We have previously observed a strong correlation between tumor perfusion and the normalized area under the curve for HP lactate, the chemical endpoint associated with aerobic glycolysis. A pharmacokinetic model of HP substrate evolution that balances physiological accuracy and computational burden includes two physical pools (intravascular/extravascular) and two chemical pools (pyruvate/lactate). In the analytical solution for this model, terms for substrate extravasation and the fractional intravascular volume can be recognized as analogues for KTRANS and Vb that are derived from analysis of DCE-MRI data using the extended Tofts model. Use of these DCE-MRI parameters as prior information could eliminate unknowns in the measurement of HP agents and improve the specificity of quantitative estimates for kPL, the apparent conversion rate for HP pyruvate into lactate. Experimental Procedures: Athymic nude mice bearing orthotopic anaplastic thyroid cancer tumors were anesthetized and scanned using a 7T Biospec small animal MR system (Bruker Biospin Corp.). A dual-tuned 1H/13C volume resonator was used for anatomic imaging and for 13C excitation, and a surface coil was used for 13C detection. HP pyruvate was prepared using a HyperSense DNP system (Oxford Instruments). Dynamic 13C spectroscopic imaging data was acquired using a radial multi-band frequency encoding sequence beginning prior to intravascular administration of HP pyruvate via tail-vein catheter. DCE-MRI data was acquired after HP measurements, using a fast spoiled gradient echo sequence. DCE-MRI data was fit to the extended Tofts model on a pixel-by-pixel basis using software developed in Matlab (The Mathworks). Parametric maps for perfusion and vascular blood volume fraction were resampled to the resolution of HP 13C scans and used as priors in a constrained reconstruction algorithm that enforces consistency between undersampled 13C projection data, the kinetic model, and prior information from 1H MRI. Results: With prior information about extravasation and fractional intravascular blood volume, the constrained reconstruction algorithm needs only solve for a global parameterized vascular input function and values for chemical conversion (kPL) and signal relaxation/loss for each voxel in the imaging volume. Elimination of nuisance parameters with strongly correlated effects reduces the computational burden of constrained reconstruction and clarifies interpretation of changes in biomarkers due to disease progression or response to therapy. Conclusions: The combination of DCE-MRI with constrained reconstruction reduces the number of unknowns in quantitative metabolic imaging using HP pyruvate, eases the computational burden, and decouples correlated effects of perfusion and chemical exchange. Citation Format: James A. Bankson, Christopher M. Walker, Yunyun Chen, Stephen Y. Lai, John D. Hazle. Metabolic imaging with hyperpolarized [1-13C]-pyruvate and DCE-MRI. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B51.

Neovascularization of osteoporotic metaphyseal bone defects: A morphometric micro-CT study

PurposeNeovascularization is essential for bone regeneration in fractures. This study aimed to investigate the microvascular morphology and distribution in the non-injured femur and the neovascularization of the metaphyseal critical size defect in a small animal model of osteoporosis. Materials and methodsFemale rats (n=7) were ovariectomized (OVX) and received a multideficiency diet. Three months after OVX, a 5mm wedge shaped critical size defect was cut at the distal femoral metaphysis and stabilized with a T-shaped mini-plate. After six weeks, the animals were euthanized, and femora were removed and decalcified for micro-CT measurement of fracture neovascularization. ResultsNo fracture healing was observed along the critical size defects. In the non-injured bone, micro-vessel distribution showed a specific pattern, thereby enabling a differentiation between epi-, meta- and diaphysis. Micro-CT based morphometry revealed a significant reduction of the vascular volume fraction as well as the vascular thickness (p<0.001) in the critical size defect compared to the intact contralateral femur. Blood volume related vascular surface (vascular surface/volume) increased significantly (p<0.001). Connectivity density and tissue volume related vascular surface (vascular surface density) did not change significantly. ConclusionsMicro-CT based vascular morphometry demonstrated differences between epi-, meta- and diaphysis in the non-injured bone as well as differences between the critical size defect and the non-injured metaphysis. As angiogenesis is a crucial prerequisite that precedes osteogenesis, our results may influence further evaluation of osteoconductive or osteogenic biomaterials in this small animal model of osteoporosis.