Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function.

The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank-order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level-dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss.

Nanotexaphyrin: One-Pot Synthesis of a Manganese Texaphyrin-Phospholipid Nanoparticle for Magnetic Resonance Imaging.

The discovery and synthesis of novel multifunctional organic building blocks for nanoparticles is challenging. Texaphyrin macrocycles are capable and multifunctional chelators. However, they remain elusive as building blocks for nanoparticles because of the difficulty associated with synthesis of texaphyrin constructs capable of self-assembly. A novel manganese (Mn)-texaphyrin-phospholipid building block is described, along with its one-pot synthesis and self-assembly into a Mn-nanotexaphyrin. This nanoparticle possesses strong resilience to manganese dissociation, structural stability, in vivo bio-safety, and structure-dependent T1 and T2 relaxivities. Magnetic resonance imaging (MRI) contrast enhanced visualization of lymphatic drainage is demonstrated with respect to proximal lymph nodes on the head and neck VX-2 tumors of a rabbit. Synthesis of 17 additional metallo-texaphyrin building blocks suggests that this novel one-pot synthetic procedure for nanotexaphyrins may lead to a wide range of applications in the field of nanomedicines.

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. METHODS: Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. RESULTS: We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. CONCLUSIONS: Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.

MR-guided prostate biopsy for planning of focal salvage after radiation therapy.

PURPOSE: To determine if the integration of diagnostic magnetic resonance (MR) imaging and MR-guided biopsy would improve target delineation for focal salvage therapy in men with prostate cancer. MATERIALS AND METHODS: Between September 2008 and March 2011, 30 men with biochemical failure after radiation therapy for prostate cancer provided written informed consent and were enrolled in a prospective clinical trial approved by the institutional research ethics board. An integrated diagnostic MR imaging and interventional biopsy procedure was performed with a 1.5-T MR imager by using a prototype table and stereotactic transperineal template. Multiparametric MR imaging (T2-weighted, dynamic contrast material-enhanced, and diffusion-weighted sequences) was followed by targeted biopsy of suspicious regions and systematic sextant sampling. Biopsy needle locations were imaged and registered to diagnostic images. Two observers blinded to clinical data and the results of prior imaging studies delineated tumor boundaries. Area under the receiver operating characteristic curve (Az) was calculated based on generalized linear models by using biopsy as the reference standard to distinguish benign from malignant lesions. RESULTS: Twenty-eight patients were analyzed. Most patients (n = 22) had local recurrence, with 82% (18 of 22) having unifocal disease. When multiparametric volumes from two observers were combined, it increased the apparent overall tumor volume by 30%; however, volumes remained small (mean, 2.9 mL; range, 0.5-8.3 mL). Tumor target boundaries differed between T2-weighted, dynamic contrast-enhanced, and diffusion-weighted sequences (mean Dice coefficient, 0.13-0.35). Diagnostic accuracy in the identification of tumors improved with a multiparametric approach versus a strictly T2-weighted or dynamic contrast-enhanced approach through an improvement in sensitivity (observer 1, 0.65 vs 0.35 and 0.44, respectively; observer 2, 0.82 vs 0.64 and 0.53, respectively; P < .05) and improved further with a 5-mm expansion margin (Az = 0.85 vs 0.91 for observer 2). After excluding three patients with fewer than six informative biopsy cores and six patients with inadequately stained margins, MR-guided biopsy enabled more accurate delineation of the tumor target volume be means of exclusion of false-positive results in 26% (five of 19 patients), false-negative results in 11% (two of 19 patients) and by guiding extension of tumor boundaries in 16% (three of 19 patients). CONCLUSION: The integration of guided biopsy with diagnostic MR imaging is feasible and alters delineation of the tumor target boundary in a substantial proportion of patients considering focal salvage.

Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition.

To test the effects of hedgehog (Hh) pathway inhibition on the stroma of orthotopically grown primary pancreatic cancer xenografts, and investigate the potential to monitor these effects non-invasively using magnetic resonance imaging (MRI), mice bearing orthotopically grown primary pancreatic cancer xenografts were treated with the Hh neutralizing antibody 5E1. Pathway inhibition was determined by RT-PCR using primer sets for human and mouse Hh pathway genes, and effects on stroma assessed by automated image analysis of tissue sections stained for collagen and α-smooth muscle actin (αSMA). MRI provided quantitative biomarkers of stromal density based on magnetization transfer (MT-MRI) and dynamic contrast enhancement (DCE-MRI). Modest growth inhibition was seen in both models tested using 5E1, but was greater in OCIP19, which showed high expression of mouse Hh pathway genes and an extensive fibrous stroma. However, despite profound inhibition of both mouse and human Hh pathway genes, in neither model did we observe depletion of the stroma. Alignment of MT-MRI ratio images to histological sections showed co-registration with areas of fibrosis, although this was confounded by the presence of tumor necrosis. Due to the lack of stromal depletion by 5E1 it was not possible to determine the utility of MT-MRI for monitoring this effect. Cancer- and stromal cell-derived Hh signaling elements are expressed in orthotopic primary pancreatic cancer xenografts, and selective targeting is growth-inhibitory. In contrast to some recent reports, growth inhibition does not involve attenuation of the tumor stroma, pointing to additional effects of Hh signaling in pancreatic cancer.

Changes in apparent diffusion coefficient and T2 relaxation during radiotherapy for prostate cancer.

PURPOSE: To evaluate regional and temporal changes in apparent diffusion coefficient (ADC) and T2 relaxation during radiation therapy (RT) in patients with low and intermediate risk localized prostate cancer. MATERIALS AND METHODS: Seventeen patients enrolled on a prospective clinical trial where MRI was acquired every 2 weeks throughout eight weeks of image-guided prostate IMRT (78 Gy/39 fractions). ADC and T2 quantification used entire prostate, central gland, benign peripheral zone, and tumor-dense regions-of-interest, and mean values were evaluated for common response trends. RESULTS: Overall, the RT responses were greater than volunteer measurement repeatability, and week 6 appeared to be an optimum time-point for early detection. RT effects on the entire prostate were best detected using ADC (5-7% by week 2, P < 0.0125), effects on peripheral zone were best detected using T2 (19% reduction at week 6; P = 0.004) and effects on tumors were best detected using ADC (14% elevation at week 6; P = 0.004). CONCLUSION: ADC and T2 may be candidate biomarkers of early response to RT warranting further investigation against clinical outcomes.

Brain-Penetrating and Disease Site-Targeting Manganese Dioxide-Polymer-Lipid Hybrid Nanoparticles Remodel Microenvironment of Alzheimer's Disease by Regulating Multiple Pathological Pathways.

Finding effective disease-modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well-characterized mouse model of Alzheimer's disease. The application of brain-penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid ß plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging-based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid ß. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease-modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

Human aortic endothelial cell labeling with positive contrast gadolinium oxide nanoparticles for cellular magnetic resonance imaging at 7 Tesla.

Positive T1 contrast using gadolinium (Gd) contrast agents can potentially improve detection of labeled cells on magnetic resonance imaging (MRI). Recently, gadolinium oxide (Gd2O3) nanoparticles have shown promise as a sensitive T1 agent for cell labeling at clinical field strengths compared to conventional Gd chelates. The objective of this study was to investigate Gado CELLTrack, a commercially available Gd2O3 nanoparticle, for cell labeling and MRI at 7 T. Relaxivity measurements yielded r1  =  4.7 s⁻¹ mM⁻¹ and r2/r1  =  6.2. Human aortic endothelial cells were labeled with Gd2O3 at various concentrations and underwent MRI from 1 to 7 days postlabeling. The magnetic resonance relaxation times T1 and T2 of labeled cell pellets were measured. Cellular contrast agent uptake was quantified by inductively coupled plasma-atomic emission spectroscopy, which showed very high uptake compared to conventional Gd compounds. MRI demonstrated significant positive T1 contrast and stable labeling on cells. Enhancement was optimal at low Gd concentrations, attained in the 0.02 to 0.1 mM incubation concentration range (corresponding cell uptake was 7.26 to 34.1 pg Gd/cell). Cell viability and proliferation were unaffected at the concentrations tested and up to at least 3 days postlabeling. Gd2O3 is a promising sensitive and stable positive contrast agent for cellular MRI at 7 T.

Quasi-static magnetic resonance elastography at 7 T to measure the effect of pathology before and after fixation on tissue biomechanical properties.

Evaluation of imaging for cancer detection and localization can be achieved by correlation of gold-standard histopathology with imaging data. Usage of a 3D biomechanical-based deformable registration for correlation of the histopathology of whole-tissue specimens with ex vivo imaging necessitates measurement of the distribution of biomechanical properties in the ex vivo tissue specimen and changes that occur during pathology fixation. To measure high-resolution 3D distributions of Young's modulus (E) prefixation and postfixation, a quasi-static magnetic resonance elastography method was developed at 7 T. Use of echo-planar imaging allowed for shorter imaging times, in line with limited time frames allowable for pathology specimens. The finite element modeling algorithm produced voxel-wise E measures, and mechanical indentation was used for comparison. An initial preclinical evaluation with canine prostate specimens (n = 5) demonstrated a consistent increase in E with fixation (P < 0.002) by a factor of 4 (± 1). Increases were a function of distance from the tissue edge and correlated with fixation time (ρ = 1, P < 0.02). The technique will be used to generate population-averaged data of E from clinical ex vivo specimens prefixation and postfixation to inform registration of whole-mount histopathology with in vivo imaging.

A novel technique to enable experimental validation of deformable dose accumulation.

PURPOSE: To propose a novel technique to experimentally validate deformable dose algorithms by measuring 3D dose distributions under the condition of deformation using deformable gel dosimeters produced by a novel gel fabrication method. METHOD: Five gel dosimeters, two rigid control gels and three deformable gels, were manufactured and treated with the same conformal plan that prescribed 400 cGy to the isocenter. The control gels were treated statically; the deformable gels were treated while being compressed by an actuation device to simulate breathing motion (amplitude of compression = 1, 1.5, and 2 cm, respectively; frequency = 16 rpm). Comparison between the dose measured by the control gels and the corresponding static dose distribution calculated in the treatment planning system (TPS) has determined the intrinsic dose measurement uncertainty of the gel dosimeters. Doses accumulated using MORFEUS, a biomechanical model-based deformable registration and dose accumulation algorithm, were compared with the doses measured by the deformable gel dosimeters to verify the accuracy of MORFEUS using dose differences at each voxel as well as the gamma index test. Flexible plastic wraps were used to contain and protect the deformable gels from oxygen infiltration, which inhibits the gels' dose sensitizing ability. Since the wraps were imperfect oxygen barrier, dose comparison between MORFEUS and the deformable gels was performed only in the central region with a received dose of 200 cGy or above to exclude the peripheral region where oxygen penetration had likely affected dose measurements. RESULTS: Dose measured with the control gels showed that the intrinsic dose measurement uncertainty of the gel dosimeters was 11.8 cGy or 4.7% compared to the TPS. The absolute mean voxel-by-voxel dose difference between the accumulated dose and the dose measured with the deformable gels was 4.7 cGy (SD = 36.0 cGy) or 1.5% (SD = 13.4%) for the three deformable gels. The absolute mean vector distance between the 250, 300, 350, and 400 cGy isodose surfaces on the accumulated and measured distributions was 1.2 mm (SD < 1.5 mm). The gamma index test that used the dose measurement precision of the control gels as the dose difference criterion and 2 mm as the distance criterion was performed, and the average pass rate of the accumulated dose distributions for all three deformable gels was 92.7%. When the distance criterion was relaxed to 3 mm, the average pass rate increased to 96.9%. CONCLUSION: This study has proposed a novel technique to manufacture deformable volumetric gel dosimeters. By comparing the doses accumulated in MORFEUS and the doses measured with the dosimeters under the condition of deformation, the study has also demonstrated the potential of using deformable gel dosimetry to experimentally validate algorithms that include deformations into dose computation. Since dose less than 200 cGy was not evaluated in this study, future investigations will focus more on low dose regions by either using bigger gel dosimeters or prescribing a lower dose to provide a more complete experimental validation of MORFEUS across a wider dose range.

Time-course assessment of 3D-image distortion on the 1.5 T Marlin/Elekta Unity MR-LINAC.

PURPOSE: The efficacy of MR-guided radiotherapy on a MR-LINAC (MR-L) is dependent on the geometric accuracy of its MR images over clinically relevant Fields-of-View (FOVs). Our objectives were to: evaluate gradient non-linearity (GNL) on the Elekta Unity MR-L across time via 76 weekly measurements of 3D-distortion over concentrically larger diameter spherical volumes (DSVs); quantify distortion measurement error; and assess the temporal stability of spatial distortion using statistical process control (SPC). METHODS: MR-image distortion was assessed using a large-FOV 3D-phantom containing 1932 markers embedded in seven parallel plates, spaced 25 mm × 25 mm in- and 55 mm through-plane. Automatically analyzed T1 images yielded distortions in 200, 300, 400 and 500 mm concentric DSVs. Distortion measurement error was evaluated using median absolute difference analysis of imaging repeatability tests. RESULTS: Over the measurement period absolute time-averaged distortion varied between: dr = 0.30 - 0.49 mm, 0.53 - 0.80 mm, 1.0 - 1.4 mm and 2.28 - 2.37 mm, for DSVs 200, 300, 400 and 500 mm at the 98th percentile level. Repeatability tests showed that imaging/repositioning introduces negligible error: mean ≤ 0.02 mm (max ≤ 0.3 mm). SPC analysis showed image distortion was stable across all DSVs; however, noticeable changes in GNL were observed following servicing at the one-year mark. CONCLUSIONS: Image distortion on the MR-L is in the sub-millimeter range for DSVs ≤ 300 mm and stable across time, with SPC analysis indicating all measurements remain within control for each DSV.

Bridging the macro to micro resolution gap with angiographic optical coherence tomography and dynamic contrast enhanced MRI.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is emerging as a valuable tool for non-invasive volumetric monitoring of the tumor vascular status and its therapeutic response. However, clinical utility of DCE-MRI is challenged by uncertainty in its ability to quantify the tumor microvasculature ([Formula: see text] scale) given its relatively poor spatial resolution (mm scale at best). To address this challenge, we directly compared DCE-MRI parameter maps with co-registered micron-scale-resolution speckle variance optical coherence tomography (svOCT) microvascular images in a window chamber tumor mouse model. Both semi and fully quantitative (Toft's model) DCE-MRI metrics were tested for correlation with microvascular svOCT biomarkers. svOCT's derived vascular volume fraction (VVF) and the mean distance to nearest vessel ([Formula: see text]) metrics were correlated with DCE-MRI vascular biomarkers such as time to peak contrast enhancement ([Formula: see text] and [Formula: see text] respectively, [Formula: see text] for both), the area under the gadolinium-time concentration curve ([Formula: see text] and [Formula: see text] respectively, [Formula: see text] for both) and [Formula: see text] ([Formula: see text] and [Formula: see text] respectively, [Formula: see text] for both). Several other correlated micro-macro vascular metric pairs were also noted. The microvascular insights afforded by svOCT may help improve the clinical utility of DCE-MRI for tissue functional status assessment and therapeutic response monitoring applications.

Prostate T(1) quantification using a magnetization-prepared spiral technique.

PURPOSE: To adapt a magnetization-prepared spiral imaging technique, termed T1prep, for time-efficient radiofrequency (RF)-insensitive prostate T(1) quantification at 1.5 T and evaluate signal-to-noise ratio (SNR) limits to voxel-based versus subregion analysis. MATERIALS AND METHODS: A magnetization-prepared spiral imaging technique was adapted for robust T(1) contrast development, multislice imaging within 5 minutes, and data regression to a monoexponential decay. In vitro testing evaluated RF insensitivity of the multislice acquisition plus method accuracy. A pilot study was performed in 15 patients with low or intermediate risk localized prostate cancer. RESULTS: The multislice design displayed excellent RF insensitivity (<1% error for RF mistunings to ± 20%) and accuracy (within 3% of gold standard for T(1) values between 140 and 2100 msec). A clinical pilot study reported significantly reduced T(1) from PZ to CG to tumor subregions (PZ: 1421 ± 168 msec, n = 11; CG: 1314 ± 49 msec, n = 13; 1246 ± 68 msec, n = 8). SNR measurements identified an inappropriateness of voxel-based analysis. CONCLUSION: T1prep can quantify prostate T(1) as an adjunct measure for quantitative perfusion measurements and longitudinal treatment response monitoring. Intrapatient heterogeneities support T(1) assessment within individual patients. SNR calculations will support a transition to voxel-based analysis in future trials.

Long-term tracking of bone marrow progenitor cells following intracoronary injection post-myocardial infarction in swine using MRI.

Magnetic resonance imaging (MRI) can track progenitor cells following direct intramyocardial injection. However, in the vast majority of post-myocardial infarction (MI) clinical trials, cells are delivered by the intracoronary (IC) route, which results in far greater dispersion within the myocardium. Therefore, we assessed whether the more diffuse distribution of cells following IC delivery could be imaged longitudinally with MRI. In 11 pigs (7 active, 4 controls), MI was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Seven (0) days [median (interquartile range)] following MI, bone marrow progenitor cells (BMCs) were colabeled with an iron-fluorophore and a cell viability marker and delivered to the left anterior descending coronary artery distal to an inflated over-the-wire percutaneous transluminal coronary angioplasty balloon. T2*-weighted images were used to assess the location of the magnetically labeled cells over a 6-wk period post-MI. Immediately following cell delivery, hypointensity characteristic of the magnetic label was observed in the infarct border rather than within the infarct itself. At 6 wk, the cell signal hypointensity persisted, albeit with significantly decreased intensity. BMC delivery resulted in significant improvement in infarct volume and ejection fraction (EF): infarct volume in cell-treated animals decreased from 7.1 +/- 1.5 to 4.9 +/- 1.0 ml (P < 0.01); infarct volume in controls was virtually unchanged at 4.64 +/- 2.1 to 4.39 +/- 2.1 ml (P = 0.7). EF in cell-treated animals went from 30.4 +/- 5.2% preinjection to 34.5 +/- 2.5% 6 wk postinjection (P = 0.013); EF in control animals went from 34.3 +/- 4.7 to 31.9 +/- 6.8% (P = 0.5). Immunohistochemical analysis revealed intracellular colocalization of the iron fluorophore and cell viability dye with the labeled cells continuing to express the same surface markers as at baseline. MRI can track the persistence and distribution of magnetically labeled BMCs over a 6-wk period following IC delivery. Signal hypointensity declines with time, particularly in the first week following delivery. These cells maintain their original phenotype during this time course. Delivery of these cells appears safe and results in improvement in infarct size and left ventricular ejection fraction.

Clinical prostate T2 quantification using magnetization-prepared spiral imaging.

T(2) quantification may augment diagnostic T(2)-weighted imaging; to improve cancer detection via auto-segmentation of multi-parametric acquisitions and to potentiate longitudinal studies of prostate cancer. However, robust quantitative techniques are not generally accessible or refined for clinical translation. This research describes the adaptation of a magnetization-prepared spiral imaging technique, termed T2prep for prostate application, providing whole gland coverage within a 5-min interval with considerable insensitivity to radio-frequency (RF) inhomogeneities. Clinical piloting in two cohorts with distinct clinical histories demonstrated the anticipated differences in zonal and tumor T(2), including tumor T(2) shortening compared to peripheral zone, and post-radiotherapy shortening of peripheral zone T(2). SNR calculations were performed for data acquired with or without an endo-rectal coil in tandem with a torso phased array, to judge the potential for voxel-based T(2) mapping and thereby support focal biological characterization of cancer, hypoxia, and response to therapy within regions of dense cancer burden.

Technical note: fiducial markers for correlation of whole-specimen histopathology with MR imaging at 7 tesla.

PURPOSE: There is increasing interest in the registration of 3-D histopathology with 3-D in vivo imaging, for example, to validate tumor boundary delineation for targeted radiation cancer therapy. However, accurate correlation is compromised by tissue distortion induced by histopathological processing. Reference landmarks that are visible in both data sets are required. In this study, two iridescent acrylic paints, "Bronze" (containing iron oxide coated mica particles) and "Stainless Steel" (containing iron, chromium, and nickel), were evaluated for creating MRI-visible and histology-visible fiducial markers at 7 T, where resolution is more similar to histology, but artifacts are accentuated. Furthermore, a straight-line paint-track fiducial method was developed to assist in registration and 3-D histopathology reconstruction. METHODS: First, the paints were injected into ex vivo porcine tissue samples, which were MR imaged prefixation and postfixation, and subsequently prepared for hematoxylin and eosin staining to verify stability through histopathological processing. Second, the severity of marker susceptibility artifacts produced was compared while using spin-echo and gradient-echo MRI pulse sequences. Finally, multiple paint tracks were injected prefixation through an ex vivo canine prostate sample to validate the potential for line-based registration between MR images of prefixation and postfixation tissue and whole mount histology slides. RESULTS: The Stainless Steel paint produced excessive susceptibility artifacts and image distortion, while the Bronze paint created stable and appropriate markers in MRI and histology. The Bronze paint produced artifacts approximately three times larger in gradient-echo than in spin-echo MR images. Finally, the paint-track fiducials were visible in the prefixation and postfixation MRI and on whole mount histology. CONCLUSIONS: The Bronze iridescent acrylic paint is appropriate for fiducial marker creation in MRI at 7 T. The straight-line paint-track fiducials may assist 3-D histopathology reconstruction and can provide important information on the deformation effects of fixation, and hence may improve registration accuracy.

Sensitivity of radiomic features to inter-observer variability and image pre-processing in Apparent Diffusion Coefficient (ADC) maps of cervix cancer patients.

PURPOSE: The aims of this study are to evaluate the stability of radiomic features from Apparent Diffusion Coefficient (ADC) maps of cervical cancer with respect to: (1) reproducibility in inter-observer delineation, and (2) image pre-processing (normalization/quantization) prior to feature extraction. MATERIALS AND METHODS: Two observers manually delineated the tumor on ADC maps derived from pre-treatment diffusion-weighted Magnetic Resonance imaging of 81 patients with FIGO stage IB-IVA cervical cancer. First-order, shape, and texture features were extracted from the original and filtered images considering 5 different normalizations (four taken from the available literature, and one based on urine ADC) and two different quantization techniques (fixed-bin widths from 0.05 to 25, and fixed-bin count). Stability of radiomic features was assessed using intraclass correlation coefficient (ICC): poor (ICC < 0.75); good (0.75 ≤ ICC ≤ 0.89), and excellent (ICC ≥ 0.90). Dependencies of the features with tumor volume were assessed using Spearman's correlation coefficient (ρ). RESULTS: The approach using urine-normalized values together with a smaller bin width (0.05) was the most reproducible (428/552, 78% features with ICC ≥ 0.75); the fixed-bin count approach was the least (215/552, 39% with ICC ≥ 0.75). Without normalization, using a fixed bin width of 25, 348/552 (63%) of features had an ICC ≥ 0.75. Overall, 26% (range 25-30%) of the features were volume-dependent (ρ ≥ 0.6). None of the volume-independent shape features were found to be reproducible. CONCLUSION: Applying normalization prior to features extraction increases the reproducibility of ADC-based radiomics features. When normalization is applied, a fixed-bin width approach with smaller widths is suggested.

Noninvasive quantitative measurement of myocardial and whole-body oxygen consumption using MRI: initial results.

The purpose of this study was to investigate the feasibility of a noninvasive approach that combines magnetic resonance imaging (MRI) oximetry and flow measurement to obtain the oxygen consumption in the myocardium and in the whole body. Thirteen healthy male volunteers [mean (+/-S.D.) age: 35+/-7 years] underwent this MR study, which included myocardial oxygen consumption (MVO(2)) measurements in 11 subjects and whole-body oxygen consumption (VO(2)) measurements in 8 subjects. In six subjects, both measurements were obtained. Five subjects had repeated MRI measurements of global MVO(2) in order to verify the reproducibility of this approach. The protocol included in vitro blood sample T(2)-%O(2) calibration, coronary sinus (CS) and main pulmonary artery (MPA) T(2) and phase contrast flow measurement and left ventricular (LV) mass calculation. Based on Fick's law, a global measurement of LV MVO(2) and whole-body VO(2) using MRI was feasible. The MVO(2) values were 11+/-3 ml/min per 100 g LV mass. For repeated measurements, differences in MVO(2) of 1 ml/min per 100 g LV mass appear detectable. The whole-body VO(2) values were 3.8+/-0.8 ml/min/kg body weight. MRI techniques that combine CS and MPA T(2), flow and LV mass measurements to quantify MVO(2) and whole-body VO(2) noninvasively in healthy subjects appear feasible, based on their correspondence to previously published work.

Changes in apparent diffusion coefficient radiomics features during dose-painted radiotherapy and high dose rate brachytherapy for prostate cancer.

BACKGROUND AND PURPOSE: Dose escalation has improved cancer outcomes for patients with localized prostate cancer. Targeting subprostatic tumor regions for dose intensification may further improve outcomes. Apparent Diffusion Coefficient (ADC) maps may enable early radiation response assessment and dose adaptation. This study was a proof-of-principle investigation of early changes in ADC radiomics features for patients undergoing radiotherapy with dose escalation to the gross tumor volume (GTV). MATERIALS AND METHODS: Fifty-nine patients were enrolled on a prospective tumor dose-escalation trial. Multi-parametric MRI was performed at baseline and week six, corresponding to the time of peak ADC change. GTV and prostate contours were deformably registered between baseline and week six T2-weighted images, and applied to ADC maps, to account for diminished image contrast post-EBRT and possible differences in prostate gland volume, shape, and orientation. A total of 101 radiomics features were tested for significant change post-EBRT using two-tailed Student's t-test. All ADC features of the prostate and GTV volumes were correlated using Pearson's coefficient (p < 0.00008, based on Bonferroni correction). RESULTS: ADC feature extraction was insensitive to b = 0 s/mm2 exclusion, and to gradient non-linearity bias. GTV presented predominant changes in first-order features, particularly 10Percentile, and prostate volumes presented predominant changes in second-order features. Changes in both first and second-order features of GTV and prostate ROIs were strongly correlated. CONCLUSIONS: Our data confirmed significant changes in numerous GTV and prostate features assessed from ADC and T2-weighted images during radiotherapy; all of which may be potential biomarkers of early radiation response.