Hypoxia Detection in Infiltrative Astrocytoma: Ferumoxytol-based Quantitative BOLD MRI with Intraoperative and Histologic Validation.

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

CT texture features are associated with overall survival in pancreatic ductal adenocarcinoma - a quantitative analysis.

BACKGROUND: To assess whether CT-derived texture features predict survival in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: Thirty patients with pre-operative CT from 2007 to 2012 for PDAC were included. Tumor size and five texture features namely uniformity, entropy, dissimilarity, correlation, and inverse difference normalized were calculated. Mann-Whitney rank sum test was used to compare tumor with normal pancreas. Receiver operating characteristics (ROC) analysis, Cox regression and Kaplan-Meier tests were used to assess association of texture features with overall survival (OS). RESULTS: Uniformity (p < 0.001), entropy (p = 0.009), correlation (p < 0.001), and mean intensity (p < 0.001) were significantly different in tumor regions compared to normal pancreas. Tumor dissimilarity (p = 0.045) and inverse difference normalized (p = 0.046) were associated with OS whereas tumor intensity (p = 0.366), tumor size (p = 0.611) and other textural features including uniformity (p = 0.334), entropy (p = 0.330) and correlation (p = 0.068) were not associated with OS. CONCLUSION: CT-derived PDAC texture features of dissimilarity and inverse difference normalized are promising prognostic imaging biomarkers of OS for patients undergoing curative intent surgical resection.

Reperfusion is a stronger predictor of good clinical outcome than recanalization in ischemic stroke.

PURPOSE: To assess the predictive value of reperfusion indices, recanalization, and important baseline clinical and radiologic scores for good clinical outcome prediction. MATERIALS AND METHODS: The study was approved by the local research ethics board. Written consent was obtained from all participants or their caregivers. Baseline computed tomography (CT) perfusion less than 4.5 hours after stroke symptoms, follow-up CT perfusion at 24 hours or less, and 5-7-day magnetic resonance images were obtained for 114 patients. Baseline imaging was assessed blinded to outcome. Recanalization status was determined at follow-up CT angiography. Reperfusion index was calculated on baseline and on follow-up at-risk tissue volume. Kruskal-Wallis, Mann-Whitney rank sum, and Spearman correlation were used for group comparisons and correlation studies. Univariate and multivariate logistic regression tested the association of clinical and imaging parameters with good outcome. Models with and without recanalization and reperfusion were compared by using Akaike information criterion. RESULTS: Reperfusion indices were significantly higher in patients with recanalization than in those without (P < .001). Despite significance of recanalization at univariate analysis, only reperfusion, age, and National Institutes of Health Stroke Scale score were significant after multivariate analysis (P < .01). Time to maximum reperfusion index had the highest accuracy (area under the receiver operating characteristic curve, 0.70) for good outcome, and reperfusion was defined as time to maximum volume of 59% or greater. Patients with reperfusion but no recanalization had significantly lower total infarct volume (P = .001) and infarct growth (P = .004) and had higher salvaged penumbra (P = .009) volumes than patients without reperfusion and recanalization. A final model with reperfusion but not recanalization was the most prognostic model of good clinical outcome. CONCLUSION: Reperfusion showed stronger association with good clinical outcome than did recanalization.

Multiscale modeling of knee ligament biomechanics.

Knee connective tissues are mainly responsible for joint stability and play a crucial role in restraining excessive motion during regular activities. The damage mechanism of these tissues is directly linked to the microscale collagen level. However, this mechanical connection is still unclear. During this investigation, a multiscale fibril-reinforced hyper-elastoplastic model was developed and statistically calibrated. The model is accounting for the structural architecture of the soft tissue, starting from the tropocollagen molecule that forms fibrils to the whole soft tissue. Model predictions are in agreement with the results of experimental and numerical studies. Further, damage initiation and propagation in the collagen fiber were computed at knee ligaments and located mainly in the superficial layers. Results indicated higher crosslink density required higher tensile stress to elicit fibril damage. This approach is aligned with a realistic simulation of a damaging process and repair attempt. To the best of our knowledge, this is the first model published in which the connective tissue stiffness is simultaneously predicted by encompassing the mesoscopic scales between the molecular and macroscopic levels.

Dimensions of the human sclera: Thickness measurement and regional changes with axial length.

Scleral thickness, especially near the region of the optic nerve head (ONH), is a potential factor of interest in the development of glaucomatous optic neuropathy. Our goal was to characterize the scleral thickness distribution and other geometric features of human eyes. Eleven enucleated human globes (7 normal and 4 ostensibly glaucomatous) were imaged using high-field microMRI, providing 80 microm isotropic resolution over the whole eye. The MRI scans were segmented to produce 3-D corneoscleral shells. Each shell was divided into 15 slices along the anterior-posterior axis of the eye, and each slice was further subdivided into the anatomical quadrants. Average thickness was measured in each region, producing 60 thickness measurements per eye. Hierarchical clustering was used to identify trends in the thickness distribution, and scleral geometric features were correlated with globe axial length. Thickness over the whole sclera was 670 +/- 80 microm (mean +/- SD; range: 564 microm-832 microm) over the 11 eyes. Maximum thickness occurred at the posterior pole of the eye, with mean thickness of 996 +/- 181 microm. Thickness decreased to a minimum at the equator, where a mean thickness of 491 +/- 91 microm was measured. Eyes with a reported history of glaucoma were found to have longer axial length, smaller ONH canal dimensions and thinner posterior sclera. Several geometrical parameters of the eye, including posterior scleral thickness, axial length, and ONH canal diameter, appear linked. Significant intra-individual and inter-individual variation in scleral thickness was evident. This may be indicative of inter-individual differences in ocular biomechanics.

Strain uniformity in biaxial specimens is highly sensitive to attachment details.

Biaxial testing has been used widely to characterize the mechanical properties of soft tissues and other flexible materials, but fundamental issues related to specimen design and attachment have remained. Finite element models and experiments were used to investigate how specimen geometry and attachment details affect uniformity of the strain field inside the attachment points. The computational studies confirm that increasing the number of attachment points increases the size of the area that experiences sensibly uniform strain (defined here as the central sample region where the ratio of principal strains E(11)/E(22)<1.10), and that the strains experienced in this region are less than nominal strains based on attachment point movement. Uniformity of the strain field improves substantially when the attachment points span a wide zone along each edge. Subtle irregularities in attachment point positioning can significantly degrade strain field uniformity. In contrast, details of the apron, the region outside of the attachment points, have little effect on the interior strain field. When nonlinear properties consistent with those found in human sclera are used, similar results are found. Experiments were conducted on 6 x 6 mm talc-sprinkled rubber specimens loaded using wire "rakes." Points on a grid having 12 x 12 bays were tracked, and a detailed strain map was constructed. A finite element model based on the actual geometry of an experiment having an off-pattern rake tine gave strain patterns that matched to within 4.4%. Finally, simulations using nonequibiaxial strains indicated that the strain field uniformity was more sensitive to sample attachment details for the nonequibiaxial case as compared to the equibiaxial case. Specimen design and attachment were found to significantly affect the uniformity of the strain field produced in biaxial tests. Practical guidelines were offered for design and mounting of biaxial test specimens. The issues addressed here are particularly relevant as specimens become smaller in size.

Radiomics analysis at PET/CT contributes to prognosis of recurrence and survival in lung cancer treated with stereotactic body radiotherapy.

We sought to quantify contribution of radiomics and SUVmax at PET/CT to predict clinical outcome in lung cancer patients treated with stereotactic body radiotherapy (SBRT). 150 patients with 172 lung cancers, who underwent SBRT were retrospectively included. Radiomics were applied on PET/CT. Principal components (PC) for 42 CT and PET-derived features were examined to determine which ones accounted for most of variability. Survival analysis quantified ability of radiomics and SUVmax to predict outcome. PCs including homogeneity, size, maximum intensity, mean and median gray level, standard deviation, entropy, kurtosis, skewness, morphology and asymmetry were included in prediction models for regional control (RC) [PC4-HR:0.38, p = 0.02], distant control (DC) [PC4-HR:0.51, p = 0.02 and PC1-HR:1.12, p = 0.01], recurrence free probability (RFP) [PC1-HR:1.08, p = 0.04], disease specific survival (DSS) [PC2-HR:1.34, p = 0.03 and PC3-HR:0.64, p = 0.02] and overall survival (OS) [PC4-HR:0.45, p = 0.004 and PC3-HR:0.74, p = 0.02]. In combined analysis with SUVmax, PC1 lost predictive ability over SUVmax for RFP [HR:1.1, p = 0.04] and DC [HR:1.13, p = 0.002], while PC4 remained predictive of DC independent of SUVmax [HR:0.5, p = 0.02]. Radiomics remained the only predictors of OS, DSS and RC. Neither SUVmax nor radiomics predicted recurrence free survival. Radiomics on PET/CT provided complementary information for prediction of control and survival in SBRT-treated lung cancer patients.

Quantitative Perfusion and Permeability Biomarkers in Brain Cancer from Tomographic CT and MR Images.

Dynamic contrast-enhanced perfusion and permeability imaging, using computed tomography and magnetic resonance systems, are important techniques for assessing the vascular supply and hemodynamics of healthy brain parenchyma and tumors. These techniques can measure blood flow, blood volume, and blood-brain barrier permeability surface area product and, thus, may provide information complementary to clinical and pathological assessments. These have been used as biomarkers to enhance the treatment planning process, to optimize treatment decision-making, and to enable monitoring of the treatment noninvasively. In this review, the principles of magnetic resonance and computed tomography dynamic contrast-enhanced perfusion and permeability imaging are described (with an emphasis on their commonalities), and the potential values of these techniques for differentiating high-grade gliomas from other brain lesions, distinguishing true progression from posttreatment effects, and predicting survival after radiotherapy, chemotherapy, and antiangiogenic treatments are presented.

Final infarct volume estimation on 1-week follow-up MR imaging is feasible and is dependent on recanalization status.

PURPOSE: We aim to characterize infarct volume evolution within the first month post-ischemic stroke and to determine the effect of recanalization status on early infarct volume estimation. METHODS: Ischemic stroke patients recruited for the MONITOR and VISION studies were retrospectively screened and patients who had infarcts on diffusion-weighted imaging (DWI) at baseline and had at least two follow-up MR scans (n = 56) were included. Pre-defined target imaging time points, obtained on a 3-T MR scanner, were 12 hours (h), 24 h, 7 days, and ≥30 days post-stroke. Infarct tissue was manually traced blinded to the images at the other time points. Infarct expansion index was calculated by dividing infarct volume at each follow-up time point by the baseline DWI infarct volume. Recanalization was assessed within 24 h post-stroke. Correlation and statistical comparison analysis were done using the Spearman, Mann-Whitney, and Kruskal-Wallis tests. RESULTS: Follow-up infarct volumes were positively correlated with the baseline infarct volume (ρ > 0.81; p < 0.001) where the strongest correlation existed between baseline and 7-day post-stroke infarct volumes (ρ = 0.92; p < 0.001). The strongest correlation among the follow-up imaging was found between infarct volumes 7-day post-stroke and ≥30-day time points (ρ = 0.93; p < 0.001). Linear regression showed a close-to unity slope between 7-day and final infarct volumes (slope = 1.043; p < 0.001). Infarct expansion was higher in the non-recanalized group than the recanalized group at the 7-day (p = 0.001) and ≥30-day (p = 0.038) time points. CONCLUSIONS: Final infarct volume can be approximated as early as 7 days post-stroke. Final infarct volume approximation is significantly associated with recanalization status.

Effects of scleral stiffness properties on optic nerve head biomechanics.

The biomechanical environment within the optic nerve head, important in glaucoma, depends strongly on scleral biomechanical properties. Here we use a range of measured nonlinear scleral stress-strain relationships in a finite element (FE) model of the eye to compute the biomechanical environment in the optic nerve head at three levels of intraocular pressure (IOP). Three stress-strain relationships consistent with the 5th, 50th and 95th percentiles of measured human scleral stiffness were selected from a pool of 30 scleral samples taken from 10 eyes and implemented in a generic FE model of the eye using a hyperelastic five-parameter Mooney-Rivlin material model. Computed strains within optic nerve head tissues depended strongly on scleral properties, with most of this difference occurring between the compliant and median scenarios. Also, the magnitudes of strains were found to be substantial even at normal IOP (up to 5.25% in the lamina cribrosa at 15 mmHg), being larger than previously reported values even at normal levels of IOP. We conclude that scleras that are "weak", but still within the physiologic range, will result in appreciably increased optic nerve head strains and could represent a risk factor for glaucomatous optic neuropathy. Estimations of the deformation at the optic nerve head region, particularly at elevated IOP, should take into account the nonlinear nature of scleral stiffness.

Biaxial mechanical testing of human sclera.

The biomechanical environment of the optic nerve head (ONH), of interest in glaucoma, is strongly affected by the biomechanical properties of sclera. However, there is a paucity of information about the variation of scleral mechanical properties within eyes and between individuals. We thus used biaxial testing to measure scleral stiffness in human eyes. Ten eyes from 5 human donors (age 55.4+/-3.5 years; mean+/-SD) were obtained within 24h of death. Square scleral samples (6mm on a side) were cut from each ocular quadrant 3-9 mm from the ONH centre and were mechanically tested using a biaxial extensional tissue tester (BioTester 5000, CellScale Biomaterials Testing, Waterloo). Stress-strain data in the latitudinal (toward the poles) and longitudinal (circumferential) directions, here referred to as directions 1 and 2, were fit to the four-parameter Fung constitutive equation W=c(e(Q)-1), where Q=c(1)E(11)(2)+c(2)E(22)(2)+2c(3)E(11)E(22) and W, c's and E(ij) are the strain energy function, material parameters and Green strains, respectively. Fitted material parameters were compared between samples. The parameter c(3) ranged from 10(-7) to 10(-8), but did not contribute significantly to the accuracy of the fitting and was thus fixed at 10(-7). The products cc(1) and cc(2), measures of stiffness in the 1 and 2 directions, were 2.9+/-2.0 and 2.8+/-1.9 MPa, respectively, and were not significantly different (two-sided t-test; p=0.795). The level of anisotropy (ratio of stiffness in orthogonal directions) was 1.065+/-0.33. No statistically significant correlations between sample thickness and stiffness were found (correlation coefficients=-0.026 and -0.058 in directions 1 and 2, respectively). Human sclera showed heterogeneous, near-isotropic, nonlinear mechanical properties over the scale of our samples.