Roshan Karunamuni

Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma.

PURPOSE Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. METHODS AND MATERIALS We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. RESULTS Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by -0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. CONCLUSIONS We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.

Dose-dependent white matter damage after brain radiotherapy

BACKGROUND AND PURPOSE Brain radiotherapy is limited in part by damage to white matter, contributing to neurocognitive decline. We utilized diffusion tensor imaging (DTI) with multiple b-values (diffusion weightings) to model the dose-dependency and time course of radiation effects on white matter. MATERIALS AND METHODS Fifteen patients with high-grade gliomas treated with radiotherapy and chemotherapy underwent MRI with DTI prior to radiotherapy, and after months 1, 4-6, and 9-11. Diffusion tensors were calculated using three weightings (high, standard, and low b-values) and maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ∥), and radial diffusivity (λ⊥) were generated. The region of interest was all white matter. RESULTS MD, λ∥, and λ⊥ increased significantly with time and dose, with corresponding decrease in FA. Greater changes were seen at lower b-values, except for FA. Time-dose interactions were highly significant at 4-6months and beyond (p<.001), and the difference in dose response between high and low b-values reached statistical significance at 9-11months for MD, λ∥, and λ⊥ (p<.001, p<.001, p=.005 respectively) as well as at 4-6months for λ∥ (p=.04). CONCLUSIONS We detected dose-dependent changes across all doses, even <10Gy. Greater changes were observed at low b-values, suggesting prominent extracellular changes possibly due to vascular permeability and neuroinflammation.

Radiation sparing of cerebral cortex in brain tumor patients using quantitative neuroimaging

BACKGROUND AND PURPOSE Neurocognitive decline in brain tumor patients treated with radiotherapy (RT) may be linked to cortical atrophy. We developed models to determine radiation treatment-planning objectives for cortex, which were tested on a sample population to identify the dosimetric cost of cortical sparing. MATERIAL AND METHODS The relationship between the probability of cortical atrophy in fifteen high-grade glioma patients at 1-year post-RT and radiation dose was fit using logistic mixed effects modeling. Cortical sparing was implemented using two strategies: region-specific sparing using model parameters, and non-specific sparing of all normal brain tissue. RESULTS A dose threshold of 28.6 Gy was found to result in a 20% probability of severe atrophy. Average cortical sparing at 30 Gy was greater for region-specific dose avoidance (4.6%) compared to non-specific (3.6%). Cortical sparing resulted in an increase in heterogeneity index of the planning target volume (PTV) with an average increase of 1.9% (region-specific) and 0.9% (non-specific). CONCLUSIONS We found RT doses above 28.6 Gy resulted in a greater than 20% probability of cortical atrophy. Cortical sparing can be achieved using region-specific or non-specific dose avoidance strategies at the cost of an increase in the dose heterogeneity of the PTV.

Search for novel contrast materials in dual-energy x-ray breast imaging using theoretical modeling of contrast-to-noise ratio

Contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging uses a low- and high-energy x-ray spectral pair to eliminate soft-tissue signal variation and thereby increase the detectability of exogenous imaging agents. Currently, CEDE breast imaging is performed with iodinated contrast agents. These compounds are limited by several deficiencies, including rapid clearance and poor tumor targeting ability. The purpose of this work is to identify novel contrast materials whose contrast-to-noise ratio (CNR) is comparable or superior to that of iodine in the mammographic energy range. A monoenergetic DE subtraction framework was developed to calculate the DE signal intensity resulting from the logarithmic subtraction of the low- and high-energy signal intensities. A weighting factor is calculated to remove the dependence of the DE signal on the glandularity of the breast tissue. Using the DE signal intensity and weighting factor, the CNR for materials with atomic numbers (Z) ranging from 1 to 79 are computed for energy pairs between 10 and 50 keV. A group of materials with atomic numbers ranging from 42 to 63 were identified to exhibit the highest levels of CNR in the mammographic energy range. Several of these materials have been formulated as nanoparticles for various applications but none, apart from iodine, have been investigated as CEDE breast imaging agents. Within this group of materials, the necessary dose fraction to the LE image decreases as the atomic number increases. By reducing the dose to the LE image, the DE subtraction technique will not provide an anatomical image of sufficient quality to accompany the contrast information. Therefore, materials with Z from 42 to 52 provide nearly optimal values of CNR with energy pairs and dose fractions that provide good anatomical images. This work is intended to inspire further research into new materials for optimized CEDE breast functional imaging.

Regional susceptibility to dose-dependent white matter damage after brain radiotherapy

BACKGROUND AND PURPOSE Regional differences in sensitivity to white matter damage after brain radiotherapy (RT) are not well-described. We characterized the spatial heterogeneity of dose-response across white matter tracts using diffusion tensor imaging (DTI). MATERIALS AND METHODS Forty-nine patients with primary brain tumors underwent MRI with DTI before and 9-12months after partial-brain RT. Maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were generated. Atlas-based white matter tracts were identified. A secondary analysis using skeletonized tracts was also performed. Linear mixed-model analysis of the relationship between mean and max dose and percent change in DTI metrics was performed. RESULTS Tracts with the strongest correlation of FA change with mean dose were the fornix (-0.46 percent/Gy), cingulum bundle (-0.44 percent/Gy), and body of corpus callosum (-0.23 percent/Gy), p<.001. These tracts also showed dose-sensitive changes in MD and RD. In the skeletonized analysis, the fornix and cingulum bundle remained highly dose-sensitive. Maximum and mean dose were similarly predictive of DTI change. CONCLUSIONS The corpus callosum, cingulum bundle, and fornix show the most prominent dose-dependent changes following RT. Future studies examining correlation with cognitive functioning and potential avoidance of critical white matter regions are warranted.

An examination of silver as a radiographic contrast agent in dual-energy breast x-ray imaging

Silver nanoaprticles have been investigated as an alternative to iodine in dual-energy breast x-ray imaging. Dual-energy imaging involves acquiring images at two distinct energy windows (low and high). Weighting factors are then applied to create an image where the contrast between background tissues has been suppressed. Silver (Ag) represents an attractive contrast material due to its favorable x-ray attenuation properties (k-edge of 25.5 keV). Theoretical analysis using polychromatic spectra shows that silver can provide similar, if not better, contrast to iodine. Spherical Ag nanoparticles with an average diameter of 4 ±2 nm were synthesized using the Brust method in water. The particles were surface stabilized with polyethylene glycol and showed little cellular toxicity in T6-17 fibroblast cells. These results have encouraged further investigation into validation and testing in living system models. Silver nanoparticles represent an exciting avenue for the development of a novel dual-energy, x-ray breast imaging agent.

Exploring silver as a contrast agent for contrast-enhanced dual-energy X-ray breast imaging

OBJECTIVE Through prior monoenergetic modelling, we have identified silver as a potential alternative to iodine in dual-energy (DE) X-ray breast imaging. The purpose of this study was to compare the performance of silver and iodine contrast agents in a commercially available DE imaging system through a quantitative analysis of signal difference-to-noise ratio (SDNR). METHODS A polyenergetic simulation algorithm was developed to model the signal intensity and noise. The model identified the influence of various technique parameters on SDNR. The model was also used to identify the optimal imaging techniques for silver and iodine, so that the two contrast materials could be objectively compared. RESULTS The major influences on the SDNR were the low-energy dose fraction and breast thickness. An increase in the value of either of these parameters resulted in a decrease in SDNR. The SDNR for silver was on average 43% higher than that for iodine when imaged at their respective optimal conditions, and 40% higher when both were imaged at the optimal conditions for iodine. CONCLUSION A silver contrast agent should provide benefit over iodine, even when translated to the clinic without modification of imaging system or protocol. If the system were slightly modified to reflect the lower k-edge of silver, the difference in SDNR between the two materials would be increased. ADVANCES IN KNOWLEDGE These data are the first to demonstrate the suitability of silver as a contrast material in a clinical contrast-enhanced DE image acquisition system.

Initial experience with dual-energy contrast-enhanced digital breast tomosynthesis in the characterization of breast cancer

An assessment is ongoing of the ability of dual energy contrast-enhanced digital breast tomosynthesis (CE-DBT) to depict the morphologic and vascular characteristics of breast cancer in comparison with breast MRI and digital mammography (DM). Eight patients with newly diagnosed breast cancer were imaged with an automated dual-energy CE-DBT system. High energy/low energy image pairs of the index breast were obtained at 1 pre- and 3 post-contrast timepoints. Post-contrast images were obtained after intravenous administration of Visipaque (1 mL/kg). Anatomic images were reconstructed using filtered backprojection, and contrast-enhanced images were generated using simple backprojection followed by temporal or dual-energy subtraction. Dual-energy CE-DBT was able to demonstrate the index malignant lesion in 7 of 8 patients (9 of 10 lesions). Morphologic characteristics including margin detail and associated microcalcifications were qualitatively concordant with DM. Vascular characteristics were identifiable qualitatively on post-processed images in some cases, and judged to be qualitative concordant with breast MRI.

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts

Abstract Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10−16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Edge Contrast of the FLAIR Hyperintense Region Predicts Survival in Patients with High-Grade Gliomas following Treatment with Bevacizumab

BACKGROUND AND PURPOSE: Treatment with bevacizumab is standard of care for recurrent high-grade gliomas; however, monitoring response to treatment following bevacizumab remains a challenge. The purpose of this study was to determine whether quantifying the sharpness of the fluid-attenuated inversion recovery hyperintense border using a measure derived from texture analysis—edge contrast—improves the evaluation of response to bevacizumab in patients with high-grade gliomas. MATERIALS AND METHODS: MRIs were evaluated in 33 patients with high-grade gliomas before and after the initiation of bevacizumab. Volumes of interest within the FLAIR hyperintense region were segmented. Edge contrast magnitude for each VOI was extracted using gradients of the 3D FLAIR images. Cox proportional hazards models were generated to determine the relationship between edge contrast and progression-free survival/overall survival using age and the extent of surgical resection as covariates. RESULTS: After bevacizumab, lower edge contrast of the FLAIR hyperintense region was associated with poorer progression-free survival (P = .009) and overall survival (P = .022) among patients with high-grade gliomas. Kaplan-Meier curves revealed that edge contrast cutoff significantly stratified patients for both progression-free survival (log-rank χ2 = 8.3, P = .003) and overall survival (log-rank χ2 = 5.5, P = .019). CONCLUSIONS: Texture analysis using edge contrast of the FLAIR hyperintense region may be an important predictive indicator in patients with high-grade gliomas following treatment with bevacizumab. Specifically, low FLAIR edge contrast may partially reflect areas of early tumor infiltration. This study adds to a growing body of literature proposing that quantifying features may be important for determining outcomes in patients with high-grade gliomas.