We develop quantitative imaging methods to characterize the tumor microenvironment, and to subsequently relate these imaging parameters to biomarkers that can be used for cancer surveillance, diagnosis and treatment monitoring/characterization. The focus is on 1) developing new acquisition methods and protocols to enhance quantification, 2) designing new image processing algorithms, analysis parameters and statistical models to quantitatively characterize imaging data, and 3) using advanced AI methods to further refine quantification or classification. While our methods can be used for other imaging modalities, we primarily focus on Ultrasound imaging modes such as contrast, molecular, elastography and spectroscopic ultrasound. Disease focus include liver cancer and liver metastasis, liver fibrosis/cirrhosis, and tumor blood flow characterization.
PhD, University of Toronto/Sunnybrook Research Institute, Medical Biophysics - Imaging Physics and Radiation Oncology (2014)
MSc, Ryerson University, Physics (2008)
BEng, Ryerson University, Electrical and Computer Engineering (2005)
Tumour Vascular Shutdown and Cell Death Following Ultrasound-Microbubble Enhanced Radiation Therapy
2018; 8 (2): 314–27
High-dose radiotherapy effects are regulated by acute tumour endothelial cell death followed by rapid tumour cell death instead of canonical DNA break damage. Pre-treatment with ultrasound-stimulated microbubbles (USMB) has enabled higher-dose radiation effects with conventional radiation doses. This study aimed to confirm acute and longitudinal relationships between vascular shutdown and tumour cell death following radiation and USMB in a wild type murine fibrosarcoma model using in vivo imaging. Methods: Tumour xenografts were treated with single radiation doses of 2 or 8 Gy alone, or in combination with low-/high-concentration USMB. Vascular changes and tumour cell death were evaluated at 3, 24 and 72 h following therapy, using high-frequency 3D power Doppler and quantitative ultrasound spectroscopy (QUS) methods, respectively. Staining using in situ end labelling (ISEL) and cluster of differentiation 31 (CD31) of tumour sections were used to assess cell death and vascular distributions, respectively, as gold standard histological methods. Results: Results indicated a decrease in the power Doppler signal of up to 50%, and an increase of more than 5 dBr in cell-death linked QUS parameters at 24 h for tumours treated with combined USMB and radiotherapy. Power Doppler and quantitative ultrasound results were significantly correlated with CD31 and ISEL staining results (p < 0.05), respectively. Moreover, a relationship was found between ultrasound power Doppler and QUS results, as well as between micro-vascular densities (CD31) and the percentage of cell death (ISEL) (R2 0.5-0.9). Conclusions: This study demonstrated, for the first time, the link between acute vascular shutdown and acute tumour cell death using in vivo longitudinal imaging, contributing to the development of theoretical models that incorporate vascular effects in radiation therapy. Overall, this study paves the way for theranostic use of ultrasound in radiation oncology as a diagnostic modality to characterize vascular and tumour response effects simultaneously, as well as a therapeutic modality to complement radiation therapy.
View details for DOI 10.7150/thno.19010
View details for Web of Science ID 000417098700002
View details for PubMedID 29290810
View details for PubMedCentralID PMC5743550
Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging
2017; 20 (4): 547–55
Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment (P = 0.005), but not in CT26 tumors (P > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors (P < 0.001), but not in treated versus control CT26 tumors (P = 0.796). Early decrease in both PE and AUC by 45-50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.
View details for PubMedID 28721500
Molecular Contrast-Enhanced Ultrasound Imaging of Radiation-Induced P-Selectin Expression in Healthy Mice Colon.
International journal of radiation oncology, biology, physics
2017; 97 (3): 581-585
To evaluate the feasibility of using molecular contrast-enhanced ultrasound (mCEUS) to image radiation (XRT)-induced expression of cell adhesion molecules that mediate inflammatory response to XRT in healthy mouse colon tissue.The colons of male BALB/c mice (aged 6-8 weeks, n=9) were irradiated with 14 Gy using a Kimtron IC-225 x-ray irradiator operating at 225 kV/13.0 mA at a dose rate of 0.985 Gy/min. The head and thorax regions were shielded during irradiation. A second control cohort of mice was left untreated (n=6). Molecular CEUS was carried out before and 24 hours after irradiation using a VEVO2100 system and MS250 21-MHz center frequency transducer. Each imaging session comprised mCEUS imaging with P-selectin targeted microbubbles and control microbubbles targeted with an isotype control IgG. Quantification of mCEUS was carried out by measuring the differential targeted enhancement (dTE) parameter. The perfusion parameters peak enhancement and area under the curve were also extracted from the initial injection bolus. Animals were sacrificed at 24 hours and the colon was resected for immunohistochemistry analysis (P-selectin/CD31-stained vessel).For P-selectin targeted microbubble, a significant increase (40 a.u.; P=.013) in dTE (P-dTE) was observed in irradiated mice over 24 hours. In contrast, a nonsignificant change in P-selectin dTE was observed in control mice. For control microbubbles, no significant difference in the IgG dTE parameter was noted in treated and control animals over 24 hours. A nonsignificant increase in the peak enhancement and area under the curve perfusion parameters associated with blood volume was noted in animals treated with radiation. Quantitative histology indicated significantly elevated P-selectin expression per blood vessel (36% in treated; 14% in control).Our results confirm the feasibility of using mCEUS for imaging of XRT-induced expression of P-selectin as a potential approach to monitoring healthy tissue inflammatory damage during radiation therapy.
View details for DOI 10.1016/j.ijrobp.2016.10.037
View details for PubMedID 28126307
Ultrasound Elastography: Review of Techniques and Clinical Applications
2017; 7 (5): 1303-1329
Elastography-based imaging techniques have received substantial attention in recent years for non-invasive assessment of tissue mechanical properties. These techniques take advantage of changed soft tissue elasticity in various pathologies to yield qualitative and quantitative information that can be used for diagnostic purposes. Measurements are acquired in specialized imaging modes that can detect tissue stiffness in response to an applied mechanical force (compression or shear wave). Ultrasound-based methods are of particular interest due to its many inherent advantages, such as wide availability including at the bedside and relatively low cost. Several ultrasound elastography techniques using different excitation methods have been developed. In general, these can be classified into strain imaging methods that use internal or external compression stimuli, and shear wave imaging that use ultrasound-generated traveling shear wave stimuli. While ultrasound elastography has shown promising results for non-invasive assessment of liver fibrosis, new applications in breast, thyroid, prostate, kidney and lymph node imaging are emerging. Here, we review the basic principles, foundation physics, and limitations of ultrasound elastography and summarize its current clinical use and ongoing developments in various clinical applications.
View details for DOI 10.7150/thno.18650
View details for Web of Science ID 000396574200021
View details for PubMedID 28435467
Quantitative Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging: First-In-Human Pilot Study in Patients with Liver Metastases
2017; 7 (15): 3745–58
Purpose: To perform a clinical assessment of quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) feasibility and repeatability in patients with liver metastasis, and to evaluate the extent of quantitative perfusion parameter sampling errors in 2D compared to 3D DCE-US imaging. Materials and Methods: Twenty consecutive 3D DCE-US scans of liver metastases were performed in 11 patients (45% women; mean age, 54.5 years; range, 48-60 years; 55% men; mean age, 57.6 years; range, 47-68 years). Pairs of repeated disruption-replenishment and bolus DCE-US images were acquired to determine repeatability of parameters. Disruption-replenishment was carried out by infusing 0.9 mL of microbubbles (Definity; Latheus Medical Imaging) diluted in 35.1 mL of saline over 8 min. Bolus consisted of intravenous injection of 0.2 mL microbubbles. Volumes-of-interest (VOI) and regions-or-interest (ROI) were segmented by two different readers in images to extract 3D and 2D perfusion parameters, respectively. Disruption-replenishment parameters were: relative blood volume (rBV), relative blood flow (rBF). Bolus parameters included: time-to-peak (TP), peak enhancement (PE), area-under-the-curve (AUC), and mean-transit-time (MTT). Results: Clinical feasibility and repeatability of 3D DCE-US using both the destruction-replenishment and bolus technique was demonstrated. The repeatability of 3D measurements between pairs of repeated acquisitions was assessed with the concordance correlation coefficient (CCC), and found to be excellent for all parameters (CCC > 0.80), except for the TP (0.74) and MTT (0.30) parameters. The CCC between readers was found to be excellent (CCC > 0.80) for all parameters except for TP (0.71) and MTT (0.52). There was a large Coefficient of Variation (COV) in intra-tumor measurements for 2D parameters (0.18-0.52). Same-tumor measurements made in 3D were significantly different (P = 0.001) than measurements made in 2D; a percent difference of up to 86% was observed between measurements made in 2D compared to 3D in the same tumor. Conclusions: 3D DCE-US imaging of liver metastases with a matrix array transducer is feasible and repeatable in the clinic. Results support 3D instead of 2D DCE US imaging to minimize sampling errors due to tumor heterogeneity.
View details for PubMedID 29109773