Ahmed El Kaffas

Ultrasound Elastography: Review of Techniques and Clinical Applications.

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.

Biomechanical effects of microbubbles: from radiosensitization to cell death

Ultrasound-stimulated microbubbles have been demonstrated to mechanically perturb cell membranes, resulting in the activation of biological signaling pathways that significantly enhance the effects of radiation. The underlying mechanism involves augmented ceramide production following both microbubble stimulation and irradiation, leading to rapid and extensive endothelial apoptosis and tumor cell death as a result of vascular collapse. Endothelial cells are particularly sensitive to ceramide-induced cell death due to an enriched presence of sphingomyelinase in their membranes. In tumors, this consequent rapid vascular shutdown translates to an overall increase in tumor responses to radiation treatments. This review summarizes the groundwork behind endothelial-based radiation enhancement with ultrasound-stimulated microbubbles, and presents ongoing research on the use of microbubbles as therapeutic agents in cancer therapy.

Quantitative ultrasound molecular imaging for antiangiogenic therapy monitoring

The link between cancer growth and angiogenesis has led to the development of new techniques for cancer imaging and therapy. Ultrasound molecular imaging permits the visualization of angiogenesis by use of novel targeted ultrasound contrast agents, (tUCA), consisting of ligand-bearing microbubbles designed to specifically bind molecular angiogenic expressions. Discrimination between bound and free microbubbles is crucial to quantify angiogenesis. Currently, the degree of binding is assessed by the differential targeted enhancement, requiring the application of a destructive burst in the late phase (usually 5-10 min after injection) to isolate the signal from bound microbubbles. Recently, we proposed a novel method for quantitative assessment of binding by modeling the microbubble binding kinetics during the tUCA first pass, reducing the acquisition time to 1 min with no need for a destructive burst. The feasibility of the method for angiogenesis imaging was shown in prostate tumor-bearing rats. In this work, we evaluate the proposed method for monitoring the response to angiogenic treatment in human colon cancer xenograft-bearing mice.

Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses

Abstract Background High-dose radiotherapy (>8–10 Gy) causes rapid endothelial cell death via acid sphingomyelinase (ASMase)–induced ceramide production, resulting in biologically significant enhancement of tumor responses. To further augment or solicit similar effects at low radiation doses, we used genetic and chemical approaches to evaluate mechano-acoustic activation of the ASMase-ceramide pathway by ultrasound-stimulated microbubbles (USMB). Methods Experiments were carried out in wild-type and acid sphingomyelinase (asmase) knockout mice implanted with fibrosarcoma xenografts. A cohort of wild-type mice received the ASMase-ceramide pathway inhibitor sphingosine-1-phosphate (S1P). Mice were treated with varying radiation doses, with or without a priori USMB exposure at different microbubble concentrations. Treatment response was assessed with quantitative 3D Doppler ultrasound and immunohistochemistry at baseline, and at three, 24, and 72 hours after treatment, with three to five mice per treatment group at each time point. All statistical tests were two-sided. Results Results confirmed an interaction between USMB and ionizing radiation at 24 hours (P < .001), with a decrease in tumor perfusion of up to 46.5% by three hours following radiation and USMB. This peaked at 24 hours, persisting for up to 72 hours, and was accompanied by extensive tumor cell death. In contrast, statistically nonsignificant and minimal tumor responses were noted in S1P-treated and asmase knockout mice for all treatments. Conclusions This work is the first to confirm the involvement of the ASMase-ceramide pathway in mechanotransductive vascular targeting using USMB. Results also confirm that an acute vascular effect is driving this form of enhanced radiation response, and that it can be elicited at low radiation doses (<8–10 Gy) by a priori USMB exposure.

Quantitative Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging: First-In-Human Pilot Study in Patients with Liver Metastases

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.

Tumour Vascular Shutdown and Cell Death Following Ultrasound-Microbubble Enhanced Radiation Therapy

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.

Volumetric contrast-enhanced ultrasound parametric maps and texture feature extraction for tissue treatment response characterization

Volumetric dynamic contrast-enhanced ultrasound (DCE-US) can be used to yield 3D parametric maps to assess spatial changes in tumor perfusion heterogeneity during cancer treatment. Here, quantitative image features (texture and histogram-based features) extracted from 3D parametric maps were evaluated as surrogates of treatment response, and compared to conventional perfusion parameters.

Assessment of vascular remodeling therapy in patients with liver metastasis with 3D dynamic contrast-enhanced ultrasound

Vascular remodeling agents that can enhance the effects of chemotherapy have gained significant attention. However, timing and dosing of combinatory treatment regimens requires longitudinal biomarkers to optimize regimens on a patient-by-patient basis. 3D dynamic contrast-enhanced ultrasound (DCE-US) has been proposed as an inexpensive bedside tool to longitudinally guide dosing and scheduling of combined treatments. The purpose of this pilot study was to demonstrate the feasibility of using 3D DCE-US to identify patients with remodeled vasculature before secondary chemotherapy delivery.

Quantitative ultrasound spectroscopy to differentiate between hepatocellular carcinoma and at-risk liver parenchyma

Early detection of hepatocellular carcinoma (HCC) is critically needed to improve patient survival. Ultrasound is the first-line technology to screen patients at increased risk but has low sensitivity and specify in particular in hepatic cirrhosis. Quantitative ultrasound spectroscopy (QUS) is a promising tool that may increase diagnostic accuracy of ultrasound by enabling quantitative assessment and computerized screening. This study aimed to perform a clinical assessment of QUS parameters for differentiating HCC lesion tissue from liver parenchyma.

Assessment of 3D dynamic contrast-enhanced ultrasound of liver metastases from gastrointestinal tumors to overcome sampling errors: Assessment of feasibility and reproducibility

Dynamic contrast enhanced ultrasound (DCE-US) is a low-cost tool proposed for identifying early responders to cancer therapy. To date, sampling errors due to 2D imaging has restricted DCE-US in assessing highly heterogeneous tumors. The purpose of this study was to perform a clinical assessment of 3D DCE-US feasibility and reproducibility.