VIDI Grant / P-CUDI Prostate cancer detection by contrast-ultrasound diffusion imaging

Prostate cancer:

Prostate cancer is the form of cancer with the highest incidence in western males, accounting for 25% and 10% of all cancer diagnoses and deaths, respectively. Nowadays, timely-detected prostate cancer can be efficiently treated. They can possibly permit avoiding a radical prostatectomy along with the related risks of the patient remaining incontinent and impotent.

Unfortunately, the implementation of an efficient mass screening, aimed at a systematic early localization of prostate cancer is hampered by the limits of the available diagnostics. In fact, in the presence of a high level of prostate specific antigen in blood, the only reliable diagnostic investigation requires performing a number of systematic biopsies. Repeated biopsy sessions are often required to obtain a sufficient sensitivity. In retrospective, about 76% of all biopsy investigations are unnecessary.

Several imaging modalities are being evaluated for early prostate cancer detection. While computerized tomography (CT) seems unsuitable for diagnostic prostate imaging, cancer detection sensitivity (on a patient basis) with magnetic resonance imaging (MRI) techniques such as diffusion weighted imaging (73%–89%), contrast-enhanced MRI (69%–95%), and MR spectroscopy (59%–94%) is promising. Transrectal ultrasound (TRUS) techniques are however equally promising and they are more suitable than MRI in terms of cost, time, resolution, and guidance of biopsies and focal therapies. Therefore, TRUS improvements could be of great value for early prostate cancer localization.

Angiogenesis:

A major breakthrough in cancer research was the discovery of a close relationship between cancer growth and angiogenesis, i.e., the formation of a dense network of microvessels. This relationship is also valid for prostate cancer, where angiogenesis correlates with cancer growth and aggressiveness. As a result, the histological assessment of the microvessel density has become an important prognostic indicator of prostate cancer.  This breakthrough has opened new possibilities for prostate cancer imaging. Angiogenesis, which is required for cancer growth beyond 1 mm, correlates with prostate cancer aggressiveness (i.e., risks of extracapsular growth and development of metastases). Therefore, imaging methods based on angiogenesis detection may help to identify life-threatening forms of prostate cancer at an early stage.

With the objective of measuring flow, the use of transrectal ultrasound (TRUS) Doppler techniques has been amply investigated. However, cancer microvessels cannot be accurately detected because of the low blood velocity and because of their small size, smaller than the TRUS spatial resolution. Therefore, the use of ultrasound contrast agents (UCAs) for an enhancement of microvascular perfusion imaging has gained interest.

Ultrasound Contrast Agents:

UCAs are dispersions of coated gas microbubbles that backscatter acoustic energy when hit by ultrasound waves. UCA microbubbles have a size comparable to that of blood cells, and can therefore flow through the microvasculature, backscattering acoustic energy when invested by ultrasonic waves. An alternative method for cancer angiogenesis assessment involves dynamic TRUS imaging of the passage of an intravenously injected UCA bolus. Up until now, only few quantitative studies have been carried out. These studies quantify perfusion by extraction of time and intensity features from the measured acoustic time-intensity curves. In addition to a bolus injection, the destruction-replenishment method, first introduced for the assessment of myocardial perfusion, has also been tested to a limited extent for prostate cancer detection. In general, up until now, none of these UCA methods has demonstrated an ability to localize prostate cancer in a reliable way.

 

Research topics:

Dispersion Imaging (view poster):

In this project, we develop a novel approach for the localization of prostate cancer by contrast-enhanced TRUS. Rather than using a destruction-replenishment approach, a peripheral intravenous injection of a small bolus of UCA is performed, followed by the echographic measurement of the time-intensity curve (TIC) representing the bolus first pass through the prostate circulation.

Although this procedure is in general not new, and has already been tested for prostate cancer detection, we introduce a new TIC analysis method: rather than aiming at the quantification of tissue perfusion features, we aim at the quantification of the UCA diffusion kinetics through the prostate circulation.

Differently from perfusion, the diffusion dynamics shows a better correlation with the microvascular architecture and, therefore, with cancer aggressiveness. Similarly to the characterization of flow through porous media, the intravascular diffusion can in fact be correlated with microvessel density, constrictively, and tortuosity.

In-vitro modeling:

Parallel with in-vivo assessment of prostate cancer, we developed an in-vitro model with possibility to study different vascular phantoms. This allows investigating of UCA diffusion dynamis in angiogenetic networks with known properties, such as tortuosity, density, permeability, branching ratio and etc. Therefore, we aim at detecting the features of vascular networks mostly influencing on UCA diffusion. This knowledge will improve our understanding of hemodynamics and properties of cancerous angiogenetic networks being studied by UCA diffusion.

Diffusion or dispersion:

The term "diffusion" is often intended as the diffusion process through a membrane and, therefore, confused with extravascular leakage. UCAs are pure intravascular agents that cannot leak into the interstitial space. In this study, diffusion addresses the effective Taylor diffusion. This is the dispersion of UCAs through the mircrovascular network, mainly due to its complex architecture (blood patways) and, therefore, dominated by the distribution of UCA transit times.