ERC Grant - CU Angio

The problem:

Prostate cancer is the leading form of cancer for man in the western world, accounting for 25% of cancers diagnosis and 10% of carcers deaths. Nowadays, prostate cancer diagnosis is performed by assessing the serum prostate-specific antigen (PSA) level in blood. In case a high PSA level is found, the patient will undergo several biopsies, in order to obtain insights on cancer location, size and grade. PSA test is in fact unable to provide these informations. Moreover, due to the low specificity of the PSA test, a large number of biopsis reveal to be retrospectively unnecessary, while representing an invasive and painfull procedure for the patient.

Differently from this diagnostic procedure, a noninvasive and more reliable diagnostic technique, which would also be able to localize prostate cancer, will allow mass screaning and guided biopsy, significantly reducing the amount of sampels to be taken. Moreover, such a technique would also be of great improtance in combination with focal therapies, ultimately allowing early treatment of prostate cancer.

 

The idea:

Cancer is associated with angiogenesis: the growth of  new vessels from preexisting vessels, which is required by the tumor to grow bigger than 1-2 mm in size. Hence, localizing angiogenetic process will ultimately allow to localize cancer. To this scope, peculiar features distinguishing angiogenetic vessels from healthy vessels, e.g. tortuosity, trifurcation, uneven diameter and the presence of arterovenous shunts, may be used. In particular, ultrasound contrast agents, which consist of encapsulated gas-filled microbubbles, can be injected intravenously and thier kinematic can be used to study the vascular architecture through which they flow.

 

Contrast agents dispersion as a mean to localize angiogenesis:


  The use of utrasound contrast agents to detect cancer is not new. However, the focus has been more on using contrast agents to estimate perfusion, i.e., blood flow per tissue volume. Perfusion may in fact be thought  as a way to measure microvascular density, and hence as a mean to localize angiogenesis. Differently from these techniques, at the Laboratory od Biomedical Diagnostics we focus on contrast agents dispersion, which we consider to better characterize the vascular architecture trough which the microbubbles flow.

After a bolus of contrast agents is injected intravenously, their kinematic when passing through the prostate can be retrieved from their time intensity curves (TICs), which can be obtained by means of a trans-rectal contrast enhanced ultrasound image of the prostate. TICs (see figure above) show the microbubbles concentration over time for a given point in the observation plane. These curves can be utilized to estimate microbubble dispersion through the prostate vasculature, e.g. a low disperse bolus will result in sharp TICs (see bottow TIC in the figure above). Dispersion maps of the prostate can be otained extracting the information from TICs using parameter estimation (fitting the curves with mathematical models describing the agents dispersion, e.g. local density random walk model) or by evaluating the spatial similarity of the TICs. Similarity relates infact to dispersion: high dispersion results in a low similarity, and viceversa.


Clinical studies

Clinical studies are demonstrating how low dispersion correlates to the presence of cancer. TRUS images have been obtained from patient suspected of having prostate cancer, and the described analysis as been performed on the data obtained and compared with histology, in case the patient underwent a radical prostatectomy. On the right, an example comparing histolgy results (cancerous areas marked in red) and contrast ultrasound dispesion imaging (CUDI) results. Preliminary studies, conducted applying this novel diagnostic technique on a group of 8 patients which underwent radical prostatectomy, show an improved sensitivity (77.3%) and specificity (86 %)  as compared to other TICs parameters proposed to measure perfusion.

3D TRUS

Recently, we have shown for the first time the application of CUDI by 4D contrast-enhanced ultrasound imaging of the prostate with a transrectal probe. This study demonstrates the possibility to characterize the vascular architecture of the entire prostate with a single UCA bolus injection.

The movie below shows a 3D dispersion map through consecutive planes obtained from a 4D scan of the prostate.