MUNIN - Ultrasound detection, characterization, and treatment of (prostate) cancer

Early diagnosis of cancer is crucial for a successful treatment. Ultrasound is an easy, cheap and portable imaging technology that is often the first method a patient is examined with. In order to diagnose, one must be able to distinguish between different tissue types, healthy and malignant tissue. This is not always possible in normal ultrasound images, and the patient often has to go through unpleasant and time-consuming examinations including several biopsies. In this project we aim to develop a completely new ultrasound imaging method that images a tissue property called the non-linear bulk elasticity (NBE). This property varies greatly between different tissue types and will give radiologists a new and complementary information that may improve diagnostics with ultrasound. We will create these images by using dual-frequency ultrasound, "SURF imaging". During the project we will design and build probes for dual-frequency ultrasound, and develop algorithms and software for processing the dual-frequency signals to create images of the NBE. The technology will be tested in cooperation with Radiumhospitalet, focusing on patients with prostate cancer, to study the clinical utility of the method. In addition to diagnosing, ultrasound can also be used in cancer therapy. Ultrasound in combination with tiny gas bubbles, microbubbles, has shown great promise. These bubbles vibrate inside the capillaries where they are hit by the ultrasound beam, and these vibrations can increase the transport of drugs into the tumor. It is however a challenge in knowing the best settings to use for the ultrasound beams, as the properties of the tumor will influence how much the bubble vibrates for a given setting. We will therefore in this project also study if it is possible to use the information we get about the tumor and the microbubbles using the new imaging method to optimize the bubble vibrations. So far in the project we have completed the design of a dual frequency 9/0.65 MHz transrectal ultrasound probe that will be used in clinical imaging of the prostate. The specification has been sent to a subcontractor, and we are now waiting for them to finish the manufacturing. In the meantime, we have done a lot of in-vitro and ex-vivo experiments to test and improve the NBE imaging method. Amongst other things we have shown that in tissue mimicking materials (phantoms) we are clearly able to distinguish between different levels of contrast in NBE, information that otherwise is invisible in a normal ultrasound image. We have also shown that the NBE is sensitive to fat content, which is highly interesting for diagnosis of liver diseases. A master thesis has also been completed which has given us a first insight into what is the values of the NBE in pancreatic tumors grown in mice. Through this work we have improved the robustness of the algorithms, for example by using multiple iterations of the estimation. We have also significantly improved the speed of the algorithms, so that we now have a version running in real-time on the ultrasound scanner Verasonics Vantage 256. However, preliminary tests of in-vivo imaging on muscle tissue shows that we still need to improve the robustness further, since in-vivo there are often more noise sources resulting in image artifacts. In the therapeutic part of the project, we have developed simulation models for the vibration of microbubbles in capillaries, and through this discovered a possible methodology for measuring the vibration amplitude of microbubbles in-vivo that we will pursue further, since it is very important for the efficiency of cancer therapy with microbubbles that the bubbles are vibrating with adequate amplitude. The cooperation between clinicians and technicians in this project has resulted in a significant brainstorming about possible methods for how vibrating microbubbles can be utilized for improved cancer therapy, and we greatly look forward to the continuation.

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The MUNIN project addresses quantitative imaging of nonlinear bulk elasticity (NBE) of soft tissues for improved ultrasound detection and characterization of cancer, together with low frequency vibration of intra-capillary micro-bubbles for mediation of drug delivery to cancer cells. With dual frequency ultrasound the NBE can be estimated from scattered waves, in contrast to other bulk parameters that require transmission of ultrasound, i.e. only breast imaging. Recent years have seen a large development of ultrasound shear wave imaging for tissue characterization, with some interesting clinical results. The NBE parameter depends on the interatomic distance potential, where the shear/deformation elasticity (SE) parameter depend on the bio-molecular structure of the tissue. The NBE and the SE parameters are hence complementary parameters that combined can improve the characterization of tissues. The project focuses on improved detection, characterization, and treatment for prostate cancer (PC), the deadliest cancer in Norway and one of the deadliest in the western world (WW). In the WW a yearly # of positive PSA tests is ~ 13 mill with ~ 90% false positives, i.e. only ~ 1 mill have PC. Further examination gives ~ 200 000 that require treatment. An estimated 200 - 300 000 die from PC each year. The final diagnosis is done by ~ 12 ultrasound-guided biopsies that require a lot of expensive examinations, with pain and anxiety for the patient. Current extensive research examines use of MR imaging for better targeted and fewer biopsies. However, this is a complex procedure and clinical studies so far show unclear results. The MUNIN project targets to help this situation with low cost ultrasound at the front of the healthcare system. Ultrasound vibration of intra-capillary micro-bubbles have also shown to improve efficacy of cancer drugs, where the MUNIN technology allows dual frequency tumor imaging and characterization for simultaneous guidance of therapy beams.