Jürgen W. Jenne

Clinical and future applications of high intensity focused ultrasound in cancer

High intensity focused ultrasound (HIFU) or focused ultrasound (FUS) is a promising modality to treat tumors in a complete, non invasive fashion where online image guidance and therapy control can be achieved by magnetic resonance imaging (MRI) or diagnostic ultrasound (US). In the last 10 years, the feasibility and the safety of HIFU have been tested in a growing number of clinical studies on several benign and malignant tumors of the prostate, breast, uterine, liver, kidney, pancreas, bone, and brain. For certain indications this new treatment principle is on its verge to become a serious alternative or adjunct to the standard treatment options of surgery, radiotherapy, gene therapy and chemotherapy in oncology. In addition to the now clinically available thermal ablation, in the future, focused ultrasound at much lower intensities may have the potential to become a major instrument to mediate drug and gene delivery for localized cancer treatment. We introduce the technology of MRI guided and ultrasound guided HIFU and present a critical overview of the clinical applications and results along with a discussion of future HIFU developments.

High-intensity focused ultrasound: Principles, therapy guidance, simulations and applications

In the past two decades, high-intensity focused ultrasound (HIFU) in combination with diagnostic ultrasound (USgFUS) or magnetic resonance imaging (MRgFUS) opened new ways of therapeutic access to a multitude of pathologic conditions. The therapeutic potential of HIFU lies in the fact that it enables the localized deposition of high-energy doses deep within the human body without harming the surrounding tissue. The addition of diagnostic ultrasound or in particular MRI with HIFU allows for planning, control and direct monitoring of the treatment process. The clinical and preclinical applications of HIFU range from the thermal treatment of benign and malign lesions, targeted drug delivery, to the treatment of thrombi (sonothrombolysis). Especially the therapy of prostate cancer under US-guidance and the ablation of benign uterine fibroids under MRI monitoring are now therapy options available to a larger number of patients. The main challenges for an abdominal application of HIFU are posed by partial or full occlusion of the target site by bones or air filled structures (e.g. colon), as well as organ motion. In non-trivial cases, the implementation of computer based modeling, simulation and optimization is desirable. This article describes the principles of HIFU, ultrasound and MRI therapy guidance, therapy planning and simulation, and gives an overview of the current and potential future applications.

Temperature mapping for high energy US-therapy

In US-hyperthermia and -surgery for cancer therapy it is important to know and to predict temperature profiles and developments. On the one hand we have investigated a new method to simulate temperature fields in tissue after application of focused high energy continuous wave ultrasound. On the other hand we developed an experimental technique to measure temperature distributions using a fiber-optic thermometer. Experiment and theory showed reasonable agreement

Control of cavitation activity by different shockwave pulsing regimes.

The aim of the study was to control the number of inertial cavitation bubbles in the focal area of an electromagnetic lithotripter in water independently of peak intensity, averaged intensity or pressure waveform. To achieve this, the shockwave pulses were applied in double pulse sequences, which were administered at a fixed pulse repetition frequency (PRF) of 0.33 Hz. The two pulses of a double pulse were separated by a variable short pulse separation time (PST) ranging from 200 micros to 1500 ms. The number and size of the cavitation bubbles were monitored by scattered laser light and stroboscopic photographs. We found that the number of inertial cavitation bubbles as a measure of cavitation dose was substantially influenced by variation of the PST, while the pressure pulse waveform, averaged acoustic intensity and bubble size were kept constant. The second pulse of each double pulse generated more cavitation bubbles than the first. At 14 kV capacitor voltage, the total number of cavitation bubbles generated by the double pulses increased with shorter PST down to approximately 400 micros, the cavitation lifespan. The results can be explained by cavitation nuclei generated by the violently imploding inertial cavitation bubbles. This method of pulse administration and cavitation monitoring could be useful to establish a cavitation dose-effect relationship independently of other acoustic parameters.

CT on-line monitoring of HIFU therapy

It was the aim of this study to evaluate the feasibility of a clinical CT scanner for temperature mapping in high intensity focused ultrasound tumor therapy. The authors used a 1.2 MHz ultrasound transducer for HIFU on fresh pig muscle. Image acquisition was performed with a clinical CT Scanner before, during and after HIFU. They were able to determine the spatial and temporal temperature development during HIFU application as hypodense zones in the performed images. Thermal necroses were shown as hyperdense areas in the CT images. Moreover, the authors were able to detect bubble formation due to vaporization during US application. Calibration showed a CT thermosensitivity of -0.43 HU//spl deg/C in pig muscle tissue.

MR monitoring of focused ultrasound surgery in a breast tissue model in vivo

The objective of this study was to investigate MRI methods for monitoring focused ultrasound surgery (FUS) of breast tumors. To this end, the mammary glands of sheep were used as tissue model. The tissue was treated in vivo with numerous single sonications which covered extended target volumes by employing a scanning technique. The ultrasound focus position was controlled by online temperature mapping based on the temperature dependence of the relaxation time T(1). This approach proved to be reliable and offers thus an alternative to proton resonance frequency methods, whose application is hampered in fatty tissues. FUS-induced tissue changes were visible on T(2)- as well as on pre- and post-contrast T(1)-weighted images. According to our initial experience, noninvasive MRI-guided FUS of breast tumors is feasible.

The 2014 liver ultrasound tracking benchmark

Abstract The Challenge on Liver Ultrasound Tracking (CLUST) was held in conjunction with the MICCAI 2014 conference to enable direct comparison of tracking methods for this application. This paper reports the outcome of this challenge, including setup, methods, results and experiences. The database included 54 2D and 3D sequences of the liver of healthy volunteers and tumor patients under free breathing. Participants had to provide the tracking results of 90% of the data (test set) for pre-defined point-landmarks (healthy volunteers) or for tumor segmentations (patient data). In this paper we compare the best six methods which participated in the challenge. Quantitative evaluation was performed by the organizers with respect to manual annotations. Results of all methods showed a mean tracking error ranging between 1.4 mm and 2.1 mm for 2D points, and between 2.6 mm and 4.6 mm for 3D points. Fusing all automatic results by considering the median tracking results, improved the mean error to 1.2 mm (2D) and 2.5 mm (3D). For all methods, the performance is still not comparable to human inter-rater variability, with a mean tracking error of 0.5–0.6 mm (2D) and 1.2–1.8 mm (3D). The segmentation task was fulfilled only by one participant, resulting in a Dice coefficient ranging from 76.7% to 92.3%. The CLUST database continues to be available and the online leader-board will be updated as an ongoing challenge.

Sonochemically induced radicals generated by pulsed high-energy ultrasound in vitro and in vivo

The aim of this study was to evaluate the role of radicals as a mechanism of tissue damage induced by pulsed high-energy ultrasound. Transient cavitation has proved to be an important mechanism for the generation of reactive radical species during pulsed high-energy ultrasound applications. The amount of radicals studied in in vitro experiments using a chemical dosimeter based on iodine release is proportional to the number of pulses. Sonications of the R3327-AT1 subline of the Dunning prostate rat tumor transplanted in the thigh of Copenhagen rats were performed applying 500 and 2000 pulses at a pulse repetition frequency of 1 Hz. Tumor growth after treatment was compared with sham-treated controls. We were able to assess a significant growth delay, but could not find a significant difference between the two groups treated. In conclusion, radical formation does not seem to be the major mechanism for tissue necrosis induced by pulsed high-energy ultrasound.

Temperature monitoring of focused ultrasound therapy by MRI

The aim of the present study was to assess the feasibility of MRI monitoring the temperature distribution induced by focused ultrasound therapy of malignant tissue in vivo. Male Copenhagen rats bearing R3327-AT1 Dunning prostate tumors were sonicated in vivo with a self-constructed CW-ultrasound source. The sonication was performed in a conventional 1.5 T whole-body MR scanner. For MRI a T1-weighted saturation recovery TurboFLASH (SRTF) sequence (TR=10.2 ms, TE=4 ms, TI=300 ms, α=12°) with an acquisition time of 1.3 s per image was used. After sonication hypo-intense regions inside the tumors were monitored expanding centripetally off the focus by time. Tumor growth delay and postmortem histology correlated with the temperature distributions calculated from the SRTF signals. This will temperature to be controlled interactively during US hyperthermia

A long arm for ultrasound: A combined robotic focused ultrasound setup for magnetic resonance‐guided focused ultrasound surgery

PURPOSE Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. METHODS The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the systems potential and suitability for MRgFUS was tested. RESULTS In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds. During in vivo experiments, a defined pattern of single thermal lesions and a therapeutically relevant confluent thermal lesion could be created. The creation of local tissue necrosis by coagulation was confirmed by post-FUS MR imaging and histological examinations on the treated tissue sample. During all sonications in phantom and in vivo, reliable MR imaging and online MR thermometry could be performed without compromises due to operation of the combined robotic FUS setup. CONCLUSIONS Compared to the existing MRgFUS systems, the combined robotic FUS approach offers a wide range of spatial flexibility so that highly flexible application of the US wave would be possible, for example, to avoid risk structures within the US field. The setup might help to realize new ways of patient access in MRgFUS therapy. The setup is compatible with any closed-bore MR system and does not require an especially designed patient table.