高强度聚焦超声（HIFU）研究现状

High-Intensity Focused Ultrasound 1 High-Intensity Focused Ultrasound (HIFU) Contenu 1. Introduction .............................................................................................................................. 2 2. History and medical applications .............................................................................................. 3 2.1 A brief history of HIFU ......................................................................................................... 3 2.2 Tumor ablation applications ................................................................................................ 3 2.2.1 Prostate cancer ......................................................................................................... 4 2.2.2 Uterine fibroids ........................................................................................................ 4 2.2.3 Breast cancer ............................................................................................................ 4 2.2.4 Liver cancer .............................................................................................................. 5 3. Principle .................................................................................................................................... 6 3.1 Thermal effects of HIFU [12] ............................................................................................... 6 3.2 Mechanical effects of HIFU [12] .......................................................................................... 7 3.3 Ultrasound focusing modes ................................................................................................. 7 3.3.1 Mechanical mode ..................................................................................................... 7 3.3.2 Phase-controlled mode ............................................................................................ 8 4. Image-guided HIFU .................................................................................................................. 10 4.1 Ultrasound-guided HIFU .................................................................................................... 10 4.1.1 Treatment planning ................................................................................................ 10 4.1.2 Dose delivery guidance by real-time ultrasound imaging ...................................... 14 4.1.3 Post-treatment assessment by contrast-enhanced ultrasound imaging ................ 15 4.2 MR-guided HIFU (MRgFUS) ............................................................................................... 16 4.2.1 Treatment planning ................................................................................................ 16 4.2.2 MR thermometry ................................................................................................... 22 4.2.3 MR ablation assessment ........................................................................................ 25 4.2.4 MRgHIFU for tumor ablation in mobile organs ...................................................... 26 5. Conclusion ............................................................................................................................... 29 6. References ................................................................................................................................ 30 High-Intensity Focused Ultrasound 2 1. Introduction High-intensity focused ultrasound (HIFU) therapy is a technology that uses ultrasound waves to transport energy to target points of body organs, thus increasing the temperature or bringing about other biological interactions. There will not be any significant negative biological effects on the intervening tissue as long as that the ultrasonic energy is appropriately located and focused. Fig. 1 – High-Intensity Focused Ultrasound (HIFU) Compared to other hyperthermia methods such as laser, microwave and radiofrequency, HIFU can treat deep-located tumors in an absolutely non-invasive manner while sparing peripheral normal tissues. The most crucial requirement for HIFU therapy is that the thermal ablation must be precisely delivered to target volume. Because of the complexity and inhomogeneity of human tissue, it is a challenge to ensure the correct coverage of the target volume. By integrating HIFU with imaging modalities, it is possible to control HIFU therapy in order to treat exactly the desired region and minimize damage to adjacent structures. Currently, MRI and diagnostic ultrasound are being used for guidance and monitoring of HIFU therapy. Especially, MRI-guided focused ultrasound surgery (MRgFUS) is quite effective in real-time temperature monitoring, thus allowing us to conduct closed-loop control of energy deposition. High-Intensity Focused Ultrasound 3 2. History and medical applications 2.1 A brief history of HIFU As early as 1927, the biological effects of HIFU were recognized [1]. Then in the 1930s, unfocused ultrasound was applied in physiotherapy [2]. In 1954, Lindstrom [3] and Fry et al. [4] investigated the possibility of using HIFU for treating neurologic disorders in humans. Fry and his colleagues were the first to apply HIFU to humans by producing elevated acoustic intensities in vivo. Then in 1960, they attempted the use of HIFU for treating Parkinson’s disease [5]. In the 1970s, ultrasound was investigated for treating tumors [6]. Unfortunately, this strategy didn’t work out mainly due to the lack of a non-invasive temperature measuring method. In such case, real-time feedback control couldn’t be realized. With the development of modern technologies, particularly advanced imaging methods such as MR thermometry, in the 1990s, HIFU gained a rediscovery period [7] [8]. Nowadays, the medical use of HIFU has been permitted in many countries. For example, MRI-guided treatments of uterine fibroids have been approved in Europe and Asia, and were granted FDA approval in the US in 2004. Every year, numerous researches are conducted in the field of HIFU. 2.2 Tumor ablation applications Not only has HIFU achieved its effective application on tumor ablation, but also on hemostasis [9], drug delivery [10], and gene expression control [11]. Yet, the major application of HIFU clinically is for the treatment of benign and malignant solid tumors [12]. HIFU can be applied to numerous kinds of tumors such as prostate cancer, uterine fibroids, breast cancer, liver cancer and pancreatic cancer. Here, we discuss several relatively widely used tumor ablations [13]. High-Intensity Focused Ultrasound 4 Fig. 1- Illustration depicts HIFU therapy of intraabdominal tumor [12] 2.2.1 Prostate cancer Prostate cancer has the longest history of clinical use of HIFU, therefore, many clinical studies have been performed on it. HIFU for early-stage, localized prostate cancer has been comparable to surgery in terms of local control, disease-free survival, and complication rates. 2.2.2 Uterine fibroids The uterus provides a good target for FUS treatment because it is static and located close to the abdominal wall. Most clinical studies on uterine leiomyoma have been done with MR-assisted HIFU devices. HIFU has been shown to be effective in controlling symptomatic uterine leiomyoma. 2.2.3 Breast cancer The breast is also a superficial and static organ. However, because of the difficulties in treating the axillary lymph nodes, the clinical application of HIFU therapy for breast cancer has been limited. High-Intensity Focused Ultrasound 5 2.2.4 Liver cancer The liver, especially the right lobe, is not a suitable organ for the application of HIFU because of the large respiratory excursions and the sonic shadowing caused by the ribs. Therefore, most clinical studies have been carried out on palliative applications rather than for curative purposes. High-Intensity Focused Ultrasound 6 3. Principle When ultrasound goes through human tissues, there are two kinds of effects: thermal effects and mechanical effects [12]. HIFU mainly takes advantage of ultrasound’s thermal effects to treat tumor, though certain mechanical effects like cavitation can contribute to the temperature rise of focal region [14]. In the focal region of the ultrasound transducer, energy is deposited rapidly, causing a rise of the local temperature, thus generating coagulation necrosis of cancer cells. Fig. 2 – Acoustic intensity in the focus region [15] 3.1 Thermal effects of HIFU [12] During HIFU therapy, the temperature raises rapidly to 60℃ or higher in the High-Intensity Focused Ultrasound 7 tissue. This will cause coagulation necrosis within a few seconds. HIFU generates one or several focuses in tumor region. In such region, the ultrasonic intensity is much higher than that outside the focal region. In this way, regions outside the focal will receive a much lower energy, thus being minimally heated. 3.2 Mechanical effects of HIFU [12] There are three main mechanical effects: Cavitation, Microstreaming and Radiation forces. Cavitation can be defined as the creation or motion of a gas cavity in an acoustic field. Cavitation occurs due to alternating compression and expansion of tissue as an ultrasound field propagates through it. There are two forms of cavitation to consider. The first is stable cavitation, in which a bubble is exposed to a low-pressure acoustic field, resulting in stable oscillation of the size of the bubble. The other is inertial cavitation, in which the exposure of the bubble to the acoustic field results in violent oscillations of the bubble and rapid growth of the bubble during the rarefaction phase, eventually leading to the violent collapse and destruction of the bubble. Stable cavitation may lead to a phenomenon called “microstreaming” (rapid movement of fluid near the bubble due to its oscillating motion). Microstreaming can produce high shear forces close to the bubble that can disrupt cell membranes and may play a role in ultrasound-enhanced drug or gene delivery when damage to the cell membrane is transient. Radiation forces are developed when a wave is either absorbed or reflected. Complete reflection produces twice the force that complete absorption does. 3.3 Ultrasound focusing modes The HIFU system utilizes piezoelectric materials to generate ultrasound. Generally, it uses an array of piezoelectric cells to form a focus. To adjust the position of the focus, there are two ways: mechanically or phase-controlled mode. 3.3.1 Mechanical mode In order to cover the target volume, focus position should be shifted from time to time. Most HIFU system uses mechanical mode to adjust the position of the acoustic focus. In such case, the focus position is relatively the same to the piezoelectric cells. We use a mechanical move system to deliver the focus to positions we desire. High-Intensity Focused Ultrasound 8 3.3.2 Phase-controlled mode Phase-controlled mode is also named electronic mode. Every piezoelectric is controlled by an electronic phase. By adjusting the phases of these cells, we can adjust the focus’s position. Compared to the mechanical mode, the phase-controlled mode is more rapid and there are no concerns about mechanical abrasion. Fig. 3 – Principle of phase-controlled HIFU (A. Spherically-curved transducer, B. Flat transducer with interchangeable lens, C. Phased-array transducer causing only steering, and D. Phased-array transducer causing steering and focusing at same time.) In addition, in phase-controlled mode, we can generate multi-focus pattern, thus reducing HIFU treatment time under certain circumstances. High-Intensity Focused Ultrasound 9 Fig. 4 – single-focus and multi-focus mode of phase-controlled HIFU [15] High-Intensity Focused Ultrasound 10 4. Image-guided HIFU In order to deliver to the target volume thermal or mechanical energy with high accuracy, it is indispensable to integrate medical imaging components to the HIFU system. Several imaging modalities can be utilized for this purpose, thus leading to the concept of image-guided acoustic therapy. Among these modalities, the most frequently used are MRI and diagnostic ultrasound. MRI not only provides superior soft tissue contrast, but also temperature pattern during ablation therapy [16]. While ultrasound has its advantages mainly in real-time aspect and low cost. 4.1 Ultrasound-guided HIFU Ultrasonic imaging has the advantage of low cost and excellent real-time performance. By integrating diagnostic ultrasound with HIFU system, we can 1) get the spatial information of the tissue and the region of interest; 2) guide ultrasound energy delivery during treatment; and 3) assess the effectiveness of HIFU therapy after treatment using contrast enhanced ultrasound imaging. To illustrate it more clearly, we take prostate cancer HIFU treatment as an example. Prostate cancer is the most commonly occurring cancer next to skin cancer and the second leading cause of cancer-related death among men in the U.S [19]. The number of men diagnosed with prostate cancer is increasing rapidly in recent years. It is true that HIFU appears to be an attractive and promising therapy in the treatment of prostate cancer [17]. Focused ultrasound therapy for the treatment of prostate cancer is usually called transrectal HIFU. The transducer probe is inserted manually into the rectum. If we use the Sonablate HIFU device, the single piezoelectric crystal alternates between high-energy power for ablative (3s) and low-energy for ultrasound imaging (6s) which provides image guidance during treatment [21]. In the case of prostate cancer ablation, there is no significant respiratory-induced prostate motion [18]. Thus, we don’t take into consideration the motion of prostate during treatment. 4.1.1 Treatment planning Before treatment, we should visualize related human organs through diagnostic ultrasound. It must then be ascertained whether there is a suitable acoustic window through which the treatment can be delivered, ensuring that the target boundaries can be clearly identified, and that no sensitive normal tissue structures lie in the beam path. Then, we should delineate prostate location and relevant treatment zone. To segment High-Intensity Focused Ultrasound 11 prostate, a semi-automatic method is used. In the meantime, we use Doppler to determinate treatment zones. 4.1.1.1 Prostate boundary delineation Prostate volumes and boundaries play an important role in treatment and follow-up of prostate cancer [20]. For the part of prostate location delineation, there are a series of segmentation algorithms (mentioned in [20]). Here we cite an accurate semi-automatic method in the following part [19]. By this method, the mean error between the computer-generated boundaries and the manual outlining is significantly less than the manual inter-observer distances. This method requires prior information of at least two points in the prostate boundary set by an expert in prostate cancer treatment. Then, from this prior information, we construct a shape model of prostate using deformable superellipses. The last step is to use probabilistic theory to final determinate the prostate boundary. A. Shape model Deformable superellipses are used to represent prostate shape in 2-D ultrasound images. A centered superellipse can be defined in a parametric form by     sin)( cos)( { y x ay ax    and (1) where the size parameters 0},{ yx aa define the lengths of the semi axes and the squareness parameter 0 specifies the squareness in the 2-D plane. The implicit form for a superellipse can be derived from its parametric form as 1)/()/( /2/2   yx ayax (2) where  can be any positive real number if the two terms on the left side of (2) are first raised to the second power. The inside-outside function which provides a simple test whether a given point lies inside or outside the superellipse is shown below:  ))/()/((),( /2/2 yx ayaxyxf  (3) The superellipse representation is powerful in modeling deformed geometric shapes through global deformations, such as tapering and bending. A superellipse can be fully characterized by a vector p = {lx, ly, r, sy, sq, xy, t, b}. The first four pp = {lx, ly, r, sy} are the pose parameters: translation, rotation, and scaling. The last four ps = {sq, xy, t, b} define the deformable superellipse shape: squareness sq, aspect ratio xy, tapering t, and bending b. High-Intensity Focused Ultrasound 12 B. Model fitting Superellipse shapes must be fitted to prior manual information in order to determine the relatively optimal superellipse parameters mentioned above. Here we illustrate the area-minimizing formulation of the squared algebraic distance method.    N i iiyx pyxfaaE 1 2)]1);,(([min (4) As illustrated in part A, f(xi,yi;p) is the inside-outside function. If its value is below 1, it means that the point (x,y) is insider the superellipse; while if value above 1, it indicates that the current point is outside the superellipse. Thus, our goal is to find a superellipse which minimizes the value of E in equation (4). We take the superellipse found as a preliminary result shown in Fig. 5. Fig. 5 – Preliminary result of superellipse fitting (solid line – manual outlining; dotted contour- deformable superellipses) C. Prostate segmentation Using the deformable superellipse as the prior shape model for the prostate, we segment the prostate boundaries in ultrasound images. The end goal is to find the optimal parameter vector p = {lx, ly, r, sy, sq, xy, t, b} that best describes the prostate in a given unsegmented image. The search can be formulated as a maximum a posterior criterion using the Bayes rule that allows seamless integration of prior shape knowledge. We model the shape prior using a multivariate Gaussian distribution Pr(Ps) and the pose prior using a uniform distribution U(pp). We also assume that shape is independent from pose based on our modeling study. The edge strength E of an image can be used as the likelihood. By using the Bayes rule, the a posterior probability density of the deformed boundary given the input edge strength can be expressed as )Pr( )|Pr()Pr()( )Pr( )|Pr()Pr( )|Pr( E pEppU E pEp Ep sp  (5) High-Intensity Focused Ultrasound 13 Pr(E) is the prior probability of the edge strength which can be derived from the image data, thus Pr(E) is equal for all p. U(pp) is constant for all p. In such case, we take the logarithm form of Pr(p|E) and find that it is only related to Pr(ps) and Pr(E|p). As illustrated in [19], the problem now is to maximize the following function   nj jjj npynpxEmpf )),(),,(()]2/()([ 22  (6) mj is the mean value of pj (mj is from the preliminary result), and pj is the jth element of the shape parameter vector ps. The variance for each of the parameters is calculated from the training set. (x(p,n), y(p,n)) is the pixel location of the nth pixel in the deformable superellipse contour.  is the weighting parameter generally associated with the image noise model. In this way, we can get the corresponding parameter vector p of the maximum value of f. In other words, we get the final optimal superellipse. Fig. 6 is two examples of the comparison between manual outlin