The first therapeutic trial of high intensity ultrasound beams was carried out in 1942[8]. The Fry brothers are credited with the first application of HIFU for neurologic disorders in humans[9]. Early attempts to generate HIFU lesions in the brain through the intact skull bone were unsuccessful[8,10]. Small lesions were found in the brain, but there was profound damage to the scalp. Although it was claimed that the symptoms of Parkinsonism were eliminated, this treatment was not taken further, probably because of the concurrent development of the drug L-dopa. The requirement to remove a section of the skull bone and the lack of imaging sophistication limited the progress of this neurosurgical research in its earlier days. In 1970s, US was used to induce hyperthermia (elevation of tissue temperature to about 43°C) in the entire tumor volume for an extended time (about 1 h)[11]. A rediscovery of HIFU for the treatment of tumors occurred in the 1990s with the refinement of modern technologies in transducer design, modes of energy delivery, and real time imaging. Precise targeting and good treatment follow-up techniques (with anatomical and functional imaging) were available with diagnostic US scanning and MRI techniques, which paved the way to realizing the full potential of HIFU treatment. The ability of HIFU to target subcutaneous tissue volumes and produce almost instantaneous cell death by coagulation necrosis in the selected regions of deep-seated soft tissue tumors has made it a candidate for direct and rapid treatment of tumors[3-5].

HIFU relies on the same principles as conventional US. The time-averaged intensities of typical diagnostic US (B-mode, pulsed or continuous Doppler) can be up to 720 mW/cm² according to United States Food and Drug Administration (USFDA) regulations. In contrast, the intensity of HIFU in the focal region is about several orders higher, 100-10 000 W/cm², with peak compression pressures of up to 70 MPa and peak rarefaction pressures up to 20 MPa.

Two main mechanisms are involved in the HIFU ablation: a thermal effect and a mechanical effect. The thermal effect of HIFU is heat generation due to absorption of the acoustic energy with a rapid elevation of temperature in the local tissue. Tissue temperature elevated to more than 60°C for 1 s will generally lead to instantaneous and irreversible cell death via coagulation necrosis in most tissues, which is the primary mechanism for tumor cell destruction in HIFU therapy. Ultrasound beam focusing results in high intensities only at a specific location within a small volume (e.g. about 1 mm in diameter and about 10 mm in length), which minimizes the potential for thermal damage to tissue outside the focal region. Since the thermal mechanism is better understood and its effect is easier to control, it is preferred in tissue ablation.

Tissue thermal damage at high-temperature exposures can be predicted by using an Arrhenius analysis or the Sapareto-Dewey iso-effect thermal dose relationship, which demonstrate that tissue thermal damage is approximately linearly dependent on exposure time and exponentially on the temperature elevation[12]. For convenience, a thermal dose, which is expressed in equivalent minutes at 43°C (EM43°C or t₄₃), is usually applied in hyperthermia or high-temperature hyperthermia. Thermal doses of 120-240 min at 43°C irreversibly damage and coagulate critical cellular protein, tissue structural components and the vasculature leading to immediate tissue destruction, however, the threshold varies with tissue type[13]. At the borders of the thermal coagulated lesion, the tissue will die within 2-3 d.

Mechanical effects induced by HIFU are associated with acoustic pulses only at high intensities, including cavitation, micro-streaming, and radiation force. Cavitation is defined as the creation or motion of a gas cavity in an acoustic field due to alternating compression and expansion of tissue as an ultrasound burst propagates through it. There are two forms of cavitation: stable and inertial cavitation[14]. Stable cavitation is the stable oscillation of the size of the bubble when exposed to a low-pressure acoustic field. Inertial cavitation is violent oscillations of the bubble and rapid growth of the bubble during the rarefaction phase when they reach their size of resonance, eventually leading to the violent collapse and destruction of the bubble. The violent collapse will produce shock waves of very high pressure (20-30 000 bars) and high temperature (2000-5000 K) in the microenvironment[14]. The oscillating motion of stable cavitation causes the rapid movement of fluid near the bubble due to its oscillating motion, which is called the “micro-streaming” effect. Micro-streaming can produce high shear forces that can cause transient damage to cell membranes and may play a role in US-enhanced drug or gene delivery[15]. Meanwhile, radiation force is developed when an acoustic wave is either absorbed or reflected. If the medium is liquid and can move freely, the liquid motion will lead to the generation of microscopic streaming, which can also induce cell apoptosis[16]. In apoptotic cells, the nucleus of the cell self-destructs with rapid degradation of DNA by endonucleases. Apoptosis may be an important delayed bioeffect in tissue exposed to HIFU, especially in cell types that regenerate poorly, such as neurons.

HIFU devices for clinical use fall into three main categories: extracorporeal, transrectal, and interstitial. Extracorporeal transducers are used for targeting organs that are readily accessible through an acoustic window on the skin, whereas transrectal devices are used for the treatment of the prostate and interstitial probes are being developed for the treatment of biliary duct and esophageal tumors.

Focusing a high-intensity US beam can be achieved by a concave self-focusing transducer (e.g. Sonablate-500, Focus Surgery, USA), or arranging multiple piston transducers on the truncated surface of a spherical bowl (e.g. FEP-BY02, Beijing Yuande Biomedical Engineering, China), or fronting a flat transducer with a suitably designed acoustic lens (e.g. Model-JC, Chongqing HAIFU™, China). The -6 dB beam size of HIFU system in its focal region is usually 1-3 mm in width and about 10 mm in length, depending on the geometrical size and acoustic parameters of the HIFU transducer applied. However, the detectable and treatable tumor/cancer in HIFU is at least 1 cm in size. In order to treat the target, HIFU focus should be scanned throughout the entire volume. Moving and/or rotating the HIFU transducer with a fixed focus in a mechanical way was the common method used in the first generation of HIFU systems because of the simplicity in control regardless of the system type. Thanks to developments in electrical control and US transducer fabrication, another focusing and scanning approach became available in the second generation by utilizing phased array technology and adjusting the amplitude and phase of each element individually. Phased array allows more rapid and electrical steering of the HIFU focus through tissue, and greater flexibility in focal geometry. Tissue inhomogeneity in abdominal-pelvic (e.g. uterine fibroids and renal tumors) or transcranial applications might cause focal beam distortion and might largely decrease the focusing ability in deep-seated tissues. Focal beam patterns can be virtually restored by using the phase correction procedure as in US imaging. Subsequently, significant improvement on the shape of temperature profiles and the accuracy of temperature control are expected.

The acoustic energy may be delivered in two ways in HIFU ablation. A single exposure may be made with the transducer held stationary. When larger volumes are to be ablated, the transducer may be moved in discrete steps either mechanically or electronically, and fired at each position, where the distance between “shots” will determine whether lesions are overlapped or separated, depending on the necessity to achieve confluent regions of cell killing (e.g. FEP-BY02 and Sonablate-500 systems). An alternative exposure strategy is to move the active therapy transducer in pre-determined trajectories (e.g. linear tracks or spirals) to conform to the required treatment volume. If the correct combination of transducer velocity and US energy is used, these result in confluent volumes of cell damage (e.g. Model-JC system).

The optimal choice of therapeutic US frequency is application-specific, and represents a compromise between treatment depth and the desired rate of heating. Frequencies near 1 MHz have been found to be most useful for heat deposition, with frequencies as low as 0.5 MHz being used for deep treatments or with large absorption portion in the propagation path (e.g. transcranial application) and as high as 8 MHz for superficial treatments (e.g. prostatic application)[17]. Usually an extracorporeal device has a wide aperture and a long focal length and is driven at high power. Wide aperture sources have the advantage of distributing the incident energy over a large skin area, thus reducing the acoustic intensity at the wave entry site and the consequent possibility of skin burn. Transrectal and interstitial sources operate at lower powers and higher frequencies as they can be placed closer to the target volume. Typical HIFU systems are shown in Figure 2.

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Figure 2 The structure of (A) an extracorporeal (FEP-BY02) and (B) a transrectal (Ablatherm) high intensity focused ultrasound transducer. HIFU: High intensity focused ultrasound.

An extracorporeal HIFU device is usually used for targets lying within the breast, abdomen, brain or limbs. Transcutaneous treatments require an appropriate acoustic window on the entry site that provides a propagation path for the focused US beam that is uninterrupted by intervening gas. In addition, it must be possible to couple the US energy to the skin surface using coupling gel, a water balloon, or other suitable liquid path. Extracorporeal HIFU treatments are guided using either US (e.g. FEP-BY02 of Beijing Yuande Biomedical Engineering and Model-JC of Chongqing HAIFU™ Co.) or a MRI modality (ExAblate 2000 of InSightec, Israel).

MRI has excellent anatomical resolution and high sensitivity for tumor detection, thereby offering accurate planning of the tissue to be targeted. In order to be used in the high magnetic fields of MRI, HIFU transducers must be specially designed for compatibility. The lead zirconate titanate (PZT) ceramic material, commonly used for US transducers, contains nickel, which is necessary for the high levels of electrical excitation and mechanical stress induced. However, nickel causes magnetic field distortion. Therefore, the new piezo-composite materials are usually used to develop MRI-compatible transducers. Using MR thermometry, it enables calculation of thermal dose and superimposes a representation of the regions in which the thermal dose has achieved cytotoxic levels on the anatomical MR image. The phase-shift image used to visualize the temperature-dependent changes in proton-resonance frequency using a fast spoiled gradient-recalled echo sequence (SPGR)[18] is more reliable than T1-weighted imaging[19]. MR proton resonance frequency thermometry at 1.5 T with segmented gradient-echo echo planar imaging (GRE-EPI) sequences has been evaluated during liver tumor radiofrequency (RF) ablation. It was found that MR proton resonance frequency thermometry at 1.5 T yields precise and accurate measurements of temperature increments (1.3 ± 0.4°C with frame rate of 0.6 s/image). Rapid GRE-EPI sequences minimize intra-scan motion effects and can be used for MR thermometry during RF ablation in moving organs[20]. In addition, T1 or T2 weighted fast spin-echo (FSE) were proven successful to image thermal lesions created by HIFU in rabbit liver in vivo. The contrast to noise ratio (CNR) with T1-weighted FSE was significantly higher than T2-weighted FSE (25 vs 14). With T1-weighted FSE, the range of repetition time (TR) under which CNR is high ranges from 400 to 900 ms[21]. Therefore, during the HIFU procedure, the temperature-sensitive MRI provides the ability of closed-loop control of energy deposition, with temperature accuracy of 1°C, spatial resolution of 1 mm, and temporal resolution of 1 s. Immediate post-treatment assessment of the therapy is also available.

Although MRI has the advantage of providing temperature data within seconds after HIFU exposure and it is superior to sonography in obese patients[22], MRI guidance is expensive, labor-intensive, and of lower spatial resolution in some cases. The temporal and spatial averaging effect of the MRI thermometry cannot be ignored and leads to the underestimation of temperature. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73°C after 7 s of continuous HIFU exposure when boiling started, which was detected by visual observation and appearance on the MR images. Theoretical simulation predicted 100°C after 7 s of exposure and the averaged temperature field over the volume of the MRI voxel 0.3 mm × 0.5 mm × 2 mm yielded a maximum of 73°C, which agreed with the MR thermometry measurement[23]. In comparison, US imaging modality is generally more convenient and mechanically compatible. US guidance provides the benefit of imaging using the same form of energy that is being used for therapy. The most significant is that the condition of the acoustic window can be verified with sonography in real-time (usually 30 Hz frame rate depending on the imaging depth and configuration). Therefore, if the target cannot be well visualized with sonography before or during the HIFU ablation, it is unlikely that HIFU therapy will be effective in the target region, and it may potentially cause thermal injury to unintended tissue (e.g. skin on the acoustic wave entry site). An US diagnostic transducer is usually incorporated into the treatment head (Figure 2), which allows real time imaging of the ablation process. However, the thermally ablated region is not visible on standard B-mode images unless gas bubbles have been induced as hyperechoic spots. In addition, the US image quality may be less than optimal.

HIFU with MRI and US guidance have their advantages and shortcomings. US guidance is good for preprocedural tumor localization, but not good for intraprocedural assessment of therapeutic boundaries because the non-specific acoustic contrast generated by heat-induced tissue bubbles. MRI is good for transient tissue temperature measurement, but cannot effectively measure the “lethal thermal dose” and is not sensitive to fat tissue[24]. In recent years, magnetic resonance-guided focused US surgery (MRgFUS) has been developed as an integrated system for HIFU therapy. Heat sensitive microbubbles have also been explored for enhanced US imaging of lethal thermal doses[25].

The transrectal devices that have been developed for the treatment of benign and malignant prostate disease can be inserted per rectum. The two commercially available devices, the Ablatherm^© (Edap Technomed, France) and the Sonablate™ (Focus Surgery, USA), incorporate therapy and imaging transducers into a treatment head mounted at the end of a transrectal probe. Prostate ablation is achieved by placing touching lesions side by side. In the Ablatherm device, lesion length is varied by adjustment of the US power. However, thicker prostates are ablated using two layers of lesions in the Sonablate system, the deeper layer being created using a longer focal length than the more superficial layer. The different focal lengths are achieved by rotating the transducer since the two sides have different geometries. Usually coupling water is circulated and cooled during the HIFU therapy to avoid thermal damage to the interface tissue due to the temperature increase on the surface of the HIFU transducer and to maintain working stability of the HIFU transducer. In contrast, because of the large size of the water balloon in the extracorporeal HIFU system, water cooling in real-time is not required and the degassed water is suggested to be changed every 1-2 h.

There has been increasing interest in the development of high intensity US probes for interstitial use, and volume destruction is obtained by rotating the probe[26]. Usually plane transducers, rather than focusing elements, are used. Once 360° of rotation has been achieved the probe can be repositioned under fluoroscopic or MRI guidance to create other adjacent rings. The interstitial devices can be used for biliary and esophageal tumors, or bloodless partial nephrectomy. It can also be developed into a MR compatible device, or percutaneous and laparoscopic devices. Commercial products are expected to enter the market in the near future.

Popular HIFU systems that have been reported in clinical use are listed in Table 1. With development of the HIFU market, more devices are being developed or are in different stages of clinical trials. Therefore their performance and specifications have not been offered to the public.

Conventionally, US exposures are characterized in terms of the acoustic field determined in the free field. The parameters necessary for describing HIFU exposures are frequency, exposure time, transducer characteristics (geometry and configuration), total power delivered, acoustic pressure and intensity, and energy delivery mode. The total acoustic output power is usually determined using a radiation force balance method[27]. The acoustic exposure power is proportional to the discrepancy of force applied to an absorbing target between HIFU on and off, and depends on the beam convergence angle, the shape and properties of the absorbing target, and the HIFU transducer configuration. Other important factors affecting the measurement are the distance of the target from the source, absorption of energy in the water bath between the transducer and the target, and acoustic streaming effects. The radiation force balance method is particularly useful when very strongly focused transducers and phased arrays are being characterized.

Acoustic pressure is measured using a hydrophone. Both needle and polyvinylidene fluoride (PVDF) membrane hydrophones have been used widely in the calibration acoustic field at low (e.g. US diagnostic system) and intermediate (e.g. physiological US devices) power level. PVDF hydrophones have the advantage of only minimally disturbing the field and high sensitivity, but may be prone to cavitation damage at their surface in a high intensity field. Once damaged, the PVDF and needle hydrophone will not be usable until recalibration. Beam profiles are usually measured at much lower output levels than are used for clinical HIFU treatment and it is assumed that a linear extrapolation to high levels is valid[28]. This method introduces errors since it ignores the effects of nonlinear propagation occurring at high pressures, which increases the amplitude of peak positive pressure significantly, reduces the wave front rise time (formation of shock wave), and introduces harmonic components. Recently, a fiber optic probe hydrophone (FOPH) was used in the HIFU acoustic field measurement[29]. FOPH is robust to the cavitation damage to sensor and has a broad bandwidth (up to 100 MHz after deconvolution) to guarantee the accurate measurement of all harmonics. A new tip can be prepared easily with self-calibration even after damage (optical fiber included in the FOPH is supposed to be used for a life time). With use, the acoustic pressure at high power can be measured directly and operation is rather straight-forward. Once the position of the focal peak has been established, the peak acoustic pressure amplitude can be measured, from which intensity will be calculated. The hydrophone is scanned in the focal region under the automatic control of the three-dimensional translational stage, and measured waveforms are transferred to a computer for further off-line processing. The beam size (usually -6 dB/half of maximum pressure in the lateral and axial directions) can be determined from the pressure distribution. Hill et al[28] defined a parameter, I_SAL, which is the acoustic intensity spatially averaged over the area enclosed by the half pressure maximum contour. It was demonstrated that there was a correlation between lesion diameter and I_SAL[30].

Transrectal HIFU treatment of prostate tumors is one of the pilot investigations. Both benign prostate hyperplasia (BPH) and prostate carcinoma have been targeted at a few medical centers in Europe and Japan in the past decade. Initial clinical trials for BPH treatment were encouraging[31,32], with increases in flow rate and decreases in post-void residual volume. However, the long-term results were disappointing[33], with 43.8% of patients requiring a salvage trans-urethral resection of the prostate (TURP) within 4 years. Therefore, HIFU has not been proved significantly better than the “gold standard” treatment (TURP), and is not recommended for treatment of this condition[34].

In contrast, treatment of prostate cancer presents different problems from those associated with BPH treatment[35]. Prostate cancer is a multi-focal disease, with the foci difficult to detect with diagnostic US. The most successful HIFU treatments have been those that have ablated the whole gland[31,32]. With experience, control rates for the treated tumor have risen from 50% at 8 mo in the early days to 90% more recently[36,37]. Mid-term follow-up (2-5 years) has shown that the prostate specific antigen (PSA) levels remain low and that the negative biopsy rate remains around 90%[36,38,39]. Success rates for the treatment of prostate cancer range from 60%[4] to 80%[40] of patients being disease-free at repeat biopsy and show a reduction of serum PSA values to less than 4 ng/mL[41]. Whole-gland versus focal treatment resulted in a reduced incidence of recurrent tumor of 35% to 17% in one series; in patients not found to be disease-free, reductions in tumor volume greater than 90% have been reported[40]. A representative complete destruction of the glandular tissue due to coagulation necrosis lesion is shown in Figure 3.

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Figure 3 Complete destruction of the glandular tissue due to coagulation necrosis lesion which reaches the capsula and the periprostatic fat 48 h after high intensity focused ultrasound treatment (A) and the necrotic prostatic tissue is replaced by a fibrotic tissue, including the capsula, 3 mo after high intensity focused ultrasound therapy (B).

Complications reported from prostate HIFU include urinary retention, incontinence, urinary infection, impotence, chronic pain, rectal anal fistulas, and incomplete treatment of disease[42]. Repeat treatment with HIFU is associated with much higher complication rates than single treatments[43,44]. To mitigate urinary retention associated with prostate HIFU, transurethral resection was performed before treatment[45,46]; and in these patients, the length of time with indwelling catheters remaining in the bladder has been reduced from 40 to 7 d[36]. Prostate HIFU seems most appropriate in men older than 65 years, those who are not candidates for surgery, and those who are obese[47,48].

The standard treatment for women with breast cancer desiring breast conservation is lumpectomy followed by external radiation therapy. There is increasing interest in recent years to use nonsurgical ablation as part of a breast-conservation therapy in patients with early breast cancer. The cosmetic results and side effects after conventional breast-conservation treatment are acceptable to most patients; however, the nonsurgical ablation methods are thought to be psychologically and cosmetically more satisfactory. HIFU is one of the noninvasive and effective techniques to induce local tumor necrosis, and is also suitable for treating patients who are at high risk for surgery with less anesthesia, reduced in-hospital recovery time and cost, less risk of infections, and no scar formation[49] (Figure 4).

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Figure 4 Sagittal contrast-enhanced T1-weighted fat-saturated magnetic resonance sagittal (A) and axial (C) images of a 1. 8-cm poorly differentiated invasive ductal carcinoma in a 44-year-old woman before MRgFUS. An irregular enhancing mass is seen in the upper outer quadrant of the right breast (arrow heads). Three days after magnetic resonance-guided focused US surgery (MRgFUS), minimal strikes of enhancement are seen without mass like enhancement in the sagittal image (arrow heads in B), which may represent hyperemia due to reactive inflammation or residual tumor. On the axial image (D), dark signal void area is seen at the site of the prior enhancing mass (long arrows). At histopathology, about 50% of the carcinoma and adjacent normal tissue showed thermal effects and the remaining portion of the carcinoma appeared viable.

The HIFU can precisely deliver energy to a given point in soft tissue without interrupting skin integrity. Very few severe (3rd-degree skin burn) and a few minor adverse events were reported. Proximity to the skin should be avoided, and it is important to keep safety margins during the HIFU treatment of breast carcinomas. In total, 19 of 24 patients were considered to have undergone successful treatment (breast biopsy free of neoplasia after 1 or 2 sessions of HIFU). All patients remained free of metastasis on routine follow-up (mean follow-up, 20.2 mo)[50]. The main argument against noninvasive treatments of breast cancer, including HIFU, is that the margin status cannot be assessed due to lack of pathological specimen. Radiological assessment, mainly post-procedure contrast-enhanced MRI, must replace histopathology.

Uterine leiomyomas (fibroids) are gonadal steroid-dependent benign smooth-muscle tumors and are one of the most common female pelvic tumors, occurring in approximately 25% of women[51]. Whereas many patients remain asymptomatic, others experience symptoms such as pelvic pain, menorrhagia, dysmenorrhea, dyspareunia, urinary frequency, and infertility. The most common organ of origin is the uterus, although fibroids can also arise from the fallopian tubes, broad ligament, or cervix. Women are, however, increasingly seeking less invasive treatment options, perhaps motivated toward fertility preservation and a reduction in procedure recovery time. MRI is an optimal modality for further characterizing fibroids because of its good inherent tissue contrast. The addition of post-intravenous gadolinium imaging further characterizes these benign tumors, detecting homogenous enhancement or areas of internal necrosis, which may affect treatment decisions. Gadolinium helps differentiate cellular from degenerating fibroids; cellular lesions usually demonstrate diffused early homogenous enhancement with dynamic imaging, whereas degenerating fibroids demonstrate irregular, delayed, or no enhancement (Figure 5).

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Figure 5 Images of a uterine fibroid pretreatment and posttreatment with MRgFUS. Top, Sagittal T2 fast spin-echo (A), coronal spoiled gradient-recalled echo sequence (SPGR) postgadolinium (B), and axial SPGR postgadolinium (C) are obtained pretreatment. The low SI homogenous fibroid depicted in Figure 3A demonstrates slight heterogenous enhancement pretreatment (Figure 3B, C). Bottom, Sagittal SPGR post-gadolinium (D), coronal SPGR post-gadolinium (E), and axial SPGR post-gadolinium (F) are obtained immediately post-treatment. A new large nonperfused area is identified, consistent with treatment-induced necrosis.

MRgFUS was approved by the USFDA in October 2004, with more than 2000 patients treated to date worldwide. Clinical trials were carried out at 5 medical centers across the United States[52,53], in addition to centers in Japan[54], the United Kingdom, Germany, and Israel. Enrollment of phase I/II began in 1999. The purpose of this study was to assess the safety and feasibility of MRgFUS in the treatment of fibroids. Suitable symptomatic candidates were chosen using an 8-item symptom severity score (SSS) of the Uterine Fibroid Quality of Life Questionnaire[55]. An SSS of 21 of a possible 40 points were required for entry into the clinical trial, as a reflection of the significant fibroid-related symptom burden. Premenopausal women with symptomatic uterine fibroids who have no desire for future pregnancy were included. This treatment is not indicated for pregnant women, postmenopausal women, or those with contrast-enhanced MRI contraindications. The MRgFUS did indeed result in hemorrhagic necrosis in the area of non-perfusion on the post-treatment MR. Only 10% of patients reported taking pain medication within 72 h of treatment. The phase III clinical trial involved treatment of larger volumes in the fibroids of women with symptomatic uterine fibroids. Seventy-nine percent of treated patients reported a 10-point reduction in their SSS, at 6 mo post-treatment, with a 13.5% mean reduction in treated fibroid volume. Most of the improvement in SSS occurs within the first 3 mo of treatment. However, at 12 mo post-treatment, only 51% of those evaluable reported a 10-point reduction in SSS and 28% of patients underwent an alternative treatment by 12 mo[56]. These results should be interpreted in view of the fact that on average only 10% of the fibroid volume was treated, as this FDA-approved study design sought to maximize safety. Gonadotrophin-releasing hormone agonists (GnRHa) are well known to cause a reduction in fibroid size when administered in a continuous fashion. It has recently been demonstrated that the pretreatment of patients who have fibroids measuring 10 cm or greater with GnRHa, before MRgFUS, has a beneficial effect, enhancing the tissue response to HIFU[57].

Although the clinical outcome is best assessed using a disease-specific questionnaire, symptom relief and fibroid volume reduction cannot be assessed until some period later. Immediately post-treatment with MRgFUS, it was found that apparent diffuse coefficient (ADC) values were significantly lower within the area of treatment, which may suggest cell necrosis and loss of membrane integrity due to this treatment. Long-term changes in ADC values on follow-up studies, and the reason for these changes, remain to be determined. In 109 patients studied, leg and buttock pain were reported after treatment. Although the MR neurography and electromyography studies failed to show any intrinsic damage, the sciatic nerve was revealed in the far field of the sonication region.

Hepatocellular carcinoma (HCC) is rapidly becoming the most common malignancy worldwide. Surgery, particularly liver transplantation, offers the only real hope for cure; but survival rates are only 25%-30% at 5 years. Despite considerable advances in diagnostic modalities, the overall prognosis of primary and metastatic liver cancer remains dismal. The poor outcome is attributed mainly to the characteristic biological behavior of hepatic cancer: multiple foci of origin, resulting in low rates of respectability and a high risk of postoperative recurrence. For such a multi-focal and frequently recurrent malignancy, a logical and attractive method of treatment would be using a noninvasive therapeutic modality that can selectively destroy multiple tumor nodules scattered throughout the liver without impairing liver function. A noninvasive therapeutic system would also allow repeated application when necessary. Tumors can be destroyed by producing a contiguous lesion lattice encompassing the tumor and appropriate margins of surrounding tissue determined by computer coordination.

Small animal models have established that HIFU can ablate areas of normal liver[58], and energy thresholds for liver tissue destruction have been published[59]. A maximum lesion size was observed on the third day after treatment, and its replacement by a thin fibrous scar after several months[58]. When intensity was kept constant and exposure time increased, the lesion size increased to a maximum, after which longer exposure times did not cause larger lesions. An optimal result was reached when the necrosis area in the liver had the same dimensions as the desired volume at the desired location. After treatment of normal rabbit livers, hyperechogenic patterns at the target location were rarely observed, even when a homogenous lesion was observed at autopsy. When this hyperechogenic pattern was present immediately, it disappeared 3 wk later. In contrast, the hyperechogenic pattern was always present after successful treatment of rabbits bearing a liver tumor. However, there was no correlation between the size of the hyperechogenic area and the volume of the coagulation necrosis at autopsy[58].

Studies of the treatment of HCC and secondary liver metastasis in human clinical trials have also been published[60,61]. Destruction rates as estimated by quantitative microscopy on millimetric tissue slices ranged from 42.5% to 100%. Histology showed a homogenous dwell-delineated coagulation necrosis corresponding to the target volume in the depth of the liver. No viable tumor tissue remained in the treated area[62]. A model-JC HIFU device has been used to treat 68 patients with liver malignancies in China. In 30 cases in which surgical excision followed HIFU ablation, the tumor was totally ablated[63]. Subsequently, 474 patients with HCC were treated using the same device[64]. HIFU has also been used for palliation in patients with advanced-stage liver cancer[65]. After treatment, 87% of patients reported symptomatic improvement. Patients were also randomized between transarterial chemoembolization (TACE) and HIFU[66]. The median patient survival times were 11.3 mo in the combined HIFU-TACE group and 4 mo in the TACE-only group (P = 0.0042). Overall, HIFU has been shown significant promise in the treatment of hepatic malignancies. Tumor growth inhibition rates from 65%-93% were seen in the HIFU-treated group. They also showed a longer median survival in groups treated with HIFU or HIFU combined with doxorubicin[67].

Surgery remains as the mainstay of treatment for renal tumors, with 5-year survival rates greater than 80% after resection[68]. Because most renal tumors are small, a noninvasive approach for their treatment would be attractive. Currently HIFU ablation of renal tumors in humans remains in the early stages of clinical trials. A clinical feasibility study has been performed on 8 patients who showed histological evidence of ablation in the treated areas after excision[69]. Wu et al[70] reported a series of 13 patients with renal cell carcinoma. Nine of 10 patients treated for palliation reported a reduction in pain. No side effects occurred after ablation using an experimental handheld device. Further investigations continue to study the efficacy of HIFU treatment of renal cell carcinoma for both cure and palliation[70].

More than 32 000 people are diagnosed with pancreatic cancer annually in the United States and as many as 200 000 patients annually worldwide; the 5-year survival rate is less than 5%[1,71]. Pancreatic adenocarcinoma accounts for 5% of cancer deaths in the United States and is the fourth leading cause of cancer mortality. However, only less than 20% of pancreatic cancer patients can undergo open surgery. Two hundred and twenty-three patients with advanced pancreatic cancer (Tumor Node Metastasis stages II-IV) have been treated in China, and the results from this open-label study suggested that HIFU can reduce the size of pancreatic tumors without causing pancreatitis and thus prolong survival[72]. Before HIFU treatment, all patients had obvious visceral pain that necessitated management with oral analgesic drugs. The pain associated with unresectable pancreatic cancer in 84% of patients, however, had resolved significantly within 24-48 h after a single session of HIFU treatment and the pain relief persisted during the follow-up period. 223 patients were followed up from 8 to 36 mo. The average survival time was 12.5 mo and 6 patients survived more than 3 years. No skin burns caused directly by HIFU were observed in this group, and no deaths had occurred 1 mo after HIFU therapy (Figure 6). During the hospital stay, no signs of tumor hemorrhage, large blood vessel rupture, or gastrointestinal perforation were detected in any patient. No dilatation of the common bile duct or pancreatic duct was visible at follow-up imaging. There was no evidence of postinterventional pancreatitis, peritonitis, or jaundice in any patient during the follow-up period[72,73]. Other initial nonrandomized open-label human studies have provided additional evidence that HIFU treatment of pancreatic tumors indeed relieves pancreatic adenocarcinoma-related pain and focally ablates malignant tissue[66].

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Figure 6 Dynamic contrast-enhanced gradient-echo T1-weighted magnetic resonance images (180/6. 0, 90° flip angle, 128 × 256 matrix, 10-mm-thick sections, 2-mm intersection gap, one signal acquired, and 18-s acquisition time) obtained with breath holding in 48-year-old man who underwent high-intensity focused ultrasound ablation for advanced pancreatic cancer. The tumor was 4.5 cm × 4.5 cm in diameter and located in the body of the pancreas. A: Image obtained before high-intensity focused ultrasound shows the blood supply in the pancreatic lesion (arrowhead); B: Image obtained 2 wk after high-intensity focused ultrasound shows no evidence of contrast enhancement in the treated lesion (arrowhead), which is indicative of complete coagulation necrosis in the pancreatic cancer.

Surgical removal and radiation therapy are commonly used strategies to treat bone tumors. The former is often used for primary bone tumors, whereas the latter is more often than not adopted for bone metastases. Initially HIFU was not considered as a suitable modality for bone diseases because of the great difference of acoustic impedance of bone from that of the surrounding soft tissue. However, Smith et al[74] found that focused US beams can target bone tissues and induce necrosis of osteocytes in normal rabbits. In fact, after the bone was destroyed by a lesion, such as an aneurismal bone cyst, the lesion inside the marrow cavity could be verified by diagnostic US imaging[75]. In the targeted region, the destruction of endothelium cells of microvessels and thrombosis was readily detected, suggesting that HIFU could potentially prevent hematogenous dissemination of the tumor cells[76]. The treatable diameters of bone tumor increased with the absorption ratio of bone marrow to tumor, acoustic window of surface skin, and diameter of bone, but decreased with muscle depth and specific absorption rate ratio (SARR) of the bone tumor to the surface skin, bone marrow, and bone[77]. The optimal driving frequency was dependent on tumor depth, US absorption of bone marrow, and bone diameter, but was independent of the acoustic window area and SARR ratio under the three SARR criteria[77].

Ninety-six cases of bone tumors have been successfully treated using HIFU technology as of 2002 in China[78]. 4 patients with primary stage II malignant bone tumors, including 3 chondrosarcoma and 1 malignant giant cell tumor of bone, and 4 patients with breast cancer bone metastases were treated with HIFU ablation alone[79]. All treated regions after HIFU had no intensification and there was an even, thin intensification rim around the region (Figure 7). In ^99mTc-MDP bone scan, disappearance of radioactive uptake was found and a radioactive cold region was produced, suggesting complete inactivation of the tumor foci. After an average follow-up of 23.1 mo, no local recurrence was found in any of the cases, which shows HIFU can be an effective stand-alone therapy to manage malignant bone tumors. However, when diagnostic US was used for guidance of HIFU treatment, nerves might not always be clearly detected. In clinics, there were no significant changes in ECG, renal function, and blood electrolytes of patients before and after HIFU. Although ALP activity (a measure of liver function) increased 3 d after HIFU, it returned to the same or lower pre-HIFU level 1 wk later. Those findings indicated that HIFU ablation had no significant influence on the vital organs.

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Figure 7 Contrast-enhanced magnetic resonance images (A) before and (B) 14-d after high intensity focused ultrasound ablation in a 45-year-old patient with osteosarcoma at the upper right tibia.

Further studies were also done using the combination of HIFU and chemotherapy for managing malignant bone tumors in a total of 44 patients[80]. After a mean follow-up time of 17.6 mo, the overall survival rate was 84.1%. For the 34 cases of stage IIb, 30 cases continued to survive disease-free, 2 died of lung and brain metastases, and the other 2 had local recurrence. Among 10 of the stage IIIb cases, 5 survived with tumor, 1 had local recurrence, and 5 died of lung metastases. It is conceivable that a limb salvage procedure can be carried out to treat malignant bone tumors of limbs using HIFU and chemotherapy because the preliminary results demonstrated that HIFU is effective and well tolerated. HIFU ablation results in fewer complications and well-preserved limb function because there were no surgical traumas and blood vessels > 2 mm in diameter were retained, which could be beneficial to revascularization and the repair of inactivated tumor bones. In addition, because surgical trauma and repair of the trauma are not involved with HIFU treatment, there would be no delay of postoperative chemotherapy, which is beneficial to ensure the efficacy of chemotherapy and to improve the prognosis[81].

Overall, representative HIFU clinical trials are summarized in Table 2. Although the summation is not complete because of unfinished publication collection, current results show HIFU as a safe and effective modality in multiple cancer treatment.

Adjunctive thermal ablation with carmustine, cyclophosphamide and doxorubicin was found to be beneficial in improving the results of HIFU treatment. It has been postulated that sono-modification of the tumor tissue may enhance tumor immunogenicity and subsequently augment the host immune response against the tumor, although the mechanisms behind this phenomenon remain unknown. Animal experiments show that while there were a few HSP70 positive cells in rabbit VX2 bone tumors before HIFU ablation, HSP70 positive cells significantly increased up to 3 wk after HIFU treatment[92]. Furthermore, HIFU ablation also increased CD25 positive cells in the same rabbit bone tumor model. The increase of HSP70 and CD25 positivity in malignant bone tumors may facilitate tumor-specific antigen presentation to T lymphocytes, which stimulate the proliferation of T lymphocytes and enhance the anti-tumor immune response. In a clinical trial, 16 patients with solid malignancies, including 6 with osteosarcoma, were treated with HIFU. There were significant increases in the population of CD4 (+) lymphocytes (P < 0.01) and in the ratio of CD4 (+)/CD8 (+) (P < 0.05) after HIFU ablation[90]. Their findings suggest that HIFU ablation may eliminate or significantly reduce potential circulating tumor cells in patients with solid malignancies. While the long-term therapeutic benefits and molecular mechanisms of HIFU-treatment-elicited host immune responses in cancer patients require further investigation, it is conceivable that HIFU ablation may induce massive tumor cell death and/or necrosis, which could lead to the release of tumor antigens to stimulate a host anti-tumor immune response. These changes may ultimately enhance the immune function of tumor-bearing patients and improve their prognosis.

Drug delivery across the blood-brain barrier (BBB) is one of the most important key factors in the treatment of diseases of the central nervous system (CNS). The BBB is a barrier system of the vessels in the brain that hampers various substances from leaking into the brain. Although this barrier system is important for the maintenance of homeostasis of the brain, it prohibits the delivery of therapeutic agents into the brain and complicates the treatment of CNS disorders[93]. The intracellular space in the BBB is so tight that even one of the smallest molecules, such as ions, cannot easily cross the barrier. Current trans-BBB delivery methods include modifying drug formats or attaching with carriers, or focusing on delivery methods such as intracarotid injection and direct catheter insertion into the brain. The major disadvantage of drug modification is its lack of site specificity and not all drugs can be modified. The invasive techniques also limit the candidates for treatment[93].

Although the possibility of using US for BBB disruption has been previously documented, reproducible and reliable opening of the BBB remains difficult[94]. Creating BBB opening without or with only an acceptable magnitude of tissue damage is one of the most challenging issues. When BBB disruption was attempted by means of US with the combined use of microbubble US contrast agent (Optison, Amersham Health Inc., Princeton, NJ), a more reliable and reproducible BBB opening was achieved compared with that when US alone was used. The BBB disruption was achieved at both 1.0- and 3.3-MPa sonication with a burst length of 100 milliseconds[95]. When temperature elevation was measured using MR thermometry, temperature elevation was only 4.8°C even at the highest amplitude tested. In addition, when the same procedure was performed without the injection of Optison, nearly no BBB opening was achieved (Figure 8). These results indicate that local temperature elevation is not the key mechanism for BBB disruption, and the presence of microbubbles is necessary for the reliable opening of the BBB. The time course study showed that the disrupted BBB repairs itself within approximately 6 h and that the BBB disruption is a transient and reversible event[96]. Long-term follow-up of the sonicated rabbit brain showed nearly no damage, suggesting that the long-term adverse effect of US-induced BBB disruption is minimal[97]. Altogether, it seems reasonable to assume that the parameters for BBB disruption in humans are similar to those used in animal studies. Electron microscopic study suggests that the transcellular pathway is enhanced with US treatment. Drugs were taken up by the endothelial cells by means of vesicle transportation through the endothelial cells and on the loosening or destruction of the tight junctions[96]. From an acoustic point of view, the BBB disruption occurred only with stable cavitation and without the presence of inertial cavitation[98]. US-induced BBB disruption technique can also deliver antibodies to the brain in a localized fashion and the delivered antibodies do not lose their innate function. Herceptin is an antibody against HER-2, which is a receptor for a growth factor and has been shown to be a powerful chemotherapeutic agent against breast tumor. When herceptin was injected into mice using ultrasound-induced BBB disruption technique, the agent was successfully delivered into the brain. Because brain metastases following breast tumors is a very common problem in the clinical field, these results seem promising in providing alternative options for curing patients with brain metastases following breast cancer.

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Figure 8 The axial (A) and the coronal magnetic resonance images (B) are presented with a tissue block showing the blood-brain barrier disruption from the mice, overview of the half hemisphere of a mouse with focused ultrasound-induced blood-brain barrier disruption (C) and high magnification of the lesions with severe damage (D).

Focusing the US through the intact skull is probably the most exciting and challenging application of the HIFU. CT-derived preliminary information must be coregistered with MR images to correct for wave distortion in bone, in particular, to determine the driving signal (amplitude and phase) for each transducer element to achieve a well-focused beam through the skull. However, until now, no clinical trials have been performed using US-induced BBB disruption techniques. In humans, the cranium is much thicker than that of mice or rats, which means that a more careful and delicate control of US is necessary to form a target inside the brain.

Beside the trans-BBB drug delivery, the cytotoxic potential of the anti-cancer drugs, such as bleomycin and adriamycin, may be restricted by its low membrane permeability. Morphological evaluation of US irradiated cells with scanning electron microscopy showed minor disruption of the cell surface and disappearance of microvilli. It suggests that low intensity US altered the cell membrane thus resulting in anticancer drug uptake into carcinoma cells[82]. Application of low-intensity US to growing tumors is found to enhance intracellular delivery after intraperitoneal or intratumoral administration, thereby potentiating its cytotoxicity. Cell death after treatment was shown to occur by an apoptotic mechanism[99,100]. HIFU was also delivered to a mouse model prior to doxorubicin hydrochloride liposomes. Mean doxorubicin concentration in tumors treated with HIFU pulses was significantly higher (124%) than in the control group. Extravasation of dextran-fluorescein isothiocyanate was observed in the vasculature of HIFU-treated tumors but not in that of untreated tumors[101]. Meanwhile, addition of microbubbles in the ultrasound-mediated drug delivery can lower the threshold of bubble cavitation and transiently increase capillary permeability in tumor cells[102]. Although no clinical trials have been performed, this technique could be developed into a localized and effective anticancer treatment with little or no systemic toxicity with enhanced efficiency of thermal ablation.

Blood vessel occlusion is useful for treating arteriovenous malformations (AVM) in different parts of the body for controlling abdominal, peritoneal and pelvic hemorrhage and also for treating some tumors with an identifiable blood supply. HIFU has recently been used to interrupt blood flow in experimental animals[92]. The renal artery branches of rabbits (diameter about 0.6 mm) were occluded by HIFU. Complete cessation of blood flow was observed by color Doppler imaging and MRI, and lack of perfusion was also observed in the renal cortex in the contrast-enhanced image. Postmortem histological evaluation showed an infracted tissue volume corresponding to the wedge shape seen in the ultrasound and MRI images. No damage to the surrounding soft tissue was noted[103]. These results demonstrated that HIFU can be used to induce arterial occlusion, thus producing infarction and necrosis of the perfusion tissue. HIFU may offer a non-invasive, non-surgical technique that effectively obliterates blood flow. However, before clinical applications can be considered, additional studies are needed to obtain data concerning the relationship between the intensity of HIFU required for flow occlusion, blood vessel diameter, and flow velocity, and to investigate possible long-term adverse effects. Blood vessel occlusion may be useful in cancer therapy, where interruption of flow to a tumor may lead to its shrinkage.

A new technique, “histotripsy”, has also been developed to achieve mechanical fractionation of tissue structure using a number of short, high intensity US pulses (20 μs duration, 1 kHz pulse repetition rate, 18 MPa rarefactional pressure)[104]. The transducer has similar geometry and acoustic intensity as the HIFU type, but its center frequency is around 750 kHz. At a fluid-tissue interface, histotripsy results in localized tissue removal with sharp boundaries, which is used to remove cardiac tissue in the treatment of congenital heart disease[105]. In bulk tissue, histotripsy produces mechanical fragmentation of tissue resulting in a liquefied core with very sharply demarcated boundaries. Histology demonstrates treated tissue within the lesion is fragmented to a subcellular level surrounded by an almost imperceptibly narrow margin of cellular injury. As shown in Figure 9B, at the lesion boundary, half of the cell is cut off, and the other half is still intact. The mechanism of histotripsy is acoustic cavitation and energetic microbubble activities fragment and subdivide tissue resulting in cellular destruction[106]. Histotripsy has vast clinical applications where precise tissue ablation and removal are needed (e.g. tumor treatment). Compared to non-invasive thermal therapy, histotripsy has some important advantages: (1) microbubbles produced at the US focus, shown as bright spots on US imaging; (2) energetic microbubble activities can be seen on imaging and provide real-time feedback; (3) the lesions appear darker on US imaging post-treatment; and (4) the lesions can be produced in a very controlled and precise manner. It suggests that in the near future, imaging guided histotripsy can be a potential non-invasive surgery tool. Current clinical targets are: kidney, breast cancer, prostate cancer, several cardiac applications (perforation of the arterial septum for congenital heart disease), BPH, and breast fibroadenoma[107,108].

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Figure 9 Representative (A) image and (B) histology of tissue erosion after histotripsy, and (C) “M” shape lesion generated by histotripsy shown in ultrasound imaging.