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Many biological studies involving ultrasound exposure report acoustic cavitation "thresholds". The purpose of these is often to convince the reader either that cavitation activity was avoided, or that it definitely occurred as the exposure was "above the threshold". Formally, the cavitation threshold is the minimum negative pressure amplitude at which pre-existing bubbles begin to oscillate (non-inertial cavitation) or collapse (inertial cavitation). The cavitation nucleation threshold is that for which bubbles can be drawn out of solution and driven to oscillate. Since the true physical cavitation threshold of a medium can only be measured if it is possible to detect single bubble activity, quoted thresholds are more likely to represent a threshold for detection than for cavitation activity. Furthermore, they may not be relevant beyond the specific experimental conditions tested. In interpreting a negative pressure threshold for cavitation in tissue it is important to know, amongst other things: the tissue status and sample geometry (in order that the in situ pressure may be calculated); details of the ultrasound exposure; method of cavitation detection and detector geometry; data gathering, processing and interpretation methods; threshold definition; sample statistics. Without these details, results may be misleading.

The efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a range of different cancers, including those of the liver, prostate and breast, has been demonstrated. As a non-invasive focused therapy, HIFU offers considerable advantages over techniques such as chemotherapy and surgical resection in terms of reduced risk of harmful side effects. Despite this, there are a number of significant challenges which currently hinder its widespread clinical application. One of these challenges is the need to transmit sufficient energy through the rib cage to induce tissue necrosis in the required volume whilst minimizing the formation of side lobes. Multi-element random-phased arrays are currently showing great promise in overcoming the limitations of single-element transducers. Nevertheless, successful treatment of a patient with liver tumours requires a thorough understanding of the way in which the ultrasonic pressure field from a HIFU array is scattered by the rib cage. In order to address this, a boundary element approach based on a generalized minimal residual (GMRES) implementation of the Burton-Miller formulation was used in conjunction with phase conjugation techniques to focus the field of a 256-element random HIFU array behind human ribs at locations requiring intercostal and transcostal treatment. Simulations were carried out on a 3D mesh of quadratic pressure patches generated using CT scan anatomical data for adult ribs 9-12 on the right side. The methodology was validated on spherical and cylindrical scatterers. Field calculations were also carried out for idealized ribs, consisting of arrays of strip-like scatterers, demonstrating effects of splitting at the focus. This method has the advantage of fully accounting for the effect of scattering and diffraction in 3D under continuous wave excitation.

This guidance is intended to encourage best practice among researchers into ultrasound bio-effects in terms of how they determine and report the exposure conditions used in their studies. It covers both diagnostic and therapeutic applications of ultrasound and is intended to be useful to the researchers themselves, to the review boards of ethical and funding committees and to the editors and reviewers of scientific journals. Recommendations are made for reporting formats, depending on the information available, and level of the study.

Cancer treatment by extracorporeal high-intensity focused ultrasound (HIFU) is constrained by the time required to ablate clinically relevant tumour volumes. Although cavitation may be used to optimize HIFU treatments, its role during lesion formation is ambiguous. Clear differentiation is required between acoustic cavitation (noninertial and inertial) effects and bubble formation arising from two thermally-driven effects (the vapourization of liquid into vapour, and the exsolution of formerly dissolved permanent gas out of the liquid and into gas spaces). This study uses clinically relevant HIFU exposures in degassed water and ex vivo bovine liver to test a suite of cavitation detection techniques that exploit passive and active acoustics, audible emissions and the electrical drive power fluctuations. Exposure regimes for different cavitation activities (none, acoustic cavitation and, for ex vivo tissue only, acoustic cavitation plus thermally-driven gas space formation) were identified both in degassed water and in ex vivo liver using the detectable characteristic acoustic emissions. The detection system proved effective in both degassed water and tissue, but requires optimization for future clinical application.

To determine whether primary extracorporeal high-intensity focused ultrasound (HIFU) is safe, feasible and effective for managing small renal tumours.

The main mechanisms by which ultrasound can induce biological effects as it passes through the body are thermal and mechanical in nature. The mechanical effects are primarily related to the presence of gas, whether drawn out of solution by the negative going ultrasound pressure wave (acoustic cavitation), a naturally occurring gas body (such as lung alveoli), or deliberately introduced into the blood stream to increase imaging contrast (microbubble contrast agents). Observed biological effects are discussed in the context of these mechanisms and their relevance to ultrasound safety is discussed.

The measurement of thermal and ultrasonic properties of biological tissues is essential for the assessment of the temperature rise induced in vivo by diagnostic ultrasound. In this paper, we present measurements of thermal conductivity, thermal diffusivity, speed of sound and ultrasonic attenuation of fresh ex vivo porcine tissue, namely 'muscle' (from abdomen and leg), 'skin with subcutaneous fat' (from abdomen and leg), 'abdominal fat' and 'bone'. The measurements of the thermal properties of biological tissue samples are based on a transient method. Thermal property measurements show that subcutaneous fat has the lowest thermal conductivity (0.23 W m(-1) K(-1)), while muscle gives the highest values (0.46 W m(-1) K(-1)). Thermal diffusivity of muscle tissue recorded the highest value among the studied tissues (0.16 mm(2) s(-1)) while that of skin with subcutaneous fat gave the lowest value (0.11 mm(2) s(-1)). A scanning acoustic macroscope was used to measure attenuation coefficient and speed of sound for the tissue samples. The results for the speed of sound are broadly similar to those reported in the literature. The power law dependence of the attenuation coefficient of the form eta = a f (b) as a function of frequency was found to be more appropriate than the linear fit in this study.

The use of gas-filled microbubbles as ultrasound contrast agents raises potential safety concerns for diagnostic ultrasound imaging. A number of biological effects have been seen in experimental systems, including the induction of physiological response to cardiac exposures (premature ventricular contractions) and damage at a microvascular level (microvascular rupture and petechial haemorrhage). The literature indicates that a mechanical index (MI) of 0.4 represents the threshold above which microvascular bio-effects are seen in in vivo studies. Above this value, the extent of biological effects appears to increase rapidly with both increasing in situ peak negative acoustic pressure amplitude and with contrast agent concentration. While there is no proven evidence of harm resulting from clinical use of these agents, caution is recommended when contrast-enhanced imaging is undertaken.

Cancer therapies usually depend on cross-sectional imaging for the assessment of treatment response. This study was designed to evaluate the ability of MRI to predict zones of necrosis following the use of high-intensity focused ultrasound (HIFU) to treat liver metastases. Patients with liver metastases, who had been scheduled for elective surgical resection of their tumours, were recruited to this non-randomized Phase II study. In each case, a proportion of an index liver tumour target was ablated. The response to HIFU was assessed after 12 days using contrast-enhanced MRI and compared directly with histological analysis at the time of surgery. Eight patients were treated, of whom six were subsequently assessed with both MRI and histology. There were no major complications. MRI predicted complete ablation in three cases. In each case, histological analysis confirmed complete ablation. In one case, the region of ablation observed on MRI appeared smaller than predicted at the time of HIFU, but histology revealed complete ablation of the target region. The predominant characteristic of HIFU-ablated tissue was coagulative necrosis but heat fixation was evident in some areas. Heat-fixed cells appeared normal under haematoxylin and eosin staining, indicating that this is unreliable as an indicator of HIFU-induced cell death. This study demonstrates that HIFU is capable of achieving selective ablation of pre-defined regions of liver tumour targets, and that MRI evidence of complete ablation of the target region can be taken to infer histological success.

Accurate temperature measurements in therapeutic ultrasound fields are necessary for understanding damage mechanisms, verification of thermal modelling and calibration of non-invasive clinical thermometry. However, artefactual heating, primarily due to viscous forces which result from motion relative to the surrounding tissue, occurs when metal thermocouples are used in an ultrasound field. The magnitude and time dependence of this artefact has been characterized by comparison with novel thin-film thermocouples (TFTs) at 1-2 cm focal depths in fresh degassed ex vivo bovine liver. High-intensity focused ultrasound exposures (1.7 MHz; free-field spatial-peak temporal-average intensities 40-600 W cm(-2)) were used. Subtraction of the TFT data from that obtained for other thermocouples yielded the time dependence of the viscous heating artefact. This was found to be intensity independent up to 600 W cm(-2) (below the threshold for cavitation and lesion formation) and remained significant at radial distances out to the first side lobe in the focal plane. The contribution of viscous heating to cooling was also found to be significant for at least 5 s after the end of insonation. The ratio of viscous artefact to absorptive heating after 5 s was: 1.76 +/- 0.07 for a fine-wire, 0.45 +/- 0.07 and 1.93 +/- 0.07 for two different sheathed-wires and 0.24 +/- 0.07 for a needle thermocouple.

To integrate a high intensity focused ultrasound (HIFU) transducer with an MR receiver coil for endocavitary MR-guided thermal ablation of localized pelvic lesions.

Therapeutic applications of ultrasound predate its use in imaging. A range of biological effects can be induced by ultrasound, depending on the exposure levels used. At low levels, beneficial, reversible cellular effects may be produced, whereas at high intensities instantaneous cell death is sought. Therapy ultrasound can therefore be broadly divided into "low power" and "high power" applications. The "low power" group includes physiotherapy, fracture repair, sonophoresis, sonoporation and gene therapy, whereas the most common use of "high power" ultrasound in medicine is probably now high intensity focused ultrasound. Therapeutic effect through the intensity spectrum is obtained by both thermal and non-thermal interaction mechanisms. At low intensities, acoustic streaming is likely to be significant, but at higher levels, heating and acoustic cavitation will predominate. While useful therapeutic effects are now being demonstrated clinically, the mechanisms by which they occur are often not well understood.

Uterine fibroids are a significant source of morbidity for women of reproductive age. Definitive treatment has traditionally been a hysterectomy, but increasingly women are not prepared to undergo such an invasive procedure for a benign and usually self-limiting condition. Although a number of minimally invasive techniques are now available, focused ultrasound has a considerable advantage over them as it is completely non-invasive and does not require an anaesthetic. Improvements in imaging techniques, particularly magnetic resonance imaging (MRI), have enabled the accurate planning, targeting and monitoring of treatments. We review the early experience of focused ultrasound surgery for the treatment of fibroids, and, in particular, the results of the recent phase I, II and III multi-centre clinical trials. These trials and other studies which demonstrate that MR-guided focused ultrasound ablation is feasible, safe and appears to have an efficacy that is comparable with other treatment modalities are described. This technique has the advantages of being non-invasive and being deliverable as an out-patient procedure.

The noninvasive ablation of tumors with high-intensity focused ultrasound (HIFU) energy has received increasingly widespread interest. The temperature within the focal volume of an ultrasound beam is rapidly raised to cytotoxic levels. HIFU can selectively ablate a targeted tumor at depth without any damage to surrounding or overlying tissues. Animal studies have shown that HIFU ablation is safe and effective for the treatment of implanted breast malignancies. The results from early clinical trials (Phase I and II) are encouraging, suggesting that HIFU is a promising treatment for small breast cancer. Once oncologic efficacy data from large-scale randomized clinical trials are available, HIFU ablation may become an attractive treatment option for patients with small breast cancer, especially the elderly.

High intensity focused ultrasound (HIFU) is gaining rapid clinical acceptance as a treatment modality enabling non-invasive tissue heating and ablation for numerous applications. HIFU treatments are usually carried out in a single session, often as a day case procedure, with the patient either fully conscious, lightly sedated or under light general anaesthesia. A major advantage of HIFU over other thermal ablation techniques is that there is no necessity for the transcutaneous insertion of probes into the target tissue. The high powered focused beams employed are generated from sources placed either outside the body (for treatment of tumours of the liver, kidney, breast, uterus, pancreas and bone) or in the rectum (for treatment of the prostate), and are designed to enable rapid heating of a target tissue volume, while leaving tissue in the ultrasound propagation path relatively unaffected. Given the wide-ranging applicability of HIFU, numerous extra-corporeal, transrectal and interstitial devices have been designed to optimise application-specific treatment delivery. Their principle of operation is described here, alongside an overview of the physical mechanisms governing HIFU propagation and HIFU-induced heating. Present methods of characterising HIFU fields and of quantifying HIFU exposure and its associated effects are also addressed.

Acoustic cavitation has been shown to play a key role in a wide array of novel therapeutic ultrasound applications. This paper presents a brief discussion of the physics of thermally relevant acoustic cavitation in the context of high-intensity focused ultrasound (HIFU). Models for how different types of cavitation activity can serve to accelerate tissue heating are presented, and results suggest that the bulk of the enhanced heating effect can be attributed to the absorption of broadband acoustic emissions generated by inertial cavitation. Such emissions can be readily monitored using a passive cavitation detection (PCD) scheme and could provide a means for real-time treatment monitoring. It is also shown that the appearance of hyperechoic regions (or bright-ups) on B-mode ultrasound images constitutes neither a necessary nor a sufficient condition for inertial cavitation activity to have occurred during HIFU exposure. Once instigated at relatively large HIFU excitation amplitudes, bubble activity tends to grow unstable and to migrate toward the source transducer, causing potentially undesirable pre-focal damage. Potential means of controlling inertial cavitation activity using pulsed excitation so as to confine it to the focal region are presented, with the intention of harnessing cavitation-enhanced heating for optimal HIFU treatment delivery. The role of temperature elevation in mitigating bubble-enhanced heating effects is also discussed, along with other bubble-field effects such as multiple scattering and shielding.

Ultrasound (US)/microbubble-mediated gene delivery is a technology with many potential advantages suited to clinical application. Previous studies have demonstrated transfection but many are unsatisfactory in respect to the exposure apparatus, lack of definition of the US field or the limitations on parameters that can be explored using clinical diagnostic US machines. We investigated individual exposure parameters using a system minimising experimental artefacts and allowing control of many parameters of the US field. Using a 1-MHz transducer we systematically varied US parameters, the duration of exposure and the microbubble and DNA concentrations to optimise gene delivery. Delivery was achieved, using lipid microbubbles (SonoVue) and clinically acceptable US exposures, to adherent cells at efficiencies of approximately 4%. The acoustic pressure amplitude (0.25 MPa peak-negative), pulse repetition frequency (1-kHz) and duration of exposure (10 s) were important in optimising gene delivery with minimal impact on cell viability. These findings support the hypothesis that varying the physical parameters of US-mediated gene delivery has an affect on both efficiency and cell viability. These data are the first in terms of their thorough exploration of the US parameter space and will be the basis for more-informed approaches to developing clinical applications of this technology.

Ultrasound/microbubble-mediated gene delivery has the potential to be targeted to tissue deep in the body by directing the ultrasound beam following vector administration. Application of this technology would be minimally invasive and benefit from the widespread clinical experience of using ultrasound and microbubble contrast agents. In this study we evaluate the targeting ability and spatial distribution of gene delivery using focused ultrasound.

The use of focused ultrasound as a minimally invasive treatment for tumours is rapidly expanding. Target organs include the liver and kidneys. Both single element and phased array transducers may be used in the clinic. The presence of the rib cage presents a problem in high intensity focused ultrasound (HIFU) treatment planning, due to its high attenuation of the HIFU beam resulting in a loss of power at the focus as well as an increase in the risk of damage at the rib and to overlying tissues, including the skin. In this paper, a linearly segmented transducer, in which all active elements are driven in phase, has been investigated. The aim of the study was to investigate how a beam with a clinically useful profile could be achieved by removing the contribution of edge segments from one side of the transducer to the field. We have considered the case in which the HIFU beam approaches the rib cage during a treatment and investigated configurations of the transducer for which up to three segments on the edge are switched off. This problem has been studied initially using a linear acoustic field program to model the segmented transducer's acoustic beam profile. Experimental measurements of the transducer's acoustic field were performed using an automated beam plotting system. Temperature measurements were made on a rib surface for two transducer configurations using a fine wire thermocouple. A thermochromic liquid crystal material was used to assess qualitatively the heating pattern generated by the ultrasound beam. We show the rib sparing potential of the segmented transducer during HIFU treatment by demonstrating a reduction in the prefocal width of the ultrasound beam when edge segments are switched off. This has been predicted with the acoustic field model and demonstrated experimentally by acoustic field measurements and observations of the heating pattern generated by the ultrasound beam. A significant decrease in the temperature rise on a rib was observed in the case for which three edge segments were switched off compared with when all segments were active. We conclude that a segmented transducer extends the potential for treating liver tumours. In the case where the tumour lies behind, but close to the edge of, the ribs, energy loss at the focus and excessive heating in the rib and overlying tissue can be avoided by switching off edge segments.

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

High-intensity focused ultrasound (HIFU) has been investigated as a tool for the treatment of cancer for many decades, but is only now beginning to emerge as a potential alternative to conventional therapies. In recent years, clinical trials have evaluated the clinical efficacy of a number of devices worldwide. In Oxford, UK, we have been using the JC HIFU system (HAIFU Technology Company, Chongqing, PR China) in clinical trials since November 2002. This is the first report of its clinical use outside mainland China. The device is non-invasive, and employs an extracorporeal transducer operating at 0.8-1.6 MHz (aperture 12-15 cm, focal length 9-15 cm), operating clinically at Isp (free field) of 5-15 KWcm(-2). The aims of the trials are to evaluate the safety and performance of the device. Performance is being evaluated through two parallel protocols. One employs radiological assessment of response with the use of follow-up magnetic resonance imaging and microbubble-contrast ultrasound. In the other, histological assessment will be made following elective surgical resection of the HIFU treated tumours. Eleven patients with liver tumours have been treated with HIFU to date. Adverse events include transient pain and minor skin burns. Observed response from the various assessment modalities is discussed.

Ultrasonic estimation of heat-induced echo strain has been suggested as a noninvasive technique for guiding focused ultrasound (US) surgery (FUS), that is, for predicting the location of the thermal lesion before it is formed. The proposed strategy is to run the FUS system at a nonablative intensity and to use a diagnostic transducer to image the heat-induced echo strain, which, over a sufficiently small temperature range, is proportional to the temperature rise. The principal aim of this in vitro study was to determine if temperature-induced strain imaging is likely to be able to visualise the small (< 0.5%) strains that one would be restricted to in vivo. Temperature rises ranging from approximately 2 degrees C to 15 degrees C (starting at approximately 25 degrees C) were induced in bovine liver samples using an FUS system. The pre- and post-heated US images were processed to produce images of the apparent axial strain. These images were found to possess excellent spatial and contrast resolution, so that the hot spot remained clearly visible even when the spatial peak strain value was approximately 0.2% (corresponding to temperature rises on the order of 2 to 5 degrees C). Good repeatability in the strain images was observed within and between tissue samples. Artefacts due to thermoacoustic refraction were seen distal to the heated region, but they did not reduce hot spot visibility. The length of the hot spot exceeded that of the subsequent ablation (by approximately 200%), which was to be expected given that temperature imaging depicts the entire area over which the temperature has increased relative to the baseline. We conclude that temperature-induced strain imaging for the guidance of FUS in the liver is likely to be feasible, provided that it will be possible either to neglect or to correct for the additional sources of error (such as cardiac-induced motion) that will arise in vivo.

We report the use of contrast-enhanced ultrasonography as an immediate means of assessing the clinical response to high-intensity focused ultrasound (US) or HIFU treatment of liver tumours. HIFU is a noninvasive transcutaneous technique for the ablation of tumours that has been shown to destroy tumour vasculature, as well as to cause coagulative necrosis of tumour cells. As a dynamic indicator of tissue perfusion, microbubble contrast agents have already been reported to increase the diagnostic sensitivity of ultrasonography in the detection of liver tumours. This report documents the ability of one i.v. microbubble contrast agent (SonoVue, Bracco, Italy) to delineate the extent of HIFU ablation by comparison of pre- and immediately posttreatment perfusion within the target tumour. Observed changes were seen to correlate well with the ablated volume on histologic evaluation of the treated volume. This is the first time that this imaging technique has been reported in this setting.

Ultrasonic estimation of heat-induced echo strain has been suggested as a noninvasive technique for guiding focused ultrasound (US) surgery (FUS), that is, for predicting the location of the thermal lesion before it is formed. The proposed strategy is to run the FUS system at a nonablative intensity and to use a diagnostic transducer to image the heat-induced echo strain, which, over a sufficiently small temperature range, is proportional to the temperature rise. The principal aim of this in vitro study was to determine if temperature-induced strain imaging is likely to be able to visualise the small (< 0.5%) strains that one would be restricted to in vivo. Temperature rises ranging from approximately 2degreesC to 15degreesC (starting at similar to25degreesC) were induced in bovine liver samples using an FUS system. The pre- and post-heated US images were processed to produce images of the apparent axial strain. These images were found to possess excellent spatial and contrast resolution, so that the hot spot remained clearly visible even when the spatial peak strain value was similar to0.2% (corresponding to temperature rises on the order of 2 to 5degreesC). Good repeatability in the strain images was observed within and between tissue samples. Artefacts due to thermoacoustic refraction were seen distal to the heated region, but they did not reduce hot spot visibility. The length of the hot spot exceeded that of the subsequent ablation (by similar to200%), which was to be expected given that temperature imaging depicts the entire area over which the temperature has increased relative to the baseline. We conclude that temperature-induced strain imaging for the guidance of FUS in the liver is likely to be feasible, provided that it will be possible either to neglect or to correct for the additional sources of error (such as cardiac-induced motion) that will arise in vivo. (C) 2004 World Federation for Ultrasound in Medicine Biology.

The effects of heat-generated changes on the attenuation of ultrasound (US) by porcine liver tissue have been studied over a frequency range of 2.0 to 5.0 MHz. Samples of fresh tissue, 4- to 5-mm thick, were pressurized and cooled before measurement. The insertion loss was measured at room temperature, using a broadband 3.5-MHz transducer of focal length 10 cm, employing a pulse-reflection technique. Fourier analysis of the results gave the frequency-dependence of the insertion loss. Samples were then heated in a water bath to a temperature in the range of 40 to 80 degrees C, for between 30 and 500 s. The insertion loss was then re-measured at room temperature. The frequency-dependence of the change in insertion loss, expressed as a coefficient, in dB/cm, was fitted by linear regression, from which the attenuation change at 3.5 MHz was determined. This change was attributed to protein coagulation. Increases of up to 2.4 dB/cm, (80 degrees C, 300 s) were found. The averaged data were fitted to a single step exponential model, resulting in a time constant on the order of 118 +/- 5 s, and an asymptotic limit to the increase of attenuation coefficient of 2.67 +/- 0.5 dB/cm.

The aim of the work is to evaluate a magnetic resonance imaging (MRI) thermometry sequence suitable for targeting of focused ultrasound (FUS) when used in vascular occlusion studies. A sliding window dual gradient echo (SW-dGRE) sequence was used. This sequence has the capability of monitoring both T1 relaxation and phase changes, which vary with temperature. Preliminary work involved quantification of the changes in T1 relaxation time with temperature and obtaining the PRF shift coefficient in polyacrylamide gel as it underwent an exothermic reaction during polymerization (avoiding the use of an external heat source). Temperature changes were visualized using thermal maps acquired with the sequence. For FUS guidance a thermal imaging technique is required with a temporal resolution <5 s, a spatial resolution of approximately 1 mm and a temperature resolution of approximately 5 degrees C. The sequence was optimized to improve the CNR (contrast to noise ratio) and SNR (signal to noise ratio) in the phase and magnitude images respectively. The PRF coefficient obtained for the polyacrylamide gel was -9.98 +/- 0.24 ppb degrees C(-1), whilst deltaT1 and temperature change were related by a proportionality factor, the T1 temperature coefficient, of 102.3 +/- 2.9 ms degrees C(-1). The sequence produces an image at every 1.4 s interval. In both magnitude and phase data, the in-plane resolution is +/- 1.2 mm and the temperature resolution is approximately 2 degrees C. The advantage of this sequence is that the temperature obtained from the magnitude data can be confirmed independently using the phase data and vice versa. Thus the sequence can essentially be crosschecked.

For 50 years, high intensity focused ultrasound (HIFU) has been a subject of interest for medical research. HIFU causes selective tissue necrosis in a very well defined volume, at a variable distance from the transducer, through heating or cavitation. Over the past decade, the use of HIFU has been investigated in many clinical settings. This literature review aims to summarize recent advances made in the field. A Medline-based literature search (1965-2002) was conducted using the keywords "HIFU" and "high intensity focused ultrasound". Additional literature was obtained from original papers and published meeting abstracts. The most abundant clinical trial data comes from studies investigating its use in the treatment of prostatic disease, although early research looked at applications in neurosurgery. More recently horizons have been broadened, and the potential of HIFU as a non-invasive surgical tool has been demonstrated in many settings including the treatment of tumours of the liver, kidney, breast, bone, uterus and pancreas, as well as conduction defects in the heart, for surgical haemostasis, and the relief of chronic pain of malignant origin. Further clinical evaluation will follow, but recent technological development suggests that HIFU is likely to play a significant role in future surgical practice.

Ultrasonic contrast agents are usually comprised of a stabilised shell encapsulating a gas bubble. When these are introduced in the body they increase the acoustic scattering from the tissues through which they pass, and especially from the vasculature. Their primary uses lie in cardiological and oncological imaging. However, these microbubbles have the potential to act as centres for acoustic cavitation activity, and so it is important to consider the safety of their use from an acoustic standpoint. The addition of ultrasonic contrast agents to in vitro suspensions of red blood cells has been shown to lead to haemolysis when the sample is exposed to ultrasound at levels which leave the cells unharmed in their absence. In vivo the infusion of gas bubble contrast agents into experimental animals has been shown to enhance the incidence of petechiae and haemorrhage in the intestine. The Mechanical Index (MI) thresholds for the effects seen in vitro lie within the range of MIs available with diagnostic clinical scanners, but in vivo the thresholds lie at the top end of the exposure levels available clinically. No adverse effects in humans arising from the ultrasonic exposure of these contrast agents have been reported to date.

The main objective of this study is to investigate the possible use of the Doppler signal from microbubbles (Levovist) to measure the arterial input function in dynamic positron emission tomography (PET). We have measured the dynamics in a fluid (water or plasma equivalent) of radioactive tracers and microbubbles contrast agents (MB) experimentally. The experimental system allows us to simulate the dispersion of these tracers in large arteries, and, using an appropriate phantom, the dispersion in the heart and lungs. Time-activity curves for Tc-99m were obtained using an NaI(TI) probe connected to a multiscaler system. A Doppler probe was used to measure scattering from the microbubble. The data were processed using MATLAB. The measurement with the radioactive tracer shows a reasonable agreement with theoretical models. Noise present in the Doppler signal, probably caused by the pump, has been reduced using a denoising procedure in the wavelet domain based on a Daubechies wavelet function. Differences in tracer kinetics between Tc-99m and MB found in water are significantly reduced in plasma-equivalent fluid. We conclude that the two methods are comparable and that this method might provide a noninvasive way of measuring arterial input functions for PET.

High intensity focused ultrasound (HIFU) is a technique that was first investigated in the 1940s as a potential method of destroying selective regions within the brain to aid neurobehavioral studies. A beam of ultrasound can be brought to a tight focus at a distance from its source, and if sufficient energy is concentrated within the focus, the cells lying within this focal volume are killed, whereas those lying elsewhere are spared. This is, therefore, a noninvasive method of producing selective and "trackless" tissue destruction in deep-seated targets in the body without damage to overlying tissues. This technique is being investigated in a number of medical fields, including urology, ophthalmology, and oncology. The mechanism for cell killing is mainly thermal in origin. Renewal of interest in this technique is due to the availability of sophisticated medical imaging, which now allows the focal volume to be accurately targeted and also allows the tissue destruction to be monitored during treatment. The burgeoning field of HIFU focused ultrasound surgery (FUS) are reviewed in this article.

High-intensity focused ultrasound (HIFU) is a technique that was first investigated in the 1940s as a method of destroying selective regions within the brain in neuro-surgical An ultrasound beam can be brought to a tight focus at a distance from its source, and if sufficient energy is concentrated within the focus, the cells lying within this focal volume are killed, whereas those lying elsewhere are spared. This is a noninvasive method of producing selective and trackless tissue destruction in deep seated targets in the body, without damage to overlying tissues. This field, known both as HIFU and focused ultrasound surgery (FUS), is reviewed in this article.

Overpressure--elevated hydrostatic pressure--was used to assess the role of gas or vapor bubbles in distorting the shape and position of a high-intensity focused ultrasound (HIFU) lesion in tissue. The shift from a cigar-shaped lesion to a tadpole-shaped lesion can mean that the wrong area is treated. Overpressure minimizes bubbles and bubble activity by dissolving gas bubbles, restricting bubble oscillation and raising the boiling temperature. Therefore, comparison with and without overpressure is a tool to assess the role of bubbles. Dissolution rates, bubble dynamics and boiling temperatures were determined as functions of pressure. Experiments were made first in a low-overpressure chamber (0.7 MPa maximum) that permitted imaging by B-mode ultrasound (US). Pieces of excised beef liver (8 cm thick) were treated in the chamber with 3.5 MHz for 1 to 7 s (50% duty cycle). In situ intensities (I(SP)) were 600 to 3000 W/cm(2). B-mode US imaging detected a hyperechoic region at the HIFU treatment site. The dissipation of this hyperechoic region following HIFU cessation corresponded well with calculated bubble dissolution rates; thus, suggesting that bubbles were present. Lesion shape was then tested in a high-pressure chamber. Intensities were 1300 and 1750 W/cm(2) ( +/- 20%) at 1 MHz for 30 s. Hydrostatic pressures were 0.1 or 5.6 MPa. At 1300 W/cm(2), lesions were cigar-shaped, and no difference was observed between lesions formed with or without overpressure. At 1750 W/cm(2), lesions formed with no overpressure were tadpole-shaped, but lesions formed with high overpressure (5.6 MPa) remained cigar-shaped. Data support the hypothesis that bubbles contribute to the lesion distortion.

This study was undertaken to investigate the ability of focused ultrasonic surgery to occlude blood flow in vivo.

Modern sophisticated ultrasonographic equipment is capable of delivering substantial levels of acoustic energy into the body when used at maximum outputs. The risk of producing bioeffects has been studied by international expert groups during symposia supported by the World Federation for Ultrasound in Medicine and Biology (WFUMB). These have resulted in the publication of internationally accepted conclusions and recommendations. National ultrasound safety committees have published guidelines as well. These recommendations and safety guidelines offer valuable information to help users apply diagnostic ultrasound in a safe and effective manner. Acoustic output from ultrasound medical devices is directly regulated only in the USA and this is done by the Food and Drug Administration (FDA). However, there is also a modern trend towards self-regulation which has implications for the worldwide use of diagnostic ultrasound. It has resulted in a move away from the relatively simple scheme of FDA-enforced, application-specific limits on acoustic output to a scheme whereby risk of adverse effects of ultrasound exposure is assessed from information provided by the equipment in the form of a real-time display of safety indices. Under this option, the FDA allows a relaxation of some intensity limits, specifically approving the use of medical ultrasound devices that can expose the fetus or embryo to nearly eight times the intensity that was previously allowed. The shift of responsibility for risk assessment from a regulatory authority to the user creates an urgent need for awareness of risk and the development of knowledgeable and responsible attitudes to safety issues. To encourage this approach, it is incumbent on authorities, ultrasound societies and expert groups to provide relevant information on biological effects that might result from ultrasonographic procedures. It is obvious from the continued stream of enquiries received by ultrasound societies that effective dissemination of such knowledge requires sustained strenuous effort on the part of ultrasound safety committees. There is a strong need for continuing education to ensure that appropriate risk/benefit assessments are made by users based on an appropriate knowledge of the probability of biological effects occurring with each type of ultrasound procedure. The primary purpose of this paper is to draw attention to current safety guidelines and show the similarities and areas of general agreement with those issued by the parent ultrasound organisation, the WFUMB. It is equally important to identify gaps in our knowledge, where applicable.

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical for predicting lesion formation in focused ultrasound (US) surgery (FUS). To date, most models have used linear propagation models to predict intensity profiles required to compute the temporally varying temperature distributions used to compute thermal dose contours. These are used to predict the extent of thermal damage. However, these simulations fail to describe adequately the abnormal lesion formation behaviour observed during ex vivo experiments in cases for which the transducer drive levels are varied over a wide range. In such experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increased transducer drive levels than would be predicted using linear-propagation models. The first set of simulations described herein use the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused US waves to demonstrate that both the peak intensity and the lesion positions do, indeed, move closer to the transducer. This illustrates that, for accurate modelling of heating during FUS, nonlinear effects should be considered. Additionally, a first order approximation has been employed that attempts to account for the abnormal heat deposition distributions that accompany high transducer drive level FUS exposures where cavitation and boiling may be present. The results of these simulations are presented. It is suggested that this type of approach may be a useful tool in understanding thermal damage mechanisms.

The primary aim of this phase I trial was to assess the tolerance of cancer patients to focused ultrasound (FUS) treatment in a variety of different sites and to document any associated acute or delayed toxicity. This would appear to be the first time that treatment has been given without sedation or anaesthesia.

Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology.

Experiments were performed to investigate the production of harmonics by high-intensity focused ultrasound (HIFU) produced by a spherical bowl; spherical radius 15 cm, frequency 1.7 MHz, as a function of beam power in excised bovine liver. The intensity of the nth harmonic, in both water and the tissue sample, varied approximately as the nth power of the incident intensity up to the point at which irreversible changes were produced in the sample. The greatest observed axial power absorption enhancement factor was approximately 6.3, and the greatest observed total absorbed power enhancement was approximately 2.3. These enhancements may have some effect on the onset of lesioning, but not much effect on its subsequent development. In water, at an intensity of about 120 W/cm2 at the focus, the -3-dB beam diameters of harmonic components were observed to vary approximately as the inverse square root of the harmonic number.

Therapeutic ultrasound has been in use for many years. Early applications were those for which tissue heating was the goal, and so it was used for soft tissue injuries such as may be incurred during sport. More recently, attention has been drawn both to high intensity focused beams that may be used for thermal ablation of selected regions, and also to low intensity fields that appear to be able to stimulate physiological processes, such as tissue repair, without biologically significant temperature rises. Ultrasonic tools are used for therapeutic effect in dentistry and are being investigated for use in thrombolysis. This paper reviews the various therapeutic applications of ultrasound.

The purpose of this investigation was to study the tissue damage (including blood vessels) on both normal and tumor-bearing experimental livers and the course of liver repair after focused ultrasound (FUS) treatment using histological evaluation. A series of experiments were carried out in vivo. Tissue was treated using arrays of ultrasound exposures with a frequency of 1.7 MHz, in situ spatially averaged focal intensity (I(SAL) in situ) of 212-266 W/cm2 (corresponding to in situ spatial peak intensity of 382-479 W/cm2), 5-10 s exposure duration and 1.5-3.0 mm exposure separation. Tissue specimens were examined using both light and electron microscopy. The damage to the blood vessel walls was studied. The results showed the existence of indirect tissue damage in both normal and tumor tissue that is outside of the treatment volume, due to disruption of the major blood vessels supplying the adjacent area. Evidence for liver regeneration was found 2 months after FUS treatment.

Although there have been numerous models implemented for modeling thermal diffusion effects during focused ultrasound surgery (FUS), most have limited themselves to representing simple situations for which analytical solutions and the use of cylindrical geometries sufficed. For modeling single lesion formation and the heating patterns from a single exposure, good results were achieved in comparison with experimental results for predicting lesion size, shape and location. However, these types of approaches are insufficient when considering the heating of multiple sites with FUS exposures when the time interval between exposures is short. In such cases, the heat dissipation patterns from initial exposures in the lesion array formation can play a significant role in the heating patterns for later exposures. Understanding the effects of adjacent lesion formation, such as this, requires a three-dimensional (3-D) representation of the bioheat equation. Thus, we have developed a 3-D finite-element representation for modeling the thermal diffusion effects during FUS exposures in clinically relevant tissue volumes. The strength of this approach over past methods is its ability to represent arbitrarily shaped 3-D situations. Initial simulations have allowed calculation of the temperature distribution as a function of time for adjacent FUS exposures in excised bovine liver, with the individually computed point temperatures comparing favorably with published measurements. In addition to modeling these temperature distributions, the model was implemented in conjunction with an algorithm for calculating the thermal dose as a way of predicting lesion shape. Although used extensively in conventional hyperthermia applications, this thermal dose criterion has only been applied in a limited number of simulations in FUS for comparison with experimental measurements. In this study, simulations were run for focal depths 2 and 3 cm below the surface of pig's liver, using multiple intensity levels and exposure times. The results also compare favorably to published in vitro experimental measurements, which bodes well for future application to more complex problems, such as the modeling of multiple lesion arrays within complex anatomical geometries.

This article reports treatment of implanted liver tumors (HSN fibrosarcoma) with focused ultrasound (FUS). Experiments were carried out on implanted liver tumors in vivo. In order to determine the optimum treatment conditions, various combinations of exposure parameters were investigated. The results showed that it is possible to achieve total destruction of tumor cells in the treatment volume using an FUS system with a frequency of 1.7 MHz, with in situ ISAL of 261 W/cm2, 5-s exposure duration, and 1.5-mm exposure separation, with an in situ ISAL of 266 W/cm2, 10-s duration, and 2-mm separation, or with in situ ISAL of 213 W/cm2, 8-s duration, and 1.5-mm separation. Fifteen selected tumors were treated with these experimentally determined "optimum" exposure conditions. All the tumors were destroyed completely. Assessment of tumor viability in the treated volume was performed using both histologic and tissue culture methods. The mechanism of tumor damage, the limitations of the tumor model, and the effect of exposure parameters and liver blood flow on the treatment are discussed.

High intensity, focused ultrasound has considerable potential as a non-invasive surgical technique, with applications which include the treatment of benign prostatic hyperplasia and the elimination of metastatic disease in the liver. In this study, the use of MRI for treatment planning and subsequent monitoring of ultrasound therapy in the liver has been evaluated. In an experimental model both tumour bearing and normal liver lobes were treated invasively with high intensity focused beam ultrasound surgery. Subsequent changes in the tissue properties were investigated using MRI, in combination with the intravenous contrast agent, Gd-DTPA. The repair of ultrasound damaged tissue was followed until 8 weeks after treatment. The appearance of the MR images was compared with histological sections prepared from parallel experiments. Imaging and histology results showed excellent agreement, illustrating that MRI is well suited to the non-invasive observation of the effects of high intensity focused ultrasound therapy on tissue. Thus, as the clinical potential of ultrasound surgery is realized, MRI, together with the use of contrast agents, will be invaluable both in treatment planning and in monitoring the progress of a treated tumour.

Temperature rise was observed as a function of time in liver and dog prostate tissue ex vivo during heating with high-intensity focused ultrasound. The temperature rise was measured using a needle thermocouple placed at the focus. The temperature vs. time behaviour closely followed the predictions of a model based on bulk and surface heating. When the tissue temperature was raised above 50 degrees C, an increase in heating rate was seen. At higher temperatures, a point was reached at which a marked, irreversible change of tissue properties was observed, consistent with protein denaturation. The change was sometimes accompanied by a sudden further rise in temperature followed by an equally sudden fall. On dissection, regions of tissue damage (lesions) were seen, sometimes containing bubbles consistent with acoustic cavitation or vaporisation.

The purpose of this study was to establish the feasibility of noninvasive treatment of small renal tumors with high-intensity focused ultrasound (HIFU). A 1.69-MHz extracorporeal HIFU transducer of 150-mm focal length was used. In vitro experiments with excised porcine kidneys allowed determination of suitable exposure parameters to be tested in vivo. For short exposure times (< 2 seconds), the minimum energy required to produce acute thermal damage was 500 +/- 100 Wcm-2 per second. Porcine kidneys (N = 18) were treated in vivo at a depth of 40 mm from the skin surface, with acute damage detected in 13. Damage was macroscopically and histologically discrete and confined to the target area within the kidney. Skin induration was observed after treatment in nine cases, and there was one skin burn. Transducer developments to prevent this morbidity and to improve energy deposition within the target are discussed.

Mammalian tissues have differing sensitivities to damage by physical agents such as ultrasound. This article evaluates the scientific data in terms of known physical mechanisms of interaction and the impact on pre- and postnatal tissues. Actively dividing cells of the embryonic and fetal central nervous system are most readily disturbed. As a diagnostic ultrasound beam envelopes a small volume of tissue, it is possible that the effects of mild disturbance may not be detected unless major neural pathways are involved. There is evidence that ultrasound can be detected by the central nervous system; however, this does not necessarily imply that the bioeffect is hazardous to the fetus. Biologically significant temperature increases can occur at or near to bone in the fetus from the second trimester, if the beam is held stationary for more than 30 s in some pulsed Doppler applications. In this way, sensory organs that are encased in bone may be susceptible to heating by conduction. Reports in animals and humans of retarded growth and development following frequent exposures to diagnostic ultrasound, in the absence of significant heating, are difficult to explain from the current knowledge of ultrasound mechanisms. There is no evidence of cavitation effects occurring in the soft tissues of the fetus when exposed to diagnostic ultrasound; however, the possibility exists that such effects may be enhanced by the introduction of echo-contrast agents.

In order to ablate tumours using high-intensity focused ultrasound (HIFU) it is necessary to irradiate the tumour with a confluent array of single ultrasound exposures. We have identified a phenomenon that we term lesion-to-lesion interaction, which occurs when the spatial separation of individual exposures is such that an existing lesions appears to affect the formation of a subsequent lesion. This article investigates the implications of this phenomenon for strategies to ablate large tissue volumes in the treatment of hepatic metastases. Experiments on pig and rat livers have been carried out using a focused ultrasound system with a frequency of 1.7 MHz, an in situ spatially averaged focal intensity (ISAL) of 133-658 W cm-2 (ISP of 239-1185 W cm-2) and an exposure duration of 5-15 s. The results show that there is interaction between lesions that spatial exposure separations that depend on the intensities and exposure durations used. As a result, either subsequent lesions form closer to the ultrasound source (if the focal peak of the ultrasound beam is placed deep inside the liver tissue) or their length is reduced (if the focal peak is near the liver surface). An explanation is suggested for this effect and a strategy for its avoidance during in vivo HIFU treatment is discussed.

The relationship between spatial peak intensity and the position of ultrasound induced tissue damage was studied in in vitro tissue models, using a 1.69 MHz spherical bowl transducer. The models corresponded to the transabdominal route to the bladder and prostate, which are potential target sites for focused ultrasound surgery. The results confirm that there is a relationship between lesion position and intensity, with lesions forming, under some exposure conditions, ahead of the geometric focus. Forward growth of lesions appears to be due to changes in the absorption characteristics of the tissue in the beam path. Using a computer model, we have demonstrated that the absorption coefficient of the tissue must increase significantly in front of the focus to enable lesions to form ahead of the predicted position. A possible mechanism for this is bubble formation as a result of acoustic cavitation. The effect of nonlinear propagation in the tissue, at the intensities studied, is shown to be relatively small.

Successful application of high intensity focused ultrasound to cancer treatment requires complete ablation of tissue volumes. In order to destroy an entire tumour it is necessary to place a contiguous array of touching lesions throughout it. In a study of how best to achieve this, exposures were selected to give single lesions that were thermal in origin, while avoiding effects due to tissue water boiling and acoustic cavitation. Arrays were formed in excised bovine liver. Under some exposure conditions, lesions were found to merge in front of the focal point, and failed to cover the desired volume. Using fine wire manganin-constantan thermocouples, temperature studies revealed a substantial rise in the temperature of surrounding untreated tissue. Cooling curves showed that it was necessary to allow surrounding tissue to cool for up to 2 min before ambient temperature was reached. By allowing the tissue to cool between exposures it was possible to form arrays of overlapping lesions thus successfully ablating the complete target region.

To determine whether high-intensity focused ultrasound can be used to ablate bladder wall tissue using a transabdominal approach in a large animal model, and whether it can be developed as a non-invasive treatment for superficial bladder tumours.

High-intensity focused ultrasound surgery (RUS) has been developed for the extracorporeal treatment of various benign and malignant soft tissue tumors. The system developed at the Institute of Cancer Research/Royal Marsden (ICR/RM) National Health Service (NHS) Trust incorporates a 150 mm focal length focused bowl transducer operated at 1.7 MHz, and is currently undergoing Phase 1 clinical trials for the treatment of benign prostatic hyperplasia and superficial bladder cancer, However, the application of this transducer is limited by its focal length to a maximum depth of 100 mn, and by power absorption in the skin to a minimum depth of 40 mm, A computer model of acoustic fields, which assumes uniform excitation of the transducer over its entire surface, has previously been published. This has been used both to calculate the intensity in nonattenuating media, and to estimate the absorbed power per unit volume in homogeneous tissues in order to allow determination of the transducer configurations (frequency, focal length, and diameter) necessary for the treatment of both deep (similar to 150 mm) and shallow (similar to 20 mm) soft tissue tumors, These depths encompass the typical range for human tissues which are likely to be treated. Calculations cover the frequency range 0.5-4.5 MHz, focal lengths from 70 to 200 mm, and transducer diameters from 30 to 190 mm, The results show that appropriate transducers can be designed for the noninvasive treatment of tumors in specific organs.

The prospect of being able to use "minimally invasive" surgical techniques is of great interest today, particularly for reasons of health economics, patient acceptability and reduced morbidity. High intensity focused ultrasound (HIFU) has long been known to offer the potential of very precise "trackless lesioning" but has only recently, with the advent of high quality methods of medical imaging, become a practicable possibility. High intensity beams can readily be achieved using either bowel or lens focusing procedures and, by choice of a suitable acoustic frequency, regions of tissue destruction--"lesions"--can be induced at depths of up to at least 10 cm with exposure times of the order of 1 s. Theoretical and experimental evidence indicates that the primary mechanism of damage is thermal, i.e. "cooking" of the tissues. Both conventional cavitation and boiling of tissue water may complicate the situation. Furthermore, substantial non-linear behaviour is involved. On histological appearance the lesions have a spatially sharp demarcation between regions of normal and dead cells. When attempts are made to ablate a block of tissue, by creating an array of adjacent elementary lesions, a phenomenon is observed of inhibition of formation of a lesion whose placing is too close to that of a neighbour. Provided that this problem is dealt with, complete ablation of an extended block of tissue can be achieved. For animal tumours in particular, this observation is reinforced by evidence both of in vitro cell survival and of tumour growth delay experiments. Clinically, the sites accessible for HIFU treatment will be limited by the need for a suitably wide acoustic window that either is available naturally or can be provided by a relatively minor surgical procedure. Tumour sites which thus offer a realistic prospect for local control (and some of which are already the subject of phase 1 trials) include liver, bladder, kidney, prostate, breast and brain. There is also considerable interest in non-cancer applications in these and other sites.

High intensity beams of ultrasound may be focused at depth within the body, thereby producing selective damage within the focal volume, with no harm to overlying or surrounding tissues. The technique is thus noninvasive, insofar as the source of ultrasound energy is situated outside the body. The mechanism for cell killing is predominantly thermal, although acoustic cavitation may also occur. Ultrasound focal surgery was first conceived in the 1940s as a possible tool for creating selective damage in the brain for neurosurgical research; its potential for more widespread clinical use was not exploited at that time, probably because of the lack of facilities for providing precise visualisation and localisation of the damage. The availability of modern imaging techniques has encouraged a revival of clinical interest, and applications in ophthalmology, urology and oncology are currently being developed.

This overview of bioeffects of ultrasound presents some key aspects of selected papers dealing with biophysical end-points. Its purpose is to establish a basis for exposure and dosimetric standards for medical ultrasonic equipment. It is intended to provide essential background resource material for the medical/scientific community, and more specifically for scientific working groups. This document was prepared by members of the Safety Committee of the World Federation for Ultrasound in Medicine and Biology. It was produced as a resource document in response to a request for information by Working Group 12 (Ultrasound exposure parameters) of the International Electrotechnical Commission Technical Committee 87, Ultrasonics. IEC TC 87, WG12 is the working group responsible for generating international standards for the classification of equipment by its acoustic fields based on safety thresholds. Our paper is intended to update and supplement information on the thermal mechanism provided in the publication, "WFUMB Symposium on Safety and Standardisation in Medical Ultrasound: Issues and Recommendations Regarding Thermal Mechanisms for Biological Effects of Ultrasound" (WFUMB 1992). It also provides an overview of trends in research into nonthermal mechanisms as a preliminary to the next WFUMB Symposium on Safety of Medical Ultrasound when this subject will be examined in detail by a select group of international experts. The WFUMB-sponsored workshop will take place in Utsunomiya, Japan during 11-15th July, 1994. The purpose of the meeting is to evaluate the scientific literature and to formulate internationally accepted recommendations on the safe use of diagnostic ultrasound that may be endorsed as official policy of the WFUMB. It should be noted that the current publication is not intended for review or endorsement as an official WFUMB document. It is produced as a scientific paper by individuals who are members of the WFUMB Safety Committee, and it therefore represents the opinions of the authors. Nevertheless, during the preparation of this document, contributions were received from members of the International Electrotechnical Commission Technical Committee 87 as well as many other individual experts, and the authors sincerely acknowledge their support.

An analytical model has been constructed for the process of formation of thermal lesions in tissue, resulting from exposure to intense, highly focused ultrasound beams such as may be used in minimally invasive surgery. The model assumes a Gaussian approximation to beam shape in the focal region and predicts, for any such focal beam, the time delay to initiation of a lesion and the subsequent time course of growth of that lesion in lateral and axial dimensions, taking into account the effects of thermal diffusion and blood perfusion. The necessary approximations and assumptions of the model are considered. Comparison of predictions with experimentally measured data on excised pig liver indicate generally good agreement. Comparisons are also made of this theory with previously published data on exposure-time dependence of lesioning threshold intensity. Deficiencies are identified in existing practice for measuring and reporting acoustic exposures for focused ultrasound surgery, and the proposal is therefore made that a quantity that would be more satisfactory, from the viewpoints both of metrology and biophysical relevance, is the intensity spatially averaged over the area enclosed by the half-pressure-maximum contour in the focal plane, as determined under linear conditions, provisionally denoted as ISAL.

Using a focused 1.7 MHz ultrasound field (focal length/transducer diameter ratio of 1.7) and in situ intensities spatially averaged within the half-pressure maximum contour in the range 100-400 W cm-2, ablative lesions have been prescriptively placed singly and in arrays, in the livers and bladder walls of adult female Large White pigs. Exposures were made through the skin with up to 8 cm of intervening tissue. Ablative lesions were placed under ultrasonic guidance, and specific lesion echoes were subsequently observed in two cases. Animals were sacrificed immediately after induction of ultrasonic lesions, post-mortems were performed, as were histological examinations of normal and damaged tissue. There was clear demarcation between ablated and normal tissue. Provided that simple rules on exposure technique had been observed, there was no evidence of inadvertent tissue damage, either locally to the treatment site, or in the tissue lying between the source and the target. This study is a useful step in demonstrating the feasibility of clinical trials for the use of this technique in treating bladder tumours and solitary liver metastases.

Methods for quantitative imaging of ultrasound propagation properties were applied to the examination of the acoustic appearance of lesions generated by high intensity focused ultrasound in excised pig livers. Single lesions, about 10 mm maximum diameter by 30 mm long, were created in each of six liver specimens. Two dimensional images (32 by 32 points) of sound speed, mean attenuation coefficient (as a function of frequency in the range 3 to 8.5 MHz) and mean backscattering coefficient (5 to 8 MHz) were obtained in 7 mm thick sections of tissue, cut to include a cross-section through the lesion. Images of these properties, presented alongside surface photographs of the samples, provided a qualitative demonstration that attenuation coefficient was the most useful and backscattering coefficient was the least useful acoustic parameter for visualizing such lesions. Quantitatively the data demonstrated significant increases in attenuation coefficient and sound speed in lesioned liver relative to normal, whereas backscattering was shown not to change in a significant manner except when undissolved gas is the mechanism for increased acoustic scattering. Samples where gas was not fully removed following lesion production gave significant increases in backscattering at the lesion centre, but the shape and size of regions of high backscattering coefficient corresponded poorly with the shape and size of the lesions, unlike attenuation and sound speed for which such correspondence was good.

The management of some tumours presents a difficult surgical problem. Focused ultrasound surgery is a technique which provides the possibility of destroying, non-invasively, a selected volume of tissue at depth within an organ such as the liver whilst sparing overlying tissues. For the safe and effective use of this technique, it is essential to understand the way in which such a focused ultrasound surgery beam interacts with normal and malignant tissue and to study the histological response of different tissues to the ultrasonic insult. In this paper the histology of lesions in normal rat liver, as viewed by light and electron microscopy, is described.

This paper reports the histological changes found in rat liver tumours treated with high-intensity focused ultrasound. HSN fibrosarcoma, implanted subcapsularly in the livers of CBH rats, were treated using an array of ultrasound exposures. At predetermined times following treatment, the rats were sacrificed and tissue specimens were examined histologically. Evident tissue damage was confined to regions that had been given high ultrasound exposures. Within these regions ("lesions") there was no evidence of intact cells whereas in the sharply demarcated surrounding tissue there was no evidence of cell damage. Where individual ultrasound lesions had been placed in sufficiently close proximity, there was correspondingly continuous and complete cell destruction. There is suggestive evidence that tissue damage may arise through two different mechanisms: direct, primarily thermal, damage and indirect damage resulting from compromised blood supply. Under the same exposure conditions, normal liver cells appear to lose their morphological structure more readily than do tumour cells.

This paper discusses the effect of blood perfusion on the ablation of rat liver tissue with high-intensity focused ultrasound (HIFU). For this study a practical method has been developed, in which the liver blood flow can be reduced by ligation of the hepatic artery and portal vein. During the treatment the rat liver was mobilized out of the abdomen and the blood flow was measured using both the radioactive microsphere method and a laser Doppler blood-flow monitor. The results show that the hepatic blood flow was about 23 ml/100 g min-1 via the hepatic artery and about 227 ml/100 g min-1 via the portal vein. The total liver blood flow was reduced by 98% when both the hepatic artery and portal vein were ligated. Comparative lesions were made on the same liver lobes of rats with both normal and reduced blood flow using a focused ultrasound beam of 1.7 MHz, 67-425 W cm-2 spatially averaged focal intensity ISAL and 2-20 s exposure duration. A marked difference has been found between the lesion dimensions obtained with normal blood flow and that with reduced blood flow. For exposures at 169 W cm-2 the lesion diameter with normal blood flow was reduced by 14% for 3 s exposure duration compared to that obtained with both hepatic artery and portal vein ligated, while the reduction was more than 20% for longer durations.

Two methods involving labelling cells with bromodeoxyuridine (BrdUrd) have been used to study by flow cytometry the effect of hyperthermia (43 degrees C for up to 1 h) on Chinese hamster V79 cells. One method involved the use of an antibody to BrdUrd after pulse-labelling the cells either before or at time intervals after treatment. In the second method, the cells were incubated continuously in BrdUrd after heat treatment, and the components of the cell cycle were then visualized by staining with a combination of a bis-benzimidazole and ethidium bromide. All three methods showed that heating at 43 degrees C stopped DNA synthesis which, at 37 degrees C, subsequently recovered reaching the normal rate 8-12 h later. The cells in S phase at the time of treatment then progressed to G2 where they were further delayed. Cells heated in G1. after the recommencement of synthesis, progressed around the cycle, albeit slower than in unheated cells. The difference between the cells in G1 and S phases at the time of treatment may account for the greater sensitivity of S phase cells to hyperthermia.

Discrete implanted liver tumours in the rat have been exposed to arrays of 1.7 MHz ultrasound lesions. Focal peak intensities in the range 1.4-3.5 k Wcm-2 were used for an exposure time of 10 s. It has been demonstrated that where the whole tumour volume was exposed to the focused ultrasound beam, no evidence of tumour growth could be detected histologically. Where the ultrasonic lesion array was not contiguous, regrowth occurred. Preliminary histological studies confirmed this finding.

Hyperthermia is now established as a successful therapy for some tumours. It has been found that, for some tumours, the combination of heat and ionizing radiation is more effective than either type of treatment on its own. Ultrasound is commonly used to produce hyperthermia. We have therefore studied the effect of combined heat, ultrasound and 60Co gamma irradiation treatments on suspension cultures of V79 Chinese hamster lung fibroblasts. Cells were exposed to 43 degrees C hyperthermia with or without simultaneous continuous wave ultrasound (2.6 MHz, 2.3 W cm-2) either before or after 60Co gamma exposure (428 c Gy). It was found that when the two types of exposure followed one immediately after the other, then the ultrasound exposure increased the amount of cell killing produced by the combination of heat and ionizing radiation, whether the heat or the ionizing radiation came first. If an interval for repair of 72 minutes was left between the heat and ionizing radiation, then this enhancement was lost. The increase in cell killing produced by the ultrasound is shown to be caused by a mechanism that is nonthermal in origin.

High intensity ultrasound may be focused within tissue to produce 'trackless' lesions, that is, to destroy selected tissue volumes without damage to structures lying between the source of the sound beam (the transducer) and the target volume. This physical property provides the potential for the use of ultrasound in a non-invasive 'surgical' technique for the destruction of tissues lying at depth within the human body.In this paper, the design of equipment to carry out such focused beam surgery is described, and its use in a case study involving a cat with metastatic melanoma of the liver is outlined. A closely defined region of liver measuring 4 x 2.5 x 2.5 cm was successfully treated, post-mortem histology showing no viable cells remaining in that volume.Although the technique as described here was designed for the treatment of discrete liver metastases, focused beam surgery may have wider applications in, for example, benign prostate hyperplasia or urological tumours.

The effect of continuous wave ultrasound exposures on the cytotoxicity of adriamycin has been studied. It has been found that 2.6 MHz, 2.3 Wcm-2 (spatial average) ultrasound can enhance the cell killing potential of adriamycin both in suspensions of single V79 chinese hamster fibroblast cells and in spheroids formed from these cells. The ratio of the slopes of the survival curves for single cell suspensions is 1.5. For spheroids, the growth delay is increased by 1.3 days by simultaneous ultrasound exposure. Flow cytometric studies of the intracellular concentration of adriamycin following ultrasound exposure reveals that this is increased when compared with that measured when the cells are only exposed to adriamycin. Evidence is presented to suggest that this is a non-thermal effect of ultrasound.

Flow cytometry was used to study the cell cycle either by pulse labelling with bromodeoxyuridine (BrdU) followed by reaction with anti-BrdU antibody or by continuous incubation in BrdU followed by staining with Hoechst 33258 and ethidium bromide. Following heat treatment, the rate of DNA synthesis decreased dramatically. After a lag period, cells recommenced movement out of G1. DNA synthesis recovered slowly until, 48 hours later, in the surviving cells, it had returned to normal. Concomitant treatment with ultrasound gave qualitatively the same results, apparently increasing the effect of heat.

Surface temperatures of a variety of transducers used with common commercial ultrasonic diagnostic equipment have been measured. Transducers operating in imaging mode, in both continuous and pulsed Doppler modes, and in mixed modes were investigated. A total of 30 transducers and scan-heads used with equipment from 10 manufacturers were examined, including a range of array types, mechanical sectors and continuous-wave Doppler transducers. Measurements were made using an infrared radiometer, or a thermocouple probe, with the transducers operating in air. Surface temperatures of 13 transducers operating in imaging mode were found to be in the range 0.0-13.1 degrees C above ambient after 5 min operation. Some transducers operating in pulsed Doppler mode reached considerably higher temperatures. The most extreme example increased the surface temperature by 36.5 degrees C after 1 min and reached a steady-state temperature of almost 80 degrees C. Transducers operating at these temperatures cannot be retained on the skin of a conscious subject without pain, and will cause skin burns within a brief period of time. A linear relationship has been demonstrated between temperature increase and spatial-average acoustic intensity. The rate of increase in air was found to be about 10 times greater for pulsed arrays than for continuous-wave Doppler transducers.

The treatment of discrete liver tumours is often a difficult clinical problem. High intensity, focused ultrasound may provide one form of therapy for such disease. The ability to focus ultrasound precisely on a predetermined volume allows the possibility of selective tissue destruction at this position without damage to intervening tissues. We have investigated this both in vivo and in excised liver samples in vitro. Quantitative and qualitative studies have been carried out on the relationship between the ultrasonic exposure and the lesion shape, position and volume. In addition, the highly echogenic nature of the ultrasonic lesion has been studied, in an attempt to determine whether 'real time' observation of the extent of tissue damage is feasible.

The use of diagnostic ultrasound can be justified if it can be shown to provide only negligible or small risk while giving good benefit to the patient. In the absence of biological evidence, one way of assessing a new (or existing) piece of diagnostic equipment would be to predict the biophysical changes (i.e. heat and cavitation) that may be produced by its ultrasonic fields in tissue. An assessment of risk may then be made from our knowledge of thermal and cavitational biology. To this end, this study has sought to measure temperature rise, bubble formation, sonoluminescence and acoustic streaming arising from clinical transducers that have been carefully calibrated using a Beam Calibrator, and to determine whether there is good correlation between measured acoustic parameters in water and any of these biophysical characteristics. The results are inconclusive.

No significant differences were found when the obstetric outcome of 515 rural adolescents aged 16 years and younger was compared with that of an equal number of matched young adult rural women aged 20-29 years in respect of booking status, postpartum haemoglobin content, operative/instrumental delivery, mean neonatal birth mass and the incidence of infants weighing under 2,500 g. These results support the conclusions of recent studies in Australia and the USA that adolescence per se confers no increased obstetric risk. On the other hand, unwed motherhood (among all age groups) constitutes a most disturbing social trend in black rural society and this, rather than teenage pregnancy as such, ought to be the focus of concern for social workers and the medical profession.

The thermal enhancement of radiation-induced damage in pig skin has been investigated. Heating at 43 degrees C for 60 min was produced by a scanned 3MHz ultrasound transducer, immediately after single doses of X rays. The ED50 values for the dermal reactions of dusky/mauve erythema and necrosis after irradiation alone were 18.6 +/- 0.5 Gy and 20.5 +/- 0.4 Gy, respectively. The reduction in the ED50 values to 15.3 +/- 0.4 Gy and 17.7 +/- 0.5 Gy after irradiation plus heating was significant and suggested a thermal enhancement ratio (TER) of between 1.15 and 1.22. These TER values were within the range obtained in both pig and rat skin using other 'dry' heating methods. This would suggest that the non-thermal effects of ultrasound do not influence the thermal enhancement of x-irradiation damage.

Macroscopically visible gas bubbles can be produced in an agar based gel by irradiation with either continuous or pulsed ultrasound at frequencies from 0.75 to 3.0 MHz. The variation in the number of bubbles formed with frequency, acoustic pressure, pulse length, duty cycle, and temperature closely resembles that seen in vivo. Furthermore, the acoustic pressure required to initiate bubble formation is also close to that required in vivo. It has been observed that alterations in the concentration and pH of the gels can have a profound effect on the nature and quantity of bubbles. This suggests that not only is this gel model suitable for the representation of the macroscopic features of bubble formation in vivo, but can be used to gain information about the preexisting bubble nuclei. Based on the experimental results obtained it can be suggested that for peak negative acoustic pressures of up 1 MPa (equivalent, for a plane travelling sinusoidal wave, to a time averaged intensity of 30 W/cm2) bubble formation can be avoided by the use of high frequencies, short pulse lengths and long duty cycles.

Visible size gas bubbles can be produced in an agar based gel when irradiated with either continuous wave (CW) or pulsed ultrasound. It is shown that many aspects of the production of these bubbles can be explained in a qualitative manner by a theoretical model based upon growth of a cavitation nucleus by rectified diffusion. Quantitative predictions for the number of bubbles produced as a function of various parameters tend to be different from measured values by less than an order of magnitude. The results given here provide a useful theoretical basis for the explanation of earlier measurements of ultrasonically induced bubbles in vivo.

A questionnaire was sent out to physiotherapists in Britain in 1985 requesting information about their use of therapeutic ultrasound. Replies were obtained from National Health Service (NHS) departments and private practitioners. Twenty percent of all physiotherapy treatments in NHS departments involved ultrasound, and 54% of all private treatments. Information was obtained about the range and pattern of ultrasonic frequencies and intensities used. The conditions for which ultrasound is used as a treatment modality are listed, as are the contraindications for its use.

A system is described in which large superficial areas of tissue may be heated using a single plane ultrasonic transducer scanned in a raster fashion. The shape of the heated area is determined by the movement of a microswitch which is activated when it strikes the rigid edge of a hole of the required shape cut in a plate. Temperature profiles are presented. They are measured in pig thigh muscle, and are generated by 0.75 and 3.0 MHz ultrasound scanned over areas up to 7 cm X 7 cm. It was found that uniform heating could be obtained over the area scanned by the central portion of the ultrasonic beam.

This paper describes work in which subharmonic emissions from ultrasonically irradiated biological samples are integrated over time, and the resultant signal (which is believed to be indicative of cavitation activity) is found to correlate well with the extent of cellular damage. Specifically, three studies have been carried out, in which the subharmonic energy emitted from suspension cultures of V79 cells is integrated during exposure to 1 MHz ultrasound. The effect of raised ambient pressure and sample rotation speed on the occurrence of cavitation, and of cavitation related cell death, have been investigated. Use of the subharmonic emission technique has also yielded additional evidence for the occurrence of an ultrasonically induced mechanism for damage that is neither thermal nor cavitational in origin, in experiments where cells are exposed to ultrasound whilst being held at an elevated temperature (43 degrees C). The potential of the use of subharmonic emission monitoring as a quantitative predictor of ultrasonically induced biological damage, both in vitro and in vivo, is discussed.

The temperature distributions that may be achieved in mammalian tissues by ultrasonic heating have been studied. Thigh muscle of Large White pigs has been irradiated with 0.75 and 3.0 MHz ultrasound at spatial average intensities in the range 1.5-3.0 W cm-2 in both pulsed and continuous modes of delivery. Resultant temperature profiles are described and some of the problems arising are discussed.

Suspensions of V79 cells have been irradiated with 1 MHz ultrasound at spatial average intensities up to 0.25 W cm-2. The effects seen are described in this paper. Acoustic emissions at the first subharmonic of the drive frequency (0.5 MHz) were monitored during irradiation. Subharmonic emission is characteristic of cavitation activity within the sample. A strong correlation was found between cell damage and a measure of the total emitted subharmonic energy. Damage was assayed in terms of cell lysis, the ability of the cells to take up the vital dye trypan blue and loss of reproductive integrity. It is concluded from these data that cavitation can play an important part in the interaction of ultrasound with biological systems in vitro, and that subharmonic emission may provide a non-invasive and somewhat quantitative means of predicting the magnitude of such interactions.

Suspensions of V79 cells and HeLa cells have been irradiated with continuous 3 MHz ultrasound at a spatial average intensity of 3W cm-2. This irradiation condition did not give rise to cell lysis. When the cells were irradiated with ultrasound for up to six hours at 37 degrees C no cell killing was observed. However, at temperatures in the hyperthermia range 42--45 degrees C the increase in cell killing that resulted from the irradiation was greater than that which could be attributed to its heating effect alone.