Gail ter Haar

Thermal ablation of uterine fibroids using MR-guided focused ultrasound-a truly non-invasive treatment modality

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.

Safety and bio-effects of ultrasound contrast agents

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.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.

Influence of ablated tissue on the formation of high-intensity focused ultrasound lesions.

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.

HISTOLOGICAL STUDY OF NORMAL AND TUMOR-BEARING LIVER TREATED WITH FOCUSED 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.

Spatial and acoustic pressure dependence of microbubble-mediated gene delivery targeted using focused ultrasound

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.

High-intensity focused ultrasound ablation of breast cancer

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.

International consensus on use of focused ultrasound for painful bone metastases: Current status and future directions

Abstract Focused ultrasound surgery (FUS), in particular magnetic resonance guided FUS (MRgFUS), is an emerging non-invasive thermal treatment modality in oncology that has recently proven to be effective for the palliation of metastatic bone pain. A consensus panel of internationally recognised experts in focused ultrasound critically reviewed all available data and developed consensus statements to increase awareness, accelerate the development, acceptance and adoption of FUS as a treatment for painful bone metastases and provide guidance towards broader application in oncology. In this review, evidence-based consensus statements are provided for (1) current treatment goals, (2) current indications, (3) technical considerations, (4) future directions including research priorities, and (5) economic and logistical considerations.

Towards a dosimetric framework for therapeutic ultrasound

Abstract There is a need for a coherent set of exposure and dose quantities to describe ultrasound fields in media other than water (including tissue and tissue-simulating materials). This paper proposes an outline dosimetry scheme, with quantities for free field exposure, in situ exposure, dose (both instantaneous and cumulative) and effect, to act as a structure for organising a more complete set of definitions. It also presents findings from a survey of the views of the therapeutic ultrasound community which generally supports the principle of using modified free field quantities to describe the in situ field, and the prioritising of dose quantities which are related to heating and thermal mechanisms. Although there is no one-to-one relationship between any known ultrasound dose quantity and a specific biological effect, this can also be said of radiotherapy and other modalities where weighting factors have been developed to calculate the degree of equivalence between different tissues and radiation types. This same separation is recommended for ultrasound, provided that an appropriate set of recognised ‘engineering’ quantities can be established for exposure and dose quantities.

Principles of High-Intensity Focused Ultrasound

Although its use for therapeutic purposes predates diagnostic applications by several decades, ultrasound is most widely known for its imaging capabilities. The passage of ultrasound (US) through tissue can lead to biological changes that may be reversible or irreversible. The biological significance of these effects depends to a large extent on the energy in the ultrasound beam and the goal of the exposure. At diagnostic levels, any changes are largely believed to be biologically insignificant. For therapeutic ultrasound, beneficial cellular or functional effects are deliberately sought, whether these are at the cell membrane level (e.g., transient changes in permeability to facilitate drug delivery) or less subtle effects such as the localised temperatures rises that are required to achieve immediate thermal necrosis in high intensity focused ultrasound (HIFU; this technique is sometimes also referred to as FUS).

The Resurgence of Therapeutic Ultrasound – A 21st Century Phenomenon

The last few years have seen a considerable surge of interest in the clinical applications of therapeutic ultrasound. These uses of ultrasound have a long history, predating those of diagnostic medical ultrasound by at least two decades. The modes of interaction of ultrasonic waves with tissue are commonly broadly classified as ‘‘thermal” and ‘‘non-thermal” (or ‘‘mechanical”). It is undoubtedly true that the ultrasonic energy absorbed during many therapeutic ultrasound exposures lead to bulk tissue heating. This has been used to considerable advantage, with the temperature rise sought depending on the therapeutic application. The therapeutic uses of ultrasound can be divided into a number of categories. At the lowest exposure levels ( 30 mW), ultrasound has been shown to accelerate bone fracture repair [1–3]. The mechanism of action is still unclear, but is thought to be non-thermal in origin. At the other end of the power spectrum, high intensity focused ultrasound (HIFU) is used to cause thermal ablation of selected target volumes. Here, temperatures in excess of 56 C are induced within the focal volume, and are maintained for times of 1 s or longer. It is known from thermal biology studies that this temperature time combination leads to instantaneous thermal necrosis [4–6]. At the exposure levels used in HIFU, it seems certain that acoustic cavitation also plays a rôle. The new technique of histotripsy uses cavitation (in the absence of heating) for the localised destruction of tissue [7]. At intermediate acoustic powers, temperature rises that may lead to beneficial reversible biological effects ( 1–3 C) can be induced, as for example, in physiotherapy [8], although there is a current trend to use low powers (and thus reduced thermal effects) for physiotherapy applications. Ultrasound may also be used to set gas filled microbubbles into oscillation, thus creating mechanical effects (for example shear stresses) at cell membranes. These may result in improved transport of drugs or genetic material into cells [9–14]. Physiotherapy currently remains the only therapeutic ultrasound application in common clinical use, but its uses in fracture repair and HIFU are rapidly gaining clinical acceptance. If clinical trials of sonothrombolysis, ultrasound enhanced drug delivery and gene therapy fulfil their pre-clinical testing promise, ultrasound therapy will become much more widely used. This will reinforce the urgent need for good calibration and quality assurance (QA) techniques for ultrasound devices. While standardised calibration methods are available for diagnostic ultrasound, parallel methods for most high power ultrasound techniques are not yet available. Calibration and beam characterisation standards are