Extracorporeal high intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview

The ideal treatment of localized cancer should directly cause an irreversible and complete death of tumor cells without damage to surrounding normal tissue. High intensity focused ultrasound (HIFU) is such a potential treatment, which induces a complete coagulative necrosis of a tumor at depth through the intact skin. The idea that using an extracorporeal source of therapeutic ultrasound was introduced more than 50 years ago [J. Gen. Physiol. 26 (1942) 179]. However, up to now, most of the studies on HIFU have been dealing with animal experiments because this extracorporeal technique is very complicated in clinical applications. The purpose of this study is to introduce Chinese clinical experience of using extracorporeal HIFU for the treatment of patients with various kinds of solid tumor. From December 1997 to October 2001, a total of 1038 patients with solid tumors underwent HIFU ablation in China. Among them, 313 patients were treated at the Chongqing University of Medical Sciences, China. Pathological examination showed that the target region presented clear evidence of cellular destruction. Small blood vessels less than 2 mm in diameter were severely damaged. Follow-up diagnostic imaging revealed that there was no, or reduced, blood supply, and no uptake of radioisotope in the treated tumor after HIFU, both indicating a positive therapeutic response and an absence of viable tumor. Imaging at 6-12 months showed obvious regression of the lesion. Four-year follow-up data were significantly observed in patients with hepatocellular carcinoma, osteosarcoma, and breast cancer. An extremely low major complication rate was noted. It is concluded that HIFU ablation is a safe, effective, and feasible modality for the ablation of carcinomas.     

The affection on the tissue lesions of difference frequency in dual-frequency high-intensity focused ultrasound (HIFU)

The lesions induced by dual-frequency high-intensity focused ultrasound (HIFU) in freshly excised porcine livers were investigated and compared with the lesions induced by conventional single-frequency HIFU. The results have shown that using different exposure time resulted in lesions of different sizes in both dual-frequency and single-frequency HIFU modes at the same intensity level (ISAL = 808 W cm(-2)), but the dimensions of lesions in dual-frequency mode were obviously larger than those in single-frequency mode. A much possible explanation was suggested for the results and the possibilities of applications in the future were also discussed in brief.     

Ultrasound thrombolysis

Ultrasound energy for thrombolysis dates back to 1976. Trubestein et al. demonstrated first in vitro that a rigid wire delivery low frequency ultrasound energy could disrupt clot. These investigators also showed that this system had potential for peripheral arterial clot dissolution in vivo in animal studies [G. Trubestein, C. Engel, F. Etzel, Clinical Science 51 (1976) 697s-698s]. Subsequently, four basic approaches to ultrasonic thrombolysis have been pursued - two without pharmacological agents: (1) catheter-delivered external transducer ultrasound, (2) transcutaneous-delivered HIFU external ultrasound without drug delivery and ultrasound in conjunction with thrombolytic drugs and/or microbubbles or other agents, (3) Catheter-delivered transducer-tipped ultrasound with local drug delivery, and (4) transcutaneous-delivered low frequency ultrasound with concomitant systemic (intravenous) drug delivery for site specific ultrasound augmentation. This article reviews recent data on therapeutic ultrasound for thrombolysis in vitro, in vivo, in animal studies, as well as in human clinical trials.     

Hemorrhage control in arteries using high-intensity focused ultrasound: a survival study

High-intensity focused ultrasound (HIFU) has been shown to provide an effective method for hemorrhage control of blood vessels in acute animal studies. The objective of the current study was to investigate the long-term effects of HIFU-induced hemostasis in punctured arteries. The femoral arteries ( approximately 2mm in diameter) of 25 adult anesthetized rabbits were surgically exposed, and either punctured and treated with HIFU (n=15), served as control (no puncture and no HIFU application: n=7), or were punctured and left untreated (n=3). Treated animals were allowed to recover, and examined and/or sacrificed on days 0, 1, 3, 7, 14, 28, and 60 after treatment to obtain ultrasound images and samples of blood and tissue. Hemostasis (arrest of bleeding) was achieved in all 15 of the HIFU-treated arteries. Eleven of the arteries were patent after HIFU treatment, and four arteries were occluded, as determined by Doppler ultrasound. The median HIFU application time to achieve hemostasis was 20s (range 7-55 s) for the patent arteries and 110 s (range 50-134 s) for the occluded arteries. In untreated animals, bleeding had not stopped after 120 s. One of the occluded arteries had reopened by day 14. No immediate or delayed re-bleeding was observed after HIFU treatment. Maximal blood flow velocities were similar in HIFU-treated patent vessels and control vessels. No significant difference in hematocrits was found between HIFU-treated and control groups at different time points after the procedure. Light microscopy observations of the HIFU-treated arteries showed disorganization of adventitia, and coagulation and thinning of the tunica media. The general organization of the adventitia and tunica media recovered to normal appearance within 28 days, with some thinning of the tunica media observed up to day 60. Neointimal hyperplasia was observed on days 14 and 28. The results show that HIFU can produce effective and long-term (up to 60 days) hemostasis of punctured femoral arteries while preserving normal blood flow and vessel wall structure in the majority of vessels.     

Measurement of high intensity focused ultrasound fields by a fiber optic probe hydrophone

The acoustic fields of a high intensity focused ultrasound (HIFU) transducer operating either at its fundamental (1.1 MHz) or third harmonic (3.3 MHz) frequency were measured by a fiber optic probe hydrophone (FOPH). At 1.1 MHz when the electric power applied to the transducer was increased from 1.6 to 125 W, the peak positive/negative pressures at the focus were measured to be p(+) = 1.7-23.3 MPa and p(-) = -1.2(-) -10.0 MPa. The corresponding spatial-peak pulse-average (I(SPPA)) and spatial-average pulse-average (I(SAPA)) intensities were I(SPPA) =77-6000 W/cm2 and I(SAPA) = 35-4365 W/cm2. Nonlinear propagation with harmonics generation was dominant at high intensities, leading to a reduced -6 dB beam size (L x W) of the compressional wave (11.5 x 1.8-8.8 1.04 mm) but an increased beam size of the rarefactional wave (12.5 x 1.6-13.2 x 2.0 mm). Enhancement ratio of absorbed power density in water increased from 1.0 to 3.0. In comparison, the HIFU transducer working at 3.3 MHz produced higher peak pressures (p(+) = 3.0-35.1 MPa and p(-) = -2.5(-) - 13.8 MPa) with smaller beam size (0.5 x 4 mm). Overall, FOPH was found to be a convenient and reliable tool for HIFU exposimetry measurement.     

Compensation of fat layer effects in ultrasound imaging using an inclined-fat-layer model derived from magnetic resonance images

When cutaneous fat layers are in the ultrasound imaging region, the phase aberration caused by the fat layers induce image distortion as well as spatial resolution degradation. The phase aberration may complicate clinical procedures particularly when ultrasound imaging is employed for spatial positioning of medical devices like a biopsy needle or HIFU. To compensate the fat layer effects more precisely in beamforming, an inclined-fat-layer model has been established from the magnetic resonance images of the same imaging region as in the ultrasound scanning. We have verified utility of the fat layer model by taking images of a metal needle put into an inclined-fat-layer mimicking phantom. The ultrasound images taken with a 128-element linear phase array operating at 6 MHz have shown better resolution and less distortion when receive beamforming was performed with the phase delay data derived from the inclined-fat-layer model.     

Targeted damage effects of high intensity focused ultrasound (HIFU) on liver tissues of Guizhou Province miniswine

HIFU can pass through tissues and accurately damage target tissues inside organisms. This article reports on the oriented damage effects of HIFU upon miniswine internal and external liver tissues, and suggests a new conception of the 'biological focal field'. The results revealed that: (1) HIFU can be used to damage accurately liver tissues under the guide of a B-modal ultrasound device; (2) the scope of the injury is connected with sound intensity and irradiation time; and (3) the different layers of tissue through which the ultrasound has passed remain undamaged.     

The use of a micro-bubble agent to enhance rabbit liver destruction using high intensity focused ultrasound

Liver tissues in New Zealand rabbits were ablated using high intensity focused ultrasound (HIFU, 14300 W/cm(2), 1.0 MHz). The animals were intravenously administered 0.2 ml of micro-bubble agent in the experimental (n=20) group and an isovolumetric normal saline solution in the control (n=27) group before HIFU treatment which was performed as a linear scan. In both groups, the preselected tissue volumes were destroyed without harming the overlying tissues. Necrosis rate (NR, cm(3)/s) was used to reflect the ablation efficiency, which was the tissue volume of occurring coagulative necrosis per 1s HIFU exposure. NR was improved in the experimental group (0.0570+/-0.0433 vs 0.0120+/-0.0122, P=0.0002). Pathological studies confirmed that there were no residual intact targets within the exposed volume. These findings suggested that the introduction of the micro-bubble agent enhanced HIFU liver destruction.     

高强度聚焦超声(HIFU)——一门多学科的研究课题

高强度聚焦超声(high intensity focused ultrasound,简称HIFU)已作为一种无创外科工具而应用于门诊治疗肿瘤。文章介绍了它的基本原理、有关的研究现状和存在的问题,以及对今后研究工作的建议。文章特别强调高强度聚焦超声是一门多学科的综合研究课题,需要各方面的科学工作者通力协作。     

Study of a peak in cavitation activity from HIFU exposures using TA fluorescence

Methods of measuring the sound field and focal region of a 1.05 MHz high intensity focused ultrasound (HIFU) are described in this paper. 1.05 MHz pulsed HIFU with intensity 2400 W/cm(2) with a 1:1 duty cycle ("on" phase equaled "off" phase) was used to irradiate terephthalic acid (TA). Pulse periods of 0.5 ms, 1 ms, 3.3 ms, 10 ms, 15 ms, 33 ms, 0.1s and 1s were used. The irradiation time was 2 min. To indicate the intensity of inertial cavitation activity, the fluorescence intensity of hydroxyterephthalic acid (HTA) was measured. The result shows that the cavitation activity of pulsed HIFU peaks at a pulse period of 10 ms, cavitation activity is significantly greater for pulse periods from 2 to 20 ms than for others.     

Prostatic tissue ablation by transrectal high intensity focused ultrasound: histological impact and clinical application

In a phase-I clinical trial the morphologic impact and safety of high-intensity focused ultrasound (HIFU) administered transrectally for tissue ablation in human prostates (n = 54) was evaluated. Location and size of the tissue lesions correlated well with the predefined target area and revealed sharply delineated coagulative necrosis in all cases. Intervening tissues, such as the rectal wall and posterior prostate capsule were invariably intact. In a subsequent phase-II clinical trial safety and efficacy of transrectal HIFU as a novel minimally invasive treatment modality for patients with symptomatic benign prostatic hyperplasia (BPH; n = 102) was determined. The maximum urinary flow rate (Qmax, ml/s) increased from 9.1+/-4.0 to 12.9+/-6.1 (3 months, n=86), 12.7+/-5.1 (6 months, n=78) and 13.3+/-6.1 (12 months, n=56). In the same time period the post void residual volume (ml) decreased from 131+/-115 to 46+/-45, 57+/-46 and 48+/-36 and the AUA symptom score decreased from 24.5+/-4.7 to 13.3+/-4.4, 13.4+/-4.7 and 10.8+/-2.5. A subset of patients (n=30) underwent multichannel pressure flow studies, which demonstrated that transrectal HIFU reduces bladder outflow obstruction. These data demonstrate that transrectal HIFU is capable of inducing coagulative necrosis in the human prostate via a transrectal approach while preserving intervening and adjacent tissue. A 48% improvement of uroflow and a 53% decrease of urinary symptoms 1 year after treatment prove that transrectal HIFU is an effective and safe minimally invasive treatment option for BPH.     

Ultrasound enhanced thrombolysis in acute arterial ischemia

In vitro and animal studies have shown that thrombolysis with intravenous tissue plasminogen activator (tPA) can be enhanced with ultrasound. Ultrasound delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. Moreover, intravenous gaseous microspheres with ultrasound have been shown to be a potential alternative to fibrinolytic agents to recanalize discrete peripheral thrombotic arterial occlusions or acute arteriovenous graft thromboses. Small phase I-II randomized and non-randomized clinical trials have shown promising results concerning the potential applications of ultrasound-enhanced thrombolysis in the setting of acute cerebral ischemia. CLOTBUST was an international four-center phase II trial, which demonstrated that, in patients with acute ischemic stroke, transcranial Doppler (TCD) monitoring augments tPA-induced arterial recanalization (sustained complete recanalization rates: 38% vs. 13%) with a non-significant trend toward an increased rate of clinical recovery from stroke, as compared with placebo. The rates of symptomatic intracerebral hemorrhage (sICH) were similar in the active and placebo group (4.8% vs. 4.8%). Smaller single-center clinical trials using transcranial color-coded sonography (TCCD) reported recanalization rates ranging from 27% to 64% and sICH rates of 0-18%. A separate clinical trial evaluating the safety and efficacy of therapeutic low-frequency ultrasound was discontinued because of a concerning sICH rate of 36% in the active group. To further enhance the ability of tPA to break up thrombi, current ongoing clinical trials include phase II studies of a single beam 2 MHz TCD with perflutren-lipid microspheres. Moreover, potential enhancement of intra-arterial tPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter) in ongoing phase II-III clinical trials. Intravenous platelet-targeted microbubbles with low-frequency ultrasound are currently investigated as a rapid noninvasive technique to identify thrombosed intracranial and peripheral vessels. Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.     

Applications of high-intensity focused ultrasound in medicine: Spotlight on neurological applications

High-intensity focused ultrasound (HIFU) has the potential to become a modality of treatment for a wide range of clinical conditions. HIFU enables non-invasive, selective ablation of tissues including tumors and punctured vessels. Another promising area of research within the field of therapeutic ultrasound is the application of HIFU to treat neurological disorders by selectively targeting the brain, spinal cord, or nerves. This paper provides an overview of the current applications of focused ultrasound in medicine with an emphasis on its use in the fields of neurology and neurosurgery.     

The inception of cavitation bubble clouds induced by high-intensity focused ultrasound

In many therapeutic applications of high-intensity focused ultrasound (HIFU) the appearance of cavitation bubbles is unavoidable, whereas the dynamics of the bubbles induced by HIFU have not been clarified. The objective of the present work is to observe the inception process of cavitation bubble clouds generated by HIFU transducer in water using high-speed photography. Sequential images captured within 600 micros after the onset of ultrasound transmission show the dynamics of cavitation bubbles' generation, growth, deformation, expansion and collapse in the focal region. However, when the observation time is narrowed to the initial 145 micros, both the still and streak images reveal that the cavitation bubbles astonishingly stay stable in the focal region for at least 60 micros. The results imply that through adjusting the HIFU exposure time while other physical parameters are appropriately chosen, it might be possible to control the generation of stable cavitation bubbles locally in the focal region.     

高强聚焦超声(HIFU)无创外科

本文从简要回顾超声治疗的发展历史开始,重点介绍了90年代初在国际上兴起的HIFU无创外科技术及我国在该领域中的成就.文章继而对HIFU“切除”肿瘤的机理,治疗质量及其及发展前景做了讨论。     

高强聚焦超声(HIFU)无创外科─21世纪治疗肿瘤的新技术

本文从简要回顾超声治疗的发展历史开始,重点介绍了９０年代初在国际上兴起的ＨＩＦＵ无创外科技术及我国在该领域中的成就．文章继而对ＨＩＦＵ“切除”肿瘤的机理,治疗质量及其及发展前景做了讨论．     

高强聚焦超声(HIFU)无创外科─21世纪治疗肿瘤的新技术

本文从简要回顾超声治疗的发展历史开始,重要介绍了90年代初在国际上兴起的HIFU无创外科技术及我国在该领域中的成就。文章继而对HIFU“切除”肿瘤的机理,治疗质量及其发展前景做了讨论。     

Nakagami-m parametric imaging for characterization of thermal coagulation and cavitation erosion induced by HIFU

Nowadays, both thermal and mechanical ablation techniques of HIFU associated with cavitation have been developed for noninvasive treatment. A specific challenge for the successful clinical implementation of HIFU is to achieve real-time imaging for the evaluation and determination of therapy outcomes such as necrosis or homogenization. Ultrasound Nakagami-m parametric imaging highlights the degrading shadowing effects of bubbles and can be used for tissue characterization. The aim of this study is to investigate the performance of Nakagami-m parametric imaging for evaluating and differentiating thermal coagulation and cavitation erosion induced by HIFU. Lesions were induced in basic bovine serum albumin (BSA) phantoms and ex vivo porcine livers using a 1.6 MHz single-element transducer. Thermal and mechanical lesions induced by two types of HIFU sequences respectively were evaluated using Nakagami-m parametric imaging and ultrasound B-mode imaging. The lesion sizes estimated using Nakagami-m parametric imaging technique were all closer to the actual sizes than those of B-mode imaging. The p-value obtained from the t-test between the mean m values of thermal coagulation and cavitation erosion was smaller than 0.05, demonstrating that the m values of thermal lesions were significantly different from that of mechanical lesions, which was confirmed by ex vivo experiments and histologic examination showed that different changes result from HIFU exposure, one of tissue dehydration resulting from the thermal effect, and the other of tissue homogenate resulting from mechanical effect. This study demonstrated that Nakagami-m parametric imaging is a potential real-time imaging technique for evaluating and differentiating thermal coagulation and cavitation erosion.     

Characterization of a fiber-optic displacement sensor for measurements in high-intensity focused ultrasound fields

A fiber-optic sensor is presented that is capable of measuring the particle displacement in high-intensity focused ultrasound (HIFU) fields. For this probe, a secondary calibration was performed, and the resulting complex frequency response is discussed. As a first practical application, the setup was used to measure the pressure in the field of a weakly focusing ultrasound transducer. The result is compared with that of a membrane hydrophone measurement. The feasibility of measurements in HIFU fields is demonstrated by means of measurements of the spatial distribution of the peak particle velocity within the focus of a HIFU transducer and of the dependence of the peak values on the acoustical power level.     

Microbubble-enhanced hemorrhage control using high intensity focused ultrasound

Our objective was to investigate whether hemorrhage control can be achieved faster when high-intensity focused ultrasound (HIFU) is applied in the presence of ultrasound contrast agents (UCA) as compared to HIFU only application. Incisions (3 cm long and 0.5 cm deep) were produced in the livers of anesthetized rabbits. UCA Optison (0.18 ml/kg) was injected into the mesenteric vein. A HIFU applicator (5.5 MHz, 6800 W/cm² in situ) was scanned at a rate of 1–2 mm/s in one direction over the incision (with multiple passes if needed), until hemostasis was achieved. Hemostasis times were 59 ± 23 s (n = 21) in the presence of Optison and 70 ± 23 s (n = 29) without Optison. The presence of Optison produced on average 37% reduction in hemostasis times normalized to initial bleeding rates (p < 0.05), as well as 60% faster formation of the coagulum seal over the incision (p < 0.05). Gross and histological observations showed similar appearance of HIFU lesions produced in the presence of Optison and HIFU lesions produced without Optison. Our results suggest potential utility of UCA for increasing efficiency of HIFU-induced hemostasis of solid organ injuries.