High-intensity focused ultrasound (HIFU) may produce a well-delineated lesion of coagulation necrosis in deep organs, by means of an extracorporeal transducer. Applications of this method to the liver in animal models have been studied for many years. The effects of HIFU on the normal liver parenchyma and on hepatic tumors are reviewed. In the normal rabbit liver in vivo we showed the relation between intensity levels and exposure times and the need to adapt intensity to the depth of the target. No severe complications were observed when an intensity of 1,000 W/cm² was used. HIFU is a noninvasive method for the local destruction of liver tumors. In experimental models, safety and efficacy were demonstrated. HIFU may be interesting for the treatment of some human liver tumors.

High-Intensity Focused Ultrasound (HIFU) can produce radical tissue necrosis. We wanted to assess tumor destruction, proliferation, and tumorigenesis after HIFU, in an animal model of hepatic tumor. New Zealand rabbits bearing VX-2 solitary liver tumors were treated with extracorporeal HIFU under ultrasound (US) guidance and standardized conditions. Groups differed only for the administration of either one or two consecutive HIFU procedures. Tissue destruction was assessed by stereomicroscopy and planimetry, cell proliferation was estimated by in vivo intra-arterial injection of 1200 muCi [3H]thymidine, and tumorigenesis was tested by reimplantation of treated or untreated pieces of liver tumors into the thighs of nontumor-bearing animals. Mortality was 0. Tumor destruction rates were 76.3% +/- 16% after one procedure and 94.2% +/- 7.3% after two procedures. Nuclear staining was heavy in control tumors and was absent in treated tumors. Untreated hepatic tumors induced measurable tumors at 3 weeks in thighs of all recipients, 7.8 +/- 2.4 cm3 in volume. Hepatic tumors treated with one HIFU procedure induced tumors in the thigh of recipients in 31.3% of cases (0.47 +/- 0.06 cm3), and those treated with two HIFU procedures induced tumors in 0% even after 8 weeks of follow-up. In conclusion, HIFU allows a noninvasive approach to the destruction of liver tumors in this model, with little toxicity but significant effects on proliferation and tumorigenesis. The repetition of HIFU procedures may improve results.

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A new device was used to achieve focused tissue ablation by shockwave induced cavitation. The device produced a half cycle of negative pressure followed by a shock wave, thus enhancing cavitation. Twenty eight New Zealand rabbits were treated. Therapeutic ultrasound was targeted at the centre of the liver under ultrasound guidance. The focal volume was scanned with a computer operated x-y-z micropositioner. The number and frequency of bursts as well as the distance between two x-y-z displacements were preselected. The relation of tissue ablation seen to preselected parameters, effects on surrounding tissues, biological side effects, and mode of healing were studied. Macroscopy, planimetry, and quantitative microscopy were used. Focused and homogeneous tissue ablation was achieved within well defined limits. Maximal tissue ablation was seen in the centre of the target. Liver surrounding the target remained unaffected. Lesions were made of a-cellular spots surrounded by disorganised rims of necrotic hepatocytes; 24 hours after treatment, the changes (mean (SEM)) in alanine transaminase and haemoglobin were +225 (36)% and -2-4 (2)% respectively. Serum transaminases, haemoglobinaemia, and packed cell volume were normal 21 days after treatment and the target area was replaced by a fibrous scar. It is concluded that ultrasound cavitation may achieve extracorporeal intrahepatic tissue ablation inside a predetermined target. This technique should now be tested in an animal hepatic tumour model. (Gut 1994; 35: Recurrences can now be detected at early stages with the help of modern diagnostic methods.5 Hence, it seems reasonable to contemplate a minimally invasive method providing radical and selective cancer destruction, which could be applied to such tumours with some benefit. It was our hypothesis that acoustic cavitation induced by shock waves could be such a method. Cavitation is defined as the non-linear oscillation and collapse ofgas bubbles suspended in a liquid under the influence of acoustic (mechanical) pressure waves$'0; the expansion of bubble nuclei results from a depression within the medium and their collapse may be induced by a sudden compression wave after expansion." It has been shown that cavitation, when occurring at an interface near a cell membrane for example, was deleterious to biological media through mechanical, non-thermal effects. 12-18 We showed the feasibility of radical tissue destruction in the rabbit liver in vivo by a concomitant administration of focused extracorporeal electrohydraulic shock waves with intravascularly infused gas microbubbles.'9 Our results showed improvement shortcomings, however, which made the method inapplicable to the human or even to animal models of tumours without an unacceptable toxicity: tissue ablation was not focused, non-homogeneous, and needed an invasive and potentially toxic intra-arterial infusion of gas microbubbles to be efficient. Our objectives were thus to perfect the method to enhance cavitation, eradicate bubble injection, and to improv...

Summary Cavitation (volume oscillations and collapse of gas bubbles), as generated by a co-administration of shockwaves (SW) and microbubbles (SWB) Group, 1984;Calabresi & Chabner, 1990;Valeriote & Santelli, 1984) and only surgery is able to improve survival in less than 10% of the patients with liver metastasis (Nakamura et al., 1992;Registry of Hepatic Metastases, 1988). New therapeutic instruments are thus clearly needed to improve the prognosis of metastasis from bowel malignancies. Despite disappointing results from radiotherapy and conventional hyperthermia, physical methods may be interesting as an alternative approach to, or in combination with, chemotherapy. Biological effects of acoustic waves, like high intensity ultrasound and shock waves have been studied for many years (Flynn, 1964;Church & Miller, 1983); while direct cytotoxic effects may play a minor role, several studies have shown that damage is caused to microvessels and endothelial cells, causing vascular disruption as well as the production of free radicals, leading to hypoxia and indirect toxicity to the affected tissue (Miller, 1987). It has also been demonstrated that the cytotoxicity of shock waves was obtained mostly through acoustic cavitation, which is the transitory volume oscillations of gas microbubbles induced by rapidly varying pressure waves, eventually resulting in the collapse of bubbles (Dear et al., 1988). When a bubble collapses near an interface with a cell membrane, such dramatic damage is inflicted to the cell as to induce cell death (Delius et al., 1989;Miller, 1987;Miller et al., 1991). However, the therapeutic potentialities of cavitation have so far remained confined to in vitro experimental studies and have not evolved toward clinical applications for two reasons: (1) ultrasound was not able to induce cytotoxicity unless generated in vitro in specific experimental conditions (Church & Miller, 1983); (2) (Prat et al., 199 la). Further experiments with HT-29 cells in suspension and viable rat colon peritoneal metastases treated in vitro showed that cavitation could hinder cell proliferation and induce complete tissue necrosis (Prat et al., 1991b). In a more recent study (Prat et al., personal communication), the cytotoxicity of FUra to HT-29 cells was greatly enhanced by a preliminary exposure of the cells to cavitation, through potentially synergistic mechanisms.In the present study, we aimed at investigating the relevance of cavitation to the treatment of a disseminated digestive tumour in vivo. Materials and methodsCells DHD K12 PROb cells (a gift from Pr Martin, INSERM U252, Dijon, France) originated from a dimethyl-hydrazineinduced rat colon carcinoma were cultured in Dulbecco's modified Eagle's medium supplemented with 8% fetal calf serum under 8% CO2. The cells were cultured to confluence in 75 cm2 flasks and detached after 12 days of culture by 2.5/1000 trypsin/0.2/1000 EDTA. Cell viability was assessed before each use by trypan blue exclusion; it was always over 90%. AnimalsMale and female BD IX rats, syng...