Intraluminal ultrasound applicator compatible with magnetic resonance imaging "real-time" temperature mapping for the treatment of oesophageal tumours: an ex vivo study.

High intensity ultrasound has shown considerable ability to produce precise and deep thermal coagulation necrosis. Focused, cylindrical, spherical or plane transducers have been used to induce high temperatures in tissues to coagulate proteins and kill cells. Recently magnetic resonance imaging (MRI) has been used, with extracorporeal or intracavitary focused transducers and cylindrical interstitial applicators, to monitor temperature distribution and provide feedback during heating procedures. If intraluminal applicators are used, the active part is in contact with the region of interest and it is essential to provide an accurate view of heat deposition and the extent of coagulation necrosis close to the transducer. The purpose of this study was to develop a 10 mm diameter intraluminal ultrasound applicator, designed to treat oesophageal cancers and compatible with MRI "real-time" temperature mapping. The active part of the ultrasound applicator, covered by a latex balloon, is a 15 X 8 mm2 plane transducer, which is in contact with the tumours during treatment. Each ultrasound exposure generates coagulation necrosis, in an area with the approximate shape of a rectangular parallelepiped up to 10 mm deep. When the exposures were repeated by rotating the applicator on its axis, sector-based or cylindrical volumes of necrosis could be produced, matching the shape of oesophageal cancers. Ex vivo trials were performed to demonstrate the applicator's compatibility with a clinical MRI scanner (1.5 T). MRI signals were acquired without any magnetic susceptibility distortion, even close to the applicator. Fast (0.72 images per second) 2D temperature mapping was performed during ultrasound exposure, using temperature-related proton resonance frequency shift at a resolution of 0.5 degrees C. Coagulation necrosis viewed with inversion recovery sequences, were in good agreement with the qualitative macroscopic observations made for the few cases tested in this study.

Design and preliminary results of an ultrasound applicator for interstitial thermal coagulation.

The extracorporeal high-intensity focused ultrasound (HIFU) techniques are not still transposable for tumors of the digestive tract because of their locations. This study was designed to evaluate the feasibility of interstitial applicators (3.8 mm O.D.) to comply with this therapeutic lack and to demonstrate the possibility of producing coagulation necrosis by a specially designed probe and with a short exposure time (20 s). The active surface of the applicators consists of plane water-cooled PZT transducers working at 10 or 5 MHz. They were evaluated in terms of acoustic power emitted as a function of the frequency, and applied electrical input (electroacoustic efficiency of 75% at their working frequency) and in vitro and in vivo pig liver tissue destruction. The in vitro and in vivo necroses depth from the applicator surface ranged from 8 to 20 mm. This showed the advantage of a nondivergent source: the pressure decay is only due to the tissue absorption in the Fresnel zone. The lesions dimensions are slightly dependent on perfusion: 8 +/- 2 mm deep in vitro for a 10.7-MHz transducer working at 14 W/cm2 against 10 mm in vivo. Operating at 5 MHz makes it possible to increase the therapeutic heating depth. For example, at a similar close-to-transducer temperature, the 5-MHz applicator induced, at a depth of 10 mm, a temperature elevation of 27 degrees C against 15 degrees C for that working at 10 MHz.

Development of an interstitial ultrasound applicator for endoscopic procedures: animal experimentation.

Biliary cancer is very difficult to treat, mainly because of the advanced stage at which such tumours are detected and the low efficacy of systemic therapeutic modalities like radiotherapy. Palliative measures designed to clear the duct (either by means of surgery or an endoscopic procedure) are presently performed. A relatively noninvasive alternative could be developed to fill this gap in the therapeutic arsenal. To this end, we have designed an interstitial ultrasound (US) applicator suitable for use with a digestive endoscope. This applicator is based on a water-cooled plane transducer that operates at 10 MHz. Although, because the target zone is cylindrical in shape, it might have seemed more logical to use a cylindrical transducer. Nevertheless, a plane transducer was chosen because the pressure field from this kind of emitter decreases less quickly, which means faster and deeper heating. However, to generate coagulation necrosis all around the duct, the applicator has to be rotated around its axis; this is achieved by means of a flexible metallic shaft (2 m in length and 3. 8 mm in diameter) that joins the device's active head (which contains the transducer) to the casing with all the connectors. A holder is fixed at the endoscope channel inlet; it controls the rotation of the applicator. Trials were conducted on pigs. The duodenoscope was introduced via the oesophagus down through the duodenum as far as the hepatopancreatic ampulla. Using a guide wire, the applicator was navigated into the duct via the endoscope instrument channel. Well defined, reproducible volumes of coagulation necrosis with a diameter of 20 mm were generated in the biliary tissue and the liver. These promising results indicate that this kind of endoscopic US delivery system may represent an effective tool for the treatment of biliary tumours in humans. An Independent Ethics Committee recently approved preliminary clinical trials of this applicator.

Prostatic tissue destruction by high-intensity focused ultrasound: experimentation on canine prostate.

High-intensity focused ultrasound (HIFU) has been used transrectally to induce intraprostatic coagulation necrosis lesion in the canine prostate. The device combines a firing system (power amplifier and therapy transducer) and a localization system (ultrasound scanner). Thirty-seven dogs have been treated with ultrasound intensity ranging from 720 W/cm2 to 2300 W/cm2 and shot durations ranging from 1 to 4 seconds. The threshold for focal ultrasonic lesions was determined to be 1000 W/cm2 with a 1-second shot duration. Intraprostatic lesions were obtained without any damage to the rectal wall. These lesions were homogeneous coagulation necroses and progressed first to an inflammatory fibrosis and then to sclerosis with cavity formation. Intraprostatic lesions also occurred with a combination of moderate acoustic intensity (720 W/cm2) and longer shot duration (4 seconds). The temperature reached at the focal point of the transducer was 85 degrees C. The study confirms the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall. The destruction of localized prostatic cancer seems to be possible in the near future using HIFU delivered by the transrectal route.

High-efficiency shock-wave generator for extracorporeal lithotripsy.

In extracorporeal lithotripsy, the electro-acoustic efficiency of electrohydraulic generators is limited by the inductance of the electrical discharge circuit. A new shock-wave generator is described that uses a coaxial discharge line enabling electro-acoustic efficiency to be greatly increased. The line is built using a para-electric ceramic with a relative dielectric constant of 1700, manufactured for use in high-voltage impulse mode. A coaxial spark gap, with minimal inductance, has been developed to obtain the triggered breakdown of the discharge line. Shock waves are created with a coaxial electrode plugged directly into the spark gap and immersed in an electrolyte of degassed saline. Electrode gap and electrolyte resistivity are adjusted to match the resistivity of the electrolyte volume between the underwater electrodes to the characteristic impedance of the line. The discharge line generates in the medium a rectangular current pulse with an amplitude of about 6000 A and a rise time of 50 ns. Compared with conventional generators, measurements of the expansive peak pressure pulse show an increase of 105% at 10 kV, 86.5% at 12 kV and 34.5% at 14 kV charging voltage. Electro-acoustic efficiency is found to be 11% instead of 5.5% for a conventional discharge circuit.

Design and in vitro results of a high intensity ultrasound interstitial applicator.

Interstitial technologies were proposed for the treatment of deep-seated and unresectable tumours. This study was designed to demonstrate the possibility of producing coagulation necrosis for a short exposure duration (20s) and a large volume with an interstitial ultrasonic applicator equipped with a plane transducer. The applicator was evaluated in terms of electroacoustic efficiency (58% at 10.7 MHz), temperature pattern and in vitro pig liver tissues destruction. The temperature elevation reached 52, 39, 22 and 15 degrees C at, respectively, 2.5, 7.5 and 10 mm from the applicator surface along the propagation axis. The evident cigar-shaped lesions spread on a depth of (8 +/- 2) mm from the surface applicator, (10 +/- 1) mm high and (3 +/- 1) mm high and (3 +/- 1) mm wide. The temperature measurements showed the limitations encountered with a 10 MHz transducer. The high increase in temperature of tissues close to the transducer can induce vaporisation and a gaseous barrier opaque to ultrasound. Owing to the shape and the operating frequency of the transducer, we hope to obtain the same satisfactory performances in vivo with weakly perfusion-dependent lesions. Axial and longitudinal applicator motions will enable us to treat more important volumes.

The feasibility of constructing a cylindrical array with a plane rotating beam for interstitial thermal surgery.

Thermal surgery has been shown to be a useful therapeutic option when external ultrasound applicators cannot be used as their beam will not reach the target site. If plane transducers are used, the ultrasound beam has to be rotated in order to generate a sufficiently large volume of necrosis. However, rotating deep-seated interstitial applicators and controlling their shooting direction presents major technical problems. The purpose of this study is to evaluate the feasibility of constructing a cylindrical array with a plane rotating beam for ablating esophageal tumors by interstitial hyperthermia. The feasibility of such an array has been initially evaluated using a plane array (which is easier to make from a technical point of view). This array was made with a new piezoelectric material because its mechanical properties make it ideal for the construction of a cylindrical array in the future. We showed that the beam of each array element is sufficiently divergent and that cross-coupling is small enough to generate a plane wave from a cylindrical array. In addition, power tests and electro-acoustic efficiency measurements demonstrated that the output was sufficient to induce tissue necrosis in the relevant conditions.

Bloodless partial nephrectomy with a new high-intensity collimated ultrasonic coagulating applicator in the porcine model.

OBJECTIVES: To evaluate the long-term hemostatic efficacy of a new high-intensity collimated ultrasonic (HICU) applicator for open subhilar partial nephrectomy (PN) in the porcine model. METHODS: An applicator was designed with a planar 3.78-MHz HICU transducer and a reflector to optimize the delivery of acoustic energy to coagulate renal tissue. Six female pigs underwent right PN, followed at day 7 by left PN. The 6 pigs were killed on day 14. The treatment consisted of delivering HICU to a lower pole subhilar location, under a vascular clamp, then releasing the clamp, and cutting the kidney lower pole. The immediate and delayed hemostatic efficacy, treatment parameters, blood loss, complications, and renal function were evaluated at each surgical event and at necropsy. RESULTS: Perfect hemostasis was achieved with all 12 kidneys, with a mean treatment time of 7.2 minutes (range 5 to 9.2). The mean proportion of resected parenchyma was 21% (range 14% to 32%). No renal function impairment and no major complications were recorded. At necropsy, no secondary hematoma was observed, and three urinomas (25%) were found. CONCLUSIONS: Our HICU applicator has shown promising results during PN in the pig model with no other method of hemostasis. More studies are needed to refine our probe for laparoscopic surgery, improve its ergonomics, and extend our experiments to human laparoscopic nephron-sparing surgery.

Effects of high-energy focused ultrasound on kidney tissue in the rat and the dog.

In vivo tissue destruction was performed on 124 rat and 16 canine kidneys by focusing high-intensity ultrasound with a 1- and 2.25-MHz transducer. A precise tissue lesion was obtained in both models which varied in size according to the number of firings and the acoustic intensity. In the rat experiments, which were used to define the constants necessary to produce a localized tissue lesion at the focus of the transducer, the lesions obtained were either coagulating necrosis or a 'punched out' cavity which represented the threshold of tissue ablation. In the canine experiments, a kidney lesion was achieved in 10 animals (63%) extracorporally. These lesions were also histologically determined to be coagulation necrosis. These lesions are created by highly focused ultrasound and are caused most likely by a combination of cavitation and thermal effects, depending on the duration and frequency of the ultrasound bursts. Exact mechanism of this effect is explored as well as potential clinical applications in treating kidney, liver, and prostate tumors in humans.

Cylindrical thermal coagulation necrosis using an interstitial applicator with a plane ultrasonic transducer: in vitro and in vivo experiments versus computer simulations.

Extracorporeal HIFU techniques still cannot be used to treat tumours of the digestive tract, therefore an interstitial applicator has been developed to fill this gap. The object of the study was to validate the use of a plane ultrasonic transducer in an interstitial applicator to obtain large sector based or cylindrical coagulation necrosis. Two very different shot sequences were performed in vitro and in vivo and compared with numerical calculations. Each sequence consisted of 20 shots. After each shot the applicator was rotated through an angle of 18 degrees. Each shot in sequence 1 lasted 20 s, with a 2-min interval between shots which can be considered as independent. The second sequence involved coupling the shots so that each benefits from the heat deposited by the preceding ones. The first shot lasted 20 s to establish the lesion, then the duration of the subsequent 19 shots was 10 s to take into account the temperature rise due to preceding shots. In both cases, it was shown that cylindrical necrosis resulted in vivo and in vitro: 20 mm diameter and 8mm in height. The dimensions and the shapes of the necrosed volumes agreed with numerical predictions: the necrosed area induced by sequence 1 had a serrated border, whereas that of the second sequence was much more uniform. It was also shown that, for the two sequences, less than 20 s were necessary to coagulate the tissues in each direction. The results with sequence 2 showed that coupling the shots could be used to reduce treatment time without modifying the necrosed volume.

In vivo effects of cavitation alone or in combination with chemotherapy in a peritoneal carcinomatosis in the rat.

Cavitation (volume oscillations and collapse of gas bubbles), as generated by a co-administration of shockwaves (SW) and microbubbles (SWB), induces cytotoxicity in vitro. Moreover, cavitation potentiates the effects of Fluorouracil (FUra) on colon cancer cells. We aimed at reproducing such effects in vivo. A peritoneal carcinomatosis was induced in BDIX rats by intraperitoneal (IP) injection of DHDK12PROb cells. Cavitation was produced by various SW regimens (250 to 750SW) combined with bubbles (air/gelatin emulsion) infused through an IP catheter. In two consecutive experiments, microtumours (day 3 after cell injection) were submitted to various combinations of cavitation and/or Fluorouracil (FUra) and Cisplatinum (CDDP) at either high or low doses. After 30 days, 100% of control animals were dead or presented carcinomatosis with ascites, vs 60% after FUra 5 mg kg dy, day 4 through 8, and 0% after 250 SWB, day 4 and 6 + FUra 5 mg kg dy, day 4 through 8 (P < 0.001); similar differences were found with CDDP. Survival after low dose FUra + SWB was comparable to high dose FUra (25 mg kg dy day through 8) and was improved as compared to low-dose FUra alone. Only a high dose FUra + SWB schedule induced 40% long term (> 150 days) disease-free survival, but also a higher undesirable toxicity (40% toxic deaths within 1 month). It is concluded that cavitation is cytotoxic in vivo and that it potentiates the effects of FUra and CDDP in this animal model.

High-intensity focused ultrasound experimentation on human benign prostatic hypertrophy.

High intensity-focused ultrasound (HIFU) has been used transrectally to induce an intraprostatic coagulation necrosis lesion in human prostatic adenoma. The device to produce HIFU combines a firing system (power amplifier and therapy transducer) and an imaging system (ultrasound scanner). Nine patients have been treated on epidural anaesthesia with an ultrasound intensity similar to or higher than the acoustic intensity used in previous experiments on canine prostates. Intraprostatic lesions were obtained without any damage to the rectal wall. These lesions were also histologically determined to be coagulation necrosis with a complete destruction of the glandular tissue. These studies confirm the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall. The destruction of localised prostatic cancer would seem to be possible in the near future by using HIFU delivered by the transrectal route.

A high-intensity US probe designed for intraductal tumor destruction: experimental results.

BACKGROUND: Many digestive tract tumors spread inside the lumen and are not amenable to curative surgical treatment. An intraluminal method of tumor destruction would be useful for palliative or even curative purposes. High-intensity ultrasound (US) is suitable for such purposes. Our objective was to perform experiments with animal models that would lead to development of a high-intensity US probe for intraductal tumor destruction suitable for insertion through a large-channel endoscope. METHODS: The active part of the high-intensity US applicator consisted of a water-cooled piezoceramic plane transducer (3 x 10 mm) operating at 5 MHz for deep or 10 MHz for shallow tissue penetration. A cylinder of tissue was destroyed by means of rotating the transducer on its axis through a flexible shaft. Experiments were conducted in vitro on livers of butchered pigs (10 lesions), in vivo on exteriorized pig livers (15 lesions), and on metastatic Dunning tumors (AT(2 ) subline) implanted subcutaneously in 28 rats (treated n = 16, controls n = 12). RESULTS: In experiments on pig livers, high-intensity US induced highly reproducible cylinders of coagulation necrosis (diameter 20 +/- 1 mm, height 8 +/- 1 mm) with sharply demarcated and serrated boundaries. The exposure duration to achieve such lesions was 5 minutes. Regions of coagulation necrosis obtained in vivo were similar in size and shape. All 12 control rats died or were killed because of diffuse cancer by day 15 after implantation; 64% of the treated rats were tumor free 30 days after treatment, and 36% had local recurrences. CONCLUSION: This high-intensity US probe induces highly reproducible cylinders of coagulation necrosis and is effective against tumors in animals.

Extracorporeal ablation of liver tissue by high-intensity focused ultrasound.

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.