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.

Rat multiple organ blocks: microsurgical technique of removal for ex vivo aerobic organ preservation using a fluorocarbon emulsion.

A multiple organ block (MOB) is composed of en bloc removed organs (heart, lungs, liver, pancreas, kidneys, and bowel), connected by the vascular system, of which blood circulation is maintained by the heart and oxygenation by the lungs under artificial ventilation. The aim of this study is the description of a surgical technique of MOB removal in the rat. Ninety-five MOBs were removed from Wistar rats. The rats were anesthetized, a tracheotomy was performed, and the cannula was connected to a pressure-regulated respirator. A colectomy was performed. Ureters, vena cava inferior, aorta, and bile duct were cannulated using an operative microscope. The vessels that joined the MOB to the carcass were tied or coagulated to make removal of the MOBs possible. Once removed, the MOBs were placed in a vaseline oil bath at 37 degrees C and the aorta and vena cava were connected to an accessory vascular circuit to stabilize arterious pressure. Success rate (ex vivo survival of more than 10 min) after the 30th attempt was 90% and after the 60th attempt was 95% (global success rate 82%). Ex vivo survival of MOBs at 37 degrees C ranged from 1 to 450 min. Rat MOBs allows us to study the normothermic preservation of all the organs susceptible of being transplanted in one single series of experiments. We showed that removal of rat MOBs is feasible. This microsurgical technique is codified. Rat MOBs are suitable if perfusion liquids are difficult to obtain or if a great number of experiments are required. As MOBs are composed of synergically functioning organs in the absence of striated muscle, bone, and nervous system, they also could be useful for physiologic and pharmacologic studies.

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.

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.

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.

Aerobic preservation of organs using a new perflubron/lecithin emulsion stabilized by molecular dowels.

The purpose of the study reported here was to explore a new strategy for the aerobic preservation of transplants using stable concentrated fluorocarbon emulsions as an oxygen delivery system. Fluorocarbons (FCs) are synthetic molecules, chemically and biologically inert, with a high oxygen-dissolving capacity. As they do not mix with water, it is necessary to emulsify them for intra-vascular use. Perfluorooctyl bromide (or perflubron) can be emulsifled with egg-yolk phospholipid (EYP), a nontoxic emulsifiant. The recent adjunction of amphiphilic fluorocarbon-hydrocarbon diblock molecules allows the obtaining of stable emulsions. By contrast with hemoglobin, fluorocarbons release oxygen following Henry's linear law rather than Barcroft's sigmoid curve. Release of oxygen by the FCs is only slightly influenced by temperature, which is an advantage for the preservation of organs. We tested a new 90% w/v fluorocarbon stem emulsion (perflubron/EYL/F6H10) diluted to 36% w/v with a hydroelectrolytic solution containing albumin, on four multiple organ blocks (MOBs; heart-lungs, liver, pancreas, kidneys, small intestine) of rats (EMOBs). Five control MOBs were perfused with a 50% v/v mixture of rat-blood and Krebs solution (KBMOBs). The lungs were ventilated with a FiO2 = 100%. In all cases the survival of the MOBs was greater than 210 min, with stable hemodynamics and preserved hydroelectrolytic and acid-base balances. The levels of lactate, amylase, and CK of the EMOBs were inferior (P < 0.05) to those of the KBMOBs between the first and the second hour. The diuresis of the EMOBs was higher (P < 0.05) than that of the KBMOBs (5.65 +/- 1.76 vs 1.21 +/- 0.28 mg/min). The production of bile, and the AST and ALT levels, were not significantly different. The PaO2 of the EMOBs was higher (P < 0.01) than for the KBMOBs. In normothermy, the maintenance of an aerobic metabolism using the FC emulsion caused less damage to the organs. Aerobic preservation of organs using FC emulsions therefore appears to be an attractive alternative to the presently used cold ischemia.

Normothermic preservation of "multiple organ blocks" with a new perfluorooctyl bromide emulsion.

To evaluate the efficiency of fluorocarbon emulsions as oxygenating media for the normothermic preservation of organs (multiple organ blocks, MOB), a new perfluorooctyl bromide (perflubron) emulsion was compared with a mixture of modified Krebs solution and blood. The fluorocarbon emulsion used (90% w/v of fluorocarbon) contained a low amount of egg yolk phospholipid (EYP, 2% w/v) and was stabilized by a mixed fluorocarbon-hydrocarbon amphiphile C6F13C10H21 (F6H10). Blood of 4 rat MOBs was replaced with a 36% w/v fluorocarbon emulsion which has been complemented with albumin and electrolytes (EMOBs). 5 MOBs were perfused with a mixture of blood and albumin-containing Krebs solution (KBMOBs). Lactate, amylase and creatine kinase were lower (p < 0.05) at 60 and 120 min in EMOBs than in KBMOBs,

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-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.

In vivo effects of high-intensity ultrasound on prostatic adenocarcinoma Dunning R3327.

High-intensity ultrasound has been used to treat Dunning R3327 prostatic adenocarcinoma implanted s.c. in Fischer Copenhagen rats. Focused ultrasound was generated with a 1-MHz transducer and energy was provided by a 7.5-kW power amplifier. Seventy-four rats were treated using two different sublines of Dunning tumor. Study 1 dealt with 49 rats with the Mat-Ly-Lu subline, treated with acoustic intensities ranging from 300 to 2750 W/cm2. Of the 49 rats in Study 1, 30 had complete tumor necrosis and 19 had no effect; of the 30 who had complete local tumor necrosis, 14 had local relapse, 9 had distance metastases to lung and nodes without local occurrence, and 7 remained free of tumor and were still alive 12 months after treatment. In Study 2, 25 rats with AT2 subline were treated with an intensity of 820 W/cm2. Similarly for Study 2, there was complete local tumor necrosis in 24 of 25 animals, with local regrowth in 7 of 24 and no recurrence of metastasis in the remaining 16 after a follow-up of 3 months. These results suggested that high-intensity focused ultrasound could be useful for the treatment of small localized cancerous tumors such as low-grade prostate carcinoma.

[Tumor ablation with focalized ultrasound. In vivo experiment with prostatic adenocarcinoma R3327 Mat-Ly-Lu]. / Ablation tumorale par ultrasons focalisés (A.T.U.F.). Expérimentation in vivo sur l'adénocarcinome prostatique R3327 Mat-Ly-Lu.

Ultrasound can induce tissue lesions by a combination of thermal and mechanical effects related to the tissue absorption of the energy emitted at the focal point of the transducer. The effects of focused ultrasound were studied in vivo in Fisher/Copenhagen hybrid rats bearing Dunning R3327 experimental prostatic carcinoma. The experimental tumour was transplanted by subcutaneous injection into the abdomen of 20 mg of tumour tissue derived from the Mat-Ly-Lu strain. Treatment was performed under general anaesthesia. The animal, maintained in a sarcophage exposing the tumour, was immersed in degassed water ensuring the interface between the tumour and the 1 MHz transducer. The displacements of the transducer were guided by computerised ultrasound screening, allowing irradiation of the entire tumour. The energy was supplied by a 7.5 kW amplifier in the form of series of impulses of variable duration. 77 rats were treated and the tumour growth was compared to that of non-irradiated control rats. Comparative series demonstrated the following results: 1. Immediate tumour destruction was obtained with a very high acoustic intensity (9,000 Watts/cm2) and a brief exposure time. 2. A transient slowing of the tumour growth rate was observed for an acoustic intensity of between 3,500 and 5,500 Watts/cm2. 3. Partial or total necrosis of the tumour was obtained with intensities of between 300 and 2,750 Watts/cm2 and a long exposure time. Total tumour destruction was obtained in 30 of the 49 rats treated under these conditions. 14 animals developed a local recurrence, 9 animals did not develop a local recurrence but developed metastases and 7 animals obtained long-term survival without local recurrence or metastasis. Under certain experimental conditions, focused ultrasound, without any adjuvant treatment, was able to destroy the Dunning R3327 Mat-Ly-Lu strain experimental tumour and, in certain cases, induced complete cure of this experimental cancer.

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.

[Tissue ablation by focused ultrasound]. / Ablation tissulaire par ultrasons focalisés (ATUF).

Tissue lesions can be induced at the focal point of highly focused transducers with a frequency of 1 and 2.25 MHz for exposure times of less than 1 second. The energy generated by a high power amplifier (7.5 kilowatts effective at 1 MHz) is delivered in the form of series of impulses lasting between 10 and 1,000 milliseconds. The experimentation was conducted in the rat kidney (the left kidney, normally supplied by its vascular pedicle, was exteriorised during ultrasound treatment and then returned to the abdomen). The animal was sacrificed 3 days later and the lesions were studied by serial histological sections. 248 ultrasound shots were performed between January and September 1990. They allowed the definition of the time and intensity constants necessary to induce total destruction of the renal tissue at the focal point. Depending on the energy delivered, an elliptical cavity with a mean height of 1.2 to 4.6 mm and a mean diameter of 0.6 to 3 mm is observed at the focal point after a single shot. No cell structures were visible in the cavities and, in general, the cavity was prolonged by a cone-shaped region of coagulated necrosis with an inferior base. The mechanism responsible for this focused ultrasonic tissue destruction (FUTD) involves a variable combination of thermal and mechanical effects which depends on the ultrasound intensity delivered at the focal point of the transducer.

[Extracorporeal survival and normothermia preservation of multiple ex vivo organ in rats]. / Maintien en survie extracorporelle et en normothermie de blocs multiviscéraux chez le rat.

A multiple organ block is composed of "en bloc" removed organs, connected by the vascular system, whose blood circulation is maintained by the heart, and oxygenation by the lungs under artificial ventilation. To develop the removal technique and the reanimation proceeding, and to validate this new physiological model, we used 70 Wistar rats. Some multiple organ blocks (heart-lungs, liver, pancreas, kidneys and bowel) functioned in vitro at 37 degrees C for more than 150 minutes with stable haemodynamics and preserved electrolyte and acid-base balances. Bile secretion and bilateral diuresis were present. Histopathological examination confirmed the integrity of these different organs. This physiological model could be used for the study of new preservation solutions.

Orthopedic aspects of sickle cell anemia and allied hemoglobinopathies.

The study of 23 cases of hemoglobinopathies in Nigeria using electrophoresis, showed that 16 cases were HB-SS, 5 cases HB-SC, and 2 cases HB-S Th. There were infarcts of long bones, which were usually multiple in the diaphyses in 17 cases, septic arthritis of big joints in 4 patients and aseptic necrosis of the hip in one, and in the hip and knee in one. Infection was proved by culture in only the 4 joints and 7 of the affected long bones, 8 of the causative organisms were Salmonella and 3 were Staphylococci. Only 2 of the infected cases needed sequestrectomy and the other 9 responded to simpler methods like aspiration and incision of abscess U.L.A. without resulting in a sinus formation. The aseptic necrosis in the hip may simulate Perthe's disease and dysbaric osteonecrosis, the massive periosteal reaction may simulate Caffey's disease and hypervitaminosis A, and give rise to difficulties in diagnosis when hemoglobinopathies are not suspected.