Experimental gallstone dissolution with methyl-tert-butyl ether (MTBE) and transcutaneous ultrasound energy.

The simultaneous application of ultrasound energy greatly accelerated the rate of cholesterol gallstone dissolution by methyl-tert-butyl ether (MTBE). In vitro experiments using this treatment showed that a 498-mg stone burden could be dissolved in 19.5 minutes, approximately 100% faster than what could be achieved with MTBE alone. Pigs (n = 13) with surgically implanted gallstones were treated with MTBE and transcutaneously applied ultrasound from a prototype system built for clinical studies. The average stone reduction of all pigs was 470.46 mg +/- 60.44 mg; 91.39% of an average implanted burden of 515.08 +/- 18.03 mg. Control group pigs (n = 9), receiving only an MTBE infusion, showed an average stone reduction of 51.77%. Enzymes indicative of hepatocellular injury showed no significant abnormalities after 6 weeks. Gallbladder ablation with a fibrous remnant (ie, no mucosa, no lumen, patent cystic duct) occurred in 10 (70%) of the pigs.

A large animal model (swine) to study the diagnosis and treatment of cholelithiasis.

Human gallstones were surgically placed into the gallbladders of 200 swine. Eight of these swine were used as a prospective series to verify that the placement and presence of human gallstones in their gallbladders caused no significant pathologic changes in the gallbladder and that the gallstones were not spontaneously dissolved. Although limitations exist, the advantages of this procedure demonstrate that the surgically prepared swine is an appropriate model for controlled in vivo experiments in radiologic imaging or interventional treatment. A 4 F pig-tailed catheter designed for Trocar insertion was developed as a companion to this model.

Extracorporeal liver ablation using sonography-guided high-intensity focused ultrasound.

RATIONALE AND OBJECTIVES: High-intensity focused ultrasound (HIFU) is the only radiation beam that can remotely destroy deep-seated tissue targets without causing damage to the intervening tissues. This study evaluates the ability of sonography-guided HIFU to extracorporeally induce liver ablation in a rabbit model. METHODS: Under sonographic guidance, the HIFU beam was transcutaneously focused at the target tissue in the liver through a subcostal approach. A computer controlled the HIFU exposure and transducer movement to destroy a preselected tissue volume. Simultaneous sonography monitored the tissue response. Ten insonated rabbits were killed from days 0 to 10, and the liver and intervening tissues were examined histologically. RESULTS: A sharply demarcated sonolesion of coagulation necrosis was produced in the liver in 9 of 10 animals. No damage was found in the intervening tissues (n = 6) when adequate acoustic coupling and proper beam path was applied. CONCLUSION: Sonography-guided HIFU might be a potential new modality for extracorporeal inducement of liver cancer ablation without resorting to laparatomy.

Ultrasonic diagnostic system for interactive interrogation of adult brain through intact skull.

An integrated ultrasonic system has been developed employing static gray scale imaging, digital image processing, and analyses of quantitative ultrasonic backscatter for interactive interrogation of brain through the adult human skull. Operating at 750 kHz, to avoid severe spatial and temporal pulse distortion which accompany ultrasonic transkull transmission at higher frequencies, storage and image processing of successive images taken at selected gain settings in the same image plane allow the reconstruction of a composite cross-section of the brain and skull and enable visualization of internal brain structure. Analyses of digitized backscatter data obtained with the visualization transducer over selectable interrogation paths referenced to the cross-sectional image permit quantitative classification of tissue type independent of qualitative visual image analysis, such that enhanced diagnostic potential is provided. A previous paper described in detail the modifications of the commercial ultrasound diagnostic unit which serves as the core of this system. The present paper presents the rationale for the integrated system design approach, as well as a description of graphics display and tissue classification features which have been incorporated into the instrumentation configuration and are deemed necessary for successful transkull ultrasonic imaging and diagnosis.

High-intensity focused ultrasound in the treatment of experimental liver cancer.

High-intensity focused ultrasound (HIFU) was used to treat Morris rat hepatoma 3924A implanted in the liver. Treatment was administered with a lens-focused 4-MHz transducer that created a focused beam of 550 W/cm2 at peak intensity. One hundred twelve rats with liver tumors were divided into two groups of 56 each. Group 1 received HIFU therapy while group 2 (the control group) did not. All rats were killed immediately or 1, 3, 7, 14, 21, or 28 days after treatment. Eight rats in each group were killed at each interval for pathologic and biochemical studies. Significant inhibition of the tumor growth was seen in the HIFU-treated group, with tumor growth inhibition rates of 65.4% to 93.1% from the third to the 28th day after treatment. Ultrasound-treated tumors showed direct thermal cytotoxic necrosis and fibrosis. An additional 56 ACl rats with liver tumors were divided into four groups of 14 each. Group 1 received doxorubicin hydrochloride intraperitoneally and HIFU therapy; group 2, HIFU therapy; group 3, doxorubicin hydrochloride; and group 4 (the control group), neither HIFU nor doxorubicin hydrochloride. Significantly improved survival rates were noted in HIFU-treated animals (groups 1 and 2) compared with those of groups 3 and 4. These data suggest that HIFU may be a useful method for local treatment of hepatic tumors.

High-intensity focused ultrasound in the treatment of prostatic tissue.

OBJECTIVE: Beginning in 1987, high-intensity focused ultrasound was investigated in the canine model to determine the feasibility of destroying prostate tissue. After demonstrating the ability to ablate prostate tissue reliably in a canine model, a 15-patient pilot clinical study was undertaken at Indiana University in the fall of 1992. This pilot study was undertaken to assess the safety in the human clinical situation, as well as to give some early efficacy results. METHODS: The early canine feasibility studies were conducted via a suprapubic extracorporeal approach using two separate transducers, one for imaging and the other for therapy. Subsequent to this, a transrectal probe, which had the dual capability of both imaging and therapy, was developed and used to treat canine prostates in a formal, "good laboratory practice" study to determine the safety of this technology prior to beginning treatment of human benign prostatic hypertrophy. RESULTS: The formal canine studies demonstrated that prostatic tissue could be reliably ablated in the therapy zone. The dosimetry and duty cycle required to ablate canine prostatic tissue effectively was also determined in this study. The study also demonstrated that the prostatic tissue could be ablated without injury to the intervening rectal tissue or periprostatic tissue. The human pilot study has also demonstrated safety of high-intensity focused ultrasound, as well as early efficacy. CONCLUSIONS: These early clinical results are encouraging, but assessment of efficacy will require a randomized study comparing high-intensity focused ultrasound to sham and to transurethral prostatectomy. This multicenter trial is currently planned.

Comparison of computed sonographic tomography and pulse-echo imaging in the head.

Computed sonographic transmission tomograms of infant and adult human cadaver heads are presented and compared with sonographic pulse-echo and x-ray tomograms of the same horizontal planes. The sonographic attenuation tomograms were reconstructed from broadband transmission data obtained using the rotate/translate axial scan mode in much the same way as x-ray tomography is performed. The formalin-fixed infant cadaver head was scanned through the anterior fontanelle using pulse-echo and in a horizontal plane (3.3 cm superior to the Frankfort plane) using both pulse-echo (3.5 MHz and 5 MHz) and transmission sonography (5 MHz). The computed sonographic transmission tomogram revealed superior anatomic detail as compared with the pulse-echo images obtained in the horizontal plane and compared favorably with x-ray scans. The quantitative, noninvasive nature of sonographic tomography shows promise for clinical applicability in the infant. In the adult human cadaver, sonographic tomograms at 750 kHz are presented in both the transskull and excised brain conditions. These scans also offer promise for the possible clinical exploration of the method.

Transkull focal lesions in cat brain produced by ultrasound.

Focused ultrasound has been used for focal modifications of brain tissue and in preliminary studies of the application of ultrasonic techniques for tissue modification in human stereotaxic neurosurgery; however, the technique has been seriously compromised by the necessity of removal of intervening skull. Such removal was necessary to avoid distortion and extremely large attenuation of the ultrasonic beam which resulted from passage through bone. Recent studies have shown that under proper conditions focal beams of ultrasound can be transmitted with tolerable and attenuation through skull, suggesting the possibility of transkull lesion production in brain. This report describes the acoustical parameters and histological features of focal brain lesions produced in 10 craniectomized cats with intense focal ultrasonic beams which first had passed through a formalin-fixed human skull overlay. The histological appearance of these lesions produced to date is similar to that produced previously without intervening skull.

Losses in tissue associated with finite amplitude ultrasound transmission.

The ultrasonic absorption coefficient of freshly-excised rat liver is measured as a function of intensity in a 1 MHz focused field. The 7 cm diameter source has a geometric focus of 20 cm and a half-intensity linear focal beamwidth of 4.65 mm. Free-field harmonic content and radiation force measurements within the focal region indicate that quasilinear shock (sigma = 1) is attained in the intensity range of 225 W cm-2 to 275 W cm-2 SPTP intensity. Radiometric measurements of focal beamwidth and intensity response (focal intensity versus transducer input voltage squared) demonstrated beam narrowing up to 700 W cm-2 and focal intensities greater than would be expected from linear theory. This nonlinear acoustic field is employed to measure the absorption coefficient of liver at the beam focus. The pressure absorption coefficient, measured via the transient thermoelectric technique, was 0.038 Np cm-1 at low intensities (below 100 W cm-2 SPTP) and rose to approximately 0.117 Np cm-1 at 750 W cm-2 SPTP intensity. The absorption predicted using spherically converging beam theory is in agreement with the experimental data at the lower (below 200 W cm-2) and the higher (above 650 W cm-2) intensities. Gaussian theory provided a poor fit to the experimental data even after deficiencies in the model were considered.

Absorption in liver at the focus of an ultrasonic shock wave field.

This experimental study is an extension of a previous investigation of finite amplitude ultrasound absorption at 1 MHz fundamental frequency in freshly excised rat liver at 37 degrees C (Fry et al. 1989). The work reported here includes measurements of the absorption as a function of intensity under a variety of conditions (temperature, pressure, and tissue state). The maximum intensity employed in the investigation (700 W/cm-2) corresponds to a shock parameter of approximately 1.7 based on previous characterization of the acoustic field which established that shock (sigma = 1) occurred in the range 225 W/cm-2 to 275 W/cm-2 (Fry et al. 1989). Of the three temperatures chosen for the thermal study (30 degrees C, 37 degrees C, and 41 degrees C), the only statistically significant differences (p less than 0.05) in absorption were between the 30 degrees C and 41 degrees C data in the intensity range just above sigma = 1 (300-500 W/cm-2). The intensity-dependent absorption coefficient was also determined for excised liver under hyperbaric conditions and for liver in situ at 37 degrees C. At a pressure of 350 psi, the absorption was generally less than at atmospheric pressure. In situ liver at 37 degrees C had a lower absorption above 200 W/cm-2 than freshly excised liver, but the difference was only significant between 200 and 300 W/cm-2 and between 600 and 700 W/cm-2.

Ultrasound and microbubbles: their generation, detection and potential utilization in tissue and organ therapy--experimental.

Ultrasound-induced cavitation in tissue and organs has been well recognized and documented. Generally, this phenomenon has been seen as something to be avoided except in cases such as lithotripsy, where its production is considered an essential part of the treatment process or as a desirable contrast media in some areas of visualization enhancement. This article covers three areas in which the phenomenon has been observed, and shows how the effect can or may be therapeutically beneficial. Studies in the pig show that implanted human gallstones and the gallbladder itself can be eliminated in a nonsurgical procedure using ultrasound-induced cavitation in the gallbladder. In the dog brain, relatively stable cavitation-induced microbubbles have been transported through the vascular system to regions outside a focal seeding site. These bubbles produce ablation of tissue volumes at a remote site when irradiated with appropriate ultrasound. The cavitation phenomenon has been observed in the dog and human prostate. In the human prostate, microbubbles transported from ultrasound-induced focal seeding sites can be readily visualized with ultrasound and may be potentially useful under controlled conditions in tissue debulking for the treatment of benign prostatic hyperplasia (BPH). A similar microbubble transport has not been seen in the dog prostate under similar ultrasound treatment parameters. The ability to detect cavitation-induced microbubbles, follow their transportation through the vascular system and excite them at the appropriate time and place provides interesting possibilities for therapy. Of course, the entire microbubble process can be avoided by working below the cavitation threshold, thereby using only the absorption of ultrasound in tissue to produce focal thermal lesions. The term microbubble is used here in the context of those bubbles which can be transported in the vascular system down to vessels diameters below the 100-microns range. This is the vessel size in the vascular field into which microbubbles are transported and can be both visualized as well as disrupted with ultrasound.

Effects of high-intensity focused ultrasound in the treatment of experimental neuroblastoma.

This report evaluates the effect of high-intensity focused ultrasound (HIFU) on subcutaneous murine neuroblastoma C1300. HIFU treatment was administered with a focused 4-MHz quartz transducer with a peak intensity of 550 W/cm2. In experiment 1, 60 animals with tumor were divided into four groups. Group I (n = 15) were controls; group II (n = 15) received adriamycin, 5 mg/kg intraperitoneally; group III (n = 15) received HIFU; and group IV (n = 15) received both adriamycin and HIFU. All the animals in groups I and II died of tumor by 35 days. Fifty-three percent (8/15) of mice in group III and 80% (12/15) in group IV were cured with no evidence of tumor (NET) at 200 days. Log-rank statistics showed significant prolongation of survival in the groups III and IV as compared with groups I or II (P less than .05). In experiment 2, 45 animals with tumor were divided into three groups. Group I (n = 15) were controls; group II (n = 15) received HIFU; and group III (n = 15) received repeated HIFU. The results showed 47% (7/15) of mice in group II and 67% (10/15) in group III were NET at 200 days. Significant survival prolongation was achieved in groups II and III in comparison with group I (P less than .05). In experiment 3, 90 mice received either tumor (n = 60) or saline (n = 30) inoculation in the left flank. On day 5, 45 mice with tumor were treated with HIFU (group I), while the other 15 mice with tumor (group II) had a sham procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of high-intensity therapeutic ultrasound irradiation in the treatment of experimental hepatoma.

A study evaluating the efficacy of high-intensity therapeutic ultrasound (HITU) as a treatment modality in experimental hepatoma is reported. Morris hepatoma (3924) 1 x 10(6) cells were transferred subcutaneously into 40 male ACI rats (weight, 150 to 200 g). Animals were divided into four experimental groups: group 1 (n = 10) consisted of untreated controls; group 2 (n = 10) received intraperitoneal cyclophosphamide 50 mg/kg as a single dose; group 3 (n = 10) underwent HITU only; and group 4 (n = 10) received both chemotherapy (as in group 2) and HITU (as in group 3). HITU was administered with a 5.5-cm diameter 4-MHz quartz transducer creating a continuous wave with 400 W/cm2 focal intensity. The entire tumor was irradiated in 1-mm increments (horizontal and vertical) using treatment cycles of 4 seconds on and 11 seconds off. Total body weight and tumor volume were measured on the day of treatment, and 4 weeks later. At 4 weeks, the animals were killed, the tumor was excised and weighed, and tumor volume was determined. Tumor volume in all treated animals (groups 2, 3 and 4) was significantly smaller than in controls (P less than .001) at 4 weeks, and tumor volume for animals in group 4 was significantly smaller than for those in groups 2 and 3 (P less than .01). These data indicate that HITU significantly reduces tumor size when compared with control rats with Morris hepatoma. A synergistic effect of chemotherapy and HITU was observed and resulted in an enhanced tumor response and reduction of tumor size.(ABSTRACT TRUNCATED AT 250 WORDS)