A scanned, focused, multiple transducer ultrasonic system for localized hyperthermia treatments. 1987.

A commercial diagnostic ultrasound scanner (Octoson) was modified for performing hyperthermia treatments. The temperature elevations were induced in tissues by four large, focused ultrasonic transducers whose common focal zone was scanned along a computer controlled path as determined from B-scan images. The system is described and the results of preliminary tests demonstrating some of its capabilities are given. Extensive tests with canine thighs and kidneys were performed. The blood flow to the kidneys was controllable, and thus tumours having different blood perfusion rates could be simulated. The results showed that the system is capable of inducing a local temperature maximum deep in tissues (up to 10 cm was tested) and that tissues with high perfusion rates could be heated.

Patterns of changes of tumour temperatures during clinical hyperthermia: implications for treatment planning, evaluation and control.

The patterns of changes in tumour temperatures were studied at selected times throughout 104 hyperthermia sessions. Temperature change patterns were analysed in the context of the known patterns of change of the applied power. First, of 69 extracranial treatments analysed, 74% indicated relatively flat temperatures at constant applied power during a major portion of the treatment, thereby indicating that during that time there were no major changes in any of the physical or physiological tissue parameters which contribute to the ability of the tumour tissue to remove energy (Pattern 1). Second, after reaching an initial steady state, approximately 14% of these extracranial treatments showed either steadily decreasing temperatures at constant power, or constant temperatures at steadily increasing applied power, thereby indicating that the tumour's ability to remove energy was steadily increasing in time following the initial steady state (Pattern 2). Finally, after reaching an initial steady state, the remaining 12% of these treatments showed a pronounced decrease in temperature occurring about 10-20 min into the treatment followed by increasing temperatures or levelling off of temperatures at a higher value than the temperature minimum that had occurred, all at constant applied power (Pattern 3). Of 35 brain treatments analysed, 80% followed Pattern 1, 14% followed Pattern 2, and 6% followed Pattern 3. Intratumoral heterogeneity was evident in some cases with approximately 44% of all treatments having at least one individual temperature sensor change in a manner that did not follow the average direction of change when all sensors were combined. For seven patients with permanent probes, the patterns of change presented in the first treatments were also observed during six out of seven of the second treatments. In addition, three out of the five patients who had an evaluable third treatment showed a pattern of change during that third treatment that was similar to the pattern observed in both treatment one and treatment two.

Heparan sulfate-mediated cell aggregation. Syndecans-1 and -4 mediate intercellular adhesion following their transfection into human B lymphoid cells.

Because syndecans are present at sites of cell-cell contact in vivo it has been hypothesized that they play a role in mediating cell-cell adhesion. However, there has been no direct evidence to support this notion. To address this question, B lymphoid (ARH-77) cells were transfected with the cDNA for murine syndecan-1. Unlike the parental cells, the transfectants form large multicellular aggregates in suspension cultures and stain intensely for syndecan-1 at sites of cell-cell contact. Using rotation-mediated aggregation assays, we find that aggregation of syndecan-1-transfected cells is dependent on divalent cations and is inhibited by the following: (i) addition of heparin and heparin-like glycosaminoglycans, (ii) removal of heparan sulfate from the cell surface, or (iii) addition of exogenous purified syndecan-1. Mixing of syndecan-1-transfected and control-transfected cells results in aggregates containing both cell types indicating that aggregation occurs through a heterophilic adhesion mechanism in which heparan sulfate chains bind to a counter-receptor present on these cells. Importantly, syndecan-4-transfected cells also aggregate in a heparan sulfate-dependent manner, while in contrast, betaglycan-transfected cells aggregate poorly. Thus, syndecans may be important mediators of cell-cell adhesion, but this function may not be common to all transmembrane heparan sulfate-bearing proteoglycans.

A phase I study of the toxicity of regional hyperthermia with systemic warming.

This study examines the consequences of allowing moderate systemic hyperthermia during regional heating of the abdomen and pelvis in 29 patients participating in Phase I studies of hyperthermia combined with chemotherapy or radiation therapy. In Group 1 (20 patients, 42 treatments), systemic temperatures were limited by employing surface cooling, while in Group 2 (9 patients, 24 treatments), surface warming and insulation were used so that systemic temperature would rise. Mean time-averaged oral temperatures were 38.4 degrees C and 39.9 degrees C for Groups 1 and 2, respectively. Time-averaged mean regional temperatures were 40.2 +/- 0.7 degrees C and 41.5 +/- 0.2 degrees C for Groups 1 and 2, respectively (p < .001). Regional temperatures > or = 41.0 degrees C were achieved by 64% of Group 1 and all Group 2 patients. The mean time-averaged power required was significantly lower for Group 2 (453 W vs 740 W; p = .032), as was the incidence of pain. Mean maximum pulse rate was significantly higher in Group 2, although this was not associated with symptoms. Allowing systemic temperature to rise decreased power requirements and treatment-related pain, at the cost of an asymptomatic increase in heart rate. The results suggest that regional heating may be more readily achieved in the setting of elevated systemic temperature.

Thermocouples--the Arizona experience with in-house manufactured probes.

The performance of several different types of multisensor thermocouple probes have been tested to determine the feasibility of each type for use in the hyperthermia clinic. All of the probes tested were manufactured in-house, and a detailed description of the construction process will be presented. The overall performance of the probes in terms of robustness, calibration, conduction errors, and response time will be described. In particular, this study describes our experience with in-house manufactured thermocouples over the past several years. The results indicate that when strict quality assurance guidelines are followed, in-house manufactured thermocouples perform satisfactorily--thereby providing an alternative to purchasing probes and measurement systems from commercial vendors if the proper resources are available.

Development of scanned focussed ultrasound hyperthermia: clinical response evaluation.

Selective heating of irregularly shaped tumors at depth can now be accomplished through focussing and controlled scanning of energy deposition patterns by ultrasound. A scanned focussed ultrasound (SFUS) hyperthermia system developed at the University of Arizona has been used to deliver 220 treatments to 87 tumors in 71 patients with extracranial malignancies between October 1986 and May 1990. Patients received an average of three SFUS hyperthermia treatments, spaced weekly, during ongoing fractionated radiotherapy. The most common anatomic sites treated were the pelvis (22 patients), chest wall or breast (14), neck (8), and axilla (7), while the most common histologies were adenocarcinoma (36), squamous cell carcinoma (11), and melanoma (10). Concurrent radiotherapy was delivered (range 1000-7640 cGy, mean 4320 cGy) to 67 SFUS hyperthermia patients; 4 received concomitant chemotherapy. Tumor volumes ranged from 1-2100 cubic centimeters (mean 325 cc), and 75% were located at depths greater than 3 cm from skin. A 62% overall response rate was observed, with 22% of treated tumors demonstrating a complete response (defined as complete disappearance of treated tumor), and 40% exhibiting a partial response (defined as greater than or equal to 50% reduction in tumor volume). Dramatic local pain reduction was achieved in 42% of the tumors treated. The acute tolerance of SFUS hyperthermia was quite good, and chronic toxicities (persistent skin blisters/burns) were identified in two patients. The versatility of the SFUS system is discussed, as well as its future potential for improving control of advanced loco-regional malignancies treated with curative intent.

Rapid admixture blood warming: technical advances.

The technique of rapid admixture blood warming of cold erythrocyte units is designed to warm erythrocyte units rapidly (less than 30 sec) while simultaneously providing saline for dilution. However, questions have been raised about the recommended use of a standard 250-ml bolus of 70 degrees C admixture saline, the uniformity and speed of blood unit warming, the difficulties inherent in keeping saline bags at 70 degrees C, and the safety of the methodology. To answer these questions, a series of tests were performed and modifications of the technique were introduced. The mean weight of 1000 successive units of erythrocytes for adult infusion was 305 g (range 220 to 410). The maximum temperature was 44 degrees C, using an internal temperature probe (1-cm temperature gradations; 2-sec recording intervals) when the smallest unit was admixed with a 250 ml 70 degrees C saline bolus; the largest unit had a minimum temperature of 30 degrees C. Plasma Hgb, osmotic fragility, and K of the minimum size erythrocyte unit showed no significant deviation from its control. Both thermographic photographs and the internal temperature recordings of the erythrocyte units demonstrated that solely due to fluid turbulence, uniform mixing occurs within approximately 30 sec of beginning the admixture process. Inverting the blood units caused a thermal layering of fluids and an unacceptable maximum blood temperature of 50 degrees C. There was no difference between the mixing time or efficacy in the presence of standard or large-bore iv tubing or additional in-line filters. Volumes of the 250-ml saline bags for admixture decreased markedly with deviations in electrolyte composition after greater than 2 wk at 70 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature distributions during clinical scanned, focused ultrasound hyperthermia treatments.

In this study a scanned focused ultrasound (SFUS) system was used to heat 66 tumours at various anatomical locations in 52 patients. A total of 160 treatments were given. On average, temperatures were measured in 14 or 15 locations in the scanned volume. The time-averaged temperatures over the 30 min treatment period in the best treatment of each tumour were 44.0 +/- 2.4 degrees C (mean +/- SD) and 39.6 +/- 1.5 degrees C at the location of the highest and lowest sensor, respectively. On average, 39% of the sensors were above 42.5 degrees C. When only the cases that were judged to be good candidates for the hyperthermia device were analysed, 64% of the sensors reached a temperature over 42.5 degrees C with the highest temperature achieved being 45.9 +/- 2.3 degrees C and the lowest 40.7 +/- 1.4 degrees C. Although the system tested has many technical limitations (for example, fixed frequency, beam geometry and power during the scan cycle), the results demonstrate that therapeutic temperatures can be achieved in many tumours. Significantly better temperatures are expected when all of the theoretical potential of scanned focused ultrasound systems has been used.

The CDRH Helix: an in vivo evaluation.

The Helix is an electromagnetic heating device used to induce regional/systemic hyperthermia for cancer therapy. It is a resonant device operating at about 82 MHz with an aperture size of 60 cm x 40 cm (elliptical) x 40 cm long. The Helix deposits power in tissues (or phantoms) by producing a predominantly axial electric field within its radiating aperture. Five pig experiments were performed to provide in vivo verification of specific absorption rate (SAR) measurements and electric field measurements which were obtained earlier in tissue-equivalent phantom and 0.9% saline, respectively. In addition to verifying the power deposition patterns found in phantoms, the pig experiments provided valuable insight into the capabilities and limitations of electromagnetic regional heating. For example, a kidney with limited blood flow, simulating a necrotic tumor, heated very well-although the highest temperature was not always measured there. Also, fat heating may be a problem, since excessive temperatures in the fat were observed in approximately 20% of the heatings. This paper compares the in vivo temperature measurements in pigs with SARs and electric field measurements obtained in phantoms, and also provides a brief overview of results of the Helix in clinical situations.

The CDRH helix. A phase I clinical trial.

Seventeen patients have been given regional hyperthermia treatments using the Center for Devices and Radiologic Health (CDRH) Helix, a resonant helical coil unit. Most of these patients had large, clinically advanced tumors, whose mean volume exceeded 1000 cc. Mean maximum, minimum, and average temperatures were 40.6, 38.6, and 39.6 degrees C, respectively, for all sites combined. The pelvic heating capabilities of the CDRH Helix and the BSD-1000 annular phased array were compared, and generally were equivalent. Although the Helix could be used in a wider variety of locations, and was more comfortable and easier to use than the BSD-1000 annular phased array, neither device was particularly effective in generating clinically useful temperatures; the Helix is currently under investigation for use in regional-systemic hyperthermia in combination with antineoplastic drugs and biologic response modifiers.

Scanned focussed ultrasound hyperthermia: initial clinical results.

Between November 1986 and July, 1987, a preliminary study to determine the feasibility of scanned focussed ultrasound for clinical hyperthermia at various sites was conducted. Fourteen patient (17 tumors) have been treated using a microprocessor-controlled apparatus developed at the University of Arizona by modifying a commercially available diagnostic ultrasound unit. We have treated nine pelvic tumors, four extremity tumors, two brain tumors, and two extracranial head and neck tumors for a total of 42 treatments. Multipoint thermometry was achieved for all patients, with 2-25 (mean = 10) points monitored during each treatments within the scanned tumor volume. Average maximum temperature within the scanned tumor volume was 44.2, 44.7, 44.8, and 42.0 degrees C for pelvic, extremity brain, and extracranial head and neck tumors, respectively; similarly, 55%, 45%, 71%, and 0 of monitored points exceeded 42.5 degrees C. Pain limited applied power in 15 of 42 treatments, and bone pain with a periodicity similar to the scanning periodicity was seen in 11 treatments. A non-randomized comparison of temperatures achieved using scanned focussed ultrasound to those achieved using the microwave annular array and the CDRH Helix suggests that scanned focussed ultrasound may have promise and potential advantages in heating selected pelvic tumors.

The efficiency of clinical microwave applicators measured by a calorimetric method.

When inducing localized hyperthermia for superficial cancer therapy with microwaves there has often been question about the total power output from the applicator. Although specific absorption rates and thermograms are used to obtain localized power distributions and heating patterns, these provide, at best, only an approximation of the total power applied to tissues or phantoms. In this paper a calorimetric technique for obtaining total microwave output power from applicators is described. An experimental apparatus was constructed and it was found to be accurate to approximately +/- 5 W. The power output from four clinical microwave applicators as a function of applied electric power was measured and the efficiency was found to be 40% in average. Along with enhancing quality assurance, the areas of hyperthermia research which may benefit the most from this calorimetric technique are computer modeling and patient treatment planning.

A scanned, focused, multiple transducer ultrasonic system for localized hyperthermia treatments.

A commercial diagnostic ultrasound scanner (Octoson) was modified for performing hyperthermia treatments. The temperature elevations were induced in tissues by four large, focused ultrasonic transducers whose common focal zone was scanned along a computer controlled path as determined from B-scan images. The system is described and the results of preliminary tests demonstrating some of its capabilities are given. Extensive tests with canine thighs and kidneys were performed. The blood flow to the kidneys was controllable, and thus tumours having different blood perfusion rates could be simulated. The results showed that the system is capable of inducing a local temperature maximum deep in tissues (up to 10 cm was tested) and that tissues with high perfusion rates could be heated.