Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas.

PURPOSE: The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. METHODS AND MATERIALS: Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. RESULTS: Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Radiation inhibition of mdx mouse muscle regeneration: dose and age factors.

A single hind limb was irradiated with 12, 18, 24, or 30 Gy in mdx and C57 mice aged 12, 21, or 42 days to determine regeneration inhibition dose-response curves in different aged dystrophic mice and to characterize radiation side-effects in normal mice. The anterior tibial muscle mass (8 weeks postirradiation) and percent central nucleated (i.e., regenerated) muscle fibers were measures of regeneration inhibition. Twenty-one-day-old mdx mice irradiated with 18 Gy had complete inhibition of muscle regeneration, but 30 Gy only partially blocked regeneration in mdx mice irradiated at 12 and 42 days in age. In working to produce a clinically relevant model for Duchenne dystrophy, it is crucial to regard mouse age as a major factor in determining radiation effects on mdx muscle regeneration.

Therapeutic responses of spontaneous canine malignancies to combinations of radiotherapy and hyperthermia.

The goals of this ongoing Phase III study of adjuvant local hyperthermia with radiotherapy were to evaluate how tumor control and normal tissue complications were related to patient and treatment variables. Canine veterinary patients with localized malignancies were stratified by histology and anatomic site and randomized into three groups. All patients received radiotherapy (60CO) in 3.5 Gy fractions given Mon-Wed-Fri to 14 treatments (49 Gy). One group received radiotherapy alone while the others also received microwave-induced hyperthermia (44 degrees C) for 30 minutes once each week. Hyperthermia followed radiotherapy and was given to one group immediately and delayed 4-5 hours in the other. Adjuvant hyperthermia resulted in a significant (p less than .05) increase in complete response rate, reduction in the frequency of non-responders, and increased persistent local control relative to radiotherapy alone. Hyperthermia increased the complete response rate regardless of histology, site, or volume and with the current sample size control was significantly (p less than .05) greater for sarcomas, tumors of the trunk and extremities, and those with volumes less than 10 cc. Quantitative clinical assessment of the acute response of skin and oral mucosa indicated that hyperthermia significantly enhanced these acute reactions, which required roughly twice the healing time observed with radiotherapy alone. Quantitative histologic scoring of changes seen between pre- and post-therapy skin biopsies indicated that a treatment induced decline in the frequency of dermal blood vessels, sebaceous glands, and hair follicles was enhanced by adjuvant hyperthermia, particularly in the late response evaluation interval. The probability of tumor control and adverse normal tissue responses correlated with several measures of thermal dose. Thermal doses in excess of 120 equivalent minutes at 43 degrees C correlated positively with increased skin reactions and negatively with the complete response rate, and these trends were usually evident during the animals' first treatment.

The modification of specific absorption rates in interstitial microwave hyperthermia via tissue-equivalent material bolus.

Patterns of specific absorption rates generated by interstitial, microwave antenna arrays must be experimentally ascertained and quantified to facilitate their clinical incorporation. Phantom studies involved the use of four single-gap, coaxial antennas oriented in a 2 cm square array. These dipoles were driven in phase by a microwave generator at a frequency of 915 MHz. The inherent limitations in modifying the specific absorption rate patterns were addressed with the addition of bolus to the phantom. These additions of Guy's muscle tissue-equivalent material were made either proximal or distal to the phantom proper. Experiments conducted in the presence and absence of tissue-equivalent material bolus showed the ability to achieve broader bands of 50% power deposition in certain bolus conditions. These heating patterns were sufficiently reproducible and predictable to warrant clinical application of the bolus addition. A through-and-through method of catheter implantation allowed for bolus addition when deemed necessary. Treatments with veterinary and human patients using the bolus method to modify heating patterns yielded augmented patterns of power deposition. The effective length of the antennas that would radiate efficiently was essentially broadened via introduction of a microwave-interacting medium. As a result of the tissue equivalent material's ability to absorb microwave power, it was necessary to interpose minimally-interactive styrofoam spacers to limit heat transfer effects at the tissue-bolus interfaces.

Management of radiation-induced moist skin desquamation using hydrocolloid dressing.

Moist skin desquamation has been of concern to radiation oncologists, nurses and patients since the inception of this mode of therapy. As radiation treatment machines became more sophisticated, severe reactions became less of a problem. However, with the increasing use of chemotherapy and radiation as combined modalities, moist skin reaction is occurring with greater frequency. A noncomparative study of 20 patients using a hydrocolloid occlusive dressing (Duoderm) was initiated. The purpose of the study was to determine whether moist occlusive healing would be beneficial. The dressing was evaluated on the basis of healing time, safety, wound temperature, bacterial growth, and comfort. Data were collected using photographs, bacterial cultures, temperature probes, and patient evaluations. Eighteen patients completed the study. All patients' skin reactions healed. There were no wound infections evident. Mean healing time was 12 days, with mean wound temperature relative to body core -0.8 degree C on day 1 and -1.2 degrees C on the healed site. Patient results on comfort were: 8 of 18 excellent, 7 of 18 good, 3 of 18 fair, and 0 of 18 poor. The results of this study indicate that a hydrocolloid occlusive dressing can be effective in the healing process of moist skin reaction that is due to radiation therapy.

Use of hyperthermia and radiotherapy in treatment of a large mast cell sarcoma in a dog.

A large infiltrating mast cell sarcoma in a dog, which had been refractory before surgical excision, was controlled 2 months after completion of a combined radiotherapy and hyperthermia regimen. Treatment resulted in rapid tumor necrosis and resultant ulceration of adjacent skin. Ulceration was transient, resolving concurrently with tumor control. Radiation was administered as 3.5-Gy fractions 3 times/week, resulting in a total dose of 45.5 Gy in 13 treatments. Hyperthermia (44 C for 30 minutes) was given 4 to 5 hours after radiotherapy, once a week during the first 3 weeks of treatment.

The distribution of power and heat produced by interstitial microwave antenna arrays: II. The role of antenna spacing and insertion depth.

The distribution of power and temperature generated by 915 MHz interstitial microwave antenna arrays was studied in static muscle-equivalent phantoms and both perfused and non-perfused canine thigh muscle. These arrays, which would form the geometric basis of larger volume implants, consisted of four parallel antennas oriented such that transverse to their long axes they formed the corners of a square. Arrays with 2 and 3 cm sides were compared at various depths of insertion where the nodes for all four antennas were coincident at the same depth. The position relative to the antenna nodes of the maximum power and highest temperature within the array volume varied with the depth of insertion of the antennas. Though power dropped rapidly distal to the nodes at all depths, a shift in the location of the maximum power proximal to the nodes resulted in an increase in the effective heating volume at certain insertion depths. For 2 cm array spacing the highest power and temperature were measured along the central axis of the array at all insertion depths. However, arrays using 3 cm spacing generated their maximum power adjacent to the antennas with only 50% of this level occurring along the central axis. When the temperature produced by 3 cm arrays was measured in phantoms midway through simulated 30-minute hyperthermia treatments, the effect of thermal conduction on the temperature distribution was evident. Though power was only 50% centrally, the highest temperatures occurred there. This same pattern of central heating occurred in perfused canine muscle demonstrating the importance of conductive and convective heat redistribution in reducing thermal gradients within the array volume.

The distribution of power and heat produced by interstitial microwave antenna arrays: I. Comparative phantom and canine studies.

To adequately plan and administer localized hyperthermia with interstitial microwave antennas, the thermal distribution patterns generated by such antennas must be characterized. This study evaluated the performance of single node 915 MHz antennas operating either alone or as a 2 cm square array of four parallel antennas using both muscle-equivalent phantoms and canine thigh muscle. Two types of measurements were compared. Specific absorption rate (SAR), where temperature increases resulting from short duration microwave pulses were used to define power distribution, and temperature gradients during simulated hyperthermia treatments. SAR measurements in phantoms were comparable to those obtained in non-perfused canine muscle demonstrating the usefulness of the phantom for these measurements. For a single antenna there was a rapid decrease in power radially which resulted in a steep thermal gradient at distances within 0.5 cm. However, the power generated by a four-antenna array was highest along its central axis and declined to approximately 50% near the antennas at the array periphery. Along the central axis of the array power decreased most rapidly distal to the antenna nodes. The distribution of temperature measured during simulated hyperthermia treatments in phantoms paralleled the SAR distribution and was comparable to the temperature gradient observed in perfused canine muscle, suggesting that phantoms could be used to predict temperature distributions in resting muscle tissue.

Specific absorption rates in simulated tissue media for a 10 x 10 cm 915-MHz waveguide applicator.

The use of hyperthermia in combination with radiotherapy is currently being investigated at many cancer treatment facilities. Several different types of heating modalities are presently being used and for each of these systems it is important to determine the power distributions of their hyperthermia applicators in tissue-equivalent phantoms. This information will be used for treatment planning, routine quality assurance, and acceptance testing as well as for comparison between these various modalities and systems. This report describes the power distribution characteristics of the Clini-Therm 10 x 10 cm 915-MHz waveguide applicator measured within muscle tissue phantom materials arranged in several clinically relevant treatment configurations. The net increase in temperature that resulted from 20-s pulses of microwave power was measured at various points within each phantom by the system's implantable fiberoptic temperature sensors. From these temperature measurements the distribution of power was calculated as specific absorption rates (SAR). The results are displayed as two-dimensional ISO-SAR maps which relate power levels throughout the irradiated volume to those obtained on the central axis of the applicator. When the applicator was in direct contact with the muscle phantom the highest SAR measured was 2 cm lateral to its central axis along the muscle surface. On the central axis approximately 50% of the power was attenuated by each centimeter of muscle material. The introduction of either fat, bone, or a water-filled pad between the applicator and the muscle altered the pattern of power distribution within the irradiated volume without substantially altering the relative distribution of power along the central axis.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of urethane sponge matrix to assess in vivo recovery of murine cellular immunity following syngeneic bone marrow transplantation.

A unique method for assessing the in vivo recovery of cellular immunity following sublethal irradiation and syngeneic bone marrow transplantation of CBA/J mice is described. This method employs the serial surgical implantation of a urethane sponge matrix followed by impregnation of the sponge matrix with alloantigen. Sponge matrices were harvested from each mouse subject at 2 weeks, 4 weeks, and 8 weeks post transplant with and without treatment with interleukin-2. Recovery of cellular immunity was assessed as a function of cytotoxic T lymphocyte activity via cell-mediated lympholysis using chromium labeled targets. Repetitive procedures of implantation and removal of the matrices from the same animal were surgically feasible and were exceptionally well tolerated by the animals with insignificant morbidity thereby permitting continuous monitoring of immunologic recovery. Although the results of treatment with interleukin-2 were inconclusive, this method provides a sensitive, technically manageable means by which to assess an antigenic response in vivo at predetermined time intervals utilizing the same mouse subject. The method additionally affords the potential of being applicable to the in vivo assessment and manipulation of other aspects of the immune response.

Recurrent adenocarcinoma in a ferret.

A 4.5-year-old, neutered male ferret with a history of recurrent adenocarcinoma in the preputial region was given 2 radiation treatment courses designed to control the rapidly growing neoplasm. The tumor regressed completely after the first 3.5-week course of therapy. The ferret remained clinically disease-free for 4 months, at which time small masses were noticed in the inguinal area and the original tumor site. A second course of therapy was administered, which again resulted in complete clinical regression of the neoplasm. However, the duration of remission was brief. Local recurrence and abdominal metastasis were observed within 2 months of the completion of therapy.

Effect of hyperthermia on isolated DNA polymerase-beta.

Hyperthermia has been shown to inhibit the activity of DNA polymerase-beta when either the intact Chinese hamster cells or partially purified enzyme samples from CHO cells are heated (42.2 or 45.5 degrees C). However, the loss of activity from heating isolated enzyme samples can be either greater or less than the loss from heating intact cells. For example, treating cells with the membrane-active agent procaine-HCl greatly sensitizes the cells to heat-induced loss of enzyme activity but has no effect on the heat sensitivity of isolated enzyme. Furthermore, the heat sensitivity of the isolated enzyme depends greatly on the purification steps and can be reduced by heating the enzyme in the presence of bovine serum albumin, activated DNA, or Langendorf salts. These observations, considered in relation to others in the literature, suggest that heat inactivation of polymerase-beta occurs from heat-induced changes in the intracellular environment, which in turn modify the direct thermal denaturation of the enzyme within the cell.

Induction of colonic adenocarcinoma in the rat by X-irradiation.

In work to determine whether X-radiation could be used to induce tumors of the colon in outbred Holtzman rats, a technique was devised so that only the descending colon could be irradiated with a collimated X-ray beam and tumorigenic exposures in the kilo-Roentgen range were delivered. Ninety male Holtzman rats were divided into 6 exposure groups of 15 animals each. In the first group only the colon was exposed to 2500 R; in the second group the colon was exposed to 3500 R and the exposures were increased by 1000-R increments up through 6500 R; the sixth group was sham irradiated. Animals in each of the irradited groups developed mucoid adenocarcinomas with the highest incidence (47%) obtained inthe 4500-R group. Histopathologically, the induced tumors bear a close resemblance to human colon adenocarcinoma, and the development of pulmonary metastases in one of the animals with multiple primary tumors demonstrated their malignancy. The usefulness of the animal model is discussed.