Robert J. Scott

Response of canine oral carcinomas to heat and radiation

Thermal enhancement of radiation response improved the probability for local tumor control without increasing the risk for late complications in this study of relatively advanced stage tumors. Thirty-eight dogs with naturally occurring oral carcinomas were randomized to two radiation dose response groups to receive radiation alone or combined with local hyperthermia. Radiation was delivered in 10 fractions over 22 days. Heating was done 3 hours after seven of the radiation doses. The objective was to maintain a minimum tumor temperature of 42 degrees C and a maximum normal tissue temperature of 40 degrees C for 30 minutes. Normal tissue temperatures were usually 40 degrees C or less but there was great heterogeneity in tumor temperatures. Temperatures at tumor margins never exceeded 41.5 degrees C. The TCD50 for radiation was 38 Gy (32-46 Gy, 95% C.I.) and for radiation and heat it was 33 Gy (30-36 Gy, 95% C.I.). The slope of the dose response was much steeper for radiation and heat than for radiation alone indicating that the heterogeneity of tumor response was decreased with heat. All tumors were controlled at 40 and 45 Gy with heat whereas only 57% and 75% were controlled with 40 and 45 Gy radiation only. There were no late necroses for radiation and heat. The tumor control enhancement might be improved with different sequences, number of heatings or other time temperature relationships. It is not possible to predict the optimum treatment scheme because of the lack of knowledge of the influence of hyperthermia on subsequent heat or radiation treatments. That influence could be affected greatly by changes in tumor microcirculation, pH, and oxygenation as well as development and decay of thermotolerance in tumor and normal tissue.

Effects of intraoperative hyperthermia on canine sciatic nerve: histopathologic and morphometric studies

Failure to achieve local control in the treatment of pelvic and retroperitoneal tumours results in a high rate of recurrences. The objective of intraoperative hyperthermia (IOHT) is to enhance the effect of intraoperative radiation therapy and to increase local tumour control. The tolerance of peripheral nerves to heat may limit the heat dose that can be applied to tumours. Histopathologic and histomorphometric changes of canine sciatic nerve after 60-min IOHT were studied in three groups of five dogs each for temperatures of 43, 44 and 45 degrees C. IOHT was performed using a water-circulating hyperthermia device with a multichannel thermometry system on surgically exposed sciatic nerve. Histopathologic and histomorphometric studies were done immediately, 3 weeks and 12 months after IOHT. Histologic changes observed immediately after treatment were minimal but at 3 weeks following 60-min 45 degrees C IOHT both axon and myelin loss and an increase in endoneurial fibrous tissue were observed. Twelve months after treatment a statistically significant decrease in axon, myelin and small vessel percentages as well as an increase in endoneurial and epineural connective tissue were observed for dog treated to 45 degrees C. Dog treated to 44 degrees C for 60 min had similar statistically significant but less severe changes. Twelve months after 43 degrees C IOHT for 60 min, nerve fibres appeared normal and endoneurial connective tissue was only increased mildly around small and medium-sized vessels. These results suggest that temperatures to the peripheral nerve > 44 degrees C for 60 min are likely to cause significant histopathologic changes that can be found 12 months after treatment. A hypothesis of the mechanism of heat injury to peripheral nerves was developed.

Intraoperative radiation (IORT) injury to sciatic nerve in a large animal model.

Peripheral nerve appears to be a dose-limiting normal tissue in the clinical application of intraoperative radiation therapy (IORT). To assess IORT injury to peripheral nerve, three groups of five beagle dogs received doses of 12, 20 or 28 Gy to the surgically exposed and isolated right sciatic nerve in the mid-femoral region using 6 MeV electrons. The left sciatic nerve of each dog served as its own control. As a surgical control five dogs received surgical exposure of the nerve only. Monthly neurologic exams, electromyogram and nerve conduction studies were performed following treatment for 12 months. After that dogs were euthanatized and histologic studies of nerves were done to define the degree of axon and myelin loss as well as presence of fibrosis and vascular lesions for different doses of IORT. Results showed that the threshold dose most likely related to expression of severe radiation damage to the nerve in this model is between 20 and 25 Gy. Radiation injury to peripheral nerve appears to be the result of direct radiation effects on Schwann cells and nerve vasculature and secondary effects resulting from damage to regional muscle and vasculature. A theoretical mechanism of radiation injury to peripheral nerve is proposed.

Effects of intraoperative irradiation and intraoperative hyperthermia on canine sciatic nerve: Neurologic and electrophysiologic study

PURPOSE Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raises specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. METHODS AND MATERIALS Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12,16, 20, 24, or 28 Gy simultaneously with 44 degrees C of IOHT for 60 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and monthly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) examinations of motor function, as well as motor nerve conduction velocities studies. RESULTS Two years after treatment, the effective dose for 50% complication (ED50) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. CONCLUSION The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44 degrees C of IOHT for 60 min.

Effects of intraoperative hyperthermia on peripheral nerves: Neurological and electrophysiological studies

The tolerance of peripheral nerves to heat may limit the heat dose which can be applied to tumours. This may be particularly important in intraoperative hyperthermia (IOHT) for pelvic and retroperitoneal tumours. Furthermore the effects of hyperthermia alone must be known before its effects can be assessed in combination with irradiation. In this study injury to sciatic nerves was evaluated in 30 beagle dogs for 1 year following IOHT. IOHT was performed using a water circulating hyperthermia device with multichannel thermometry system. Neurological and electrophysiological examinations were done before, during and after IOHT treatment. Electrophysiological examinations showed a significant decrease in sciatic nerve conduction velocity and potential amplitude immediately after 60 min of heating for all temperatures. The greatest decrease in conduction velocity was observed for a temperature of 45 degrees C. Full recovery of nerve conduction velocity was observed 3 weeks following hyperthermia for all dogs except for those exposed to 45 degrees C. Neurological findings correlated with electrophysiological results. All five dogs which had nerve exposed to 45 degrees C for 60 min had severe neurological changes, with recovery taking place between 3 and 11 months after treatment. Based on these results it appears that temperatures to the peripheral nerve exceeding 44 degrees C for 1 h are likely to cause significant, but not necessarily permanent, nerve injury.

Whole body hyperthermia in dogs using a radiant heating device: Effect of surface cooling on temperature uniformity

Rectal and subcutaneous temperatures were measured during a total of 10 whole body hyperthermia treatments conducted in six dogs. During five of the treatments skin cooling, by means of initiating air flow through the radiant heating device, was necessary during the plateau phase because rectal temperature exceeded the target value. Skin cooling was not necessary in the other five treatments. Although the rectal temperatures were similar in all 10 treatments, extensive and rapid subcutaneous temperature non-uniformity, of approximately 4 degrees C, developed during treatments where skin cooling was necessary. During the treatments where skin cooling was not necessary, the subcutaneous temperature remained approximately equal to the rectal temperature. These data indicate that the environment in the radiant heating device during the plateau phase can have a profound effect on the temperature at superficial sites, which is not reflected by the temperature measured at deeper sites. The temperature at superficial sites should be measured during whole body hyperthermia to assure that the prescribed heat dose is administered to the largest percentage of body mass possible. Active skin cooling during whole body hyperthermia should be avoided if possible.

Biomechanical characteristics of allogeneic cortical bone pins designed for fracture fixation

The biomechanical characteristics of 1.2 mm diameter allogeneic cortical bone pins harvested from the canine tibia were evaluated and compared to 1.1 mm diameter stainless steel pins and 1.3 mm diameter polydioxanone (PDS) pins using impact testing and four-point bending. The biomechanical performance of allogeneic cortical bone pins using impact testing was uniform with no significant differences between sites, side, and gender. In four-point bending, cortical bone pins harvested from the left tibia (204.8 +/- 77.4 N/mm) were significantly stiffer than the right tibia (123.7 +/- 54.4 N/mm, P = 0.0001). The site of bone pin harvest also had a significant effect on stiffness, but this was dependent on interactions with gender and side. Site C in male dogs had the highest mean stiffness in the left tibia (224.4 +/- 40.4 N/mm), but lowest stiffness in the right tibia (84.9 +/- 24.2 N/mm). Site A in female dogs had the highest mean stiffness in the left tibia (344.9 +/- 117.4 N/mm), but lowest stiffness in the right tibia (60.8 +/- 3.7 N/mm). The raw and adjusted bending properties of 1.2 mm cortical bone pins were significantly better than 1.3 mm PDS pins, but significantly worse than 1.1 mm stainless steel pins (P < 0.0001). In conclusion, cortical bone pins may be suitable as an implant for fracture fixation based on initial biomechanical comparison to stainless steel and PDS pins used in clinical practice.

COMBINED PHARMACOLOGIC AND SURGICAL TREATMENTS FOR ACUTE SPINAL CORD TRAUMA

Acute spinal cord trauma was induced by the Allen method at T12 in 48 dogs. Six groups of 7 dogs each were treated with combinations of pharmacologic and surgical treatments; a 7th group of 6 dogs remained as traumatized nontreated controls. Results indicate an additive therapeutic effect in those patients treated with myelotomy and dimethyl sulfoxide. Dexamethasone, reserpine, and perfusion with hypertonic dextrose solution were of no benefit.

Whole-body hyperthermia combined with hyperfractionated irradiation of the thorax in dog: Acute physiological response

Whole-body hyperthermia has potential as an adjuvant treatment with chemotherapy and radiation therapy for diseases such as lung cancer which require both local and systemic control. The acute toxicity of whole-body hyperthermia combined with whole-thorax irradiation was studied in dogs. Twenty-eight dogs received three 2-h whole-body hyperthermia (WBH) treatments at 42.0 degrees C deep rectal temperature. Twenty-four of these dogs were also randomized to receive radiation doses of 18, 22.5, 27, 31.5, 40.5 or 45 Gy. Irradiation was given in 1.5 Gy fractions over 6 weeks. Three WBH treatments were given to 28 dogs with all dogs surviving treatment. WBH was given on days 1, 22 and 40 of the 6-week interval. Thirty-one dogs received radiation doses of 18-49.5 Gy without WBH. Deep rectal temperature was maintained at 41.9 +/- 0.3 degrees C over 2 h with an average of 20 min outside the chamber for irradiation. Two dogs required intervention with emergency medications during WBH treatment. One of the two dogs developed permanent neurological injury. Continuous physiological monitoring was necessary for successful WBH. WBH plus thoracic irradiation was well tolerated. All dogs survived all treatments. A significant but transient increase in peripheral blood leucocytes and a decrease in platelet counts occurred after each WBH treatment. The addition of thoracic irradiation up to 45 Gy in 1.5 Gy fractions did not appear to alter the acute toxicity of WBH with the exception of an increase in the protein content of lung lavage fluids. In conclusion, multiple WBH treatments of 2 h at a target temperature of 42 degrees C in addition to thoracic irradiation up to 45 Gy in 1.5 Gy fractions was administered with only mild acute toxicities occurring. Core temperature could be maintained for up to 20 min outside of the WBH chamber which allowed irradiation to be given concurrently with hyperthermia at a core temperature of 42 degrees C +/- 0.1 degree C.