Biomedical subjects

R L Page

Publications and source records attributed to R L Page.

At least 181 records · Page 10Linked to original sources

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Cystic meningiomas in 2 dogs.

Two dogs with signs of forebrain disease had hypodense lesions on computed tomography evaluation. Magnetic resonance imaging of the first dog showed a hypointense lesion on the T1-weighted scan and a hyperintense lesion on T2-weighted scanning. At surgery, both dogs had a primary cystic intracranial lesion, and the abnormal tissue adjacent to the cyst had histological features of meningioma. Each dog underwent whole brain irradiation after surgery, and 1 dog lived for 3 years after treatment. While uncommon, meningioma should be considered as a differential diagnosis in dogs with cystic intracranial lesions.

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Vertebral plasma cell tumors in 8 dogs.

The case histories of 8 dogs with spinal pain and neurologic deficits associated with vertebral plasma cell tumor are reviewed. Four dogs had solitary plasmacytoma, 3 had multiple myeloma, and 1 dog had 2 vertebral lesions with no evidence of disseminated disease. Four dogs were treated: 2 with multiple myeloma received chemotherapy only and survived 17 and 26 months, respectively. Two dogs with solitary plasmacytomas of the spine had chemotherapy and radiotherapy: the 1st survived 4 months and was euthanized after developing radiation myelopathy; the 2nd survived 65 months before developing multiple myeloma. The diagnosis of solitary plasmacytoma of the spine versus multiple myeloma is discussed.

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Retrospective analysis of axial skeleton osteosarcoma in 22 large-breed dogs.

Medical-records of 22 large-breed dogs (>15 kg) with osteosarcoma (OSA) of the axial skeleton were reviewed to determine prevalence of metastasis and survival associated with this neoplasm. All dogs were treated with more than 1 mode of therapy including palliative radiation (n = 12), definitive radiation (n = 8), surgery (n = 7), chemotherapy (n = 12), or some combination of these therapies. Metastasis was documented in 10 of 22 dogs (46%), and the median survival for all dogs was 137 days. Primary cause of death was local tumor recurrence (54%). Breed (retriever versus purebred versus mixed-breed survival was 100, 182, and 264 days, respectively) and radiation therapy protocol (survival in dogs treated with palliative radiation therapy versus those treated with definitive radiation therapy was 79 and 265 days, respectively) were significantly related to survival (P < .05). Prevalence of metastasis and median survival for large-breed dogs with axial skeleton OSA seems to be similar to that reported for large-breed dogs with appendicular skeleton OSA. Definitive radiation therapy may have a role in the treatment of axial skeleton osteosarcoma.

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Feline vaccine-associated sarcomas.

Feline vaccine-associated sarcomas have presented many challenges. Initially, the etiopathogenesis and biological behavior of these tumors had to be characterized, and strategies implemented to move tumors away from problematic sites. Next, diagnostic and treatment recommendations evolved as the biologic behavior of vaccine-associated sarcomas forced early and aggressive intervention. Current therapeutic strategies are expensive, at times debilitating, and frequently fail to effect tumor control. This review summarizes the known history, epidemiology, etiology, and clinical management of vaccine-associated sarcomas after a decade of work. The next challenges must be to find more practical and effective solutions, and to eliminate the cause of vaccine-associated sarcomas.

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Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats.

Intravenously administered docetaxel (DT) is problematic in cats because of the requirement for premedication to ameliorate acute vehicle-induced hypersensitivity reactions. Previously we have revealed that therapeutic plasma concentrations of DT can be achieved in normal and tumor-bearing dogs when DT is administered PO in combination with oral cyclosporin A (CSA). The purpose of this study was to identify the maximally tolerated dosage and characterize the pharmacokinetic disposition of oral DT combined with CSA in cats with tumors. Eighteen tumor-bearing cats were enrolled in this phase I dose escalation and pharmacokinetic study. DT was administered by gavage with CSA (5 mg/kg) twice over a 3-week period. The starting dose of DT was 1.0 mg/kg. Based on the clinical toxicity profile, with gastrointestinal adverse effects and hematologic toxicity the maximal tolerated dose of oral DT was 1.75 mg/kg in combination with 5 mg/kg CSA. Additional studies are necessary to determine the efficacy of DT/CSA in cats with epithelial tumors.

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Effect of hyperthermia on cisplatin pharmacokinetics in normal dogs.

In vitro and in vivo cisplatin pharmacokinetic studies were conducted at 37 degrees C and 42-43 degrees C in dogs. Cisplatin at 1, 2, 3, 4 and 5 micrograms/ml was incubated with canine serum at 37 degrees and 43 degrees C. Aliquots were processed immediately for atomic absorption spectrophotometry to determine total as well as free, ultrafilterable cisplatin concentrations. Thirteen healthy, average-sized mongrel dogs received 1 mg/kg cisplatin as an intravenous bolus. Four were maintained unanaesthetized at 37 degrees C, two were anaesthetized and maintained at 37 degrees C and seven were anaesthetized and maintained at a rectal temperature of 42 degrees C for 60 min. Serum samples were obtained and processed for free and total cisplatin. There were no detectable concentration effects present in either in vitro group. The rate constant reflecting the decay of free cisplatin at 37 degrees C was 0.0035 +/- 0.0007 min-1 and increased significantly (P less than 0.0001) to 0.0053 +/- 0.001 min-1 at 43 degrees C. In vivo pharmacokinetic analysis consisted of model-independent parameters (total body clearance, volume of distribution, half-life and mean residence time). A significant increase (P less than or equal to 0.05) in all parameters was observed with free-cisplatin at 42 degrees C. This data would indicate that at the elevated temperatures encountered in whole body hyperthermia, the rate of formation of reactive metabolites from parent cisplatin is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

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Clinical application of thermal isoeffect dose.

Clinically, there is strong rationale for developing a method which will provide a scientific basis for comparing the efficacy of one hyperthermia treatment with another. In order to accomplish this goal, methods must first be developed which will allow the clinician to know the three-dimensional temperature distribution in heated tissue. In this paper, examples of how this goal can be achieved are presented. Techniques for compensating for various modifiers of hyperthermia effectiveness are proposed. The limitations and advantages of these approaches are described and directions for future research are discussed.

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Cardiovascular and metabolic response of tumour-bearing dogs to whole body hyperthermia.

Whole body hyperthermia was induced in older, tumour-bearing dogs using a radiant heat device. Dogs were anaesthetized (thiopental), paralysed (atracurium), and mechanically ventilated (100 per cent O2) during the heating procedure. Heart rate, systolic/diastolic, and mean arterial blood pressure, and arterial blood gases were monitored throughout the procedure. Serum biochemical parameters, complete blood count, and coagulation profiles were evaluated before, during, and after whole body hyperthermia. Significant increases (p less than 0.05) were noted in heart rate, systolic pressure, diastolic pressure, and mean arterial pressure during the treatment period. A significant decrease in arterial oxygen partial pressure due to unknown causes occurred during the treatment period. Clinical evidence of cardiac decompensation was not manifested in any dog following whole body hyperthermia. Total white blood cell count, neutrophil count, alkaline phosphatase, and creatinine kinase were significantly (p less than 0.05) increased 24 h following whole body hyperthermia. These elevations returned to normal within 1 week of treatment in all dogs. Changes in coagulation profiles 24 h following the procedure were not clinically significant. Adequate pretreatment evaluation of cardiovascular, metabolic, and haemostatic function in tumour-bearing dogs is necessary to identify candidates for treatment with systemic hyperthermia. Otherwise healthy, tumour-bearing dogs withstand the physiological stress of whole body hyperthermia without significant acute or persistent toxicity and represent a valuable model for whole body hyperthermia research.

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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.

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The use of hydralazine to manipulate tumour temperatures during hyperthermia.

Hydralazine is an antihypertensive drug which theoretically could increase tumour temperatures during hyperthermia via reduction in tumour blood flow from a vascular 'steal' phenomenon. Doses that are therapeutically effective in reducing blood pressure in hypertensive patients would probably cause postural hypotension and other side-effects in normotensive patients beyond the hyperthermia treatment session, however. This study was designed to evaluate whether hydralazine, when administered at a safe dose for normotensive patients (0.125 mg/kg, i.v.) would be effective in increasing tumour temperatures during hyperthermia. The working hypothesis was that hydralazine at a dose of 0.125 mg/kg would be effective in raising tumour temperatures during hyperthermia treatment with minimal change in blood pressure. Fourteen human and five canine subjects were given hydralazine (0.125 mg/kg, i.v.) at the midpoint of a hyperthermia session. Temperatures and blood pressures were monitored before and after drug administration. Although hydralazine resulted in slight reduction in blood pressure, it was ineffective in increasing tumour temperatures in human patients (average maximum rise in median temperature was 0.26 +/- 0.32 degrees C). In canine subjects the same dose of hydralazine was effective in reducing blood pressure in four of five subjects studied (mean maximum drop was 22.7 +/- 4.1 mmHg) and the median temperature rose 0.8 +/- 0.7 degrees C. In the canine subjects the greater the decrease in blood pressure, the greater the increase in temperature. These results suggest that a rise in tumour temperature induced by hydralazine is dependent on creating a drop in blood pressure. Future studies in this laboratory will include tumour blood flow manipulation with antihypertensives which have a shorter half-life and a titratable effect. Using this approach, hypotension, which seems to be required to raise tumour temperature, will be more controllable in terms of magnitude and duration.

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A comparison of temperatures in canine solid tumours during local and whole-body hyperthermia administered alone and simultaneously.

Temperature measurements were made in canine solid tumours during whole-body hyperthermia (WBH) alone, local hyperthermia alone and local hyperthermia given simultaneously with WBH. During the plateau phase of WBH alone, mean intratumoral temperature ranged from 41.3 +/- 0.2 degrees C to 41.7 +/- 0.1 degrees C and was statistically lower (P = 0.0028) and more variable than rectal temperature, which ranged from 42.0 +/- 0.02 degrees C to 42.1 +/- 0.03 degrees C. The temperature distribution in solid tumours during WBH is more uniform than during local hyperthermia. The simultaneous administration of whole-body and local hyperthermia in five dogs resulted in increased tumour temperatures in comparison to WBH and in more uniformly increased tumour temperatures in comparison to local hyperthermia alone. Median intratumoral temperatures (+/- 95% confidence intervals) resulting from local hyperthermia alone and local hyperthermia given simultaneously with WBH were 39.9 degrees C (39.7-40.1) and 42.9 degrees C (42.6-43.1), respectively, and were statistically different (P = 0.0012). Local applied power requirements to meet predetermined intratumoral temperature limits were decreased by 50% (P = 0.011) in dogs undergoing combined local/whole-body hyperthermia versus local hyperthermia alone. Dogs tolerated the combination of local and WBH without complication.

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Effect of hyperthermia on the in vitro hydrolysis of melphalan.

The pharmacokinetics of melphalan was investigated at 37 degrees C and 42 degrees C in vitro in canine and porcine plasma to assess heat-induced changes in the in vivo rate of melphalan hydrolysis. Melphalan concentrations were assayed using HPLC. Rate of spontaneous hydrolysis of melphalan at 42 degrees C was increased 1.5-fold in canine and 1.9-fold in porcine plasma. These results should be considered when interpreting in vivo disposition studies.

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Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma.

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.

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Quantitative estimation of the thermal dose-modifying factor for cis-diamminedichloroplatinum (CDDP) in tumour-bearing dogs.

A statistical method for estimating clinical toxicity was used to determine a theoretical isoeffect dose-modifying factor for dogs with disseminated or refractory neoplasia treated with cis-diammine dichloroplatinum (II) plus whole-body hyperthermia or CDDP alone. CDDP was administered every 3 weeks with vigorous saline hydration to 54 dogs (CDDP alone n = 21, CDDP/WBH n = 33) that were eligible for entry into this non-randomized study. CDDP was administered during the plateau phase of WBH in dogs receiving combined therapy. Acute toxicity included myelosuppression (CDDP n = 7; CDDP/WBH n = 5), nephrotoxicity (CDDP n = 1, CDDP/WBH n = 1) and respiratory distress (CDDP/WBH n = 2). Eight dogs experienced chronic renal dysfunction as a result of CDDP (n = 2) or CDDP/WBH (n = 6). A theoretical thermal dose-modifying factor was determined for both acute and cumulative toxicity by comparing the maximum tolerated dose of each treatment group. The maximum tolerated dose (MTD) of CDDP +/- WBH was defined as that dose producing a 50% incidence of moderate acute toxicity or acute plus mild chronic toxicity as estimated from logistic regression analysis of the toxicity data. The MTD (+/- .standard error) of CDDP/WBH for acute toxicity only was 54.6 (4.3) mg/M2 and for CDDP alone the MTD was 73.6 (40) mg/M2. Thus, the isoeffect dose-modifying factor for acute toxicity was 1.35 (0.12). The MTD (SE) of CDDP/WBH for cumulative toxicity (acute plus chronic toxicity) was 46.4 (2.7) mg/M2 and for CDDP alone waas 70.0 (2.9) mg/M2. The isoeffect dose-modifying factor for total cumulative toxicity was 1.5 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

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Phase III evaluation of doxorubicin and whole-body hyperthermia in dogs with lymphoma.

Sixty-one dogs with histologically confirmed, untreated, high-grade lymphoma were evaluated and treated with doxorubicin (DOX, 30 mg/m2) alone. Forty-seven dogs (77%) achieved a complete response. Forty-six of the 47 dogs were randomized to receive five additional treatments with doxorubicin +/- whole-body hyperthermia (WBH). Median disease-free survival for the group treated with DOX alone (n = 22) was 189 days and for the DOX plus WBH (n = 24) was 239 days (p = 0.17). After the analysis was adjusted for stratification variables (i.e. institution, weight, stage), the effect of heat on disease-free survival remained statistically insignificant (p = 0.10), but suggested a tendency towards increased disease-free survival in hyperthermic dogs. Intact male dogs had significantly shorter disease-free survival than neutered males and neutered females (178 days vs 266 days, respectively; p = 0.013). No intact females were treated. Body weight, when evaluated as a continuous variable, was found to be a negative prognostic factor (p = 0.036). Tumour volume, stage and institution were not significant. Clinical incidence of cardiac dysfunction was not increased in dogs receiving DOX and WBH; however, post-mortem histological analysis of cardiac tissue suggested that the combined therapy of DOX and WBH was associated with greater myocyte degeneration (p = 0.012) and a tendency for increased cardiac fibrosis (p = 0.08). We concluded that continued refinement of DOX-WBH protocols is warranted, and may ultimately result in significant therapeutic improvement.

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Response of canine soft tissue sarcomas to radiation or radiation plus hyperthermia: a randomized phase II study.

Sixty-four dogs with spontaneous soft tissue sarcomas without evidence of metastases were stratified by tumour volume and randomized to receive graded doses of radiotherapy (XRT) alone or radiotherapy plus hyperthermia (HT). An improvement in duration of local control was achieved with the addition of hyperthermia as compared with XRT alone (Wilcoxon, p = 0.040; log rank, p = 0.064). Overall frequency of late complications was not different for the two treatment arms when comparing across equivalent XRT dose groups. Frequency of distant metastases after therapy completion was not significantly different for the two treatment arms at 1 year (7.4% for XRT versus 20% for HT plus XRT) or 2 years (11.5% for XRT versus 25% for HT plus XRT) post therapy. These results suggest that a therapeutic gain was achieved for this group of tumour-bearing animals. Uni- and multivariate analyses were performed to examine the potential for various factors to influence treatment outcome. Patient related variables included tumour stage, histologic subtype and grade and tumour site. Treatment related variables included total radiation dose and 15 descriptors of temperature distributions achieved during hyperthermia. When considering patient related factors, tumour histology, grade and location were important predictors of time to minimum volume, but only tumour location influenced time to tumour regrowth. When considering treatment related factors, radiation dose was not significantly correlated with time to minimum volume or time to local regrowth, but it was correlated with probability for late normal tissue damage in the XRT alone group (p = 0.005). For the hyperthermia treatments, 13 of 15 tumour temperature distribution descriptors were correlated with time to minimum volume, but none were correlated with time to local regrowth. These results suggest that caution should be used in interpreting the value of temperature distribution descriptors in predicting for long-term local control after hyperthermia and radiotherapy, based on analysis of short-term responses.

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Serious toxicity associated with annular microwave array induction of whole-body hyperthermia in normal dogs.

Using a regional annular microwave array it was possible to produce a systemic temperature of 42 degrees C in approximately 80 min with applied net power levels of approximately 150 W. Resulting temperature distributions were non-uniform. Sites within the array were above systemic temperature during heating but approximated systemic temperature during the plateau phase. Sites outside of the array were lower than systemic temperature during heating and plateau phases. Dogs allowed to recover from the procedure experienced severe toxicity consisting of lumbar muscle haemorrhage, pain and swelling, and pelvic limb paralysis. Histologically, there was severe myopathy and haemorrhage and oedema in neural tissue in the caudal lumbar spine. Acute necrosis of lymphoid tissue was observed in all dogs. Temperatures in muscle reached 43-46 degrees C and were higher than at other measured sites. Spinal canal temperatures were essentially equal to rectal temperature, approximating 42-43 degrees C during heating and plateau phases. These data suggest regionally induced whole-body hyperthermia may result in: (1) power deposition non-uniformity leading to muscle and spinal canal temperatures which exceed systemic temperature and which are sufficient to cause serious toxicity; (2) systemic temperature non-uniformity which is undesirable for systemic thermochemotherapy; and (3) possible immunological dysfunction associated with lymphoid necrosis. Extreme caution must be exercised in administering energy to localized regions of human patients with the intent of elevating systemic temperature.

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Kidney trace metal response to combined cisplatin (CDDP) and hyperthermia.

The effects of hyperthermia (HY) on cisplatin (CDDP) nephrotoxicity and kidney metal concentrations were evaluated in female F344 rats. Rats were anaesthetized with a xylazine/ketamine mixture, heated on a water-bed for 1 h to an intraperitoneal temperature of 41.1 +/- 0.2 degrees C, and maintained at hyperthermia for an additional 30 min (HY plateau). CDDP (5 mg/kg body weight) was administered at the start of the heating or at the HY plateau. Neither HY alone nor CDDP (5 mg/kg) at normothermia produced a significant effect on weight loss or nephrotoxicity. CDDP administered at the start of heating produced a moderate 1.5-fold increase in serum urea nitrogen (SUN) and serum creatinine concentrations. CDDP administered at the HY plateau produced a significant six-fold increase in SUN and a four-fold increase in creatinine concentration. Weight loss increased two- to three-fold from the combined regimen, but only the rats given CDDP at the HY plateau continued to lose weight through day 7. A loss of kidney copper (50-60%) resulted from the combined regimen, similar to losses observed with higher doses of CDDP at normothermia. HY alone had little effect on concentrations of kidney copper or zinc up to 4 days post-treatment. The results demonstrate that systemic hyperthermia significantly increases CDDP nephrotoxicity in F344 rats and that kidney copper loss from CDDP exposure at hyperthermia is similar to the loss observed from CDDP at normothermia.

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