Tumor necrosis following radiation therapy and/or chemotherapy for canine osteosarcoma.
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Animals↗
Biomedical subjects
S J Withrow
Publications and source records attributed to S J Withrow.
Limb-sparing treatment for osteosarcoma in dogs.
Twenty dogs with spontaneously developing osteosarcoma of the extremities were treated with 1 of 3 multimodality limb-sparing procedures. Excision of the tumor was preceded by intra-arterial (IA) administration of cisplatin (cis-diamminedichloroplatinum) alone directed to the affected extremity, irradiation plus IA administration of cisplatin, or irradiation plus IV administration of cisplatin. All dogs were free of apparent metastatic disease at the time of initial treatment. After diagnosis, dogs administered cisplatin IA had selective angiography performed on arteries supplying the tumor, and 70 mg of cisplatin/m2 of body surface was administered over 2 hours. This protocol was repeated 3 weeks later. Dogs that were irradiated received 25 or 40 Gy in 10 fractions over a 22-day period. The first and last radiation doses were immediately preceded by IA administration of cisplatin. Dogs given IV treatment received 10 mg of cisplatin/m2 2 hours before each radiation fraction was administered. Three weeks after the last treatment, tumors were excised and the limb underwent orthopedic reconstruction, generally using cortical allografting and bone plating. Limb function, allograft healing, local tumor control, and metastatic dissemination were monitored. Limb function was good to excellent in 69% (11/16) of dogs evaluated. Forelimb-sparing procedures were generally associated with better function than were limb-sparing procedures performed on hind limbs. Local tumor control was obtained in 79% (11/14) of dogs thoroughly evaluated, with local recurrences in 3 dogs at 3, 4, and 7 months after treatment. Fifteen dogs developed metastatic disease at a median time of 8 months from the time of diagnosis. Mean and median survival times for all dogs, regardless of cause of death, were 11.7 and 8 months, respectively. Tumor necrosis greater than 80% was statistically associated with lack of recurrence. Of 16 dogs, 5 (31%) developed infections at the surgical site. Multimodality limb-sparing treatment is believed to be a viable alternative for appropriately selected dogs with osteosarcoma. The optimal method of treatment prior to or after tumor excision has not yet been established.
Angiography↗
Multilobular osteochondrosarcoma of the canine skull: 16 cases (1978-1988).
The medical records of 12 dogs with multilobular osteochondrosarcoma (MLO) and examined at the Veterinary Teaching Hospital, Colorado State University from August 1979 to January 1987 were reviewed. Medical records of 1 dog with MLO and 3 dogs with MLO examined at the Ontario Veterinary College, University of Guelph and the Veterinary Medical Teaching Hospital, University of California, Davis, respectively, were also reviewed and included in the study. The mean age of affected dogs was 7.5 years, a single breed did not appear to be overrepresented, and males were affected as frequently as were females. All of the primary lesions affected either the mandible, maxilla, or cranium. Excision was the only treatment in 11 dogs, 2 dogs had radiotherapy in addition to excision, and 1 dog had radiotherapy and chemotherapy after excision. Twelve treated dogs had follow-up information available. Of the 12 treated dogs, 7 (58%) had local recurrence, with median time to recurrence of 14 months. Seven dogs (58%) developed metastatic disease after treatment, with median time to metastasis of 14 months. The median disease-free interval was 12 months, and the median survival time was 21 months. Excision with histologically complete surgical margins appeared to offer good opportunity for long-term tumor control. The role of adjuvant chemotherapy and radiotherapy in the management of MLO remains unclear.
Animals↗
Phase II evaluation of doxorubicin for treatment of various canine neoplasms.
One hundred eighty-five dogs with histologically confirmed, measurable malignant tumors were used in a prospective study to determine the response to 2 doses of the anthracycline antitumor antibiotic, doxorubicin. Eighty-three dogs had been refractory to one or more previous treatment modalities (surgery, n = 54; chemotherapy, n = 22; radiation, n = 10; hyperthermia, n = 1; biological response modifier, n = 1). The extent of neoplastic disease was determined immediately prior to and 3 weeks after 2 doses of doxorubicin were administered (30 mg/m2 of body surface area, iv) 21 days apart. Eighty-four percent (n = 157) of the dogs received 2 doses of doxorubicin and were evaluated. Of the 28 dogs ruled ineligible, 4 had serious side effects to the first dose of doxorubicin, and 24 others acquired complications resulting from their malignant tumors. A partial or complete remission was obtained in 41% (64/157) of all evaluable dogs: 26% (11/43) of the dogs with carcinoma, 67% (42/63) of the dogs with lymphoma, and 22% (11/51) of the dogs with sarcoma. Tumors in which there was at least a 50% volume reduction (partial or complete remission) included malignant lymphoma (42/63), fibrosarcoma (1/14), solid follicular thyroid carcinoma (3/13), mammary adenocarcinoma (2/8), hemangiosarcoma (2/8), osteosarcoma (1/6), circumanal carcinoma (3/5), synovial cell sarcoma (2/3), undifferentiated sarcoma (2/3), nasal adenocarcinoma (1/2), liposarcoma (1/2), infiltrating lipoma (1/1), malignant melanoma (1/1), sclerosing mesothelioma (1/1), and neurofibrosarcoma (1/2).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Acute and short-term toxicoses associated with the administration of doxorubicin to dogs with malignant tumors.
One hundred eighty-five dogs with histologically confirmed, measurable malignant tumors were used in a study to determine the toxicity of the anthracycline antitumor antibiotic, doxorubicin, which was administered once or twice (at a 21-day interval) at the rate of 30 mg/m2 of body surface area, iv. During this study, 7 dogs died as a direct result of doxorubicin-induced toxicosis and 16 died as a direct result of the malignant neoplastic disease. Each dog was evaluated for signs of toxicosis for 3 weeks after the last dose was administered (15 dogs received 1 dose, 170 dogs received 2 doses) or until the dog died, whichever came first. The most common signs of toxicosis were vomiting, diarrhea, colitis, anorexia, and pruritus. The probability of doxorubicin-induced toxicosis decreased significantly (P less than 0.0001) in inverse relationship to body weight. Dogs with signs of toxicosis during the 21-day interval from administration of the first dose of doxorubicin were 17.2 times (P less than 0.01; 95% confidence interval; 5.5, 54.2) more likely to develop signs of toxicosis during the 21-day interval from the second dose of doxorubicin. The performance status of each dog was evaluated using a modified Karnofsky performance scheme; the only time the performance status was adversely affected to a significant extent by doxorubicin-induced toxicosis was during the 21-day period, starting with the second dose (P less than 0.0001).
Animals↗
Classification of primary lung tumors in dogs: 210 cases (1975-1985).
Two hundred ten dogs that had primary lung tumors diagnosed between 1975 and 1985 were evaluated. The majority of the tumors were classified as adenocarcinoma (74.8%) and alveolar carcinoma (20%). The most common clinical signs of disease were cough (52%), dyspnea (23.8%), lethargy (18.1%), weight loss (12.4%), and tachypnea (4.8%). The clinical methods that were most successful in directly or indirectly leading to a diagnosis of primary lung tumor were thoracic radiography (77.1%) and cytologic examination of fine-needle aspirate specimens (24.8%).
Adenocarcinoma↗
Prognostic factors for tumor remission and survival in dogs after surgery for primary lung tumor: 76 cases (1975-1985).
The association of various prognostic factors with remission and survival after the excision of lung tumors was evaluated in 76 dogs. Overall, the median survival time of treated dogs was 120 days; 72% had tumor that underwent remission (median duration of remission, 120 days). Dogs with tumors that underwent remission had significantly (P = 0.001) increased survival time (median, 330 days vs 28 days for dogs with tumors that did not undergo remission). The finding of normal-sized lymph nodes at the time of therapeutic thoracotomy was significantly (P = 0.001) correlated with increased remission probability (85.4% remission rate vs 43.6% in dogs with large lymph nodes). Use of various diagnostic methods to find normal regional lymph nodes before surgery indicated that such finding was significantly (P less than or equal to 0.01) correlated with increased remission duration (median remission duration, 365 days, vs 60 days for tumors in dogs with large lymph nodes), and the finding of normal lymph nodes at the time of surgery was significantly (P less than or equal to 0.01) correlated with increased survival time (median, 345 days, vs 60 days for dogs with large lymph nodes).
Adenocarcinoma↗
Radiotherapy of soft tissue sarcomas in dogs.
Megavoltage radiotherapy was administered to 42 dogs with soft tissue sarcoma. Acceptable local control of these aggressive tumors was achieved after one year of treatment. Control rates of 48 and 67% were obtained at doses of 45 and 50 gray (Gy), respectively. At 2 years, control rates decreased to 33% at the dose of 50 Gy. Serious complications developed in 4 of 42 dogs at doses of 40 to 50 Gy. The estimated dose with a 50% probability for causing serious complications was 54 Gy, given in 10 fractions. We believe that the large doses per fraction used in this study probably led to an increased probability for necrosis. Hemangiopericytomas seemed to be more responsive than fibrosarcomas. Only 2 of 11 recurrent tumors were controlled with surgery. Good local control was achieved with radiation alone for one year at doses with a low probability for serious complications; however, higher total radiation doses or combined modalities, such as surgery and radiation or radiation and hyperthermia, may be needed for longer-term control.
Animals↗
Ureteral injury following experimental intraoperative radiation.
Beagle dogs were randomized to receive a range of total dose delivered in three different protocols. Sixteen dogs received external beam radiation therapy (EBRT), 32 dogs received intraoperative irradiation (IORT), and 32 dogs received combinations of external beam radiation therapy and intraoperative irradiation. A sublumbar field was irradiated which always included the left ureter. Dogs were observed for 5 years; sequential excretory urograms were done at 6 months, and 1 and 5 years. Morphometric analysis of tissues were also done. The canine ureter tolerated 17.5 Gy intraoperative irradiation with no evidence of injury and 25 Gy intraoperative irradiation with a low probability of injury. The ED50 for radiographic abnormalities was 32.9 Gy. When 50 Gy external beam radiation therapy was given prior to intraoperative irradiation, the ureter tolerated 10 Gy intraoperative irradiation with no evidence of injury and 17.5 Gy with a low probability of injury. The ED50 was 29 Gy intraoperative irradiation after EBRT. The external beam radiation therapy had little effect on the ureter when given alone or prior to intraoperative irradiation. Clinical signs of renal disease occurred only in dogs who had received bilateral ureteral irradiation intraoperatively at doses of 32.5 Gy intraoperative irradiation and 25 Gy intraoperative irradiation after external beam radiation therapy. Histologic evidence suggests that the chronic injury of the ureter expressed at 5 years is of vascular etiology. The early injury may be due to ulceration of the epithelium.
Animals↗
Bone necrosis and tumor induction following experimental intraoperative irradiation.
The bone of the lumbar vertebrae of 153 dogs was examined 2 and 5 years after intraoperative irradiation (IORT), fractionated external beam irradiation (EBRT), or the combination. Groups of dogs received 15 to 55 Gy IORT only, 10 to 47.5 Gy IORT combined with 50 Gy EBRT in 2 Gy fractions or 60 to 80 Gy EBRT in 30 fractions. Six MeV electrons were used for IORT, and EBRT was done using photons from a 6 MV linear accelerator. The paraaortic region was irradiated and the ventral part of the lumbar vertebrae was in the 90% isodose level. Two years after irradiation, the dose causing significant bone necrosis as determined by at least 50% empty lacunae in the vertebral cortex was 38.2 Gy IORT alone and 32.5 Gy IORT combined with EBRT. Five years after irradiation, the dose causing 50% empty lacunae was 28.5 Gy IORT only and 14.4 Gy IORT combined with EBRT. The ED50 for lesions of the ventral vertebral artery was 21.7 Gy IORT only and 20.1 Gy IORT combined with 50 Gy EBRT 2 years after irradiation and 27.0 Gy IORT only and 20.0 Gy IORT combined with 50 Gy EBRT 5 years after irradiation. All lesions after EBRT only were mild. Eight dogs developed osteosarcomas 4 to 5 years after irradiation, one at 47.5 Gy IORT only and the remainder at 25.0 Gy IORT and above combined with 50 Gy EBRT. In conclusion, the extent of empty lacunae, indicating bone necrosis, was more severe 5 years after irradiation than after 2 years. The effect of 50 Gy EBRT in 2 Gy fractions was equivalent to about 6 Gy IORT 2 years after irradiation and to about 14 Gy 5 years after irradiation. Based on these estimates, IORT doses of 10 to 15 Gy have an effect 5 times or greater than the amount given in 2 Gy fractions. Osteosarcomas occurred in 21% of dogs which received doses greater than 25 Gy IORT. Doses of 15 to 20 Gy IORT in combination with 50 Gy EBRT in 2 Gy fractions may be near the tolerance level for late developing bone injury.
Animals↗
Response of aorta and branch arteries to experimental intraoperative irradiation.
Injury to the aorta was evaluated in dogs 2 and 5 years after fractionated irradiation (EBRT), intraoperative irradiation (IORT) or a combination. Doses greater than 20 Gy IORT combined with 50 Gy EBRT given in 2 Gy fractions or 30 Gy IORT alone were accompanied by a significant risk of aneurysms or large thrombi as determined at necropsy 4 to 5 years following irradiation. Narrowing of the aorta as detected by aortography occurred at 5 years but was not detected earlier. The ED50 for aortic narrowing was 38.8 Gy IORT and 31 Gy IORT plus 50 Gy EBRT. The ED50 for branch artery injury was 24.8 Gy IORT alone and 19.4 Gy IORT plus 50 Gy EBRT. The difference in ED50s for IORT alone and IORT plus EBRT indicates that the contribution of the EBRT dose in terms of an IORT dose for aortic narrowing was 7.8 Gy and for branch artery injury was 5.4 Gy. The ED50 for incidence of small thrombi in the aorta was about 29 Gy for IORT alone and 23.5 Gy for IORT combined with EBRT. Fibrous thickening of the adventitia was measured and the effect of the 50 Gy EBRT component of a combination of EBRT and IORT was determined to be equivalent to 10 to 12 Gy IORT. Based on the various estimates, IORT doses of 10-15 Gy have an effect of 5 times or greater the amount given in 2 Gy fractions. At all EBRT doses and at lower IORT doses the intima was greatly thickened. At IORT doses of 20 Gy or above there was a dose related decrease in intimal thickness to near normal values. This was probably due to cell killing or inhibition of intimal proliferation that predominated at higher doses. Although the risk of serious vascular complications appears low following IORT of humans, this may be due to short observation times and the fact that IORT doses currently used are usually 20 Gy or less; this may be near the tolerance for late response of larger arteries. Only one dog in this study had complete rupture of the aorta causing death. Five other dogs at high IORT doses had near ruptures of the aorta but were clinically normal.
Aortic Dissection↗
Characterization of osteosarcoma cells from two sibling large-breed dogs.
Neoplastic cells were isolated from 2 sibling Great Dane/Labrador Retriever mixed-breed dogs in which telangiectatic type osteosarcomas arose concurrently. Cells from various sites in the same osteosarcoma appeared similar in culture, but there were differences between the 2 osteosarcomas in growth characteristics and appearance of cells. Cells from 1 osteosarcoma had a small, but significant (P less than 0.05), cyclic adenosine monophosphate response to parathyroid hormone stimulation, indicating a low order of osteoblastic differentiation. Cells from the other osteosarcoma had no response to parathyroid hormone stimulation. Cells from both osteosarcomas and a concentrated cell-free filtrate from the osteosarcoma with osteoblastic differentiation were injected into nude mice, but osteosarcomas were not induced. Results of ultrastructural examination of osteosarcoma samples for viral particles were negative and supernatant fluids from cultured cells were considered negative for viral reverse transcriptase activity.
Animals↗
Exocrine pancreatic function following intraoperative irradiation of the canine pancreas.
Twenty-four beagles received intraoperative irradiation (IORT) with 6 meV electrons to the pancreas and the duodenum. Intraoperative irradiation doses of 17.5 to 40 Gy were given. Billroth II gastrojejunostomy was done to bypass the irradiated duodenum. Six control dogs received only the Billroth II surgery. Two weeks postoperatively, irradiated dogs were given 50 Gy of 6 MV X radiation (external-beam radiation [EBRT]) to the pancreas and duodenum in 2 Gy fractions over a 5-week period. Dogs were monitored clinically and exocrine pancreatic function was evaluated using an N-benzoyl-l-tyrosyl-para-aminobenzoic acid (BT-PABA) test between 3 and 135 days postoperatively. Necropsies were performed on the dogs at 135 days postoperatively. The degree of gross pancreatic atrophy in the irradiated group was dose related. The mean percentage of normal acinar cells correlated with IORT doses and para-aminobenzoic acid (PABA) values (P less than 0.1). Weight loss was significantly greater in the irradiated dogs compared to the control (P less than 0.05) and the mean percentage of body weight loss correlated with the mean PABA values (P less than 0.01). In this study, the use of the BT-PABA test to evaluate progressive exocrine pancreatic function following IORT and EBRT showed an expected trend. A progressive decrease in exocrine pancreatic function in the irradiated dogs as indicated by plasma PABA levels may have been partly due to late radiation damage to acinar cells, secondary to vascular and ductular damage. At 135 days postoperatively none of the dogs showed clinical signs of exocrine pancreatic insufficiency and the plasma PABA levels were within the normal presurgical range. The progressive decrease in plasma PABA levels indicated a potential for the late development of exocrine pancreatic insufficiency. The BT-PABA test could be useful for evaluating the progressive decrease in exocrine pancreatic function and residual radiation injury to the pancreas. Because the exocrine deficiency can be managed with replacement therapy, pancreatic injury may not be a serious complication after doses of less than 30 Gy IORT with 50 Gy EBRT. Data from this study are in agreement with previous clinical and experimental reports that the duodenum is dose-limiting for IORT. Doses of 20 Gy IORT or less plus 50 Gy EBRT for treatment of carcinoma of the pancreas may not result in serious long-term complications due to radiation injury of the duodenum.
Adenocarcinoma↗
Jamshidi needle biopsy for diagnosis of bone lesions in small animals.
Sixty-two bone lesions in 59 small animals were biopsied using a Jamshidi-type biopsy needle. In all instances, the Jamshidi needle biopsy diagnosis was confirmed or disputed by results of histologic examination of specimens obtained by surgical resection or by amputation or at necropsy. In 57 of 62 bone lesions, biopsy resulted in an accurate diagnosis of tumor vs nontumor, yielding an accuracy rate of 91.9%. The specific tumor type or lesion type was identified accurately by Jamshidi needle biopsy in 51 of 62 lesions, yielding an accuracy of 82.3%. Of the 62 bone lesions, 48 were intramedullary osteosarcoma and 62.5% of these were subclassified correctly by Jamshidi needle biopsy results as osteoblastic, chondroblastic, fibroblastic, osteoclastic, or poorly differentiated osteosarcoma. Jamshidi needle biopsy was easy, quick, and safe, and its high accuracy rate of diagnosis indicated that it should be a valuable aid for diagnosis of bone lesions in small animals.
Animals↗
Perianal adenomas and hypertestosteronemia in a spayed bitch with pituitary-dependent hyperadrenocorticism.
Hypertestosteronemia was diagnosed in a spayed bitch with pituitary-dependent hyperadrenocorticism and perianal adenomas. Serum concentrations of cortisol and testosterone decreased after treatment with mitotane was instituted. Excessive testosterone in this dog was thought to have been produced by the adrenal cortex, possibly in response to excessive ACTH concentrations. Development of androgen- or estrogen-responsive tumors in castrated dogs may be an early indication of adrenocortical hyperfunction.
Adenoma↗
Aortic wall injury following intraoperative irradiation.
The type, extent, and probability of vasculopathy in canine abdominal aortas were determined 5 years after large single radiation doses given intraoperatively (IORT) either alone or with fractionated doses of external beam irradiation (EBRT) to compare with the response following EBRT only. Young adult beagle dogs were used. For IORT, a 5 x 8 cm electron applicator was used to deliver 6 MeV electrons to the paraaortic region. For EBRT of the paraaortic region, 6 MV photons were given in variable total doses in 30 fractions in 6 weeks. For the combination, variable IORT doses were given following an EBRT dose of 50 Gy given in 2 Gy fractions in 5 weeks. Necropsies were performed 4 to 5 years after irradiation. Transverse sections of the aorta were examined for lesions. Probit analyses were done to determine the dose with a 50% probability to cause severe lesions of the aorta 5 years after treatment. The most severe lesions were variably organized thrombi which occupied at least a third of the luminal area or intimal surface of the aorta. Six dogs with thrombi had dissecting aneurysms. That occurred at doses as low as 25 Gy IORT plus 50 Gy EBRT (1 of 4 dogs). The doses with a 50% probability for causing aneurysms and/or severe thromboses of the aorta were 35 Gy IORT (95% C.I., 29 to 46 Gy) and 27 Gy IORT plus 50 Gy EBRT (95% C.I., 20-40 Gy). No large thrombi or aneurysms were observed 5 years after EBRT to doses as high as 80 Gy. Comparison of the ED50s for IORT alone to that of IORT combined with EBRT indicated that 50 Gy given in 25 fractions had the impact of about 8 Gy IORT. Based on the response of younger adult dogs it appears that IORT doses greater than 30 Gy alone or 20 Gy IORT combined with 50 Gy EBRT would be accompanied by a significant risk of life threatening lesions of the aorta. This is in contrast with several earlier reports indicating that the tolerance dose of canine aorta was 50 Gy IORT.
Animals↗
Pathologic response of the pancreas and duodenum to experimental intraoperative irradiation.
The pancreas and duodenum of 24 beagle dogs were given intraoperative irradiation (IORT) with 6 MeV electrons. The dose range was 17.5 Gy to 40 Gy. Billroth II gastrojejunostomy was performed on all dogs prior to irradiation. Six control dogs received only Billroth II surgery. Starting 2 weeks after surgery, dogs in the irradiation groups were given 50 Gy 6 MV X rays external beam radiation therapy (EBRT) to the pancreas and duodenum. The total dose of 50 Gy was given in 2 Gy fractions over 5 weeks. Dogs were monitored for 135 days then necropsied. Gross and histopathologic changes in the pancreas and duodenum were evaluated and quantitative analysis of pancreatic lesions done. Duodenal ulcers were found following 32.5 Gy and 40 Gy IORT. The pancreases were atrophic in irradiated dogs and exocrine pancreatic insufficiency occurred in one dog given 25 Gy. Gross pancreatic atrophy correlated with IORT dose. Histopathologic evidence of radiation damage to the pancreas was observed in acinar cells. Islet cell lesions were not apparent. There was pancreatic fibrosis and damage to blood vessels and ducts. Dose-response relationships were observed for the index of damage to the pancreas as a whole, for pancreatic fibrosis and a decrease in normal acinar cells. Although 25 Gy IORT plus 50 Gy EBRT was tolerated by the duodenum to 135 days, these doses may cause later pancreatic injury as an expression of damage to blood vessels and ducts. Exocrine pancreatic insufficiency and diabetes mellitus may thus represent potential late complications of IORT following 25 Gy or higher doses.
Animals↗