Biomedical subjects
S J Withrow
Publications and source records attributed to S J Withrow.
Skin tumors and mast cell cancer.
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Apparent interaction of dimethyl sulfoxide with cisplatin released from polymer delivery devices injected subcutaneously in dogs.
Local tissue toxicity, systemic toxicity and platinum pharmacokinetics were evaluated in 6 normal healthy beagle dogs injected subcutaneously with two formulations of a polylactide biodegradable polymer (Atrigel) system containing cisplatin. Dogs were injected 4 times at 30 day intervals at platinum dosages of 70, 105 and 157.5 mg/m2 (dose escalation). Once pharmacokinetics were established, 29 dogs with spontaneous stage IIb appendicular osteosarcoma were treated with 4 injections of the same polymer system containing cisplatin at 70 mg/m2 (20 dogs) and 100 mg/m2 (9 dogs) to establish efficacy against micrometastatic disease. Local tissue toxicity was variable. Systemic toxicity, as judged by clinicopathologic evaluation was not noted at any dose level or injection number. Interim (6 month) survival analysis revealed a median disease-free interval of 180 days. Consistent platinum release characteristics were found, however, the lack of toxicity and decreased disease-free-interval raised concerns over the biologic activity of the cisplatin. Prior to completion of the study, it was discovered that dimethyl sulfoxide, the solvent used in the co-polymer system, may be responsible for biologic inactivation of cisplatin. This was subsequently demonstrated in tissue culture assays. The clinical trial was suspended and dogs were treated with traditional chemotherapy.
Evaluation of prognostic factors for dogs with primary lung tumors: 67 cases (1985-1992).
OBJECTIVE: To determine associations between clinical and histologic factors in dogs with primary lung tumors and outcome and to develop a histologic grading method for primary lung tumors. DESIGN: Retrospective study. ANIMALS: 67 dogs undergoing thoracotomy and lobectomy for primary lung tumors. PROCEDURE: Medical records and histologic sections were reviewed to evaluate factors of prognostic importance. Association of these factors with disease-free interval (DFI) and survival time was evaluated, using the Cox proportional hazards model. Median DFI and survival time were determined, using the Kaplan-Meier product-limit method. RESULTS: Clinical and histologic factors significantly associated with prognosis were histologic score, detection of clinical signs, and metastasis to regional lymph nodes. On the basis of histologic score, a histologic grading method was developed. Dogs with well-differentiated tumors had significantly longer survival time and DFI (median DFI, 493 days) than dogs with moderately (median DFI, 191 days) or poorly (median DFI, 0 days) differentiated tumors. Dogs with clinical signs or metastasis to regional lymph nodes had shorter survival times and DFI than dogs in which lung masses were discovered as an incidental finding. CLINICAL IMPLICATIONS: Dogs with well-differentiated, nonmetastasized, primary lung tumors that do not have clinical signs associated with the tumor have a favorable prognosis. Dogs with more advanced disease or aggressive tumors histologically may require treatment, such as chemotherapy in combination with surgery. The grading method proposed here for primary lung tumors may be useful in other dogs with primary lung tumors.
Prognostic factors for surgical treatment of soft-tissue sarcomas in dogs: 75 cases (1986-1996).
OBJECTIVE: To determine results of surgery for treatment of soft-tissue sarcomas in dogs and to identify prognostic variables that can be used to predict outcome. DESIGN: Retrospective case series. ANIMALS: Dogs with soft-tissue sarcomas that had surgical treatment only. PROCEDURE: Records were examined for clinically relevant data. Histologic samples were reviewed. Follow-up information was obtained by physical examination or telephone conversations with referring veterinarians or owners. RESULTS: 75 dogs with soft-tissue sarcomas of the trunk and extremities were identified. Median age was 10.6 years. Malignant peripheral nerve sheath tumors were of a significantly lower grade than other tumors. Tumors recurred locally in 11 of 75 (15%) dogs. Evaluation for lack of tumor cells at surgical margins was prognostic for local recurrence. Metastatic disease developed in 13 of 75 (17%) dogs. Tumor mitotic rate was prognostic for development of metastasis. Twenty-five of 75 (33%) dogs died of tumor-related causes. Percentage of tumor necrosis and tumor mitotic rate were prognostic for survival time. Median survival time was 1,416 days. CLINICAL IMPLICATIONS: On the basis of a low local recurrence rate and high median survival time, wide excision of tumor margins or radical surgery appeared to be an effective means for managing soft-tissue sarcomas of the trunk and extremities. Analysis of histologic characteristics for prognosis supported use of preoperative biopsy. Surgical margins should be evaluated, and early use of aggressive surgery is indicated in the management of soft-tissue sarcomas in dogs.
Pancreatic beta cell tumor in ferrets: 20 cases (1986-1994).
OBJECTIVE: To characterize survival times, disease-free intervals, and prognostic variables in ferrets with pancreatic beta cell neoplasia. DESIGN: Retrospective study. ANIMALS: 20 ferrets with histologically confirmed pancreatic beta cell tumors. PROCEDURE: Medical records of ferrets with pancreatic beta cell tumors were reviewed. Variables such as age, sex, duration of clinical signs, existence of other neoplasia, single versus multiple masses in the pancreas, benign or malignant histologic features, and the type of treatment used at redevelopment of clinical signs were examined to determine their relationship to survival times and disease-free intervals. RESULTS: Duration of clinical signs prior to diagnosis and initial surgery was inversely correlated with survival time and disease-free interval. Overall median survival time for all ferrets with pancreatic beta cell tumors was 483 days. Median disease-free interval for ferrets that had abdominal surgery for pancreatic beta cell tumor removal was 240 days. Distant tumor metastasis was not found in this group of ferrets, but local tumor recurrence was common. In 4 ferrets that had a second celiotomy, removal of recurrent pancreatic tumors did not prolong survival but did result in a second disease-free interval. CLINICAL IMPLICATIONS: Pancreatic beta cell tumors should be considered in ferrets over 2 years of age that have clinical signs of seizures, episodic lethargy, ptyalism, ataxia, and hind limb weakness. In the study reported here, complete surgical excision of the tumor resulted in temporary resolution of clinical signs in ferrets; however, redevelopment of clinical signs at a later time was common.
Limb-sparing surgery versus amputation for dogs with bone tumors.
Recently, limb-sparing surgeries have been used in the treatment of dogs with malignant bone tumors. These new techniques are fraught with potential complications. As amputation is a time-honored technique in veterinary medicine for the control of primary bone tumors, the use of newer, more complicated surgeries such as limb sparing may be considered controversial. In this article, amputation and limb sparing are discussed with reference to case selection, outcome, and possible complications.
Efficacy of intralesionally administered cisplatin-impregnated biodegradable polymer for the treatment of 9L gliosarcoma in the rat.
OBJECTIVE: Use of biodegradable polymers for the local delivery of chemotherapy is a promising new strategy in the treatment of high-grade gliomas. We examine the benefit of local delivery of cisplatin, via biodegradable polymer, in the treatment of intracranial glioma in rats. This treatment is compared against intralesionally administered free cisplatin and systemic cisplatin. METHODS: The Fischer 344 9L gliosarcoma rat model was used with a cannula placed in the right frontal lobe. On Day 0, 5 x 10(3) 9L gliosarcoma cells were infused. Treatment was initiated on Day 7. In Experiment 1, polymer alone was infused intralesionally to rule out any inherent toxic or tumoricidal properties. In Experiment 2, polymer impregnated with 0.5, 5.0, and 25 mg/m2 cisplatin was infused intralesionally. In Experiment 3, the most effective dose of drug containing polymer was compared against a similar dose of intralesionally administered free cisplatin and the systemic administration of cisplatin. RESULTS: In Experiment 1, polymer alone demonstrated no inherent toxic or tumoricidal properties. In Experiment 2, polymer impregnated with 0.5 mg/m2 was 100% effective in eradicating intracranial tumor with minimal histological evidence of toxicity. At the 5.0 and 25 mg/m2 doses, local brain toxicity was significant. In Experiment 3, at Day 60, 8 of 12 animals treated with polymer containing 0.5 mg/m2 cisplatin were alive and tumor free. This compared with 3 of 13 tumor-free survivors for the group treated with intralesionally administered free cisplatin, and 0 of 13 and 0 of 11 survivors for the 50 and 100 mg/m2 intraperitoneally administered doses, respectively. CONCLUSION: The local instillation of cisplatin-impregnated biodegradable polymer, allowing the sustained release of high-dose chemotherapy locally, seems to be effective treatment for intracranial 9L gliosarcoma in the rat. Treatment was superior to intralesionally administered free or systemic cisplatin.
Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989).
Of 82 dogs with thyroid carcinoma seen between January 1981 and October 1989, 20 had freely movable tumors without evidence of metastasis and were treated with surgical excision alone. Uncensored mean and median survival times for these 20 dogs were both 20.5 months. Kaplan-Meier survival analysis, which censors for nontumor-related deaths and dogs lost to follow-up, indicated that median survival time was greater than 36 months. Seven dogs died of tumor-related causes: 2 died because of metastasis or local recurrence of the tumor, 5 died of treatment-related complications (eg, laryngeal paralysis, hypocalcemia, tracheostomy complications). Eight dogs died of unrelated causes; 1 dog was lost to follow-up at 26 months after surgery; 3 dogs were alive 19, 24, and 26 months after surgery. Cause of death could not be determined in the remaining dog. Long-term survival is possible following surgical removal of mobile thyroid carcinomas in dogs.
The science of surgical oncology: past progress and future direction.
The future of surgical oncology is not simply to remove more body parts but to better select the best treatment for each individual patient. The area of predictive assays is growing quickly, and although generally mentioned in relation to chemotherapy or radiation response, these assays can also be applied to surgery. More accurate staging is crucial to surgeons in customizing the operative procedure to the individual.
Evaluation of prognostic factors for dogs with synovial sarcoma: 36 cases (1986-1991).
Medical records of 36 dogs with synovial sarcoma confirmed by microscopic examination of H&E-stained sections of tissue were selected for retrospective analysis from dogs admitted between 1986 and 1991 to participating institutions of the Veterinary Cooperative Oncology Group. Metastasis was evident at the time of diagnosis in 8 (22%) dogs, and 15 (41%) dogs ultimately developed metastatic tumors. Median survival time for all dogs, as determined by life-table analysis, was 17 months. For dogs that were subsequently treated and became tumor free, the median disease-free interval was 30 months. Nine dogs had previously had localized excision attempted, but all had recurrence of the tumor locally (median, 4.5 months). Of 29 dogs that underwent amputation, including the 9 with localized recurrence, 2 had tumor recurrence on the amputation stump. Most dogs had survival time and disease-free interval of > 36 months after amputation. Four dogs that had received chemotherapy for tumors of advanced clinical stages did not respond to treatment. One dog that had received locally applied radiotherapy after localized excision did not have evidence of tumor recurrence 2 years after radiotherapy. Clinical stage, histologic grade, and a positive result for tests that used cytokeratin immunohistochemical staining significantly (P < 0.05) influenced survival time and disease-free interval. Analysis of data for the study reported here suggested that histologic criteria can be an excellent predictor of dogs that are likely to have tumor recurrence after amputation and that would most likely benefit from aggressive treatment with adjuvants.
Thymoma in dogs: 23 cases (1980-1991).
Medical records of 23 dogs in which thymoma was diagnosed between Jan 1, 1980 and Dec 31, 1991 were reviewed. All thymomas were located in the cranial mediastinum. Eleven dogs had megaesophagus, and myasthenia gravis was confirmed in 7 of these 11. One dog developed clinical signs of myasthenia gravis after removal of the thymoma. Concurrent, nonthymic neoplasms were found in 5 dogs, and 2 had hypercalcemia. Three dogs developed third-degree atrioventricular heart block, 1 of which had generalized myositis involving the cardiac muscle. None of the dogs had evidence of distant metastasis. Histologically, the predominant tumor types were differentiated epithelial type (9/23) and lymphocyte-rich type (6/23). Clear cells (large cells with nonstaining cytoplasm) comprised > or = 50% of the cell population in tumors from 5 dogs. Mast cells were detected histologically in 85% of the thymomas evaluated. Sixteen dogs were treated, and in 15 of these, surgery was the primary means of treatment. Six of the 9 dogs with megaesophagus that underwent surgery died or were euthanized within 1 week of diagnosis; whereas only 1 of the 4 dogs without megaesophagus that underwent surgery died within 1 week of diagnosis. Two dogs underwent surgery and received adjuvant chemotherapy. One dog died of complications associated with chemotherapy. One dog was treated with chemotherapy alone and survived 14 months. Seven dogs did not undergo treatment; 4 of these were euthanatized immediately after the mass was first discovered.(ABSTRACT TRUNCATED AT 250 WORDS)
Infiltrative lipoma in dogs: 16 cases (1981-1992).
Medical records of 15 dogs with infiltrative lipoma, 1 of which had 2 lesions, were reviewed. Median age of affected dogs was 6.0 years, and median weight was 30.5 kg. The ratio of females to males was 4:1. Eight of the dogs were Labrador Retrievers. In 8 dogs, the lesions had previously been excised. There was not any apparent site predilection. Excision was the only treatment in all 15 dogs, and follow-up information was available for all dogs. Two dogs, each of which had 1 tumor, were euthanatized immediately after surgery, because the tumor could not be completely excised. Of the remaining 14 tumors, 5 (36%) recurred. Median time to recurrence for these 5 tumors was 239 days (range, 96 to 487 days). By means of Kaplan-Meier analysis, the percentage of dogs disease free 1 year after surgery was calculated to be 67%.
Impact of heterogeneity in the predictive value of kinetic parameters in canine osteosarcoma.
Intratumoral heterogeneity has been identified as a potential problem in the efficacy of predictive assays. Canine osteosarcoma is an extremely heterogeneous solid tumor that has been shown to be an excellent model for the human disease. Intratumoral heterogeneity of kinetic parameters and the effect of heterogeneity on predicting outcome of treatment (time until metastasis) were studied in dogs with naturally occurring osteosarcoma. Dogs were treated with amputation or tumor excision and limb-sparing followed by chemotherapy with cisplatin. Kinetic parameters evaluated included v, duration of DNA synthesis (Ts), and potential doubling time (Tpot), determined using in vivo labeling with bromodeoxyuridine and flow cytometry. In 30 tumors, multiple samples were obtained and evaluated. There was significantly more variation between tumors from different dogs than intratumoral variation of v, Ts, and Tpo. Variations in v, Ts, and Tpot within a tumor were associated with both sample location and tumor subpopulation. Time to metastasis was determined in 51 dogs with tumors sampled for kinetics. Multiple samples were available from 25 of these tumors. Cox proportional hazard analysis was performed using either the fastest or slowest Tpot from each sample. The fastest available Tpots were highly significant (P < 0.001) for prediction of outcome. The slowest available Tpots were also significant predictors, although the statistical strength was compromised (P = 0.024). Obtaining at least two samples in large tumors known to be heterogeneous is recommended to improve the predictive ability of Tpot. v is a more limited predictor but can useful when Tpot is not available. In canine osteosarcoma, an extremely heterogeneous tumor, kinetic parameters were shown to be predictors of outcome.
Histologically low-grade, yet biologically high-grade, fibrosarcomas of the mandible and maxilla in dogs: 25 cases (1982-1991).
Medical records of 25 dogs with histologically low-grade fibrous masses of the maxilla and mandible were reviewed. Most of the dogs had extensive clinical histories and had had previous biopsies of the affected regions, from which specimens were often interpreted as benign fibrous connective tissue. The most common breed represented was Golden Retriever (13/25 dogs, 52%). Skull radiographs were evaluated for 22 dogs, and 16 dogs (72%) had evidence of bone lysis. At admission, none of the dogs had radiographic evidence of pulmonary metastasis. On subsequent examinations and necropsy, prevalence of pulmonary metastasis was 12% (3/25 dogs) and of regional lymph node metastasis, 20% (5/25 dogs). Histologic appearance of all specimens was similar and was characterized by proliferation of fibrous connective tissue, with moderate to low cellularity, that aggressively infiltrated adjacent normal tissue. Treatment modalities varied considerably. Surgical excision in combination with radiation therapy, surgery alone, radiation therapy alone, and radiation therapy used adjunctly with localized hyperthermia prolonged survival times in some dogs. The clinical signs, tumor behavior, and histologic characteristics of these lesions were distinctive from those in previously described oral fibrosarcomas in dogs. Comparatively, these tumors most closely resembled aggressive fibromatoses in human beings in regard to clinical signs, local invasive behavior, and histologic appearance, but differed in the prevalence of metastasis.
Effects of cis-diamminedichloroplatinum II released from D,L-polylactic acid implanted adjacent to cortical allografts in dogs.
This study was performed to determine the pharmacokinetics and local and systemic effects of cis-diamminedichloroplatinum II (cisplatin) released from an open-cell polylactic acid polymer when the drug delivery device was placed adjacent to a cortical allograft. Bilateral intercalary femoral allografts were implanted in six normal beagles. The polymer containing cisplatin was implanted adjacent to the allograft in one femur, and the polymer without cisplatin was implanted adjacent to the allograft in the contralateral femur. Systemic toxicity was evaluated clinically by hematologic and serum biochemistry tests and urinalysis. Healing of the allograft was monitored radiographically. The femora were evaluated biomechanically, histologically, and histomorphometrically 7.5 months after surgery. Total serum platinum levels were measured by atomic absorption spectrophotometry, and pharmacokinetic parameters were calculated. Healing was impaired slightly by the presence of the polymer with cisplatin, and systemic and local toxicity was mild and transient. After implantation of the polymer with cisplatin, the mean peak total serum platinum concentration was low (1.71 +/- 0.19 micrograms/ml). However, the area under the curve for total serum platinum concentration versus time for the first 21 days was large (27,050 +/- 3,201 micrograms.min/ml). When cisplatin was given as an intravenous bolus at a dose of 70 mg/m2 to six other beagles, the mean peak total platinum concentration was 8.80 +/- 2.1 micrograms/ml and the area under the curve was 940.3 +/- 256.7 micrograms.min/ml. These results indicate that a sustained release of cisplatin can be delivered safely from an open-cell polylactic acid polymer. This device may be useful in the treatment of solid tumors.