Computed tomography characteristics of canine tracheobronchial lymph node metastasis.

Tracheobronchial lymph node evaluation is critical for accurate staging of canine thoracic neoplasia and is more accurately achieved with computed tomography (CT) than radiography. Thoracic CT scans of 18 canine patients with known tracheobronchial lymph node histopathology and 10 clinically normal dogs were compared to establish if enlargement or contrast enhancement pattern correlated with metastatic status. Absolute lymph node size and three anatomically normalized lymph node ratios were significantly correlated with metastasis or severe granulomatous lymphadenitis (P < 0.0003). Transverse maximum lymph node diameter of 12 mm or lymph node to thoracic body ratio of 1.05 are proposed cutoffs, above which metastatic involvement is very likely; however, only minimal accuracy was gained with normalized ratios. Lymph node contrast enhancement pattern was also significantly correlated to disease. A heterogenous and/or ring pattern was related to metastatic disease (P = 0.03). Recommended protocol for CT examination of the tracheobronchial lymph nodes is 1-1.5 mm slices and intervals, intravenous contrast, and control of respiratory motion.

Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs.

BACKGROUND: Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. METHODOLOGY/PRINCIPAL FINDINGS: This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. CONCLUSIONS/SIGNIFICANCE: Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease.

Launching a novel preclinical infrastructure: comparative oncology trials consortium directed therapeutic targeting of TNFalpha to cancer vasculature.

BACKGROUND: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. METHODOLOGY/PRINCIPAL FINDINGS: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alphaV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5x10(12) transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). CONCLUSIONS/SIGNIFICANCE: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies.

Comparative oncology today.

The value of comparative oncology has been increasingly recognized in the field of cancer research, including the identification of cancer-associated genes; the study of environmental risk factors, tumor biology, and progression; and, perhaps most importantly, the evaluation of novel cancer therapeutics. The fruits of this effort are expected to be the creation of better and more specific drugs to benefit veterinary and human patients who have cancer. The state of the comparative oncology field is outlined in this article, with an emphasis on cancer in dogs.

CCNU for the treatment of dogs with histiocytic sarcoma.

BACKGROUND: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis. HYPOTHESIS: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease. ANIMALS: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU. METHODS: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma. RESULTS: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (< 100,000 platelets/microL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of < 1 month survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.

Comparison of results of computed tomography and radiography with histopathologic findings in tracheobronchial lymph nodes in dogs with primary lung tumors: 14 cases (1999-2002).

OBJECTIVE: To compare results of computed tomography (CT) and radiography with histopathologic findings in tracheobronchial lymph nodes (TBLNs) in dogs with primary lung tumors. DESIGN: Retrospective case series. ANIMALS: 14 client-owned dogs. PROCEDURES: Criteria for inclusion were diagnosis of primary lung tumor, use of thoracic radiography and CT, and histologic confirmation of TBLN status. Medical records were reviewed for signalment; history; and physical examination, clinicopathologic, radiographic, CT, surgical, and histopathologic findings. RESULTS: Tracheobronchial lymphadenopathy was not identified via radiography in any dogs. Tracheobronchial lymphadenopathy was diagnosed in 5 dogs via CT. Six dogs had histologic confirmation of metastasis to TBLNs. Radiographic diagnosis yielded 6 false-negative and no false-positive results for tracheobronchial lymphadenopathy. Computed tomography yielded 1 false-negative and no false-positive results. Sensitivity of CT for correctly assessing TBLN status was 83%, and specificity was 100%. Positive predictive value was 100%, and negative predictive value was 89%. Dogs with lymphadenopathy via CT, histologic confirmation of TBLN metastasis, or primary tumors with a histologic grade > 1 had significantly shorter survival times than their counterparts. CONCLUSIONS AND CLINICAL RELEVANCE: Results of CT evaluation of TBLN status were in agreement with histopathologic findings and more accurate than use of thoracic radiography for evaluating TBLNs in dogs with primary lung tumors. Computed tomography imaging should be considered as part of the staging process to more accurately assess the TBLNs in dogs with primary lung tumors.

Ultrasonographic and clinicopathologic findings in 21 dogs with intestinal adenocarcinoma.

In a retrospective study of 21 dogs with intestinal adenocarcinoma, the signalment, clinical presentation, laboratory findings, ultrasonographic features, treatment, and outcome were reviewed. Anorexia (n = 16), vomiting (n = 15), diarrhea (n = 10), and weight loss (n = 9) were the most common clinical signs reported. Ultrasonographic features that were evaluated included location, length, wall thickness, echogenicity, regional motility, layering, regional lymphadenopathy, and fluid accumulation proximal to the lesion site. All lesions were transmural and associated with complete loss of wall layering. Maximum wall thickening at the lesion site ranged from 7 to 17 mm (median 12 mm, mean 11.9 mm). Most of the dogs had a lesion measuring from 23 to 63 mm in length, (median 40 mm, mean 42 mm). Most intestinal lesions were poorly echogenic and had an irregular lumen. Fluid accumulation proximal to the lesion site was identified in 17 of 21 dogs, and in 13 of 17 dogs the fluid accumulation was considered moderate to severe. Regional lymphadenopathy and/or nodular mesentery/omentum were noted in 12 of 21 dogs. The tumor was located in small intestine for 15 dogs and in the colon for the remaining 6 dogs. Fifteen dogs were treated by surgical resection of the intestinal mass. Their median survival time was 233 days. Only gender appeared to influence survival. Female dogs lived a median of 28 days, whereas male dogs lived a median of 272 days.