Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial evaluating treatment with amputation and up to 4 doses of carboplatin given every 21 days. The median disease-free interval (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI ( P = .016) and survival ( P = ,037) times than dogs with OSA at other locations. Dogs with lower body weights (<40 kg) had longer DFI (P = .0056) and survival (P anine appendicular osteosarcoma (OSA) is an aggres-C sive tumor that has a poor prognosis without treatment.1.2 This tumor has been estimated to affect 8,000 to 10,000 dogs annually in the United States, and accounts for 85% of all primary bone tumors in dogs.'.' Amputation, which rarely results in a cure but relieves local discomfort, has traditionally been the standard treatment modality. Because 80% to 90% of patients have microscopic occult metastatic disease at presentation, amputation is only a palliative pr~cedure.~.' The median survival of dogs with OSA treated by amputation alone is 126 to 134 days, and only 10% to 12% of the dogs are alive at 1 year.' Therefore, to improve survival, some form of systemic therapy is necessary.Recently, cis-diamminedichloroplatinum (cisplatin) has shown activity against OSA in dogs and people.',7-" The median survival of dogs receiving cisplatin after surgery improved to 262 to 325 days, and 33% to 45% of the dogs

Response to DNA vaccination in dogs with oral MM may be useful in development of plasmid DNA vaccination protocols for human patients with similar disease.

We studied 232 dogs that underwent mastectomy for mammary epithelial neoplasms. The mastectomy specimens were evaluated according to structural parameters found to be prognostically significant in human mammary neoplasms, such as grade of atypia in non-invasive proliferations of duct epithelium, extent of malignant disease, and nuclear differentiation in malignant neoplasms. In this study, the biologic behavior of mammary lesions was assessed according to the frequency of development of de novo or recurrent invasive carcinoma within two years. Our data indicate that we can recognize structural variables which permit classification of mammary neoplasms into categories with distinct patterns of biologic behavior. In addition to normotypic proliferative lesions and invasive malignant neoplasms, we were able to identify precancerous atypic and non-invasive malignant neoplasms that are considered precursor lesions in women. Also, as in women, nuclear differentiation was found to be a prognostically significant variable. Lymphoid cellular reactions, considered to be structural correlates of host-tumor immune responses in women, were noted in 35% of dogs with precancerous or malignant neoplasms. Application of the described parameters should facilitate comparative studies of canine and human mammary carcinogenesis and use of the dog as a model for the development of new therapeutic modalities and immunoprophylaxis of human mammary cancer.

Purpose: Genetically modified bacteria are a potentially powerful anticancer therapy due to their tumor targeting capacity, inherent antitumor activity, and ability to serve as efficient vectors for gene delivery. This study sought to characterize the acute and short-term toxicities and tumor colonization rates of a genetically modified Salmonella typhimurium (VNP20009) in dogs with spontaneous tumors, in the context of a phase I dose escalation trial. Experimental Design: Forty-one pet dogs with a variety of malignant tumors received weekly or biweekly i.v. infusions of VNP20009, at doses ranging from 1.5 × 105 to 1 × 108 cfu/kg. Vital signs and clinicopathologic variables were monitored regularly. Incisional biopsies were obtained before and 1 week following the first infusion for histopathology and bacterial culture. Results: The nominal maximum tolerated dose was 3 × 107 cfu/kg, with refractory fever and vomiting being the dose-limiting toxicities. One treatment-related acute death occurred. Bacteria were cultured from tumor tissue in 42% of cases. Thirty-five patients were evaluable for antitumor response. Major antitumor responses were seen in 15% (4 complete response and 2 partial response), and disease stabilization for at least 6 weeks in 10%. Conclusions: Administration of VNP20009 at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.

In cats, TCC of the urinary bladder appears to be a rare and aggressive disease that is more prevalent in male cats and frequently develops at sites distant from the trigone (unlike TCC in dogs). Nevertheless, initial clinical signs of TCC in cats in this study were similar to those reported for affected dogs.

The purpose of this randomized, multicenter study was to evaluate the toxicity and efficacy of liposome-encapsulated doxorubicin (LED) and doxorubicin (DOX) in the treatment of feline vaccine-associated sarcoma (VAS). Cats were divided according to their disease status into a microscopic arm (no evidence of gross disease) and a macroscopic arm (evidence of gross disease). Each arm was randomized to receive either LED (1-1.5 mg/kg i.v. q3 weeks) or DOX (1 mg/kg i.v. q3 weeks). Thirty-three cats were entered in the macroscopic arm of the study with an overall response rate of 39% (5 complete response and 8 partial response) and a median time to progression of 84 days. Response rates were not different between LED and DOX. Seventy-five cats were entered into the microscopic arm. When compared to a similar historical control population treated with surgery alone, the cats receiving chemotherapy had a prolonged median disease-free interval (388 days versus 93 days). No difference in efficacy was detected between LED and DOX. LED at 1.5 mg/kg induced delayed nephrotoxicosis in 23%, necessitating a decrease in the recommended dosage to 1 mg/kg, and cutaneous toxicosis in 21.7% of treated cats. This study showed that both DOX and LED are efficacious in the treatment of VAS and should be considered in the treatment of this tumor.

We present the first comparison of global transcriptional changes in canine and human diffuse large B-cell lymphoma (DLBCL), with particular reference to the nuclear factor-kappa B (NF-κB) pathway. Microarray data generated from canine DLBCL and normal lymph nodes were used for differential expression, co-expression and pathway analyses, and compared with analysis of microarray data from human healthy and DLBCL lymph nodes. The comparisons at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa. A considerable number of differentially expressed genes between canine lymphoma and healthy lymph node samples were also found differentially expressed between human DLBCL and healthy lymph node samples. Principal component analysis using a literature-derived NF-κB target gene set mapped to orthologous canine array probesets and human array probesets clearly separated the healthy and cancer samples in both datasets. The analysis demonstrated that for both human and canine DLBCL there is activation of the NF-κB/p65 canonical pathway, indicating that canine lymphoma could be used as a model to study NF-κB-targeted therapeutics for human lymphoma. To validate this, tissue arrays were generated for canine and human NHL and immunohistochemistry was employed to assess NF-κB activation status. In addition, human and canine B-cell lymphoma lines were assessed for NF-κB activity and the effects of NF-κB inhibition.

To further define the role of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in osteosarcoma (OS), human OS cell lines with low (SAOS-2) and high (SAOS-LM2) metastatic potential and three canine OS-derived cell lines were studied. Cell lines were evaluated for: IGF-1R expression; expression of IGF binding proteins (IGFBPs); effect of IGF-1 on tumor cell growth, invasion, expression of urokinase plasminogen activator (uPA), and soluble uPA receptor (suPAR), and; ectopic and orthotopic tumorigenicity of the canine OS cells in athymic mice. All cell lines exhibited steady-state mRNA expression of IGF-1R. The SAOS-2 and SAOS-LM2 cells expressed 9,138 and 10,234 cell-associated binding sites, respectively. Canine OS cells expressed from 1,728 to 3,883 binding sites. Two IGF-1-treated cell lines displayed enhanced proliferation. Two cell lines formed colonies in semisolid media, and IGF-1 increased colony number. Matrigel invasion was enhanced in one cell line following IGF-1 treatment. uPA and suPAR were unchanged in SAOS-2 and SAOS-LM2 cells following IGF-1 treatment, but the highly metastatic OS line SAOS-LM2 expressed five times more suPAR and displayed enhanced invasion compared to the parental, low metastatic SAOS-2. IGFBP-5 was detected in four of five cell lines, and IGFBP-3 was detected in two canine OS cell lines. Two canine OS lines were tumorigenic, and one metastasized spontaneously. In conclusion, OS cells express IGF-1R, which can contribute to their growth and invasion. There is suggestive evidence that increasing receptor number may contribute to in vivo tumorigenesis. Additional studies are needed to determine how IGF-1/IGF-1R interactions contribute to the malignant phenotype of OS.