c-Kit Mutation and Localization Status as Response Predictors in Mast Cell Tumors in Dogs Treated with Prednisone and Toceranib or Vinblastine.

BACKGROUND: KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c-kit mutations. HYPOTHESIS/OBJECTIVES: To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c-kit mutated MCT would have a better response to TOC than VBL. ANIMALS: Eighty-eight client-owned dogs with macroscopic MCT. METHODS: Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c-kit mutation status using an adaptive randomization scheme. RESULTS: Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c-kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62-3.92]; P = 0.28). Median progression-free survival (PFS) for dogs receiving VBL was 78 days (7-1,521) and for TOC 95.5 (14-990); hazard ratio (HR) = 1.34 [0.72-2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10-1,521) for the VBL group and 159 (20-990) for the TOC group; HR = 0.80 ([0.45-1.41]; P = 0.44). CONCLUSIONS AND CLINICAL IMPORTANCE: Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c-kit mutations was not different between treatment groups in this population of dogs, c-kit mutation status did not predict treatment response.

Expression of Phosphorylated KIT in Canine Mast Cell Tumor.

Canine cutaneous mast cell tumor (MCT) is the most common canine skin tumor and exhibits variable biologic behavior. Signaling through the KIT receptor tyrosine kinase promotes cellular proliferation and survival and has been shown to play a role in MCT progression. Despite investigations into numerous biomarkers and the proposal of several grading schemas, no single marker or grading system can accurately predict outcome in canine MCT. The first aim of this study was to develop an immunohistochemical assay to measure phosphorylated KIT (pKIT) to investigate its association with 2 commonly used grading systems and other established prognostic markers for canine MCT. Thirty-four archived MCTs were evaluated for expression of pKIT and Ki-67, KIT localization, mitotic count, mutations in exons 8 and 11 in c-kit, and grading by the Patnaik and 2-tier systems. Expression of pKIT was significantly ( P < .05) correlated with the 2-tier grading scheme and c-kit mutation. Correlation approached significance ( P = .06) with Mitotic Index (MI) and Ki-67. An additional aim was to determine whether pKIT labeling provides a pharmacodynamic marker for predicting response to the receptor tyrosine kinase inhibitor toceranib (TOC). MCTs from 4 of 7 patients demonstrated a partial response to TOC. pKIT expression was assessed by immunohistochemistry in biopsies obtained before and 6 hours after the patients were treated with TOC. Reduced pKIT expression after TOC treatment was demonstrated in 3 of the 4 patients with a partial response compared to 1 of the 3 nonresponders. Collectively, these results demonstrate that immunohistochemical detection of pKIT may be a clinically relevant assay to evaluate the activation status of the major oncogenic pathway in canine MCT.

Criteria for designation of clinical substage in canine lymphoma: a survey of veterinary oncologists.

Clinical substage is frequently reported to be prognostic in dogs with lymphoma, yet formal criteria for defining this parameter are lacking. The World Health Organization TNM Classification of Tumors of Domestic Animals simply defines substage as the absence or presence of systemic signs (substages a and b, respectively). We designed a survey to query veterinary oncologists on the criteria they use to determine clinical substage in practice. Gastrointestinal, constitutional and respiratory signs were the most commonly identified clinical factors, with greater than 90% respondents indicating that inappetence, vomiting, diarrhoea, changes in attitude, weakness and dyspnea were integral in assigning clinical substage. Nevertheless, more than three-quarters of respondents also considered metabolic, neurologic and nutritional parameters when making this determination. For most factors, respondents reported mild-to-moderate severity of clinical signs was sufficient for substage b designation.

Correlation of nodal mast cells with clinical outcome in dogs with mast cell tumour and a proposed classification system for the evaluation of node metastasis.

Lymph node metastasis in dogs with mast cell tumour has been reported as a negative prognostic indicator; however, no standardized histological criteria exist to define metastatic disease. The primary aim of this study was to determine whether different histological patterns of node-associated mast cells correlate with clinical outcome in dogs with mast cell tumour. A secondary goal was to propose a criteria-defined classification system for histological evaluation of lymph node metastasis. The Colorado State University Diagnostic Medicine Center database was searched for cases of canine mast cell tumours with reported lymph node metastasis or evidence of node-associated mast cells. Additional cases were obtained from a clinical trial involving sentinel lymph node mapping and node extirpation in dogs with mast cell neoplasia. Forty-one cases were identified for inclusion in the study. Demographic data, treatment and clinical outcome were collected for each case. Lymph nodes were classified according to a novel classification system (HN0-HN3) based on the number of, distribution of, and architectural disruption by, nodal mast cells. The findings of this study indicate that characterization of nodal mast cells as proposed by this novel classification system correlates with, and is prognostic for, clinical outcome in dogs with mast cell tumours.

Effects of cooked navy bean powder on apparent total tract nutrient digestibility and safety in healthy adult dogs.

Dry beans (Phaseolus vulgaris L., Fabaceae) are a low glycemic index food containing protein, fiber, minerals, essential vitamins, and bioactive compounds and have not been evaluated for inclusion in commercial canine diets. The objective of this study was to establish the apparent total tract digestibility and safety of cooked navy bean powder when incorporated into a canine diet formulation at 25% (wt/wt) compared with a macro- and micro-nutrient matched control. Twenty-one healthy, free-living, male and female adult dogs of different breeds were used in a randomized, blinded, placebo controlled, 28-d dietary intervention study. Apparent total tract energy and nutrient digestibility of the navy bean powder diet were compared with the control diet. Digestibilities and ME content were 68.58 and 68.89% DM, 78.22 and 79.49% CP, 77.57 and 74.91% OM, 94.49 and 93.85% acid hydrolyzed fat, and 3,313 and 3,195 kcal ME/kg for the navy bean diet and control diet, respectively. No differences were observed between the groups. No increased flatulence or major change in fecal consistency was observed. Navy bean powder at 25% (wt/wt) of total diet was determined to be palatable (on the basis of intake and observation) and digestible in a variety of dog breeds. No changes were detected in clinical laboratory values, including complete blood counts, blood biochemical profiles, and urinalysis in either the bean or control diet groups. These results indicate that cooked navy bean powder can be safely included as a major food ingredient in canine diet formulations and provide a novel quality protein source, and its use warrants further investigation as a functional food for chronic disease control and prevention.