Background: Imatinib mesylate is a small molecule targeted at dysregulated protein-tyrosine kinase. Mutation of c-kit exon 11, which induces constitutive phosphorylation of KIT, is one of the mechanisms for the development or progression of mast cell tumor (MCT) in dogs. The purpose of this study was to examine the therapeutic potential of imatinib mesylate in canine MCT.Hypothesis: Imatinib mesylate has activity against MCT in dogs, and response to treatment can be correlated to presence of mutation within exon 11 of c-kit.Animals: Twenty-one dogs with MCT with gross tumor burden and median tumor size of 7.2 cm (range, 1.0-25.3 cm) before treatment.Methods: Tumors were analyzed for mutation of c-kit exon 11. Imatinib mesylate was administered PO to the dogs at a dose of 10 mg/kg daily for 1-9 weeks.Results: Ten of 21 dogs (48%) had some beneficial response to imatinib mesylate treatment within 14 days of treatment initiation. All 5 dogs with a demonstrable c-kit mutation in exon 11 responded to the drug (1 complete remission, 4 partial remission).Conclusions and Clinical Importance: Imatinib mesylate has clinical activity against MCT in dogs. Response could not be predicted based on presence of absence of a mutation in exon 11 of c-kit.

Abstract— Two Pugs and two Miniature Schnauzers with multiple pigmented epidermal nevi were investigated. The four dogs had pigmented cutaneous maculae and plaques. Histopathological evaluation showed papillated or digitated epidermal hyperplasia with hypermelanosis and giant keratohyalin granules in the stratum granulosum. Immunohistochemical staining revealed papillomavirus group‐specific antigen in the skin specimens from all four dogs. Electron microscopic study of the specimens from two dogs revealed numerous round viral particles within the nuclei of the keratinocytes in the upper stratum granulosum. It was suspected that papillomavirus was the etiologic agent of the lesions, and that Pugs and Miniature Schnauzers might be predisposed to infection. These findings indicate this canine dermatosis resembles epidermodysplasia verruciformis (EV) of humans, a rare chronic disease caused by human papillomavirus. The potential for transformation of the lesions to squamous cell carcinoma is also suspected and discussed. Résumé— Deux Carlins et deux Schnauzers nains présentant de multiples naevi épidermiques pigmentés sont examinés. Les quatre chiens présentent des macules et des plaques pigmentées. Les lésions histopathologiques montrent une hyperplasie épidermique papillaire ou digitée avec une hypermélanose et la présence de grains de kératohyaline dans le stratum corneum. Les colorations immunohistochimiques révèlent des antigènes spécifiques du groupe des papillomas virus dans les biopsies des quatre chiens. L'étude ultrastructurale à partir des biopsies de deux chiens montrent de nombreuses particules virales rondes dans les noyaux des kératinocytes des couches supérieures du stratum granulosum. II a été suspecté que le papilloma virus était l'agent causal des lésions et que les Carlins et les Schnauzers nains pouvaient être prédisposés à cette infection. Ces éléments font que cette dermatose observée chez le chien ressemble à l'épidermodysplasie verruciforme de l'homme, une dermatose chronique rare causée par un papilloma virus humain. La potentialité de transformation des lésions en épithélioma spinocellulaire est aussi suspectée et discutée. [Nagata, M., Nanko, H., Moriyama, A., Washizu, T., Ishida, T. Pigmented plaques associated with papilloma virus infection in dogs: Is this epidermodysplasia verruciformis? (Plaques hyperpigmentées associées à une infection à papilloma virus chez le chien: est‐ce épidermodysplasie verruciforme?). Resumen— Se investigó dos perros de raza Pug y dos de raza Schnauzer Miniatura con múltiples nevos epidérmicos pigmentados. Los cuatro perros presentaban máculas y placas cutáneas pigmentadas. El estudio histológico mostró hiperplasia epitelial con papilas y digitaciones, así como hipermelanosis y gránules de queratohialina gigantes en el estrato granuloso. Las tinciones immunohistoquimicas detectaron antígeno grupo‐específico de papilomavirus en las muestras de los cuatro animales. Mediante estudios de microscopía electrónica en muestras de dos de los perros se observaron numero...

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The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67.7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.

Plasma glucose and immunoreactive insulin (IRI) concentrations and activities of enzymes related to glucose metabolism in livers were measured in dogs and cats. Nucleotide sequences of the conserved region of glucokinase (GK) cDNA that contained ATP- and glucose-binding domains were determined in canine liver and feline pancreas for design of the species-specific oligonucleotide primers for reverse transcription-polymerase chain reaction (RT-PCR) analysis. There were no significant differences in plasma glucose and IRI concentrations between dogs and cats. In feline liver, although GK activities were not detected, activities of hexokinase, fructokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, fructose-1,6-bisphosphatase and glucose-6-phosphatase were significantly higher than those in canine liver. The partial sequences of canine liver GK and feline pancreas GK cDNA were respectively 88% and 89% identical with the rat liver GK cDNA. Expression of GK gene was observed in canine liver and pancreas and feline pancreas with RT-PCR using species specific primers based on the cDNA sequences.