Overexpression of HER-2 via immunohistochemistry in canine urinary bladder transitional cell carcinoma - A marker of malignancy and possible therapeutic target.

Transitional cell carcinoma (TCC) is the most commonly diagnosed neoplasm in the urinary bladder. Distant metastases to the regional lymph nodes, lungs, abdominal organs or bones are noted in up to 50% of dogs at time of death. Surgical excision is often not practical as TCC typically involve the trigone of the bladder and/or occurs multifocally throughout the bladder with field cancerization. Therapeutic approaches are very challenging and the requirement to evaluate alternative therapeutic protocols that may prolong survival times in dogs bearing these tumours is compelling. We assessed the immunohistochemical expression of HER-2 in 23 cases of canine TCCs of the urinary bladder and compare it with non-neoplastic urothelium in order to evaluate a rationale for targeted therapies and gene-based vaccines. HER-2 positivity was recorded in 13/23 (56%) neoplastic lesions. The receptor was significantly overexpressed in neoplastic than in non-neoplastic samples (P = .015). According to our preliminary results, it would be of interest to further evaluate the role of HER-2 in canine TCCs as a marker of malignancy and a therapeutic target for cancer vaccine and antibodies. Moreover, the significantly different overexpression of HER-2 in TCCs than in non-neoplastic urothelium further supports to investigate its role in the progression toward malignancy of non-neoplastic lesions.

Treatment time, ease of use and cost associated with use of Equashield™, PhaSeal® , or no closed system transfer device for administration of cancer chemotherapy to a dog model.

This prospective experimental simulation study evaluated the efficiency, ease of use (EOU) and cost of administering chemotherapy with two closed system transfer devices (CSTD, Equashield™ and PhaSeal® ) and no CSTD. Forty-six veterinary technicians (VT) working in oncology specialty practices were timed during chemotherapy administration simulated with water and a model canine limb 10 times with each system and with no CSTD. EOU and likelihood of recommending each system were rated by VT using visual analog scales. Costs were obtained from veterinary distributors. Administration was fastest with Equashield™ (P = 0.0003), but the difference was not enough to affect case flow. Equashield™ was easier to use than PhaSeal® or no CSTD (P = 0.002), however VT recommended both CSTD more strongly than no CSTD (P < 0.0001). Equashield™ cost less than PhaSeal® but was sold only in bulk quantities. CSTD did not decrease efficiency in administering chemotherapy and were readily accepted by VT.

The treatment of canine mast cell tumours with electrochemotherapy with or without surgical excision.

To describe the results of electrochemotherapy (ECT) in dogs with mast cell tumours (MCTs) either as first line therapy or as an adjuvant to surgery. The treatment combines administration of low dose chemotherapeutic drugs with the application of microsecond electric pulses, which cause the temporary permeabilization and increased porosity of the tumour cell membranes. The design of this study is a retrospective case series. A total of 51 dogs with MCTs were included and classified according to ECT procedure into 4 groups (ECT only, 15 cases, intra-surgery ECT, 11, ECT Adjuvant to surgery, 14, Surgery followed by ECT, 11). The four groups (staged with location, size and grade) were evaluated to assess complete or partial remission, disease free interval, overall survival time and local toxicity. In this case series, Boxers, mixed breed and Labrador Retrievers, male dogs, between 4 and 9 years old were more represented. MCTs were predominantly grade 2 (Patnaik) and T stage 0-1, I-1 (World Health Organization). Treated lesions were most commonly identified on the hindlimb and head where curative surgery would involve cosmetic or functional compromise. The intra-surgery group of dogs showed the best disease free interval with Kaplan-Meyer analysis. Local toxicity induced by ECT ranged mostly from 1 to 4 in a 5-point arbitrary scale with 0 - no toxicity to 5 - highest toxicity. In this study, ECT can be applied successfully as an exclusive therapy in smaller MCTs as an alternative to surgery. ECT can be combined with surgery either intra-operatively or post operatively for larger lesions without significant toxicity.

Electroporation in veterinary oncology.

Cancer treatments in veterinary medicine continue to evolve beyond the established standard therapies of surgery, chemotherapy and radiation therapy. New technologies in cancer therapy include a targeted mechanism to open the cell membrane based on electroporation, driving therapeutic agents, such as chemotherapy (electro-chemotherapy), for local control of cancer, or delivery of gene-based products (electro-gene therapy), directly into the cancer cell to achieve systemic control. This review examines electrochemotherapy and electro-gene therapy in veterinary medicine and considers future directions and applications.

Electro-gene-transfer as a new tool for cancer immunotherapy in animals.

The concept of vaccines based on the direct inoculation of plasmid DNA gained initial proof-of-concept in small rodent species. Further development was hampered by the difficulty to confirm immunogenicity and efficacy in large animal species and, most importantly, in human clinical trials. These negative findings led to the search of complementary technologies which, in combination with intradermal or intramuscular plasmid DNA injection would result in more robust delivery, decreased interindividual variability, clear evidence of clinical efficacy and which would eventually lead to market approval of new vaccine products. The use of high-pressure, needleless devices as an enhancing tool for plasmid DNA delivery led to recent approval by USDA of Oncept™, a therapeutic cancer vaccine directed against tyrosinase for the therapy of melanoma in dogs. An alternative approach to improve plasmid DNA delivery is electro-gene-transfer (EGT). In this article, we briefly review the principles of DNA-EGT and the evidences for efficacy of a telomerase reverse transcriptase vaccine in a dog clinical trial, and provide perspectives for the use of this technology for broader applications in pet animals.

ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine.

BACKGROUND: Dogs that harbor the naturally occurring ABCB1-1Delta polymorphism experience increased susceptibility to avermectin-induced neurological toxicosis as a result of deficient P-glycoprotein function. Whether or not the ABCB1-1Delta polymorphism affects susceptibility to toxicity of other P-glycoprotein substrate drugs has not been studied. HYPOTHESIS: Dogs that possess the ABCB1-1Delta mutation are more likely to develop hematologic toxicity associated with vincristine than ABCB1 wild-type dogs. ANIMALS: Thirty-four dogs diagnosed with lymphoma were included in this study. METHODS: Cheek swab samples were obtained from dogs diagnosed with lymphoma that were to be treated with vincristine. DNA was extracted from cheek swabs and the ABCB1 genotype was determined. Hematologic adverse drug reactions were recorded for each dog and graded according to the Veterinary Comparative Oncology Group's criteria for adverse event reporting (Consensus Document). In order to avoid possible bias, ABCB1 genotype results for a particular patient were not disclosed to oncologists until an initial adverse event report had been submitted. RESULTS: Dogs heterozygous or homozygous for the ABCB1-1Delta mutation were significantly more likely to develop hematologic toxicity, specifically neutropenia (P= .0005) and thrombocytopenia (P= .0001), after treatment with vincristine than ABCB1 wild-type dogs. CONCLUSIONS AND CLINICAL IMPLICATIONS: At currently recommended dosages (0.5-0.7 mg/M(2)), vincristine is likely to cause hematologic toxicity in dogs with the ABCB1-1Delta mutation, resulting in treatment delays and unacceptable morbidity and mortality. Assessing the ABCB1-1Delta genotype before vincristine administration and decreasing the dosage may prevent toxicity and treatment delays resulting from neutropenia or thrombocytopenia.

Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999-2004).

BACKGROUND: Epitheliotropic lymphoma (ELSA) is an uncommon cutaneous canine malignancy of T lymphocytes. A consensus regarding the therapeutic standard of care is lacking, warranting evaluation of chemotherapeutic agents traditionally employed against canine nodal lymphoma in the treatment of ELSA. HYPOTHESIS: The purpose of this retrospective, multi-institutional study was to evaluate the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in the treatment of ELSA. ANIMALS: Forty-six dogs with adequate follow-up and treatment response information. METHODS: All cases were diagnosed histopathologically. Immunohistochemisty (CD3, CD79a) was performed on 42/46 samples. RESULTS: Presenting skin lesions included generalized scales (25/46), plaques or nodules (22/46), mucocutaneous lesions (14/ 46), and corneal involvement (1/46). Lymph node involvement and Sézary syndrome were documented in 7 and 2 dogs, respectively. The median number of CCNU treatments was 4 (range, 1-11), with a median starting dose of 60 mg/m(2) (range, 30-95). Of the 46 dogs, 15 achieved complete remission, 23 achieved partial remission, 5 had stable disease, and 3 had progressive disease, for an overall response rate of 83%. The median number of treatments to achieve a response was 1 (range, 1-6). The overall median duration of response was 94 days (range, 22-282). Sixteen dose reductions were required because of neutropenia (10/46), thrombocytopenia (1/46), anemia (1/46), increased liver enzyme activity (3/46), or unspecified reasons (1/46). CONCLUSIONS AND CLINICAL IMPLICATIONS: Given the high response rate and well tolerated protocol, prospective studies are warranted to investigate the utility of CCNU alone or in multi-agent protocols for the treatment of ELSA.

Effect of weight reduction on clinical signs of lameness in dogs with hip osteoarthritis.

OBJECTIVE: To determine the effect of weight reduction on clinical signs of lameness among overweight dogs with clinical and radiographic signs of hip osteoarthritis. DESIGN: Nonblinded prospective clinical trial. ANIMALS: 9 client-owned dogs with radiographic signs of hip osteoarthritis that weighed 11 to 12% greater than their ideal body weight and were examined because of hind limb lameness. PROCEDURE: Dogs were weighed, and baseline body condition, hind limb lameness, and hip function scores were assigned. Severity of lameness was scored using a numerical rating scale and a visual analogue scale. Dogs were fed a restricted-calorie diet, with amount of diet fed calculated to provide 60% of the calories needed to maintain the dogs' current weights. Evaluations were repeated midway through and at the end of the weight-loss period. RESULTS: Dogs lost between 11 and 18% of initial body weight. Body weight, body condition score, and severity of hind limb lameness were all significantly decreased at the end of the weight-loss period. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in overweight dogs with hind limb lameness secondary to hip osteoarthritis, weight reduction alone may result in a substantial improvement in clinical lameness.