Feline vaccine-associated sarcomagenesis: Is there an inflammation-independent role for aluminium?

Aluminium has been found in feline vaccine-associated sarcomas. In this study, we investigated the potential for aluminium to contribute directly to tumourigenesis. Our results indicated that an aluminium hydroxide adjuvant preparation was cytotoxic and mutagenic in human-Chinese hamster ovary (CHO) hybrid cells in vitro. Moreover, CHO cells deficient in DNA double strand break (DSB), but not single-strand break (SSB), repair, were particularly sensitive to aluminium exposure compared with repair proficient cells, suggesting that aluminium is associated with DSBs. In contrast to CHO cells, primary feline skin fibroblasts were resistant to the cytotoxic effects of aluminium compounds and exposure to an aluminium chloride salt promoted cell growth and cell cycle progression at concentrations much less than those measured in particular feline rabies vaccines. These findings suggest that aluminium exposure may contribute, theoretically, to both initiation and promotion of tumours in the absence of an inflammatory response.

Abdominal ultrasonographic findings at diagnosis of osteosarcoma in dogs and association with treatment outcome.

The purpose of this study was to describe abdominal ultrasonographic findings present at diagnosis of osteosarcoma (OSA) in dogs and to investigate for associations with treatment outcome. Medical records from 118 dogs diagnosed with OSA that had abdominal ultrasonography performed as part of their initial evaluation were reviewed. Fifty-seven percent had ultrasonographic abnormalities identified. The organ with the highest frequency of ultrasonographic changes was the spleen. While most sonographic changes were considered to be either benign or of unknown clinical consequences, metastases were identified in three dogs (2.5%), two of which (1.7%) did not have other evidence of metastasis. Dogs with any ultrasonographic abnormality were less likely to receive definitive therapy (P = 0.005) and exhibited shorter survival, although the latter observation was not statistically significant (P = 0.071). However, the identification of lesions in either the liver (P = 0.021) or the kidney (P = 0.003) was statistically associated with shorter survival.

A randomized trial investigating the efficacy and safety of water soluble micellar paclitaxel (Paccal Vet) for treatment of nonresectable grade 2 or 3 mast cell tumors in dogs.

BACKGROUND: Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early-phase studies. HYPOTHESIS/OBJECTIVES: The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was µ(p) = µ(L) (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively). ANIMALS: Two hundred and fifty-two dogs with advanced stage nonresectable grade 2 or 3 MCT. METHODS: Prospective multicenter randomized double-blind positive-controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE). RESULTS: Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)-treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty-seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7). CONCLUSIONS AND CLINICAL IMPORTANCE: Paclitaxel (micellar)'s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols.

Evaluation of microsatellite instability in urine for the diagnosis of transitional cell carcinoma of the lower urinary tract in dogs.

BACKGROUND: The accumulation of frame-shift mutations in microsatellites (MS), termed microsatellite instability (MSI), is associated with certain tumors. MSI and its detection in urine samples has been used to aid in the detection of human bladder cancer. HYPOTHESIS: Evaluation of MSI in urine is a useful assay test for diagnosis of transitional cell carcinoma (TCC) in dogs and is more specific than the commercially available, veterinary bladder tumor analyte (V-BTA) test. ANIMALS: Seventy-three dogs: healthy controls (n=21), proteinuric (n=12), lower urinary tract disease excluding TCC (n=17), and TCC (n=23). METHODS: Prospective observational study. Urine samples collected from each animal were evaluated for MSI and using the V-BTA. For MSI detection, 22 MS sequences were polymerase chain reaction amplified from urine and blood, subjected to capillary electrophoresis, and the MS genotypes were compared. Aberration in ≥15% of MS was considered indicative of MSI. RESULTS: MSI was detected in 11 of 23 (48%) urine samples from dogs with TCC. MSI was also detected in 12 of 50 (24%) of the control animals, including 29, 16, and 24% of healthy, proteinuric, and lower urinary disease dogs, respectively. In this population, sensitivity and specificity of MSI analysis was 48 and 76%, respectively, compared with 83 and 64%, respectively, for the V-BTA test. CONCLUSIONS: MS analysis as performed in this study is not useful in the diagnosis of TCC.

NOD/SCID mouse model of canine T-cell lymphoma with humoral hypercalcaemia of malignancy: cytokine gene expression profiling and in vivo bioluminescent imaging.

Lymphoma is a malignant neoplasm arising from B or T lymphocytes. In dogs, one-third of lymphomas are highly aggressive multicentric T-cell lymphomas that are often associated with humoral hypercalcaemia of malignancy (HHM). There are no cell lines or animal models to investigate the pathogenesis of T-cell lymphoma and HHM in dogs. We developed the first xenograft model by injecting lymphoma cells from an Irish Wolfhound intraperitoneally into NOD/SCID mice. The mice developed multicentric lymphoma along with HHM and increased parathyroid hormone-related protein (PTHrP) as occurs in dogs with T-cell lymphoma. Using cytokine complementary DNA arrays, we identified genes that have potential implications in the pathogenesis of T-cell lymphoma. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of T-cell lymphoma samples from hypercalcaemic canine patients showed that PTHrP likely plays a central role in the pathogenesis of HHM and that hypercalcaemia is the result of a combinatorial effect of different hypercalcaemic factors. Finally, we monitored in vivo tumour progression and metastases in the mouse model by transducing the lymphoma cells with a lentiviral vector that encodes a luciferase-yellow fluorescent protein reporter and showed that in vivo trafficking patterns in this model were similar to those seen in dogs. This unique mouse model will be useful for translational research in lymphoma and for investigating the pathogenesis of T-cell lymphoma and HHM in the dog.

Evaluation of risk and clinical outcome of mast cell tumours in pug dogs.

Mast cell tumours (MCT) are common in dogs and characterized by diverse biologic behaviour. Our objective was to evaluate the risk of MCT in pugs and to describe the clinical behaviour of MCT in this breed. Data obtained from the Veterinary Medicine Database demonstrate significantly increased frequency of MCT in pugs compared with other dogs (OR = 2.28, 95% CI = 1.81-2.86). The medical records for 25 purebred pugs with a histologic diagnosis of MCT were reviewed. Multiple cutaneous tumours were documented in 14 (56 %) of the dogs. Histologic review of 64 tumours from these dogs confirmed that most tumours (94%) were low to intermediate grade. Sixty-four per cent of these dogs are still living, while only three dogs (12%) have died due to mast cell disease. A median survival time has not been reached. The median follow-up time is 660 days from the diagnosis of the first MCT. We conclude that MCT in pugs are relatively benign, despite the presence of multiple cutaneous tumours in most cases. Multiple tumours in breeds with predisposition to MCT may indicate separate primaries rather than advanced stage disease.

Vaccine-associated sarcomas in cats: a unique cancer model.

Epidemiologic evidence supports a relationship between vaccination of cats for rabies and feline leukemia virus with the development of soft tissue sarcomas at the site of administration. These tumors are locally invasive and histologically aggressive. As with high-grade soft tissue sarcoma in humans, combination treatment with radiation therapy and surgery provides for optimum tumor control. Feline vaccine-associated sarcoma has become a difficult issue for the veterinary profession for legal, ethical, and clinical reasons. Although most research efforts have focused on therapeutic intervention, this tumor has great potential to provide an informative model for carcinogenesis and genetic susceptibility applicable to cancer in all species, including humans.

Platelet function in dogs treated for lymphoma and hemangiosarcoma and supplemented with dietary n-3 fatty acids.

A prospective randomized, double-blind clinical trial was performed to test the hypothesis that dogs with malignancies that are supplemented with n-3 fatty acids do not have clinical or laboratory evidence of coagulation disorders or altered platelet function when compared with unsupplemented dogs with similar malignancies. Thirteen dogs with hemangiosarcoma and 66 dogs with lymphoma were evaluated. Coagulation status of the dogs with lymphoma and hemangiosarcoma was evaluated with prothrombin time, partial thromboplastin time, platelet count, and in vitro platelet aggregometry using the whole-blood method. These tests were performed at 5 time points: before beginning the diet (week 0), at weeks 3, 15, and 21, and at 1 year or when progressive disease was evident. Alterations in platelet function in dogs receiving a diet supplemented with dietary n-3 fatty acids were not identified when compared to dogs fed a control diet. Dietary n-3 fatty acid supplementation using this dosage and ratio in dogs with lymphoma or hemangiosarcoma did not induce clinically significant hemorrhage in these animals. Therefore, supplementation with n-3 fatty acids did not result in clinical or laboratory evidence relating to uncontrolled hemorrhage in these dogs.

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin.

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.

Principles of adjunctive radiation therapy.

Radiation therapy is becoming increasingly available to the practicing veterinarian. It is important that veterinarians be familiar with mechanisms and biologic effects of radiation used as a therapeutic modality in the treatment of cancer. It is also important that the veterinarian understand oncologic decision making and indications for various modalities including radiation therapy, surgery, and chemotherapy. Surgery and radiation therapy can be particularly complementary in combined therapy to achieve a functional and cosmetic result. This review introduces basic radiation therapy concepts, particularly regarding combination of radiation and surgery in the treatment of cancer in animals.

Evaluation of prognostic factors for dogs with primary lung tumors: 67 cases (1985-1992).

OBJECTIVE: To determine associations between clinical and histologic factors in dogs with primary lung tumors and outcome and to develop a histologic grading method for primary lung tumors. DESIGN: Retrospective study. ANIMALS: 67 dogs undergoing thoracotomy and lobectomy for primary lung tumors. PROCEDURE: Medical records and histologic sections were reviewed to evaluate factors of prognostic importance. Association of these factors with disease-free interval (DFI) and survival time was evaluated, using the Cox proportional hazards model. Median DFI and survival time were determined, using the Kaplan-Meier product-limit method. RESULTS: Clinical and histologic factors significantly associated with prognosis were histologic score, detection of clinical signs, and metastasis to regional lymph nodes. On the basis of histologic score, a histologic grading method was developed. Dogs with well-differentiated tumors had significantly longer survival time and DFI (median DFI, 493 days) than dogs with moderately (median DFI, 191 days) or poorly (median DFI, 0 days) differentiated tumors. Dogs with clinical signs or metastasis to regional lymph nodes had shorter survival times and DFI than dogs in which lung masses were discovered as an incidental finding. CLINICAL IMPLICATIONS: Dogs with well-differentiated, nonmetastasized, primary lung tumors that do not have clinical signs associated with the tumor have a favorable prognosis. Dogs with more advanced disease or aggressive tumors histologically may require treatment, such as chemotherapy in combination with surgery. The grading method proposed here for primary lung tumors may be useful in other dogs with primary lung tumors.

Platelet hyperfunction in dogs with malignancies.

In vitro platelet aggregometry was performed on whole blood samples from 59 dogs with malignancies and 24 control dogs. Three reagents were used for the aggregation studies: collagen, arachidonic acid, and adenosine diphosphate (ADP). The parameters measured to evaluate response to collagen included delay in the aggregation response, slope of the aggregation curve, maximum aggregation, and adenosine triphosphate (ATP) secretion. The platelets of dogs with malignancies exhibited significantly (P < .05) shorter delays in the aggregation response, higher maximum aggregation, and higher ATP secretion when compared to control dogs. For the weaker reagents, ADP and arachidonic acid, the lowest concentration resulting in aggregation was determined. Platelets of dogs with malignancies tended to aggregate in response to lower concentrations of ADP than did those of controls (P < .05). The response of platelets to the concentrations of arachidonic acid employed in this study was poor, with few samples achieving measurable aggregation. The findings of this study suggest that dogs with malignancies have hyperaggregable platelets.

Pheochromocytoma in dogs and cats.

Pheochromocytomas are endocrine tumors arising from chromaffin cells (pheochromocytes) of the adrenal glands in dogs and cats. The clinical symptomatology produced results from the direct presence and space-occupying nature of the tumor, or the secondary presence of excessive amounts of excreted catecholamines. Diagnosis and management of pheochromocytomas remain great challenges for veterinary clinicians. The diagnosis is based on the results of supporting routine lab evaluation, blood-pressure determinations, selected biochemical and pharmacologic tests, and a number of imaging techniques. Surgical extirpation continues to be the only definitive treatment for the pheochromocytoma. Medical therapy is used to stabilize the metabolic and cardiovascular states of the patient in a preoperative and surgical setting as well as to manage chronic long-term effects of excess catecholamines in patients with inoperable or metastatic disease.