Tolerability and pharmacokinetic profile of a novel benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride in dogs with malignant mammary tumours.

The pharmacokinetic profile, tolerability and efficacy of benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) were studied in dogs with mammary cancer. A three-level response surface pathway designed trial was performed on seven dogs. At each level BP-C1 was administered subcutaneously daily for 7 days followed by a 7-day rest period in a dose escalating manner. Adverse events according to VCOG-CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two-compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half-life was 125 h. The maximum tolerated dose of BP-C1 was estimated to be above 0.46 mg kg-1 . A significant reduction in VCOG-CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours.

Renal microcystic tubular lesions in two 1Year-old dogs - an early sign of hereditary renal cystadenocarcinoma?

As a part of a study of early renal changes in renal cystadenocarcinoma (RC), a 5-year-old German shepherd dog and two 1-year-old German shepherd mixed-breed dogs were examined. All three animals had bilateral, microscopic renal cysts, and the 5-year-old dog also had RC. Microscopical examination showed papillary hyperplastic tubular epithelial cells lining the inner wall of the renal cysts in all dogs. These cells showed strong reactivity with a monoclonal antibody against a broad-spectrum type of cytokeratin. The dam of the young dogs had suffered from autosomal dominant inherited RC and nodular dermatofibrosis (ND) syndrome. It is likely that the microscopic renal cystic lesions seen in the young dogs represented an early renal change in the RC/ND syndrome. This suggests that the diagnosis of RC can be made on suspected carriers by microscopical examination of renal biopsies as early as 1 year of age, i.e., before the dogs are used for breeding.

Effect of ovariohysterectomy at the time of tumor removal in dogs with benign mammary tumors and hyperplastic lesions: a randomized controlled clinical trial.

BACKGROUND: Nonmalignant mammary tumors (NMT) are common in intact female dogs. Little is known about the clinical significance of these tumors, and the effect of ovariohysterectomy (OHE) on their development. HYPOTHESIS: Ovarian hormone ablation through OHE decreases the risk of new tumors and thereby improves long-term prognosis for dogs with NMT. ANIMALS: Eighty-four sexually intact bitches with NMT. METHODS: Dogs were allocated to undergo OHE (n = 42) or not (n = 42) at the time of NMT removal in a randomized clinical trial. Tumor diagnosis was confirmed histologically in all subjects. Information about new tumor development was collected via follow-up phone calls and recheck examinations. Separate survival analyses were performed with the endpoints new tumor development and death. Cause of death was classified as related or unrelated to mammary tumor. In addition to OHE status, the influence of age, body weight, breed, tumor size, tumor number, tumor duration, type of surgery, and tumor histology was investigated. RESULTS: New mammary tumor(s) developed in 27 of 42 (64%) intact dogs and 15 of 42 (36%) ovariohysterectomized dogs (hazard ratio 0.47, P = .022). Nine of the 42 dogs (21%) which developed new tumors were euthanized because of mammary tumor. Survival was not significantly different between the 2 treatment groups. In the intact group, nine dogs subsequently developed ovarian-uterine diseases. CONCLUSION: Ovariohysterectomy performed at the time of mammary tumor excision reduced the risk of new tumors by about 50% among dogs with NMT. Survival was not significantly affected. Adjuvant OHE should be considered in adult dogs with mammary tumors.

Chromosomal assignment of canine TSC2, PKD1 and CLN3 genes by radiation hybrid- and linkage analyses.

The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).

Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs.

Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs. Genetic linkage analysis of an RCND-informative pedigree has identified a linkage group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05. 771-[RCND-CPH18]-C02608-GLUT4-TP53-ZuBe Ca6-AHT141-FH2140-FH2594) thus localizing the disease to a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (theta) of 0.016, supported by a logarithm of odds score of 16.7. C02608 and the adjacent linked markers map to a region of the canine genome corresponding to portions of human chromosomes 1p and 17p. A combination of linkage analysis and direct sequencing eliminate several likely candidate genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor suppressor gene TP53. These data suggest that RCND may be caused by a previously unidentified tumor suppressor gene and highlight the potential for canine genetics in the study of human disease predisposition.

Five new linkage groups in the canine linkage map.

Nineteen further polymorphic loci were typed on the DogMap reference panel. Five new linkage groups were identified. Additionally, five markers were added to earlier defined linkage groups. Three of the new linkage groups contain markers mapped earlier to specific dog chromosomes by physical mapping. These results make a further contribution to the canine genome map and provides more linkage groups physically assigned to known chromosomes.

Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases.

BACKGROUND: There is a clear and growing need for data regarding BRCA1 and BRCA2 mutation frequencies among breast carcinoma cases not specifically ascertained on the basis of extreme family history profiles. Toward this end, the authors previously reported results with regard to BRCA1 in breast carcinoma patients drawn from a population-based study. In the current study the authors present new findings concerning BRCA2 mutation frequency in this same population, as well as summary data regarding the combined contribution of these two genes. METHODS: Subjects were drawn from two population-based, case-control studies of breast carcinoma in young women conducted in western Washington State and focused on 1) women diagnosed with breast carcinoma before age 35 years (n = 203); and 2) women with a first-degree family history of breast carcinoma who were diagnosed before age 45 years (n = 225). Similarities and differences between BRCA2 carriers and BRCA1 carriers were analyzed in terms of age at diagnosis, family history status, and disease features. RESULTS: Of cases diagnosed before age 35 years, all of whom were unselected for family history, 9.4% carried germline mutations (3.4% for BRCA2 and 5.9% for BRCA1). Of cases diagnosed before age 45 years who had a first-degree family history of breast carcinoma, 12.0% carried germline mutations (4.9% for BRCA2 and 7.1% for BRCA1). Increased frequencies of mutations were observed in cases with a personal or family history of early age at diagnosis and in those with four or more family members affected with breast carcinoma. BRCA2 mutations were less common than BRCA1 mutations in families with any history of ovarian carcinoma. CONCLUSIONS: Overall, given current constraints on health care resources, these data suggest that screening for germline mutations in these breast carcinoma susceptibility genes may have the greatest impact on overall health care if it is prioritized toward high and moderate risk populations.