Intratumoral collagen signatures predict clinical outcomes in feline mammary carcinoma.

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.

Metronomic Chemotherapy for Myxosarcoma Treatment in a Kori Bustard (Ardeotis kori).

A 22-year-old, wild-caught male kori bustard (Ardeotis kori) developed a large, slow-growing subcutaneous mass over the keel. The mass was surgically debulked and histopathologically described as a myxosarcoma. Surgical dehiscence and concurrent local tumor regrowth, with no evidence of metastasis, occurred over the subsequent 3 months, necessitating 2 additional surgical procedures to close the wound. At 19 weeks after the initial procedure, a second debulking surgical procedure was performed, at which time carboplatin-impregnated matrix beads were placed in the lesion. Moderate local tumor regrowth was clinically appreciable 4 weeks after surgery, at which time an oral metronomic chemotherapeutic protocol consisting of daily cyclophosphamide (10 mg/m(2)) and meloxicam (0.1 mg/kg) was initiated. Four months later, the tumor was no longer palpable. While oral therapy was discontinued during the breeding season, mass regrowth was observed, and the mass was surgically debulked before reinitiating oral chemotherapy. Treatment was extended for over 1 year with no hematologic evaluation or serum biochemical abnormalities, and the bird otherwise remained clinically healthy. To our knowledge, this is the first report of a myxosarcoma in a bustard species and the first report of successful clinical application of metronomic chemotherapy in an avian species.

Outcome and toxicity assessment of feline small cell lymphoma: 56 cases (2000-2010).

Feline small cell lymphoma is associated with greater response to treatment and survival when compared to large cell lymphoma. Treatment-associated toxicity, response to rescue chemotherapy and prognostic factors are largely unknown. This retrospective study was performed to identify treatment-associated toxicity, response to rescue chemotherapy and treatment outcome for cats diagnosed with small cell lymphoma of various anatomic locations. Medical records from 56 cats were evaluated. All cats were treated with glucocorticoid and chlorambucil with discontinuation of treatment recommended at 1 year if complete clinical response was documented. Chemotherapy toxicity was uncommon (33.9%) and generally mild. Grade III or IV hepatotoxicity was documented in 10.7% of patients. Overall response rate was 85.7% with glucocorticoid and chlorambucil. Median progression-free survival was 1078 days. Overall response rate for rescue chemotherapy was 59%. Reintroduction of prednisone and chlorambucil was associated with significantly longer survival than prednisone and lomustine (>1500 vs. 492 days, P = 0.01). Median overall survival times for cats with lymphoma of the gastrointestinal tract was not significantly different from those with extra-intestinal disease locations (1148 vs. 1375 days, P = 0.23). Median overall survival was 1317 days. Toxicity, other than hepatotoxicity was mild. Rescue chemotherapy with re-introduction of glucocorticoids and chlorambucil was most successful. Discontinuation of glucocorticoid and chlorambucil with subsequent reintroduction as rescue chemotherapy appears to be just as effective as continued administration in cats.

Activation of the Ras-ERK pathway inhibits retinoic acid-induced stimulation of tissue transglutaminase expression in NIH3T3 cells.

Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase) expression, and it was recently shown that phosphoinositide 3-kinase (PI3K) activity was required for RA to increase TGase protein levels. To better understand how RA-mediated TGase expression is regulated, we considered whether co-stimulation of NIH3T3 cells with RA and epidermal growth factor (EGF), a known activator of PI3K, would facilitate the induction or increase the levels of TGase expression. Instead of enhancing these parameters, EGF inhibited RA-induced TGase expression. Activation of the Ras-ERK pathway by EGF was sufficient to elicit this effect, since continuous Ras signaling mimicked the actions of EGF and inhibited RA-induced TGase expression, whereas blocking ERK activity in these same cells restored the ability of RA to up-regulate TGase expression. However, TGase activity is not antagonistic to EGF signaling. The mitogenic and anti-apoptotic effects of EGF were not compromised by TGase overexpression, and in fact, exogenous TGase expression promoted basal cell growth and resistance to serum deprivation-induced apoptosis. Moreover, analysis of TGase expression and GTP binding activity in a number of cell lines revealed high basal TGase GTP binding activity in tumor cell lines U87 and MDAMB231, indicating that constitutively active TGase may be a characteristic of certain cancer cells. These findings demonstrate that TGase may serve as a survival factor and RA-induced TGase expression requires the activation of PI3K but is antagonized by the Ras-ERK pathway.