Acute manganese toxicosis related to joint health supplement ingestion in two dogs.

Two unrelated dogs residing in the same house including an 11-year-old, female spayed, mixed breed dog and a 7-year-old, female spayed, mixed breed dog ingested approximately 75 capsules of a human joint health supplement (Ligaplex I; Standard Process, WI, USA). A total of 2,062 mg of manganese was ingested between both dogs. Dog 1 developed acute fulminant liver failure and a severe coagulopathy that led to hepatic fractures and exsanguination from hemoabdomen. The estimated maximum time from ingestion of the joint health supplement to death was 36 to 48 h. Histologic examination revealed severe periportal hepatic necrosis with mild evidence of preexisiting liver disease and renal tubular epithelial necrosis. Manganese concentrations in liver and kidney tissue were severely increased. Dog 2 developed a severe acute liver injury and was hospitalized for 6 days. Therapies provided during hospitalization included intravenous fluids, maropitant, pantoprazole, N-acetylcysteine, vitamin C, S-adenosylmethionine, and silybin. The dog was treated long-term with S-adenosylmethionine, silybin, ursodiol, and vitamin C. Clinical and biochemical resolution occurred on the recheck examination that took place on day 44. The veterinary literature is comprised of only 2 reports containing 3 dogs that describe acute manganese intoxication. Here, we provide a detailed description of 2 dogs that developed manganese-induced toxicosis after ingestion of a human joint health supplement.

MAMMARY GLAND ADENOCARCINOMA IN FOUR INDIAN CRESTED PORCUPINES (HYSTRIX INDICA).

Neoplasia in porcupines is rarely reported in the literature, and the prevalence is unknown. A retrospective review of records from a private zoo diagnostic pathology service found four cases of mammary adenocarcinoma in Indian crested porcupines (Hystrix indica) from four separate zoological institutions. All cases presented in geriatric females (14-19 yr of age) as freely movable subcutaneous masses within the mammary chain. None of the individuals had additional clinical signs, radiographic, or hematologic changes at initial presentation. All cases were managed with surgical excision in the form of either an excisional biopsy or a partial mastectomy. Histologic examination diagnosed all tumors with anaplasia and moderate to high numbers of mitotic figures. Two cases required subsequent surgeries for management of local recurrence in the years following initial diagnosis. One case is 19 months postsurgical removal without evidence of metastasis or local recurrence. Two of the cases were euthanized after diagnosis of inoperable metastases to the lungs and spinal cord, including one previously treated with an oral nonsteroidal antiestrogen medication, tamoxifen. The third case was euthanized due to degenerative mobility changes and renal dysfunction and had no evidence of metastasis. The average survival time from initial surgical excision to euthanasia for the three applicable cases was 33 months. These cases suggest that surgical excision alone may result in temporary management of mammary adenocarcinoma in this species. Metastasis can occur, and routine screening with advanced imaging may aid in early detection of these lesions.

Rhinoscopic Appearance and Clinical Features of a Nasal Transmissible Venereal Tumor in a Dog.

A 2-year-old male neutered mixed breed dog was referred for evaluation of left-sided unilateral epistaxis and mucoid discharge following adoption from Mexico 2 months prior to presentation. Computed tomography (CT) showed soft tissue that filled the entirety of the left nasal passage with mild turbinate loss. Subsequent rhinoscopy revealed multifocal patches of discrete, white, wispy, vascularized abnormal tissue in the left nasal cavity. Cytology and histopathology procured with rhinoscopic-guidance were suspicious for transmissible venereal tumor (TVT). Confirmation of a TVT diagnosis was made with polymerase chain reaction for the long interspersed element inserted upstream of the c-myc gene. The dog was treated with 4 cycles of vincristine (0.5 mg/m2, IV, once every 7 days) with complete and sustained resolution of clinical signs shortly after the third cycle. Nasal TVT in dogs is an uncommon presentation of a neoplasm that primarily results in genital or oral lesions. There is a void in the veterinary literature regarding the rhinoscopic appearance, as well as limited clinical descriptions of nasal TVT. Therefore, the objectives of this report were to provide a detailed description of the rhinoscopic appearance of a canine nasal TVT, in addition to clinical features, diagnostic findings, CT imaging, and successful therapeutic management.

Targeting Obesity-Induced Macrophages during Preneoplastic Growth Promotes Mammary Epithelial Stem/Progenitor Activity, DNA Damage, and Tumor Formation.

Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women. SIGNIFICANCE: Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophage-targeted therapies.

Obesity reduces mammary epithelial cell TGFß1 activity through macrophage-mediated extracellular matrix remodeling.

Obesity is a risk factor for breast cancer in postmenopausal and high-risk premenopausal women. Changes within the obese breast microenvironment may increase breast cancer risk. Transforming growth factor beta-1 (TGFß1) is a major regulator of mammary epithelial stem/progenitor cells, and its activity is dysregulated under conditions of obesity. Using a high-fat diet model of obesity in mice and breast tissue from women, we observed that TGFß1 activity is reduced in breast epithelial cells in obesity. Breast ducts and lobules demonstrated increased decorin in the extracellular matrix (ECM) surrounding epithelial cells, and we observed that decorin and latent TGFß1 complexed together. Under conditions of obesity, macrophages expressed higher levels of decorin and were significantly increased in number surrounding breast epithelial cells. To investigate the relationship between macrophages and decorin expression, we treated obese mice with either IgG control or anti-F4/80 antibodies to deplete macrophages. Mice treated with anti-F4/80 antibodies demonstrated reduced decorin surrounding mammary ducts and enhanced TGFß1 activity within mammary epithelial cells. Given the role of TGFß1 as a tumor suppressor, reduced epithelial TGFß1 activity and enhanced TGFß1 within the ECM of obese mammary tissue may enhance breast cancer risk.

Obesity-Activated Adipose-Derived Stromal Cells Promote Breast Cancer Growth and Invasion.

Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.

Obesity reversibly depletes the basal cell population and enhances mammary epithelial cell estrogen receptor alpha expression and progenitor activity.

BACKGROUND: Obesity is correlated with an increased risk for developing postmenopausal breast cancer. Since obesity rates continue to rise worldwide, it is important to understand how the obese microenvironment influences normal mammary tissue to increase breast cancer risk. We hypothesized that obesity increases the proportion of luminal progenitor cells, which are thought to be the cells of origin for the most common types of breast cancer, potentially leading to an increased risk for breast cancer. METHODS: To study the obese microenvironment within the mammary gland, we used a high-fat diet mouse model of obesity and human breast tissue from reduction mammoplasty surgery. We identified changes in breast epithelial cell populations using flow cytometry for cell surface markers, in vitro functional assays and expression of markers on breast tissue sections. RESULTS: In both obese female mice and women, mammary epithelial cell populations demonstrated significant decreases in basal/myoepithelial cells, using either flow cytometry or cell-type-specific markers (SMA and p63). Estrogen receptor alpha (ERα) expression was significantly increased in luminal cells in obese mammary tissue, compared with control mice or breast tissue from lean women. Functional assays demonstrated significantly enhanced mammary epithelial progenitor activity in obese mammary epithelial cells and elevated numbers of ERα-positive epithelial cells that were co-labeled with markers of proliferation. Weight loss in a group of obese mice reversed increases in progenitor activity and ERα expression observed in obese mammary tissue. CONCLUSIONS: Obesity enhances ERα-positive epithelial cells, reduces the number of basal/myoepithelial cells, and increases stem/progenitor activity within normal mammary tissue in both women and female mice. These changes in epithelial cell populations induced by obesity are reversible with weight loss. Our findings support further studies to examine how obesity-induced changes in stem/progenitor cells impact breast tumor incidence and histologic tumor types.

Bilateral Uveitis and Hyphema in a Catalina Macaw (Ara ararauna × Ara macao ) With Multicentric Lymphoma.

A 20-year-old, female Catalina macaw (Ara ararauna × Ara macao ) was presented with bilateral uveitis and hyphema. The hyphema initially improved with 0.12% prednisolone acetate ophthalmic drops (1 drop OU q4h for 7 days), but the hyphema recurred after the drops were tapered. The bird subsequently developed inappetance, weight loss, regurgitation, and lethargy and was euthanatized 24 days after initial presentation. Necropsy revealed marked splenomegaly and hepatomegaly, with significant mucosal ulcerations of the proventriculus and petechiation associated with both kidneys. Histopathologic examination revealed multicentric lymphoma, with neoplastic cells observed in ocular, splenic, hepatic, renal, proventricular, intestinal, pancreatic, and choanal tissue. Neoplastic lymphocytes effaced the iris, ciliary body, and the choroid of the eyes, and neoplastic lymphocytes were attached to the corneal endothelium and infiltrated the sclera, episclera, and conjunctivae. Immunohistochemical results indicated that the neoplastic lymphocytes were CD3(+) and CD79a(-), which is consistent with T-cell lymphoma.

Diagnosis and surgical treatment of a malignant trichoepithelioma of the ear canal in a pet rabbit (Oryctolagus cuniculus).

CASE DESCRIPTION: A 10-year-old spayed female Holland Lop-mix pet rabbit (Oryctolagus cuniculus) was evaluated because of purulent-hemorrhagic discharge from the right ear canal and a suspected mass within that ear canal. CLINICAL FINDINGS: Results of contrast-enhanced CT, video otoscopy, and histologic examination of endoscopic tissue biopsy samples indicated severe otitis media and externa and a benign trichoepithelioma of the right ear canal. TREATMENT AND OUTCOME: Total ear canal ablation and lateral bulla osteotomy were performed. Histologic examination of a surgical biopsy sample of the mass indicated malignant trichoepithelioma. Tumor recurrence was detected 22 weeks after surgery. The rabbit was euthanized 33 weeks after surgery because of the large size of the recurrent tumor and declining quality of life. Necropsy findings indicated a malignant trichoepithelioma with local and lymphatic invasion into the right mandibular lymph node. CLINICAL RELEVANCE: This was the first report of the clinical diagnosis, surgical treatment, and outcome for a domestic rabbit with a diagnosis of a malignant trichoepithelioma of the ear canal and associated otitis media and externa. Neoplasia should be included as a differential diagnosis for pet rabbits with otitis externa and media. Although such tumors are typically benign, trichoepitheliomas in rabbits can be malignant. Computed tomography and histologic examination of tissue samples were useful diagnostic techniques, but histologic examination of an endoscopic biopsy sample did not allow identification of malignant characteristics of the trichoepithelioma.

Imaging diagnosis-pulmonary-tracheobronchial prolapse in a new Caledonian giant gecko (Rhacodactylus leachianus).

A 3-year-old male New Caledonian giant gecko, or Leach's gecko (Rhacodactylus leachianus) presented with acute lethargy and coelomic distention. Findings from survey radiographs and an upper gastrointestinal tract contrast study were consistent with severe aerophagia, a collapsed left lung, and hyperinflation of the right lung due to suspected bronchial obstruction. The gecko was treated with conservative medical management, but was found dead 5 days after presentation. Necropsy findings showed intussusception of the proximal left lung into the left mainstem bronchus and trachea.

Intramedullary lumbosacral teratoma in a domestic ferret (Mustela putorius furo).

An 18-month-old, female, spayed domestic ferret (Mustela putorius furo) was presented for progressive hind limb paresis of 1 week duration. The ferret was mentally appropriate but cachexic and ataxic with neurological deficits, which localized the lesion to the lumbosacral region. A depression in the lumbosacral spine was associated with discomfort on palpation. Results of whole body radiographs were consistent with an abnormal angle between vertebrae L6 and S1, which resulted in hyperflexion of the spine. The ferret was euthanized, and histopathological examination revealed an intramedullary lumbosacral teratoma effacing much of the spine in the region of the mass.

A novel locus for canine osteosarcoma (OSA1) maps to CFA34, the canine orthologue of human 3q26.

Spontaneous tumors in dogs share many of the same features of their human orthologues including clinical behavior, response to treatment, and molecular defects. It is therefore natural to consider the use of dogs and their spontaneous malignancies in the study of complex disease such as cancer. Scottish Deerhounds are a giant breed of dogs that exhibit a high incidence of bone cancer. Our previous work suggested that osteosarcoma within this breed could be explained by the presence of a major gene of dominant effect. Herein, we use a whole genome mapping approach to evaluate a four-generation pedigree of Scottish Deerhounds for linkage of their osteosarcoma phenotype. Using this approach we found evidence of linkage (Z(max)=5.766) between their phenotype and markers located on CFA34, in a region syntenic to human chromosome 3q26. The identification of this locus provides novel insight into the genetic basis of osteosarcoma in both canines and humans.