MicroRNAs as tumour suppressors in canine and human melanoma cells and as a prognostic factor in canine melanomas

Malignant melanoma (MM) is one of the most aggressive cancers in dogs and in humans. However, the molecular mechanisms of its development and progression remain unclear. Presently, we examined the expression profile of microRNAs (miRs) in canine oral MM tissues and paired normal oral mucosa tissues by using the microRNA‐microarray assay and quantitative RT‐PCR. Importantly, a decreased expression of miR‐203 was significantly associated with a shorter survival time. Also, miR‐203 and ‐205 were markedly down‐regulated in canine and human MM cell lines tested. Furthermore, the ectopic expression of miR‐205 had a significant inhibitory effect on the cell growth of canine and human melanoma cells tested by targeting erbb3. Our data suggest that miR‐203 is a new prognostic factor in canine oral MMs and that miR‐205 functions as a tumour suppressor by targeting erbb3 in both canine and human MM cells.     

Suspected uveal metastasis of a nail bed melanoma in a dog

A 13-year-old Golden Retriever was referred for evaluation of generalized corneal edema, dyscoria, and suspected glaucoma affecting the right eye. The dog exhibited no signs of systemic illness, but had a history of a melanoma of the nail bed of the first digit of the right hind limb, excised 1 year previously. Ophthalmologic examination revealed diffuse corneal edema, mild anterior uveitis, glaucoma and a mass within the right iris. Enucleation was performed and histopathologic evaluation of the globe revealed the iris to be infiltrated with an anaplastic melanoma, suspected to represent a metastasis of the original nail bed tumor.     

Proteases as prognostic markers in human and canine cancers

The extracellular matrix (ECM) is composed of several types of proteins, which interact and form dynamic networks. These components can modulate cell behaviour and actively influence the growth and differentiation of tissues. ECM is also important in several pathological processes, such as cancer invasion and metastasis, by creating favourable microenvironments. Proteolysis in neoplastic tissues is mediated by proteinases, whose regulation involves complex interactions between neoplastic cells and non‐neoplastic stromal cells. In this review, we discuss aspects of proteinase expression and tumor behaviour in humans and dogs. Different classes of proteases are summarized, with special emphasis being placed on molecules that have been shown to correlate with prognosis, reinforcing the need for a better understanding of the regulation of this microenvironment and its influences in tumor progression and metastasis, which should significantly aid the development of improved prognosis and treatment.     

Malignant anterior uveal melanoma with diffuse metastasis in a dog.

Enucleation was performed in 10-year-old sexually intact female mixed-breed German Shepherd Dog. Histologic examination revealed that the dog had an uveal amelanotic melanoma of the eye. The tumor consisted of anaplastic cells with a high mitotic index, indicating malignancy. On examination 3 months after enucleation, the dog had difficulty breathing and nasal discharge. Radiography revealed pulmonary metastasis. The dog was euthanatized. Necropsy revealed diffuse metastasis involving various organs.     

Suspected latent vertebral metastasis of uveal melanoma in a dog: a case report

A six-year-old intact male Pomeranian was examined because of right eye discomfort. An iris neoplasm was suspected and the eye was enucleated. A uveal melanoma with malignant features was diagnosed. The dog recovered uneventfully from surgery. A general physical examination was performed at 3-month intervals afterwards without any detectable problem, but 18 months after the first presentation the dog suffered a rapid, progressive paraplegia. Radiographic examination and myelography revealed a spinal cord compression at the level of the 8th thoracic (T8) vertebral body. Surgical exploration of the area revealed a potential vertebral neoplasm: histopathology confirmed a melanoma which was suspected to have resulted from metastasis from the previously diagnosed uveal melanoma.     

Histologic classification as a prognostic criterion for canine lymphosarcoma

Neoplastic tissues from 72 dogs with lymphosarcoma were histologically classified according to the Rappaport schema to determine if the histologic features of the disease had any clinical or prognostic importance. Of 72 dogs, lymphosarcomas in 7 were classified as nodular (9.7%) and 65 were classified as diffuse (90.3%). The two principal cytologic types were lymphocytic, poorly differentiated, and histiocytic, which composed 39% and 56% of the lymphosarcomas, respectively; whereas lymphocytic, well differentiated, mixed, and undifferentiated composed 6%. Clinically, all of the dogs were stage III or IV, according to the accepted criteria for canine lymphosarcoma. The overall complete remission rate was 64% and was defined as no clinical evidence of disease after 9 weeks of chemotherapy. Median remission among nodular histiocytic, diffuse lymphocytic, poorly differentiated, and diffuse histiocytic (DH) groups of dogs was 42 days, 29 days, and 42 days (range, 0 to 1,095), respectively. Median survival for the same groups was 235 days, 190 days, and 173 days (range, 1 to 1,261), respectively. A logarithmic analysis of variance revealed no significant differences among nodular histiocytic, diffuse lymphocytic, poorly differentiated, and DH groups relative to days remission, as well as to days survival. It was observed that those dogs with neoplasms classified as DH had longer remission durations. It would appear that for any one animal, histologic classification according to the Rappaport schema cannot be used as a prognostic criterion in predicting therapeutic response, remission, or survival.     

A scoping review of autoantibodies as biomarkers for canine autoimmune disease

BackgroundAutoantibody biomarkers are valuable tools used to diagnose and manage autoimmune diseases in dogs. However, prior publications have raised concerns over a lack of standardization and sufficient validation for the use of biomarkers in veterinary medicine.ObjectivesSystematically compile primary research on autoantibody biomarkers for autoimmune disease in dogs, summarize their methodological features, and evaluate their quality; synthesize data supporting their use into a resource for veterinarians and researchers.AnimalsNot used.MethodsFive indices were searched to identify studies for evaluation: PubMed, CAB Abstracts, Web of Science, Agricola, and SCOPUS. Two independent reviewers (AET and ELC) screened titles and abstracts for exclusion criteria followed by full‐text review of remaining articles. Relevant studies were classified based on study objectives (biomarker, epitope, technique). Data on study characteristics and outcomes were synthesized in independent data tables for each classification.ResultsNinety‐two studies qualified for final analysis (n = 49 biomarker, n = 9 epitope, and n = 34 technique studies). A high degree of heterogeneity in study characteristics and outcomes reporting was observed. Opportunities to strengthen future studies could include: (1) routine use of negative controls, (2) power analyses to inform sample sizes, (3) statistical analyses when appropriate, and (4) multiple detection techniques to confirm results.ConclusionsThese findings provide a resource that will allow veterinary clinicians to efficiently evaluate the evidence supporting the use of autoantibody biomarkers, along with the varied methodological approaches used in their development.     

An update on treatment and prognostic indicators in canine myxomatous mitral valve disease

Mitral regurgitation caused by myxomatous mitral valve disease is the most common cause for congestive heart failure and cardiac-related mortality in dogs. Typically, it takes several years for the disease to progress from mild, clinically silent myxomatous mitral valve disease to severe disease with signs of congestive heart failure. A proportion of dogs will never progress into congestive heart failure before they die from other causes or old age. Some variables have been shown to be predictive of onset of congestive heart failure and they might be useful to identify dogs that need more frequent monitoring and eventually treatment. Results from several controlled clinical trials are available concerning medical treatment of dogs with myxomatous mitral valve disease with or without congestive heart failure. These trials provide estimates of treatment effects and also allow identification of other variables with prognostic value for the outcome after the onset of congestive heart failure. Use of prognostic variables together with qualitative and quantitative results from clinical drug trials may aid the clinician and owner to plan and decide on optimal management of the myxomatous mitral valve disease dog. The purpose of this article is to review the current knowledge of prognostic variables and therapy for this common condition in dogs.     

Prognostic indicators for canine monocytic ehrlichiosis

In order to identify prognostic factors for survival in canine monocytic ehrlichiosis (CME), clinical records of 40 cases of CME were retrospectively studied. The dogs were assigned as survivors (n=21) and non-survivors (n=19), and their signalment, anamnesis, clinical and clinicopathological signs, and treatment protocols were compared. Pale mucous membranes, bleeding tendencies and weakness were more prevalent in the non-survivors compared to the survivors. Dogs in the non-survivor group had significantly lower white blood cell (WBC), hematocrit (HCT), and platelet (PLT) counts. Pronounced pancytopenia (WBC < 4 x 10(3) microL(-1); HCT < 25%; PLT < 50 x 10(3) microL(-1)) was found as a risk factor for mortality. In this study, severe leucopenia (WBC < 0.93 x 10(3) microL(-1)), severe anemia (PCV < 11.5%), prolonged activated partial thromboplastin time (APTT>18.25s) and hypokalemia (K<3.65 mmol/L) were each found to predict mortality with a probability of 100%. In contrast, WBC counts above 5.18 x 10(3) microL(-1), platelet counts above 89.5 x 10(3) microL(-1), PCV > 33.5%, APTT < 14.5s and serum potassium concentration above 4.75 mmol/L, each provided 100% prediction for survival. These prognostic indicators can be easily obtained at presentation, are inexpensive, and may be useful aids when treatment and prognosis are being considered.     

Evaluation of the use of chemotherapy and other prognostic variables for surgically excised canine thyroid carcinoma with and without metastasis

This retrospective study compared the efficacy of surgery alone versus surgery in combination with chemotherapy in the treatment of canine thyroid carcinoma; potential prognostic factors were evaluated. Forty-four dogs with biopsy-confirmed thyroid carcinoma met the inclusion criteria. Twenty-eight dogs were treated with surgery alone and 16 with surgery and chemotherapy. The median survival of dogs treated with surgery and chemotherapy was 518 d, which was not statistically different from that of the dogs treated with surgery alone. The number of thyroid lobes removed at surgery was prognostic with respect to survival. Despite an overall metastatic rate of 48%, the addition of chemotherapy to surgical excision did not improve survival; however, this finding may be due to inadequate power to demonstrate a difference.     

Comparative study of anti-oncogenic microRNA-145 in canine and human malignant melanoma

MicroRNA-145 (miRNA-145; miR-145) is aberrantly expressed in most of human cancers and plays a significant role in carcinogenesis and cancer progression. In the current study, we focused on how miR-145 plays a role in canine and human malignant melanomas. MiR-145 was significantly downregulated in canine malignant melanoma tissues and canine melanoma cell lines, as well as human melanoma cell lines tested. The ectopic expression of miR-145 showed a significant growth inhibition in both canine and human melanoma cells tested, and the effect was achieved partly by suppressing c-MYC in canine melanoma LMeC and in human melanoma A2058 and Mewo cells. At the same time, a suppressive tendency on cell migration in canine melanoma KMeC cells and significant suppression of cell migration in human melanoma A2058 cells by suppressing FASCIN1 were also found. These findings suggest that miR-145 acts as a tumor suppressor in both canine and human malignant melanomas.     

Assessment of corticosteroid-induced alkaline phosphatase as a prognostic indicator in canine lymphoma

OBJECTIVES: To examine the incidence of elevated corticosteroid-induced alkaline phosphatase (sALP) in dogs with lymphoma and to determine if sALP is a reliable prognostic indicator in canine lymphoma. METHODS: The medical records of 62 canine lymphoma patients treated with a combination chemotherapy protocol from 1994 to 2003 at the University of Illinois Veterinary Teaching Hospital were examined. Variables assessed with respect to response rate and remission duration included age, bodyweight, sex, breed, World Health Organization stage (I to V), substage (a or b), pretreatment administration of corticosteroid, and serum levels of alkaline phosphatase, sALP and alanine aminotransferase. RESULTS: sALP was not statistically significant with respect to response rate or duration of remission, nor was preinduction glucocorticoid administration. Stage was significant with respect to achieving remission. CLINICAL SIGNIFICANCE: It was found that sALP is not a useful prognostic indicator for response rate and remission duration in dogs with lymphoma.     

Quantification of plasma DNA as a prognostic indicator in canine lymphoid neoplasia

Dogs have a similar incidence of spontaneous cancers as people, and a noninvasive test to monitor disease status in dogs would be of great value. Humans with cancer often have increased levels of cell‐free circulating DNA in their plasma, which has shown promise for diagnosis, prognosis and detection of residual disease. We hypothesized that dogs with cancer have increased circulating DNA compared with healthy dogs or dogs with non‐neoplastic diseases. Plasma DNA was measured in 40 healthy dogs, 20 dogs with non‐neoplastic diseases and 80 dogs with cancer. The reference interval for plasma DNA in healthy dogs was 1–15 ng mL^?1. Dogs with lymphoma and lymphoid leukaemia had significantly higher concentrations (range: 0–91 ng mL^?1, P < 0.0001). Antigen receptor rearrangement assays suggest that plasma DNA had the same clonality as the primary lymphoid tumours. Dogs with lymphoid neoplasia and plasma DNA >25 ng mL^?1 had shorter remission times than those with < 25 ng mL^?1 (P= 0.0116). In contrast to humans, where increased plasma DNA is seen in many diseases, dogs with nonlymphoid malignancies and non‐neoplastic diseases had plasma DNA concentrations similar to healthy dogs. This study shows that a portion of dogs with lymphoid neoplasia have increased tumour‐derived plasma DNA, which serves as a negative prognostic indicator.     

Survival and prognostic indicators for cycad intoxication in dogs

Background: Cycad palms are commonly used in landscaping and ingestion by dogs can cause disease or death. Objectives: Determine the morbidity and case fatality of cycad palm toxicosis in dogs from Louisiana, and examine putative prognostic factors. Animals: Thirty‐four client‐owned dogs with confirmed cycad palm toxicosis between 2003 and 2010. Methods: Retrospective cohort study. Search of all medical records for animals with cycad palm toxicosis. Results: Seventeen of 34 (50%) dogs died or were euthanized as a direct consequence of cycad intoxication. There were no differences in presenting signs and physical examination findings between survivors and nonsurvivors. Nonsurvivors had higher serum alanine transaminase activity (median 196 U/L; range 16–4,123 versus 113.5; 48–1,530) and total bilirubin concentration (0.5 mg/dL; 0.1–6.2 versus 0.25; 0–1.7) upon presentation, and their initial serum concentrations of albumin (2.9 g/dL; 1.4–4.1 versus 3.3; 2.2–3.9) were lower than those of survivors. Nadir serum albumin concentration was also lower in nonsurvivors (1.9; 1.4–3.7 versus 3.2; 1.8–3.5). A higher proportion of nonsurvivors had prolonged coagulation times, prothrombin time. and partial thromboplastin time. In a multivariate model, administration of charcoal at initial presentation was associated with longer survival (heart rate [HR] 0.019, 95% CI 0.001–0.644), while high serum aspartate aminotransferase activity was a negative prognostic factor (HR 118.2, 95% CI 2.89–4,826). Conclusions and Clinical Importance: Cycad intoxication is associated with a higher case fatality than previously published. Several laboratory parameters might help differentiating potential nonsurvivors from survivors. Administration of charcoal as part of the emergency treatment appears to have a protective effect.