Survival time for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone: the Canine Lymphoma Steroid Only trial.

OBJECTIVE: To evaluate survival times for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone. ANIMALS: 109 client-owned dogs recruited from 15 institutions in the United States. PROCEDURES: Dogs were treated with prednisone at a dosage of 40 mg/m2, PO, once daily for 7 days and at a dosage of 20 mg/m2, PO, once daily thereafter. Quality of life (QOL) was assessed by owners with a visual analog scale when treatment was started (day 0), 1 and 2 weeks after treatment was started, and every 4 weeks thereafter. The primary outcome of interest was survival time as determined by the Kaplan-Meier method. Factors potentially associated with survival time were examined. RESULTS: Median overall survival time was 50 days (95% CI, 41 to 59 days). Factors associated with survival time included substage (a vs b) and immunophenotype (B cell vs T cell). Owner-assigned QOL scores on days 0 and 14 were significantly positively correlated with survival time. When QOL score was dichotomized, dogs with day 0 or day 14 QOL scores ≥ 50 had significantly longer survival times, compared with dogs with day 0 or day 14 QOL scores < 50. No variables were predictive of long-term (> 120 days) survival. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that survival times were short for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone. Owner-perceived QOL and clinician-assigned substage were both associated with survival time. Findings provide potentially important information for clinicians to discuss with owners of dogs with lymphoma at the time treatment decisions are made.

Value, Limitations, and Recommendations for Grading of Canine Cutaneous Mast Cell Tumors: A Consensus of the Oncology-Pathology Working Group.

One of the primary objectives of the Oncology Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects and provide guidelines for oncologic pathology. Consensus is established through review of relevant peer-reviewed literature relative to a subgroup's particular focus. In this article, the authors provide a critical review of the current literature for grading of canine cutaneous mast cell tumors, suggest guidelines for reporting, and provide recommendations for its clinical interpretation. The article mainly focuses on histologic grading, but relevant information on mitotic count and cytological grading are also discussed. This document represents the opinions of the working group and the authors but does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society.

Prognostic and predictive significance of KIT protein expression and c-kit gene mutation in canine cutaneous mast cell tumours: A consensus of the Oncology-Pathology Working Group.

One of the primary objectives of the Oncology-Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects of and provide guidelines for oncologic pathology. Consensus is established through critical review of peer-reviewed literature relevant to a subgroup's particular focus. Subsequent acceptance and approval of the document by the OPWG membership at large establishes consensus. The intent of this publication is to help educate practitioners and pathologists on the value of diagnostics related to the KIT receptor tyrosine kinase for canine cutaneous mast cell tumours and to provide a guide for the use of these tests in veterinary medicine. This document represents the opinions of the OPWG and the authors and does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society.

Primary appendicular hemangiosarcoma and telangiectatic osteosarcoma in 70 dogs: A Veterinary Society of Surgical Oncology retrospective study.

OBJECTIVE: To define and compare clinical characteristics of canine primary appendicular hemangiosarcoma (HSA) and telangiectatic osteosarcoma (tOSA), including signalment, presentation, response to treatment, and prognosis. STUDY DESIGN: Multi-institutional retrospective study. ANIMALS: Seventy dogs with primary appendicular HSA or tOSA. METHODS: Patient data were obtained from institutions' medical records. Immunohistochemistry was applied to archived tissues to establish tumor type. Patient characteristics, treatment responses, and outcomes were described and compared by tumor type. RESULTS: Forty-one HSA and 29 tOSA were identified. Dogs with HSA were more likely than dogs with tOSA to be male and have hind limb tumors; 78% of HSA occurred in hind limbs, particularly the tibia. Dogs with tOSA weighed a median of 9.9 kg (95% CI 4.6-15.3) more than dogs with HSA. Most dogs received antineoplastic treatment, predominantly amputation with or without adjuvant chemotherapy. Overall survival with local treatment and chemotherapy was 299 days (95% CI 123-750) for HSA and 213 days (95% CI 77-310) for tOSA. Younger age and more aggressive treatment were associated with longer survival in dogs with HSA but not tOSA. One-year survival rates did not differ between dogs with HSA (28%) and those with tOSA (7%). CONCLUSION: Distinct clinical features were identified between HSA and tOSA in this population. Both tumors were aggressive, with a high incidence of pulmonary metastases. However, local treatment combined with chemotherapy led to an average survival 7 months for tOSA and 10 months for HSA. CLINICAL SIGNIFICANCE: HSA should be considered as a differential in dogs with aggressive lytic bone lesions, particularly medium-sized dogs with tibial lesions. HSA has a unique clinical presentation but similar therapeutic response and outcome to OSA. Amputation and chemotherapy appear to prolong survival in some dogs with HSA and tOSA.

Standardizing Immunohistochemistry: A New Reference Control for Detecting Staining Problems.

A new standardized immunohistochemistry (IHC) control for breast cancer testing comprises formalin-fixed human epidermal growth factor receptor 2, estrogen receptor, or progesterone receptor peptide antigens covalently attached to 8-µm glass beads. The antigen-coated beads are suspended in a liquid matrix that hardens upon pipetting onto a glass microscope slide. The antigen-coated beads remain in place through deparaffinization, antigen retrieval, and immunostaining. The intensity of the beads' stain provides feedback regarding the efficacy of both antigen retrieval and immunostaining. As a first report, we tested the sensitivity and specificity of the new IHC controls ("IHControls"). To evaluate sensitivity, various staining problems were simulated. IHControls detected primary and secondary reagent degradation similarly to tissue controls. This first group of IHControls behaved similarly to tissue controls expressing high concentrations of the antigen. The IHControls were also able to detect aberrations in antigen retrieval, as simulated by sub-optimal times or temperatures. Specificity testing revealed that each antigen-coated bead was specific for its cognate IHC test antibody. The data support the conclusion that, like tissue controls, IHControls are capable of verifying the analytic components of an immunohistochemical stain. Unlike tissue controls, IHControls are prepared in large bulk lots, fostering day-to-day reproducibility that can be standardized across laboratories.

Outcome and prognostic factors for osteosarcoma of the maxilla, mandible, or calvarium in dogs: 183 cases (1986-2012).

OBJECTIVE: To describe the biological behavior, clinical outcome, and prognostic factors of osteosarcoma of the maxilla, mandible, or calvarium in dogs. DESIGN: Retrospective case series. ANIMALS: 183 client-owned dogs with osteosarcoma of the maxilla, mandible, or calvarium. PROCEDURES: Medical records for dogs treated for osteosarcoma of the maxilla, mandible, or calvarium from 1986 through 2012 were reviewed. Dogs with a histopathologic diagnosis of osteosarcoma and treated for a primary tumor arising from these bones of the head were included. RESULTS: Mean age was 9.3 years, and body weight was 31.8 kg (70.0 lb). Most dogs (124/183 [67.8%]) were purebred, and the most common primary tumor site was the maxilla (80 [43.7%]). Treatments included palliative medical treatment only (11/183 [6.0%]), coarsely fractionated radiation therapy (RT; 12 [6.6%]), fractionated or stereotactic RT (18 [9.8%]), surgery (135 [73.8%]), and both surgery and fractionated RT (7 [3.8%]). Eighty-three (45.4%) dogs received adjuvant chemotherapy. Local recurrence or progression occurred in 80 of 156 (51.3%) dogs, and 60 of 156 (38.5%) dogs developed distant metastases. Median survival time for all dogs was 239 days. Dogs that underwent surgery had a median survival time of 329 days. Histologically tumor-free surgical margins were associated with significantly decreased hazards of progression or recurrence (hazard ratio [HR], 0.4) and death (HR, 0.5). Dogs with osteosarcoma of the calvarium had a significantly greater hazard of local recurrence or progression (HR, 2.0). CONCLUSIONS AND CLINICAL RELEVANCE: In this study, tumor excision in dogs with histologically tumor-free margins resulted in better local control and longer survival time than did other treatment types.

Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma.

Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease.

Expression profiling in canine osteosarcoma: identification of biomarkers and pathways associated with outcome.

BACKGROUND: Osteosarcoma (OSA) spontaneously arises in the appendicular skeleton of large breed dogs and shares many physiological and molecular biological characteristics with human OSA. The standard treatment for OSA in both species is amputation or limb-sparing surgery, followed by chemotherapy. Unfortunately, OSA is an aggressive cancer with a high metastatic rate. Characterization of OSA with regard to its metastatic potential and chemotherapeutic resistance will improve both prognostic capabilities and treatment modalities. METHODS: We analyzed archived primary OSA tissue from dogs treated with limb amputation followed by doxorubicin or platinum-based drug chemotherapy. Samples were selected from two groups: dogs with disease free intervals (DFI) of less than 100 days (n = 8) and greater than 300 days (n = 7). Gene expression was assessed with Affymetrix Canine 2.0 microarrays and analyzed with a two-tailed t-test. A subset of genes was confirmed using qRT-PCR and used in classification analysis to predict prognosis. Systems-based gene ontology analysis was conducted on genes selected using a standard J5 metric. The genes identified using this approach were converted to their human homologues and assigned to functional pathways using the GeneGo MetaCore platform. RESULTS: Potential biomarkers were identified using gene expression microarray analysis and 11 differentially expressed (p < 0.05) genes were validated with qRT-PCR (n = 10/group). Statistical classification models using the qRT-PCR profiles predicted patient outcomes with 100% accuracy in the training set and up to 90% accuracy upon stratified cross validation. Pathway analysis revealed alterations in pathways associated with oxidative phosphorylation, hedgehog and parathyroid hormone signaling, cAMP/Protein Kinase A (PKA) signaling, immune responses, cytoskeletal remodeling and focal adhesion. CONCLUSIONS: This profiling study has identified potential new biomarkers to predict patient outcome in OSA and new pathways that may be targeted for therapeutic intervention.

Reconstruction of chest wall defects after rib tumor resection: a comparison of autogenous, prosthetic, and composite techniques in 44 dogs.

OBJECTIVE: To compare short- and long-term outcome and complications of chest wall reconstruction in dogs using autogenous, prosthetic, and composite autogenous-prosthetic techniques. STUDY DESIGN: Historical cohort. ANIMALS: Dogs (n=44) with spontaneous tumors arising from or involving the chest wall. METHODS: Medical records were reviewed for dogs with rib and/or sternal tumors treated by chest wall resection and reconstruction. Signalment, preoperative clinical features, intraoperative findings and complications, reconstruction technique (autogenous muscle flap, prosthetic mesh, or composite autogenous-prosthetic technique), and short- (< or =14 days) and long-term (>14 days) postoperative complications were determined from the medical records and telephone contact with owners and referring veterinarians. Associations between chest wall reconstruction technique and postoperative complications were tested with Cox proportional hazards. RESULTS: Chest wall defects were reconstructed with autogenous muscle flaps (29 dogs), prosthetic mesh (3), and a composite technique of prosthetic mesh and either autogenous muscle or omental pedicle flap (12). Early postoperative complications were recorded in 8 dogs (18.2%) and included seroma (5) and pleural effusion and peripheral edema (3). One dog had a late complication (2.3%) with a mesh-related infection 767 days postoperatively. Overall, complications occurred in 10.3% of autogenous, 25.0% of composite, and 66.7% of prosthetic reconstructions. Chest wall reconstruction with Marlex mesh alone was associated with a significantly increased risk of postoperative complications compared with autogenous reconstruction (P=.027). Reconstruction of sternal defects (3), 2 of which were performed with Marlex mesh alone, was associated with a significantly increased risk of complications compared with lateral chest wall reconstructions (P=.037). CONCLUSIONS: Large chest wall defects can be reconstructed with autogenous and composite techniques, but prosthetic mesh should be covered with well-vascularized autogenous muscle or omentum to decrease the risk of postoperative complications. Sternal defects should be reconstructed with rigid techniques. CLINICAL RELEVANCE: Chest wall reconstruction with autogenous muscle flaps or a combination of autogenous techniques with prosthetic mesh is associated with a low rate of infection and other complications.

Oncologic outcome after curative-intent treatment in 39 dogs with primary chest wall tumors (1992-2005).

OBJECTIVE: To describe the clinical features and determine oncologic outcome and prognostic factors for dogs with primary tumors of the osseous chest wall. STUDY DESIGN: Historical cohort. ANIMALS: Dogs (n=39) with spontaneous tumors involving the chest wall. METHODS: Medical records were reviewed for dogs with rib and/or sternal tumors treated by chest wall resection and reconstruction. Signalment, preoperative clinical features, reconstruction technique, and oncologic outcome (local tumor recurrence, metastasis, and survival time) were determined from medical records and by telephone contact with owners and referring veterinarians. Oncologic outcome and prognostic factors were determined using Kaplan-Meier survival analysis and Cox proportional hazards. Logistic regression was used to determine if increased serum alkaline phosphatase (ALP) concentration was associated with tumor type. RESULTS: Of the 39 dogs with tumors arising from the chest wall, 25 had osteosarcoma, 12 had chondrosarcoma, and 2 dogs had hemangiosarcoma. Median survival time (MST) for dogs with rib osteosarcoma was 290 days. Increased activity of total ALP significantly decreased survival in dogs with osteosarcoma (210 days versus 675 days, P=.0035). MST for dogs with rib chondrosarcoma was not reached (mean 1301 days) and survival was significantly greater than all other types of rib tumors (P=.0321). CONCLUSION: Rib tumors should be resected with wide margins to decrease the risk of incomplete excision, because local tumor recurrence has a significant impact on the survival time. The prognosis for dogs with rib chondrosarcoma is very good, but guarded for other types of tumors. CLINICAL RELEVANCE: Osteosarcoma and chondrosarcoma are the most common primary tumors of the chest wall. Prognosis for dogs with primary rib chondrosarcoma is very good with surgery alone, but surgery and adjunctive chemotherapy is recommended for dogs with primary rib osteosarcoma and the prognosis remains guarded.

Fibropapilloma of the glans penis in a horse.

An 18-year-old Arabian stallion was presented for recent onset of stranguria. Physical examination of the distal portion of the glans penis revealed multiple, smooth, glistening, grayish-pink, variably sized, exophytic, nodular masses circumferentially surrounding the external urethral orifice. Partial penile amputation was performed, and the entire specimen was submitted for histological evaluation. Microscopically, the masses consisted of abundant amounts of loosely arranged fibrovascular stroma with low numbers of spindloid to stellate fibrocytes. The overlying epithelium was mildly to moderately hyperplastic with short anastomosing rete ridges (pseudoepitheliomatous hyperplasia). The lesion was diagnosed as fibropapilloma because of features similar to bovine penile fibropapilloma including anatomical location, gross appearance, and histological characteristics. A sarcoid was considered but negated as the lesion lacked the classical streaming and interlacing spindle cell population, "picket-fence" appearance at the epithelial interface, and long, thin, dissecting rete ridges typical of most equine sarcoids. Polymerase chain reaction for the Bovine papillomavirus-1 and Bovine papillomavirus-2 E5 gene and for Equine herpesvirus 1, 3, and 4 was negative on formalin-fixed tissue specimens.

Evaluation of a flexible collagen surgical patch for reinforcement of a fascial defect: Experimental study in a sheep model.

There is a need for a surgical mesh that can be used in general surgical procedures for reinforcement or repair of soft tissue. Collagen based surgical meshes may possess the appropriate qualities. In this study, the potential of a collagen product BioBlanket Surgical Mesh to facilitate soft tissue repair in an ovine fascial defect model in vivo was evaluated. BioBlanket Surgical Mesh facilitated soft tissue repair in an ovine fascial defect model in vivo. Superficial fascial surgical sites were evaluated grossly, histologically, and mechanically at 6 and 12 week time points. BioBlanket Surgical Mesh and the predicate device Restore Orthobiologic Implant both performed favorably when implanted in superficial fascial defects compared with the negative control empty defect.