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PurposeThe mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.Patients and methodsA total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.ResultsThere was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.ConclusionsIn a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Urothelial carcinoma (UC) is the most common urinary tumour in dogs. Despite a range of treatment options, prognosis remains poor in dogs. In people, breakthroughs with checkpoint inhibitors have established new standards of care for muscle‐invasive bladder cancer patients and elevated levels of programmed cell death protein 1 (PD‐1) suggest immune checkpoint blockade may be a novel target for therapy. The goal of this study was to determine if canine UC patients express elevated levels of lymphocyte‐specific PD‐1 and/or urinary cytokine biomarkers compared to healthy dogs. Paired blood and urine were evaluated in 10 canine UC patients, five cystitis patients and 10 control dogs for lymphocyte‐specific PD‐1 expression via flow cytometry and relative cytokine expression. In UC patients, PD‐1 expression was significantly elevated on CD8+ lymphocytes in urine samples. UC patients had a higher CD4:CD8 ratio in their urine compared to healthy dogs, however, there was no significant variation in the CD8:Treg ratio between any group. Cystitis patients had significantly elevated levels of CD4+ T cells, CD8+ T cells and Tregs in their blood samples compared to UC patients and healthy dogs. Cytokine analysis demonstrated significant elevations in urinary cytokines (granulocyte‐macrophage colony‐stimulating factor, interferon‐gamma [IFN‐γ], interleukin (IL)‐2, IL‐6 IL‐7, IL‐8 and IL‐15, IP‐10, KC‐like, IL‐18, monocyte chemoattractant protein‐1 and tumour necrosis factor‐alpha). Several of these cytokines have been previously correlated with both lymphocyte‐specific PD‐1 expression (IFN‐γ, IL‐2, IL‐7 and IL‐15) in muscle‐invasive urothelial carcinoma in humans. Our results provide evidence of urinary lymphocyte PD‐1 expression and future studies could elucidate whether veterinary UC patients will respond favourably to anti‐PD‐1 immune checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Veterinary Journal / Revue Vétérinaire Canadienne is the property of Canadian Veterinary Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Veterinary Journal / Revue Vétérinaire Canadienne is the property of Canadian Veterinary Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article offers information on the study conducted related to the evaluation of the ocular side effects of cancer-bearing dogs and cats treated with external-beam cobalt-60 radiation. It states that the main ocular side effect reported in both dogs and cats was conjunctivitis. It mentions that the animals showed the need for regular ophthalmic examinations as routine follow-up of radiation therapy.

The article discusses a study which sought to evaluate the laboratory methods to improve characterization of dogs diagnosed with von Willebrand disease (vWD). Using 183 clinically healthy canines, it investigated the value of additional tests such as platelet count and partial thromboplastin time (PTT) used in conjunction with the von Willebrand factor antigen enzyme-linked immunosorbent assay (ELISA). It concluded that the vWF:Collagen binding assay (vWF:CBA) was proven to be an important component of the vWD diagnostic profile.

: ObjectiveThe development of large-animal models for human hematopoiesis will facilitate the study of human hematopoietic stem cells and their progenitors in vivo. In previous studies, human hematopoietic progenitors engrafted in fetal dogs and contributed to hematopoiesis for one year. Despite initially high levels of human cells, the proportion declined to less than 0.1% at 6 months, possibly due to inability of the canine hematopoietic microenvironment to support ongoing human hematopoiesis. In the current experiments we examined the potential of co-transplanting fibroblasts expressing human hematopoietic cytokines with the hematopoietic graft to increase the contribution of human progenitors to chimeric hematopoiesis.: MethodsMid-gestation canine fetuses were injected with 1–3 × 107 human cord blood cells and 1 × 107 murine fibroblasts engineered to express human cytokines. Neonatal pups were boosted with additional injections of cytokine-expressing fibroblasts. Human cell engraftment was monitored by PCR amplification of human-specific DNA sequences from recipient hematopoietic tissues.: ResultsHuman hematopoietic cells were detected in 13/15 fetal recipients for at least 7 months. At time points up to 30 weeks of age, human DNA was detected in stimulated lymphocyte cultures, ∼0.1% of blood leukocytes and 1.5% (85/5757) of myeloid colonies. Eight months postinfusion, 1.7% of colony-forming units (CFUs) were of human origin. By one year 0.5% or less of myeloid colonies and less than 0.01% of blood leukocytes carried human DNA. Following an infusion of cytokine-expressing fibroblasts at one year, the proportion of human myeloid progenitors rose to 11.5% and remained detectable for 8 months.: ConclusionThese studies confirm that human hematopoietic progenitors can engraft in fetal pups and contribute to multilineage hematopoiesis. Infusion of cells expressing human cytokines is one approach to stimulate human hematopoietic progenitors in vivo and thus increase their contributions to chimeric hematopoiesis. [Copyright &y& Elsevier]

This retrospective study evaluated the outcomes of dogs with macroscopic pulmonary metastasis of appendicular osteosarcoma (OSA) treated with toceranib. Medical records of 20 dogs with macroscopic pulmonary metastasis of OSA that received toceranib were reviewed. The median dose and duration of toceranib administration were 2.52 mg/kg (range: 2.12 to 2.72 mg/kg) and 60 days (range: 17 to 231 days). The median progression free survival (PFS) and overall survival (OS) were 36 days (range: 17 to 231 days) and 90 days (range: 17 to 433 days), respectively. The clinical benefit rate was 10% (2/20; 1 partial response and 1 stable disease). The longest length of initial pulmonary nodules had significant impact on both PFS ( P = 0.01) and OS ( P = 0.02). The prognosis for dogs with metastatic OSA was poor with only 10% of dogs showing clinical benefit from toceranib. These results suggest that toceranib may not improve outcome in dogs with macroscopic pulmonary metastasis of OSA.

Sterile hemorrhagic cystitis (SHC) is an important complication of cyclophosphamide chemotherapy in dogs as it is reported in up to 23% of cases with various protocols. The current study reports toxicities of a protocol of metronomic cyclophosphamide, and identifies risk factors for development of adverse effects. A retrospective cohort study of dogs treated with metronomic cyclophosphamide at an intended dose of 25 mg/m 2 every other day was conducted. Fifty dogs were included with a median length of treatment of 90 days (range: 1 to 1305 days). Treatment was discontinued in 22 dogs (44%) due to adverse effects; 16 dogs (32%) developed SHC after a median time of 127.5 days (range: 54 to 1305 days). Higher cumulative dose was significantly associated with a higher risk of SHC development ( P = 0.048). Therefore, close monitoring and/or prophylactic treatments should be considered for patients receiving chronic metronomic cyclophosphamide therapy.

This retrospective study evaluated the ocular side effects of cancer-bearing dogs and cats treated with external-beam Cobalt-60 (Co-60) radiation in which one or both orbit(s) were included in the radiation field. A total of 37 dogs and 12 cats presented to the Ontario Veterinary College during the 10-year study period (1999-2009) were evaluated. The radiation protocols ranged from a maximum of 60 Gray (Gy) in 24 fractions for curative intent to a minimum of 8 Gy in 1 fraction for palliative treatment. The main ocular side effect reported in both dogs and cats was conjunctivitis (79% and 55%, respectively). Other common ocular side effects included eyelid lesions in dogs (44%), ulcerative keratitis in cats (36%), and keratoconjunctivitis sicca in both dogs and cats (44% and 27%, respectively). The high incidence of ocular side effects in both patient populations indicates a need for regular ophthalmic examinations as a component of routine follow-up for radiation therapy involving the orbit. Radiation damage to ocular tissues is also reviewed.

The objective of this study was to use a questionnaire 1) for characterization of hemorrhagic signs; 2) to assess its value as a predictor of von Willebrand Disease (vWD) status; and 3) for evaluation of the vWD diagnostic profile [platelet function analysis using the PFA-100, Collagen binding assay (vWF:CBA), and vWF antigen ELISA (vWF:Ag)], partial thromboplastin time (PTT) and Factor VIII activity (FVIII) as predictors of hemorrhagic risk. von Willebrand factor (vWF) concentration and function was assessed for each of the 165 canine participants using the vWD diagnostic profile. Hemorrhagic signs for each dog were obtained using a standardized questionnaire. Questionnaires were scored according to a previously prepared scoring key. Of the 165 dogs in the study, 43.6% had a low vWF concentration, with only 48.6% of dogs in this group having reports of hemorrhagic signs. Oral bleeding was the most commonly reported sign. The questionnaire had a sensitivity of 48.6% and a specificity of 78.5% for the prediction of vWD status. Using the Spearman correlation coefficient, a statistical association was found between the questionnaire and the vWD diagnostic profile components. However, this could not be translated into an ability to predict hemorrhage. The questionnaire allowed characterization of hemorrhagic signs in a large population of dogs over a range of vWF:Ag concentrations, and demonstrated that the vWD diagnostic profile was unsuccessful in the prediction of hemorrhagic risk. Although the sensitivity was insufficient for a screening tool, the questionnaire did have some discriminatory power in the prediction of vWD status.