Histiocytic sarcoma is a round-cell neoplasm associated with a poor prognosis in dogs. Advances in veterinary pathology and immunohistochemical techniques have enabled identification of the putative cell of origin and have resulted in the reclassification of HS in dogs.1,2 Currently, there are 3 recognized clinical manifestations of HS. Hemophagocytic HS is thought to arise from macrophages of the splenic red pulp and bone marrow and is definitively diagnosed by positive CD18 and CD11d antibody immunohistochemical staining. Clinically, it is characterized by diffuse splenomegaly, regenerative anemia, thrombocytopenia, hypoalbuminemia, and hypocholesterolemia. Hemophagocytic HS follows a rapidly progressive clinical course despite treatment; the reported MST is approximately 7 weeks.1 Localized HS and disseminated HS are thought to arise from myeloid dendritic antigen-presenting cells. The 2 are morphologically and immunohistochemically identical, with positive staining results for CD18 and CD11c antibodies and negative results for CD11d antibodies, but are distinguished on the basis of clinical presentation.2 Localized HS appears to arise from a single site, typically Objective-To evaluate and compare the outcomes of dogs with periarticular histiocytic sarcoma (PAHS) and histiocytic sarcoma of other anatomic locations (non-PAHS) and identify factors associated with outcome for dogs with PAHS. Design-Retrospective cohort study. Animals-19 dogs with PAHS and 31 dogs with non-PAHS. Procedures-Medical records of dogs with histiocytic sarcoma that underwent definitive local treatment (surgery or radiation), chemotherapy, or a combination of these were reviewed. Patient signalment, clinical signs, staging test results, clinicopathologic data, type of treatment, response, and outcome were collected, and potential risk factors in dogs with PAHS were identified and analyzed for an association with outcome. Results-Dogs with PAHS lived significantly longer than did dogs with non-PAHS, with an overall median survival times of 391 (range, 48 to 980) and 128 (range, 14 to 918) days, respectively, despite the presence of suspected metastasis at diagnosis in 13 of 19 dogs with PAHS. Dogs with PAHS without evidence of metastasis at diagnosis lived significantly longer than did dogs with PAHS with evidence of metastasis, with median survival times of 980 (range, 83 to 980) and 253 (range, 48 to 441) days, respectively. Administration of prednisone in dogs with PAHS was associated with a significantly shorter time to tumor progression (TTP) and increased risk of tumor progression and death. Conclusions and Clinical Relevance-Results indicated that dogs with PAHS may have a favorable outcome independent of metastatic status when treated with chemotherapy or aggressive multimodal treatment. The concurrent administration of prednisone may be a negative predictive factor for survival time and TTP in dogs with PAHS. (J Am Vet Med Assoc 2011;239:90-96) involving the lung, skin, subcutaneous tissues, bones, or joints.2-6 Disseminated...

The evaluation of therapeutic response using cross-sectional imaging techniques, particularly gadolinium-enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the Response Evaluation Criteria in Solid Tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging-based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and Response Assessment in Neuro-oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment-induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy-induced changes. Finally, although objective endpoints such as MR-imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.

. Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol 288: G473-G480, 2005; doi:10.1152/ajpgi.00223.2004.-The success of liver grafts is currently limited by the length of time organs are cold preserved before transplant. Novel insights to improve viability of cold-stored organs may emerge from studies with animals that naturally experience low body temperatures (T b) for extended periods. In this study, we tested whether livers from hibernating ground squirrels tolerate cold ischemia-warm reperfusion (cold I/R) for longer times and with better quality than livers from rats or summer squirrels. Hibernators were used when torpid (T b Ͻ 10°C) or aroused (Tb ϭ 37°C). Livers were stored at 4°C in University of Wisconsin solution for 0 -72 h and then reperfused with 37°C buffer in vitro. Lactate dehydrogenase (LDH) release after 60 min was increased 37-fold in rat livers after 72 h cold I/R but only 10-fold in summer livers and approximately three-to sixfold in torpid and aroused hibernator livers, despite twofold higher total LDH content in livers from hibernators compared with rats or summer squirrels. Reperfusion for up to 240 min had the least effect on LDH release in livers from hibernators and the greatest effect in rats. Compared with rats or summer squirrels, livers from hibernators after 72 h cold I/R showed better maintenance of mitochondrial respiration, bile production, and sinusoidal lining cell viability, as well as lower vascular resistance and Kupffer cell phagocytosis. These results demonstrate that the hibernation phenotype in ground squirrels confers superior resistance to liver cold I/R injury compared with rats and summer squirrels. Because hibernation-induced protection is not dependent on animals being in the torpid state, the mechanisms responsible for this effect may provide new strategies for liver preservation in humans. transplantation; cold storage; Kupffer cells; sinusoidal lining cells DESPITE MAJOR ADVANCES IN hypothermic preservation of organs before transplant, problems associated with extended cold ischemia-reperfusion (cold I/R) injury still limit the optimal use of transplantation as a therapeutic intervention for organ failure. For example, human livers can be successfully stored at 4°C for up to 12 h in University of Wisconsin (UW) solution, but graft failure is greatly increased after extended storage periods (14,33,34). In the rat liver transplant model, when livers are cold stored in UW for up to 24 h, 100% of the recipients survive (42); in contrast, without nutritional manipulation, none survive after receiving livers stored for 48 h (39).The damaging effects of cold I/R are evident on organ reperfusion with warmed, oxygenated blood, with damage increasing with the length of the cold ischemia period (10,35,40).A variety of pharmacological strategies has been explored to improve graft function after cold I/R to extend cold storage times and provide more flexibility in organ distribut...

The 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 Methods: A total of 324 pet dogs diagnosed with treatment-na€ ve 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 AE 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.Results: There 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 þ sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.Conclusions: In 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.

Introduction: Histotripsy is a non-invasive focused ultrasound therapy that uses controlled acoustic cavitation to mechanically disintegrate tissue. To date, there are no reports investigating histotripsy for the treatment of soft tissue sarcoma (STS). Objective: This study aimed to investigate the in vivo feasibility of ablating STS with histotripsy and to characterize the impact of partial histotripsy ablation on the acute immunologic response in canine patients with spontaneous STS. Methods: A custom 500 kHz histotripsy system was used to treat ten dogs with naturally occurring STS. Four to six days after histotripsy, tumors were surgically resected. Safety was determined by monitoring vital signs during treatment and posttreatment physical examinations, routine lab work, and owners' reports. Ablation was characterized using radiologic and histopathologic analyses. Systemic immunological impact was evaluated by measuring changes in cytokine concentrations, and tumor microenvironment changes were evaluated by characterizing changes in infiltration with tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) using multiplex immunohistochemistry and differential gene expression. Results: Results showed histotripsy ablation was achievable and well-tolerated in all ten dogs. Immunological results showed histotripsy induced pro-inflammatory changes in the tumor microenvironment. Conclusion & Significance: