Canine Appendicular Osteosarcoma Research Articles

Prospective pilot study utilizing changes in quantitative values obtained on serial fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) in dogs with appendicular osteosarcoma before and after stereotactic body radiation therapy (SBRT) and carboplatin chemotherapy to assess for prediction of survival and therapeutic effectiveness.

Serial fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography-CT (PET/CT) is commonly used in human oncology to prognosticate and evaluate for therapeutic effectiveness. In this pilot study, dogs with naturally occurring appendicular osteosarcoma were evaluated with serial 18F-FDG PET/CT in an attempt to assess for response to therapy, prognostic factors, and appropriateness of imaging intervals. Fourteen dogs were enrolled in the trial. All dogs had the initial 18F-FDG PET/CT (PET1), with nine dogs having their end-of-therapy 18F-FDG PET/CT (EoT PET) 3 months after stereotactic body radiation therapy (SBRT) to the primary tumor. The median percent change from the PET1 to the EoT PET for the standard uptake value maximum (SUVmax%) was -58% (range: -17 to -88%), metabolic tumor volume (MTV%) was -99.8% (range: -65 to -100%), and total lesion glycolysis (TLG%) was -99.8% (range: -75 to -100%), all of which were significant (P<.05, <.05, and <.05, respectively). On evaluation, it was found that volumes of GTV and CTV were significant for survival (P<.05 and <.05), MTV1, TLG1, and SUVmax on the EoT PET (SUVmaxEoT) were predictive of metastasis (P<.05), and the SUVmax% was significantly correlated to the time to first event (P<.05). Based on this data, serial 18F-FDG PET/CT performed 3 months after SBRT can show a significant reduction in avidity, and the quantitative data collected may help predict metastatic disease in canine appendicular osteosarcoma.

Overall and relapse-free survival of dogs with appendicular osteosarcoma after limb-sparing bio-implantation treatment

Introduction. Canine osteosarcoma is a most common bone tumor in dogs, usually involving long tubular bones lesion. Limb-sparing treatment method allows to save extremity functionality and sufficiently improve quality of life in comparison with amputation.Aim. To analyze the survival rates and local results after limb-sparing treatment of canine osteosarcoma using bio-implantation – de-immunized allogenic bone populated with recipient stromal mesenchymal cell preparation.Materials and methods. Group of 25 dogs underwent a combined treatment including cisplatinum chemotherapy (60–70 mg/m2 intravenously infusion at 14–21 day intervals, up to 4 cycles) and wide segmental resection of the affected bone with a bioimplant defect replacement. Overall survival, progression-free survival and local recurrence frequency in the group were analyzed.Results. Overall survival median was 321 day, and progression-free median was 222 days. 4 (16,6 %) cases of local relapse were recorded, 2 of which were confirmed by radiography and histological examination, and 2 other by radiography only.Conclusion. Efficiency of the canine appendicular osteosarcoma combined limb-sparing treatment is comparable with amputation practice results (according to scientific literature) while foregoing method is preferable due to higher life quality of patients.

The Prognostic Role of Preoperative Hematological and Inflammatory Indices in Canine Appendicular Osteosarcoma.

Hematological indices play a prognostic role in human osteosarcoma (OSA), but data are limited in dogs. The aim of this retrospective multicentric cohort study was to investigate the prognostic significance of pre-operative hematological/inflammatory indices in a cohort of client-owned dogs with appendicular OSA receiving standardized treatment. Cut-offs associated with progression-free survival (PFS) for pre-operative hematological values/ratios were established using the minimal p-value approach. Historical prognostic factors were also assessed. Statistical analyses were performed for the whole population and after the exclusion of sighthounds. Fifty-nine dogs were included (13 were sighthounds). Multivariable analysis revealed that a low neutrophil count (<4.37 × 109/L, HR0.28, CI 95% 0.13-0.61, p = 0.001), a high red blood cell count (≥7.91, HR3.5, CI 95% 1.56-7.9, p = 0.002), and a proximal humerus location (HR3.0, CI 95% 1.48-6.1, p = 0.002) were associated with shorter PFS. In the sighthound-only population, only OSA location was significantly associated with PFS in univariable analysis. When sighthounds were excluded, a low neutrophil count, a low monocyte count, and a proximal humerus location were associated with shorter PFS, in multivariable analysis. Neutrophil count and possibly monocyte and red blood cell counts can be useful prognostic markers in canine OSA treated with amputation and adjuvant carboplatin. However, not all indices are appropriate in sighthounds.

Exploring the prognostic significance of new vessel formation and its relationship with CD44 and hypoxic factors immunoexpression in canine appendicular osteosarcoma

Exploring the prognostic significance of new vessel formation and its relationship with CD44 and hypoxic factors immunoexpression in canine appendicular osteosarcoma

Canine appendicular osteosarcoma: Amputation and chemotherapy in cancer treatment

Osteosarcoma is a malignant bone neoplasm with a high incidence in adult and giant breed dogs, with the appendicular skeleton being the most affected compared to the axial one. The symptoms usually present are claudication, swelling and may or may not be associated with episodes of fractures. The diagnosis consists of imaging exams, and in many cases, confirmation is only possible through bone biopsy. Due to aggressiveness the prognosis is unfavorable, and the best treatment for this case is limb amputation, with the intention of removing the primary tumor. The dog, in this report, was diagnosed by bone biopsy, whose histopathological result was osteoblastic osteosarcoma. The tumor originated in the distal femur of the left pelvic limb and the patient was referred for amputation, the surgical technique used was coxofemoral disarticulation. As an adjuvant treatment, chemotherapy with carboplatin was instituted. There were fivw sessions in an interval of 21 in 21 days, without reaction or alterations in the complementary exams. Pulmonary macro metastases were not identified in the radiographic examination, and a disease-free interval was observed, guaranteeing quality of life for the patient, despite being a very aggressive tumor.

Configuration of pathologic fractures in dogs with osteosarcoma following stereotactic body radiation therapy: A retrospective analysis.

For some cases of canine appendicular osteosarcoma (OSA), limb-sparing treatment options are often desired, one of which is stereotactic body radiation therapy (SBRT). A major complication of SBRT is fracture of the irradiated bone at the site of treatment. The present study evaluated 127 appendicular OSA sites in 122 dogs treated with SBRT to identify the most common pathologic fracture locations and configurations. A total of 50 tumours experienced a pathologic fracture, and 38 had imaging sufficient to identify fracture configuration. The distal tibia was more likely to develop a fracture than other sites. Multiple types of fracture configuration (transverse, oblique, spiral and comminuted) were observed. The distal radius was significantly more likely to develop a transverse fracture than other sites. Documentation of fracture location and configuration leads to the identification of the forces contributing to fracture occurrence, since each configuration is a result of different forces acting on each affected bone. Such knowledge is imperative for the development of new approaches to diminish the occurrence of pathologic fractures.

Prognostic significance of the urokinase plasminogen activator system in tissue and serum of dogs with appendicular osteosarcoma.

Urokinase plasminogen activator (uPA) and its receptor uPAR promote cancer invasion and metastasis and are emerging therapeutic targets in both human and canine malignancies. While their clinical significance is well-characterized in multiple human tumor types, studies investigating their roles in osteosarcoma are lacking. The objectives of this study were to characterize serum and tissue uPA/uPAR expression in dogs with osteosarcoma and assess the prognostic significance. Serum samples and a tissue microarray of canine appendicular osteosarcoma were analyzed for uPA and uPAR expression by ELISA (n = 49) and immunohistochemistry (n = 38), respectively. Serum uPA activity was also measured by a chromogenic assay (n = 25). Survival analysis was performed by Kaplan-Meier survival analysis, log rank test, and Cox regression analysis. Serum uPA level was significantly higher in dogs with osteosarcoma than clinically healthy control dogs (median 1905 vs 1440 pg/ml, p = 0.008). The majority of canine osteosarcoma tissues expressed uPA (75.9%) or uPAR (77.6%), with 70.7% dual-positivity, indicating autocrine/paracrine activation of the pathway. Survival analysis revealed shorter progression free survival (PFS) in dogs with high serum uPA level in a discovery cohort (n = 29; median PFS 94 vs 266 days, p = 0.003) but not in a validation cohort (n = 23; median PFS 167 vs 490 days, p = 0.16). The difference was significant when both cohorts were combined (n = 49; median PFS 128 vs 266 days, p = 0.003). Serum uPAR and tissue uPA/uPAR levels were not prognostic. In Cox multivariate analysis, high serum uPA level and activity were both associated with poor prognosis, independent of serum ALP, tumor location, and peripheral lymphocyte/monocyte counts. These results indicate high utilization of the uPA pathway and association with disease progression in canine osteosarcoma. Further study involving prospective evaluation to confirm the prognostic significance is warranted. The high prevalence of tissue uPA and uPAR expression suggests the uPA system as a potential therapeutic target in canine osteosarcoma.

Retrospective Evaluation of Outcome in Dogs With Appendicular Osteosarcoma Following Hypofractionated Palliative Radiation Therapy With or Without Bisphosphonates: 165 Cases (2010-2019).

ObjectiveTo report the survival times in dogs that received a standardized palliative-intent radiation therapy (RT) protocol for the treatment of canine appendicular osteosarcoma (OSA), alone or in combination with bisphosphonates (BPs), and to determine whether the addition of BPs affects survival. A secondary objective was to identify prognostic features that may influence outcome in dogs undergoing treatment.DesignRetrospective case series.Materials and MethodsDogs with presumed or confirmed OSA of the appendicular limb treated with daily hypofractionated RT (8 Gy x 2) at the Flint Animal Cancer Center between 2010 and 2019 were evaluated retrospectively. Clinical data were abstracted from the medical records, and adjuvant therapies were noted. Outcome was assessed using medical records and electronic follow up.ResultsOne hundred and sixty-five dogs were included. Sixty-eight dogs received BPs as a part of their palliative-intent treatment. The median survival time from first RT treatment to death was not significantly different between groups (119 vs. 109 days for BP and non-BP groups, respectively, p = 0.758). Only age (>9 years) was found to be prognostic in this population (p = 0.031). Factors that were not found to be associated with survival time included BP drug type, timing of BP administration, tumor location, weight, breed, sex, time to treatment, concurrent administration of chemotherapy, and salvage amputation.ConclusionsThis study suggests no difference in outcome for dogs treated with and without BPs in addition to hypofractionated RT. Prospective studies are needed to determine if the addition of BPs to hypofractionated RT leads to an improved quality of life in dogs undergoing palliative-intent treatment for OSA.

Fracture rate and time to fracture in dogs with appendicular osteosarcoma receiving finely fractionated compared to coarsely fractionated radiation therapy: A single institution study.

BackgroundRadiation therapy (RT) is used for local pain alleviation in dogs with appendicular osteosarcoma (OS), especially among dogs that are poor surgical candidates for amputation. However, many historical reports of fractionated protocols lack time to fracture and fracture rates.ObjectivesThe primary objectives of this retrospective study were to determine fracture rate and time to fracture of dogs receiving RT (coarse or fine fractionated) for appendicular OS. Secondary objectives were to evaluate tolerability and disease outcome measures.MethodsFifty‐one dogs that received RT as part of treatment for appendicular OS were available for evaluation. Forty‐five received coarse fractionation (C‐RT, 8 or 6 Gy per fraction protocols [C‐RT8 or C‐RT6]) while the remaining six received fine fractionation (F‐RT).ResultsThe overall pathologic fracture rate was 37%. Pathologic fracture rate was significantly higher for dogs that received F‐RT (5/6, 83%) compared to dogs that received C‐RT (12/40, 30%, p = 0.021). In the 17 dogs that fractured, the overall median time to fracture was 57 days. For all dogs, the median progression free interval (PFI) and median overall survival time (OST) were 90 and 140 days, respectively. In a very small cohort of dogs (n = 7) treated with zoledronate and RT, fracture rate was 0% and extended survival times were noted.ConclusionsIn conclusion, C‐RT is recommended over F‐RT due to lower risk of pathologic fracture and similar PFI. Prospective evaluation of combined C‐RT and zoledronate, especially for dogs with poor surgical candidacy, is warranted for the treatment of canine appendicular osteosarcoma.

Comparative Evaluation of Nutraceuticals (Curcuma longa L., Syzygium aromaticum L. and Olea europaea) with Single-agent Carboplatin in the Management of Canine Appendicular Osteosarcoma

Background: Canine appendicular osteosarcoma (OSA) is the most common bone malignancy in dogs. Methods: Spontaneous cases of canine OSA presented for three years were treated with different standard therapeutic protocols and compared with a novel plant formulations or nutraceuticals prepared from combination of turmeric, clove and olive oil. Different diagnostic modalities like survey and three view thoracic radiograph, abdominal ultrasonography (USG) with spectral Doppler USG, greyscale USG, strain elastography, fine needle aspiration cytology (FNAC), computed tomography and excisional biopsy were used to detect appendicular OSA and for staging of the primary bone tumor.Result: Canine bone tumor of appendicular OSA primarily affects large breed dogs with median age 10.32 years (range, 2.6-13 years) and median body weight 32.95 kg (range, 14-41 kg). Among four treatment groups, disease-free interval (DFI) and overall survival times were longer in groups of amputation followed by carboplatin as adjuvant chemotherapy (9 no.) than in groups with neoadjuvant chemotherapy with carboplatin followed by amputation (2 no.) and amputation along with nutraceuticals treatment (6 no.) and were shorter in the control group with amputation alone (6 no.). Herbal nutraceuticals can be included in the therapeutic regimen of canine osteosarcoma for increasing the overall survival time.

Feasibility and safety of whole lung irradiation in the treatment of canine appendicular osteosarcoma.

Whole lung irradiation (WLI) has been used successfully in humans as an adjuvant treatment for osteosarcoma. The aim of this study is to describe the feasibility and safety of WLI in dogs with appendicular osteosarcoma. Twelve client‐owned dogs with appendicular osteosarcoma that had successfully completed amputation and four doses of carboplatin without evidence of gross metastasis were enrolled in this prospective clinical trial. Ten once‐daily fractions of 1.75 Gy were administered to the planning target volume encompassing the lungs. Overall, WLI was well tolerated in these patients. No dogs developed symptoms of pneumonitis or pulmonary fibrosis. Haematopoietic toxicity evaluated during radiation therapy was found to be mild. The median disease free interval for WLI treated dogs was not significantly different than the median DFI for a group of historic control dogs (376 days for WLI treated dogs versus 304.5 days for control dogs; p = 0.5461). Although no significant improvement in outcome was observed with this study, WLI appears to be safe in dogs and warrants further investigation to characterize the efficacy and toxicity.

Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches.

Osteosarcoma is a rare disease in children but is one of the most common cancers in adult large breed dogs. The mutational landscape of both the primary and pulmonary metastatic tumor in two dogs with appendicular osteosarcoma (OSA) was comprehensively evaluated using an automated whole genome sequencing, exome and RNA-seq pipeline that was adapted for this study for use in dogs. Chromosomal lesions were the most common type of mutation. The mutational landscape varied substantially between dogs but the lesions within the same patient were similar. Copy number neutral loss of heterozygosity in mutant TP53 was the most significant driver mutation and involved a large region in the middle of chromosome 5. Canine and human OSA is characterized by loss of cell cycle checkpoint integrity and DNA damage response pathways. Mutational profiling of individual patients with canine OSA would be recommended prior to targeted therapy, given the heterogeneity seen in our study and previous studies.

Outcome and prognosis for canine appendicular osteosarcoma treated with stereotactic body radiation therapy in 123 dogs.

Canine appendicular osteosarcoma is commonly treated with limb amputation; however, limb-sparing options are frequently desired or necessary for a subset of patients. We evaluated 123 patients and 130 sites treated with stereotactic body radiation therapy (SBRT). Eighty-two out of 98 dogs (84%) had maximum lameness improvement at a median of 3 weeks for a median of 6 months duration. Histopathologic evaluation of available samples from amputation or necropsy revealed >80% tumor necrosis in 50% of limbs consistent with local disease control. Of evaluable patients, 41% fractured and 21% pursued an amputation after treatment. Fine needle aspirate (n=52) and needle core biopsy (n=28) did not result in increased fracture risk compared to those without tumor sampling (n=50). Median survival time (MST) was 233 days and time to first event was 143 days. Gross tumor volume and planned target volume were significantly inversely associated with survival and tumor location was significantly associated with survival. Dogs with salvage amputation had a significantly longer MST compared to those without (346 vs 202 days; P=.04). The presence of metastatic disease at the time of treatment in 15 dogs did not significantly impact survival time (200 vs 237 days without metastasis; P=.58). Skin side effects correlated significantly with dose with 33% of patients with acute grade 3 effects developing consequential late grade 3 effects. While SBRT improves lameness in most patients, further investigation is needed to identify candidates with minimal early fracture risk prior to initiating therapy.

Prevalence and potentially prognostic value of C-circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma.

Alternative lengthening of telomeres (ALT) is a telomerase‐independent telomere maintenance mechanism (TMM) with high prevalence in human osteosarcomas but remains unknown in canine osteosarcomas. The aim of this study was to evaluate the prevalence of ALT by detection of extra‐chromosomal circles of telomeric DNA and to assess clinical outcome in canine patients with spontaneous occurring appendicular osteosarcoma. Fifty dogs with histopathological confirmed osteosarcomas were included into this study. Medical records were retrospectively analysed for patient characteristics, oncologic therapy and survival. DNA was isolated from archived FFPE tumour tissue specimens and applied for C‐ and G‐circle assay (CCA and GCA) and for telomeric content (TC) measurement with radiolabeled probes. ALT activity was detected for 10 of 50 (20%) cases by CCA. Four CCA positive cases were detected even with input DNA below 1 ng and demonstrated the high sensitivity of CCA for canine tumours. G‐circles and TC were not suitable to distinguish CCA positive and negative cases. CCA‐status showed an association with male gender and Rottweiler breed. Dogs with CCA positive osteosarcomas had shorter overall survival times than patients with CCA‐tumours and CCA‐status was a significant prognostic factor besides treatment in the Cox proportional hazard model. These findings make canine osteosarcomas an interesting model for comparative TMM research, but future studies are warranted to investigate if CCA‐status can serve as novel prognostic marker.

Clinical significance and in vitro cellular regulation of hypoxia mimicry on HIF-1α and downstream genes in canine appendicular osteosarcoma

Cellular adaptation to a hypoxic microenvironment is essential for tumour progression and is largely mediated by HIF-1α and hypoxia-regulated factors, including CXCR4, VEGF-A and GLUT-1. In human osteosarcoma, hypoxia is associated with resistance to chemotherapy as well as with metastasis and poor survival, whereas little is known about its role in canine osteosarcoma (cOSA). This study aimed primarily to evaluate the prognostic value of several known hypoxic markers in cOSA. Immunohistochemical analysis for HIF-1α, CXCR4, VEGF-A and GLUT-1 was performed on 56 appendicular OSA samples; correlations with clinicopathological features and outcome was investigated. The second aim was to investigate the in vitro regulation of markers under chemically induced hypoxia (CoCl2). Two primary canine osteosarcoma cell lines were selected, and Western blotting, immunofluorescence and qRT-PCR were used to study protein and gene expression.Dogs with high-grade OSA (35.7%) were more susceptible to the development of metastases (P = 0.047) and showed high HIF-1α protein expression (P = 0.007). Moreover, HIF-1α overexpression (56%) was correlated with a shorter disease-free interval (DFI; P = 0.01), indicating that it is a reliable negative prognostic marker. The in vitro experiments identified an accumulation of HIF-1α in cOSA cells after chemically induced hypoxia, leading to a significant increase in GLUT-1 transcript (P = 0.02). HIF-1α might be a promising prognostic marker, highlighting opportunities for the use of therapeutic strategies targeting the hypoxic microenvironment in cOSA. These results reinforce the role of the dog as a comparative animal model since similar hypoxic mechanisms are reported in human osteosarcoma.

Prognostic significance of circulating microRNA-214 and -126 in dogs with appendicular osteosarcoma receiving amputation and chemotherapy

BackgroundDogs with appendicular osteosarcoma (OSA) receiving standard amputation and adjuvant chemotherapy demonstrate variable outcome with treatment; however, additional biomarkers would be helpful for predicting their outcome. In the present study, we assessed the potential of circulating microRNA-214 (miR-214) and − 126 (miR-126) to predict time to metastasis and death in dogs with OSA treated with amputation and chemotherapy.ResultsSeventy-six dogs that fully met inclusion criteria were included in the analysis. The criteria included (1) a diagnosis of appendicular OSA without metastases at diagnosis, (2) treatment by amputation and chemotherapy using carboplatin, doxorubicin, cisplatin, or a combination of these agents. Circulating miR-214 and -126 levels at the time before treatment were measured by using RT-qPCR. High circulating miR-214 and serum alkaline phosphatase (ALP) significantly predicted short disease-free survival (DFS) and overall survival (OS). Conversely, high circulating miR-126 significantly predicted prolonged DFS and OS. An integrated approach using circulating miR-214, − 126, and serum ALP showed better accuracy in the prediction of DFS and OS and identification of long-term survivors than prediction using only ALP. Other variables (age, weight, sex, monocyte counts, and primary tumor site) were associated with neither DFS nor OS. miRNA levels did not strongly correlate with histopathological indices.ConclusionsCirculating miR-214, − 126, and an integrated prognostic score have strong potential to predict the outcome of canine appendicular OSA patients receiving amputation and chemotherapy.

An evaluation of TAZ and YAP crosstalk with TGF\u03b2 signalling in canine osteosarcoma suggests involvement of hippo signalling in disease progression

BackgroundOsteosarcoma (OSA) is the most common bone cancer in canines. Both transforming growth factor beta (TGFβ) and Hippo pathway mediators have important roles in bone development, stemness, and cancer progression. The role of Hippo signalling effectors TAZ and YAP has never been addressed in canine OSA. Further, the cooperative role of TGFβ and Hippo signalling has yet to be explored in osteosarcoma. To address these gaps, this study investigated the prognostic value of TAZ and YAP alone and in combination with pSmad2 (a marker of active TGFβ signalling), as well as the involvement of a TGFβ-Hippo signalling crosstalk in tumourigenic properties of OSA cells in vitro. An in-house trial tissue microarray (TMA) which contained 16 canine appendicular OSA cases undergoing standard care and accompanying follow-up was used to explore the prognostic role of TAZ, YAP and pSmad2. Published datasets were used to test associations between TAZ and YAP mRNA levels, metastasis, and disease recurrence. Small interfering RNAs specific to TAZ and YAP were utilized in vitro alone or in combination with TGFβ treatment to determine their role in OSA viability, proliferation and migration.ResultsPatients with low levels of both YAP and pSmad2 when evaluated in combination had a significantly longer time to metastasis (log-rank test, p = 0.0058) and a longer overall survival (log rank test, p = 0.0002). No similar associations were found for TAZ and YAP mRNA levels. In vitro, TAZ knockdown significantly decreased cell viability, proliferation, and migration in metastatic cell lines, while YAP knockdown significantly decreased viability in three cell lines, and migration in two cell lines, derived from either primary tumours or their metastases. The impact of TGFβ signaling activation on these effects was cell line-dependent.ConclusionsYAP and pSmad2 have potential prognostic value in canine appendicular osteosarcoma. Inhibiting YAP and TAZ function could lead to a decrease in viability, proliferation, and migratory capacity of canine OSA cells. Assessment of YAP and pSmad2 in larger patient cohorts in future studies are needed to further elucidate the role of TGFβ-Hippo signalling crosstalk in canine OSA progression.

The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

Dogs diagnosed with appendicular osteosarcoma typically succumb to metastatic disease within a year of diagnosis. The current standard of care for curative intent, amputation followed by adjuvant chemotherapy, increases survival time but chemoresistance is a major contributor to mortality. Unfortunately, the mechanisms driving the progression of metastatic disease and the development of chemoresistance are unknown. One theory is that autophagy may contribute to chemoresistance by providing neoplastic cells with a mechanism to survive chemotherapy treatment. Our objective was to evaluate the effect of combining an autophagy inhibitor with a standard chemotherapeutic drug on response to chemotherapy in canine appendicular osteosarcoma cells. We hypothesized that combining the autophagy inhibitor spautin-1 with doxorubicin treatment would enhance chemoresponsiveness. Using commercial (D17) and primary cell lines derived from 1° and 2° sites of osteosarcoma, we showed that this combination treatment enhances cell killing and inhibits colony formation. Our findings support the theory that autophagy contributes to chemoresistance in canine appendicular osteosarcoma and indicate that adding an autophagy inhibitor to the standard of care has the potential to improve outcome.

Effect of surgical site infection on survival after limb amputation in the curative-intent treatment of canine appendicular osteosarcoma: a Veterinary Society of Surgical Oncology retrospective study.

To determine the influence of surgical site infection (SSI) on the median disease-free interval (DFI) and median survival time (MST) in dogs after amputation in the curative-intent treatment of appendicular osteosarcoma (OSA). Multi-institutional retrospective cohort study. Fifteen dogs with OSA and SSI, and 134 dogs with OSA and no SSI. Medical records were reviewed, and dogs were included if the following criteria were met: histologic confirmation of OSA, no evidence of metastasis, ≥1 chemotherapy treatment, and available follow-up data. We used the definition of SSI from the Centers for Disease Control and Prevention. Kaplan-Meier estimates of median DFI and MST for the SSI and non-SSI groups were compared by log-rank test. Univariate and multivariate Cox proportional hazard regression analysis was evaluated for associations with DFI and survival. The median DFI and MST of all OSA dogs were 236 days (95% CI, 181-283) and 283 days (95% CI 237-355), respectively. The median DFI of dogs with SSI (292 days) did not differ from that of dogs without SSI (224 days, P = .156). The MST of dogs with SSI (292 days) did not differ from that of dogs without SSI (280 days, P = .417). Failure to complete chemotherapy was associated with decreased DFI and survival (P < .001). Adjustments for chemotherapy completion found no effect of SSI on survival. SSI did not influence the survival of dogs with appendicular OSA treated with amputation and curative-intent treatment. The extended survival associated with SSI after limb-spare surgery for OSA does not appear to be present after amputation. Interactions between the canine immune system and OSA warrant additional study.

Histologic Grade Does Not Predict Outcome in Dogs with Appendicular Osteosarcoma Receiving the Standard of Care.

Canine appendicular osteosarcoma is an aggressive bone neoplasm that imposes a short survival time. There are several published histologic grading systems for canine osteosarcoma but no universally accepted system. Location within the skeleton and therapy received are both correlated with survival time, but these factors were not always considered when the prognostic value of published grading systems was determined. Our objective was to compare 2 published histologic grading systems in a population of dogs with appendicular osteosarcoma treated with the standard of care for curative intent. Three evaluators graded 85 tumors using 2 histologic grading systems. The relationships between histologic grade as well as individual histologic features and outcome (survival time and disease-free interval) were evaluated using Kaplan-Meier survival functions and a univariate Cox proportional hazards model. Histologic grade, as assigned by any evaluator, did not correlate with outcome. Increased number of mitotic figures per 3 randomly selected 400× microscope fields, as assessed by 1 evaluator, was correlated with both survival time and disease-free interval; this was the only individual histologic feature that was significantly correlated with outcome for any evaluator. These findings cast doubt on the predictive value of routine histologic grading in dogs with appendicular osteosarcoma who receive amputation followed by adjuvant chemotherapy and highlight the need for better tools to predict outcome in canine appendicular osteosarcoma.