Canine Appendicular Osteosarcoma Research Articles

Impact of Telomerase Status on Canine Osteosarcoma Patients

We demonstrated previously that canine osteosarcoma (OSA) cell lines and samples from clinical patients are predominantly telomerase positive. In contrast, the majority of OSA samples from human patients appear to be telomerase negative, maintaining telomere length by an alternative lengthening of telomeres (ALT) mechanism. The purpose of the current study was to examine the telomerase status of a large number of OSA samples from dogs and determine if telomerase status can serve as a prognostic factor. The majority of clinical canine OSA appendicular lesions will be telomerase positive, and telomerase positivity will negatively impact disease outcome. Sixty-seven dogs with appendicular OSA presenting to the Colorado State University Animal Cancer Center for treatment. The Telomeric Repeat Amplification Protocol was performed on tissue samples from primary canine appendicular OSA to determine the presence of telomerase activity. Telomere restriction fragment (TRF) analysis was utilized to determine telomere length and detect ALT. Outcome data were obtained in a retrospective manner and correlated with telomerase status. Seventy-three percent of canine OSA samples were telomerase positive. Telomerase status did not have an impact on disease-free interval or survival time. Nine of 10 telomerase-negative samples examined were consistent with an ALT phenotype, based on TRF analysis. These results are consistent with the hypothesis that the majority of canine OSA are telomerase positive, suggesting that telomerase may be a valuable target for canine OSA therapy. Additionally, telomerase status does not appear to be a prognostic factor in canine OSA.

Influence of carboplatin infusion on osteosarcoma blood flow

Herein we report that carboplatin infusion influenced tumor blood flow signal independent of the mechanical decompression induced by the artificial lymphatics system technology that was being evaluated as part of a randomized veterinary clinical trial, treating spontaneously occurring canine appendicular osteosarcoma, a tumor very similar to its human counterpart. Blood flow within the central region of the tumor was recorded continuously using laser Doppler flowmetry, a real-time measurement technology. Time-averaged flow values were computed from segments taken from the recordings immediately before starting carboplatin infusion, and during infusion. Carboplatin increased the tumor blood flow signal by an additional 59 +/- 26% (mean +/- SEM; p = 0.06) over the increase induced by the decompression. The increase started within 49 +/- 46 s after the start of infusion, had a response time constant of 19 +/- 21 s and persisted throughout the infusion, ending shortly after infusion ended. The rapidity of the flow signal increase suggests that carboplatin may have an autonomic effect on circulation, either local or systemic. The observations identify a new action of this drug and suggest a possible mechanism to exploit therapeutically.

Use of an Artificial Lymphatic System During Carboplatin Infusion to Improve Canine Osteosarcoma Blood Flow and Clinical Response

The artificial lymphatic system (ALS), a mechanical system designed to reduce increased interstitial fluid pressure in solid tumors and enhance the delivery of chemotherapy, was evaluated within a randomized clinical trial treating spontaneously occurring canine appendicular osteosarcoma (OS), a tumor similar to its human OS counterpart. An ALS was investigated for its ability to increase OS blood flow and increase uptake of intravenously administered carboplatin. Blood flow increased by 314% in tumors with active ALS drains versus 126% in control tumors (P < .03). Tumor carboplatin uptake increased by 51% after drain activation (P = .07). Microvascular density (MVD) was measured in tumors after surgical amputation and in corresponding bone regions in a cohort of normal dogs. The OS tumors had equivalent MVD as normal bone, and MVD was higher in the humerus than the femur (P < .03) in both tumor and normal bone. Median survival between the ALS-treated and control cohorts was not different despite increased drug uptake or ALS manipulation. Compared with historic controls, ALS drain insertion into tumors to reduce interstitial fluid pressure did not worsen the prognosis. The findings in canine spontaneously occurring OS indicate that an ALS may be of value as a chemotherapy adjunct for enhancing the delivery of chemotherapy to tumor interstitium.

Single‐Agent Pamidronate for Palliative Therapy of Canine Appendicular Osteosarcoma Bone Pain

Background:Canine appendicular osteosarcoma (OSA) causes focal bone destruction, leading to chronic pain and reduced quality‐of‐life scores. Drugs that inhibit pathologic osteolysis might provide additional treatment options for managing cancer‐induced bone pain. Aminobisphosphonates induce osteoclast apoptosis, thereby reducing pain associated with malignant osteolysis in human patients with cancer.Hypothesis:Treatment of dogs with pamidronate administered intravenously will alleviate bone pain and reduce pathologic bone turnover associated with appendicular OSA in dogs.Animals:Forty‐three dogs with naturally occurring appendicular OSA administered pamidronate intravenously.Methods:Prospective study. Therapeutic responses in dogs treated with pamidronate administered intravenously and nonsteroidal anti‐inflammatory drugs (NSAID) were evaluated by using a numerical cumulative pain index score (CPIS), and by quantifying urine N‐telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x‐ray absorptiometry. In addition, variables, including pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx andrBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy.Results:Twelve of 43 dogs (28%) had pain alleviation for &gt; 4 months, lasting a median of 231 days. Changes in CPIS andrBMD during treatment were statistically different between responders and nonresponders (P= .046 and .03, respectively).Conclusions and Clinical Importance: Substantiated by reductions in CPIS and increases inrBMD, single‐agent pamidronate administered intravenously with NSAID therapy relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs.

Single-agent Pamidronate for Palliative Therapy of Canine Appendicular Osteosarcoma Bone Pain

Canine appendicular osteosarcoma (OSA) causes focal bone destruction, leading to chronic pain and reduced quality-of-life scores. Drugs that inhibit pathologic osteolysis might provide additional treatment options for managing cancer-induced bone pain. Aminobisphosphonates induce osteoclast apoptosis, thereby reducing pain associated with malignant osteolysis in human patients with cancer. Treatment of dogs with pamidronate administered intravenously will alleviate bone pain and reduce pathologic bone turnover associated with appendicular OSA in dogs. Forty-three dogs with naturally occurring appendicular OSA administered pamidronate intravenously. Prospective study. Therapeutic responses in dogs treated with pamidronate administered intravenously and nonsteroidal anti-inflammatory drugs (NSAID) were evaluated by using a numerical cumulative pain index score (CPIS), and by quantifying urine N-telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x-ray absorptiometry. In addition, variables, including pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx and rBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy. Twelve of 43 dogs (28%) had pain alleviation for >4 months, lasting a median of 231 days. Changes in CPIS and rBMD during treatment were statistically different between responders and nonresponders (P = .046 and .03, respectively). Substantiated by reductions in CPIS and increases in rBMD, single-agent pamidronate administered intravenously with NSAID therapy relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs.

Urine N-Telopeptide Excretion in Dogs with Appendicular Osteosarcoma

Canine appendicular osteosarcoma (OSA) is a commonly diagnosed cancer that is capable of inducing pathologic bone remodeling. Investigating surrogate indices of bone metabolism may contribute to the diagnostic and therapeutic management of bone malignancies in companion animals. This study evaluated the excretion of N-terminal telopeptide (NTx), a marker of bone resorption that is detected in urine. Sixty-three dogs with appendicular OSA were compared with 29 age-matched healthy dogs. Dogs with appendicular OSA had significantly higher baseline urine NTx excretion than healthy controls (P < .0001). In 17 dogs with OSA treated with either amputation or standardized palliative therapies, significant reductions in urine NTx excretion were observed, suggesting that excessive bone resorption in dogs with OSA may be linked with focal skeletal osteolysis or its consequences. To identify any relationship between indicators of pathologic bone turnover, baseline urine NTx excretion was correlated with serum bone alkaline phosphatase (bALP) or radiographic tumor lengths at diagnosis. No significant correlations were identified between baseline urine NTx excretion and either bALP or tumor length. The findings from this study suggest that high urinary NTx excretion may support the diagnosis of focal skeletal osteolysis in dogs, and reductions in urine NTx excretion after treatment may reflect elimination or minimization of pathologic bone resorption.

Bone allografts and adjuvant cisplatin for the treatment of canine appendicular osteosarcoma in 18 dogs.

The results achieved in 18 dogs following the use of frozen bone cortical allografts for limb-sparing resection of non-metastatic canine appendicular osteosarcoma are presented. Three to five cisplatin doses (70 mg/m2) were administered, starting the day after surgery. The mean and median survival times were 478 and 266 days (range 80 to 2,611 days), respectively. The survival rate was 94 per cent at three months, 78 per cent at six months, 35 per cent at 12 months, 23 per cent at 18 months and 19 per cent at 24 months; the disease-free interval was 80 to 1,246 days (mean 365 days, median 266 days). Lung metastasis developed in 55 per cent of the dogs within one year. Complications were observed in 14/18 dogs (78 per cent), comprising local recurrence (28 per cent), allograft infection (39 per cent) and implant failure (11 per cent). Despite complications, limb sparing is a useful alternative to amputation in selected cases of appendicular osteosarcoma.

Intramedullary cisplatin chemotherapy: Experience in four dogs with osteosarcoma

Single-agent intramedullary cisplatin chemotherapy provided effective localised control in two of four dogs with advanced stage osteosarcoma unable to withstand an amputation or limb-sparing surgery. Complete remission of the local neoplasm was observed in one of the four dogs, partial remission of the local neoplasm in one dog and progressive disease in the other two. Limb function was preserved in one dog for seven months and that dog was found to be tumour-free when euthanased due to unrelated causes. These preliminary results warrant further investigation into the use of intramedullary cisplatin chemotherapy in the localised management of canine appendicular osteosarcoma. It is possible that this mode of treatment may be combined with other treatments to maximise the survival (i.e., systemic control) in other dogs affected with appendicular osteosarcoma.

Management of Canine Appendicular Osteosarcoma

Canine appendicular osteosarcoma is a highly malignant primary bone cancer that closely resembles the same disease in humans. Although amputation alone usually controls local disease, metastatic cancer is common and is the cause of death or euthanasia in 90% of dogs by 1 year. Cisplatin (+/- doxorubicin) chemotherapy appears to improve survival time in dogs; however, metastatic cancer remains a problem. Pulmonary metastasectomy may prolong survival in carefully selected dogs. Limb-sparing, although involved and potentially fraught with complications, can result in local disease control and a functional, pain-free limb in selected dogs without adversely affecting their survival. Studies are ongoing to improve local disease control with limb-sparing and improve disease-free survival in dogs with appendicular osteosarcoma. In conclusion, dogs with osteosarcoma were previously thought to have a hopeless prognosis, but the outlook is beginning to appear more optimistic. Limb-sparing in dogs is still evolving; however, it is possible in selected cases to optimize survival and preserve limb function.