Osteosarcoma (OSA) is a rare, but disproportionately lethal cancer that predominantly affects children. Sadly, discovery of new therapies for OSA has largely been unsuccessful in the past 30 years; there is an urgent need to identify new treatments for OSA. Pet dogs with naturally-occurring OSA represent a unique comparative “model” to discover new treatments for OSA. Unlike humans, in which fewer than 1,000 cases of OSA occur each year, there are nearly 50,000 new cases each year of OSA in dogs. In addition, dogs have an intact immune system, a shared environment with humans, and more rapid progression of disease. Together these factors make dogs an important comparative model for new therapies for OSA. The purpose of this study was: 1) to validate this mouse-dog-human pipeline for drug discovery and 2) to validate CRM1 as a novel target for ostesoarcoma treatment.

We developed patient-derived cell lines and xenografts of OSA from both dogs and humans and applied these models to identify new therapies for OSA using high-throughput drug screens in vitro followed by in vivo validation. Whole exome sequencing was performed on the patient-derived models and original tumors to identify potential driver mutations.

A high-throughput screen in both dog and human OSA identified CRM1 inhibitors as effective at killing dog and human OSA patient-derived cell lines in vitro. In vivo, CRM1 inhibition led to significant tumor growth inhibition in patient-derived xenografts from dogs and humans. Western blotting demonstrated increased levels of CRM1 protein expression across nine different dog and human OSA cell lines compared to non-transformed human osteoblasts. CRM1 upregulation in OSA cells was further verified by immunofluorescence staining. Increased CRM1 expression was prognostic for poorer metastasis-free survival and poorer overall survival.

Our cross-species personalized medicine pipeline identified CRM1 as a potential therapeutic target to treat OSA in both dogs and humans. Future studies are focused on testing CRM1 inhibitors in canine clinical trials.

Giant cell tumours of tendon sheaths have been given multiple denominations due to the uncertain pathologic nature of this lesion. Various contributory factors have been accounted for a wide variation in their recurrence rates. Owing to their high recurrence rates ranging from 9% to 44%, these tumours continue to present with treatment dilemma. There is a lack of consensus regarding how to best manage the balance between extensive dissection and preservation of normal tissues for normal function and recovery versus the risk of recurrence. The authors studied 46 patients with histopathologically confirmed Giant cell tumours over a period of 9 years between 1997 and 2006. The average follow-up in this case series was 35 months. This study aims to analyse the distribution of giant cell tumours of tendon sheaths in hand and our experience with their resection in a District General Hospital with possible predictors associated with recurrence. The referral letters, radiographs, operative and histology records were reviewed. The data was carefully analysed including patients' age and sex at the time of presentation and surgery, presenting symptoms, any associated trauma and the anatomical location of the tumour. A telephonic questionnaire was conducted and the patients with any complications or recurrence were reviewed. Our recurrence rate of 8.6% (4 patients) is lower than previously reported in the literature when the patients did not receive post-operative radiotherapy. Recurrence was seen to be statistically higher in cases where the tumours were excised piecemeal as opposed to removed in one piece and in patients with osseous erosions which were confirmed radiologically and intra-operatively. No atypical mitosis was reported on histology. None of our patients received radiotherapy post-operatively. Other factors including age, size, degenerative joint disease and location within the digit were not confirmed as risk factors in our study. We recommend meticulous surgical technique by an experienced hand surgeon and warning patients of the risk of recurrence if any risk factors were identified.