Jonathan C. M. Clark

A review of clinical and molecular prognostic factors in osteosarcoma

Traditional prognostic determinants in osteosarcoma have included demographics (age, sex), tumour size, site, stage, and the response to chemotherapy. Many of these are determined using varying techniques and units of measurement, which can make comparison between studies difficult. The absence of survival difference between limb sparing surgery and amputation has been repeatedly demonstrated in primary disease, and even in the setting of pathological fracture. On the other hand, there is still some controversy over the existence of increased local recurrence for limb-sparing surgery, and the implications of this. Commonly used prognostic determinants such as metastases, and response to chemotherapy enable a high degree of prognostic accuracy but usually at a late stage in the course of disease. Leading on from this, there is a need to uncover molecular pathways with specific influence over osteosarcoma progression to facilitate earlier treatment changes. Some important pathways are already being defined, for example the association of CXCR4 with metastases on presentation, the likelihood of doxorubicin resistance with positive P-glycoprotein, and the reduced survival prediction of over expressed survivin. It is anticipated that the future of osteosarcoma treatment will involve treatment tailored to the molecular profile of tumours at diagnosis, adjuvant therapy directed towards dysfunctional molecular pathways rather than the use of cytotoxics, and a more standardised approach to the measurement of clinical prognostic factors.

The molecular pathogenesis of osteosarcoma: a review.

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management.

RECK—a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer

The RECK (reversion-inducing cysteine rich protein with Kazal motifs) protein was initially discovered by its ability to induce reversion in ras-activated fibroblasts. The key action of RECK is to inhibit matrix metalloproteinases (MMPs) involved in breakdown of the extracellular matrix (ECM), and angiogenesis—namely MMP-2, MMP-9 and MTP-1. To this effect, it plays important physiological roles in embryogenesis and vasculogenesis. Additionally, it has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumours through the ECM. RECK has been studied in the context of a number of human tumours including colorectal, breast, pancreas, gastric, hepatocellular, prostate, and non-small cell lung carcinoma. In many of these tumours, RECK is down-regulated most likely as a result of inhibition at the Sp1 promoter site. MMP-2 and MMP-9 generally show an inverse association with RECK expression, but there are exceptions to this rule. Likewise, a reduction in tumour microvascular density (MVD) and VEGF have also been correlated with increased RECK levels, although more studies are required to define this effect. The predominant finding across all human tumour studies is a significantly improved prognosis (due to decreased invasion and metastasis) in tumours with preserved RECK expression. Although further research is required, RECK is a promising prognostic marker and potential therapeutic agent in multiple cancers.

Therapeutic targeting of osteoclast function and pathways

Introduction: Osteoclasts are responsible for bone resorption and underlie a number of pathological states in which osteolysis is a feature. Over recent decades our molecular understanding of osteoclast differentiation and activation has expanded significantly, and this has allowed for the development of a number of osteoclast-targeted therapies. Areas covered: This review seeks to present the underlying molecular mechanisms of osteoclast differentiation and activity as a basis for understanding our current treatment of osteoporosis and malignant tumors in bone. Osteoclast-targeted therapies are also being evaluated for the treatment of rheumatoid arthritis, osteosarcoma and giant cell tumor of bone. Expert opinion: With concurrent advances in the fields of molecular biology, pathology and advanced imaging, osteoclast-targeted therapies show great potential for treating conditions in which excess resorption of bone is a key pathological process. Targeting of osteoclast control mechanisms offers the potential of combining ‘molecular imaging’ with therapeutic intervention and longitudinal monitoring of disease processes.

The non-vascularised fibular graft: A SIMPLE AND SUCCESSFUL METHOD OF RECONSTRUCTION OF THE PELVIC RING AFTER INTERNAL HEMIPELVECTOMY

Internal hemipelvectomy is a standard treatment for malignant tumours of the pelvis. Reconstruction using a non-vascularised fibular graft is relatively straightforward compared to other techniques. We describe the surgical and functional outcomes for a series of ten patients who underwent an internal hemipelvectomy (type I or I/IV) with reconstruction by a non-vascularised fibular graft between 1996 and 2009. A key prerequisite for this procedure was a preserved sciatic notch, confirmed pre-operatively on MRI. Graft-host union was achieved in all patients with a single fibular graft, and in the lower graft where two grafts had been used. The mean time to union was 7.3 months (3 to 12). The upper graft did not unite in four of six cases where two grafts had been used. Seven patients were eventually able to walk without a stick. The mean post-operative Musculoskeletal Tumour Society score was 75.4% (16.7 to 96.7). There were no cases of deep post-operative infection. The mean pelvic shortening was 0.9 cm (0.2 to 3.4). Recurrent tumour occurred in three cases, and death from tumour-related disease occured in one. Patients who need an internal hemipelvectomy will do well if their pelvic ring is reconstructed with a non-vascularised fibular graft. The complication rate is low, and they attain a good functional outcome.

The significance of size change of soft tissue sarcoma during preoperative radiotherapy

AIM To assess the significance of change in tumour size during preoperative radiotherapy in patients with soft tissue sarcoma (STS). METHODS A retrospective review of 91 cases with STS was performed. Inclusion criteria were localised extremity and truncal STS with measurable disease, older than 18 years, treated with preoperative radiotherapy and wide local excision, in the period between January 1966 and December 2005. Patients with head and neck STS, or who received neoadjuvant chemotherapy were excluded. A difference in excess of 10% of the greatest tumour diameter of the pre-radiotherapy and the post-radiotherapy MRI scans was considered as change in tumour size. RESULTS Increase in tumour size was noted in 28 patients (31%) (Group 1). No change or decrease in size was observed in 63 patients (Group 2). There were no significance differences in local control or overall survival rates between the 2 groups. The estimated overall actuarial local recurrence free, event-free and overall survival rates were 90.5%, 64.4%, 62.9% in Group 1, and 85.7%, 60.8%, 68.9% in Group 2 respectively. CONCLUSION Increase in tumour size during preoperative radiotherapy for soft tissue sarcoma does not seem to associate with inferior local tumour control or compromise survival. Lack of reduction in tumour size is not necessarily a sign of lack of response to preoperative radiotherapy.

Elevated leptin expression in a rat model of fracture and traumatic brain injury

A few studies have reported a relationship between leptin induced by brain injury and healing of bone tissue. Our objective was to measure serum and callus leptin expression within the setting of fracture and traumatic brain injury (TBI). Sixty‐four male Sprague‐Dawley rats were randomised equally into four groups: control, TBI group, fracture group and fracture/TBI group. Rats were sacrificed at 2, 4, 8 and 12 weeks after fracture/TBI. Serum leptin was detected using radio‐immunoassay, and callus formation was measured radiologically. Callus leptin was analysed with immunohistochemistry. Serum leptin was significantly increased in the fracture, TBI and combined fracture/TBI groups compared with the control group at 2 weeks (P < 0.05). Serum leptin was significantly higher in the combined fracture/TBI group than in the fracture and TBI groups at 4 and 8 weeks (P < 0.05). The percentage of leptin‐positive cells in the callus and callus volume were significantly higher in the fracture/TBI group than in the fracture‐only group (P < 0.001). Thus, we demonstrated elevated leptin expression within healing bone, particularly in the first 8 weeks of a rat model combining fracture and TBI. A close association exists between leptin levels and the degree of callus formation in fractures.

The evolving science of cochlear implants.

Graeme M. Clark and colleagues describe the evolving science of cochlear implants and the histopathology associated with a patient who had his implant removed when it failed in 1983 and again in 1998. Dr Clark has been awarded the 2013 Lasker-DeBakey Clinical Medical Research Award for his pioneering work in cochlear implant development. In 1978, the first multichannel cochlear implant was developed in Australia and a prototype was surgically implanted in a 48-year-old patient (MC-1). After a series of clinical trials, the US Food and Drug Administration approved the use of the Australian cochlear implant in adults in 1985, and subsequently, the agency has approved the device for use in infants as young as 6 months of age. During the past 3 decades, more than 300 000 patients have had their hearing restored with cochlear implants. In this Viewpoint, we describe how the assessment of the temporal bone of MC-1, the first patient to receive a cochlear implant, is aiding the further development of the device.

RECK in Osteosarcoma: A Novel Role in Tumour Vasculature and Inhibition of Tumorigenesis in an Orthotopic Mode

Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice.

Involvement of c-jun in human liposarcoma growth: supporting data from clinical immunohistochemistry and DNAzyme efficacy.

c-jun has been found to be upregulated in a variety of cancers. Recently, this oncogene has also been implicated in liposarcoma (LS) progression. c-jun knockdown mediated by a deoxyribozyme induced apoptosis in LS cells via evoking caspase-10, but not the Fas/FasL pathway. A novel orthotopic model for LS was established in the hindlimb of mice using human cells to extend the evaluation of effects of c-jun knockdown in vivo. Tumor take in vivo was 100%, with growths resembling high grade aggressive LS. The c-jun deoxyribozyme inhibited the growth of LS in this model. Clinically, downregulation of c-jun may proffer an improved treatment outcome for liposarcoma. The new model for LS described here will enable better testing of agents with therapeutic potential against LS.