Trauma and Stem Cells: Biology and Potential Therapeutic Implications.

Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further.

Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis.

The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78-102) and StVOrth-3 (residues 90-114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent.

Pathologic fracture of a calcaneal aneurysmal bone cyst.

A 21-year-old man presented with a pathologic fracture through the posterior aspect of the calcaneus into an aneurysmal bone cyst. The patient was treated using curettage, phenol, alcohol, and burr with open reduction and internal fixation. This is the first reported case of a pathologic fracture of an aneurysmal bone cyst of the calcaneus, highlighting the fracture potential of these lesions and the need for early management.

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.

The applied biochemistry of PEDF and implications for tissue homeostasis.

Pigment epithelium-derived factor (PEDF) is an endogenously produced glycoprotein with a spectrum of biological roles across diverse pathologies. Recent research has focused on the biochemical properties of PEDF and its associated receptors. This review discusses the recent developments in PEDF biochemistry and how this new knowledge will help progress our understanding of PEDF as a molecular mediator for anti-angiogenesis and -tumorigenesis. Additionally, pathophysiological roles for PEDF in healing and tissue homeostasis are being revealed and our enhanced understanding of the interactions between PEDF and its receptors may yet prove useful in propelling PEDF towards clinical application.

An interesting diagnosis for a presacral mass: case report.

A presacral mass can present a diagnostic dilemma for the surgical oncologist. Differential diagnoses include congenital causes such as teratoma or chordoma, neurological causes such as neurilemoma or neurofibroma or other malignancies such as lymphoma or sarcoma. Diagnosis usually requires imaging such as CT and MRI and tissue biopsy. We present an unusual cause of a presacral mass being extramedullary haematopoiesis, found incidentally in a 71 year old female. Extramedullary haematopoiesis is defined as the production of myeloid and erythroid elements outside of the bone-marrow. This diagnosis is extremely rare in the presacral area especially in a patient with no haematological abnormalities. A review of the literature is presented.

Clinical Features of High-Grade Extremity and Trunk Sarcomas in Patients Aged 80 Years and Older: Why Are Outcomes Inferior?

Background: The population of many countries is aging and a significant number of elderly patients with soft-tissue sarcoma are being seen at cancer centers. The unique therapeutic and prognostic implications of treating soft-tissue sarcoma in geriatric patients warrant further consideration in order to optimize outcomes. Patients and Methods: This is a single-institution retrospective study of consecutive non-metastatic primary extremity and trunk high-grade sarcomas surgically treated between 1996 and 2012, with at least 2 years of follow-up for survivors. Patient characteristics and oncological outcomes were compared between age groups (≥80 vs. <80 years), using Chi-square or Fisher-exact test and Log-Rank or Wilcoxon test, respectively. Deaths from other causes were censored for disease-specific survival estimation. A p< 0.05 was regarded as statistically significant. Results: A total of 333 cases were eligible for this study. Thirty-six patients (11%) were aged ≥80 years. Unplanned surgery incidence and surgical margin status were comparable between the age groups. Five-year local-recurrence-free, metastasis-free and disease-specific survivals were 72% (≥80 years) vs. 90% (<80 years) (p = 0.004), 59 vs. 70% (p = 0.07) and 55 vs. 80% (p < 0.001), respectively. A significantly earlier first metastasis after surgery (8.3 months vs. 20.5 months, mean) and poorer survival after first metastasis (p = 0.03) were observed. Cox analysis revealed "age ≥80 years" as an independent risk factor for local failure and disease-specific mortality, with hazard ratios of 2.41 (95% CI: 1.09-5.32) and 2.52 (1.33-4.13), respectively. A competing risks analysis also showed that "age ≥80 years" was significantly associated with the disease-specific mortality. Conclusions: Oncological outcomes were significantly worse in high-grade sarcoma patients aged ≥80 years. The findings of more frequent local failure regardless of a consistent primary treatment strategy, an earlier time to first metastasis after surgery, and poorer prognosis after first metastasis suggest that more aggressive tumor biology, in addition to multiple co-morbidity, may explain the inferiority.

A Biomechanical Comparison of 4-Strand and 5-Strand Anterior Cruciate Ligament Graft Constructs.

Hamstring tendon autografts are used for reconstruction of the anterior cruciate ligament. This study tested the hypothesis that a 5-strand hamstring autograft construct is superior in strength to a 4-strand construct. Four-strand and 5-strand tendon grafts constructs were prepared from ovine flexor tendons and then tested in a uniaxial electromechanical load system with suspensory fixation. The 4-strand and 5-strand constructs were pre-conditioned, stress-relaxed and loaded to ultimate failure. Stress-relaxation, stiffness and ultimate load were compared using a one-way ANOVA. There were no statistical differences in stress-relaxation, initial stiffness, secondary stiffness or ultimate load between 4-strand and 5-strand split tendon graft constructs. Inconsistent failure patterns for both 4-strand and 5-strand constructs were observed. The additional strand in the 5-strand construct may be shielded from stress with additional weakness secondary to the use of suspensory fixation. The potential biological benefit of religamentization and bony integration, with more autologous tissue in the intra-articular space and bony tunnels remains unknown.

Applying Advanced Imaging Techniques to a Murine Model of Orthotopic Osteosarcoma.

INTRODUCTION: Reliable animal models are required to evaluate novel treatments for osteosarcoma. In this study, the aim was to implement advanced imaging techniques in a murine model of orthotopic osteosarcoma to improve disease modeling and the assessment of primary and metastatic disease. MATERIALS AND METHODS: Intra-tibial injection of luciferase-tagged OPGR80 murine osteosarcoma cells was performed in Balb/c nude mice. Treatment agent [pigment epithelium-derived factor (PEDF)] was delivered to the peritoneal cavity. Primary tumors and metastases were evaluated by in vivo bioluminescent assays, micro-computed tomography, [(18)F]-Fluoride-PET and [(18)F]-FDG-PET. RESULTS: [(18)F]-Fluoride-PET was more sensitive than [(18)F]-FDG-PET for detecting early disease. Both [(18)F]-Fluoride-PET and [(18)F]-FDG-PET showed progressive disease in the model, with fourfold and twofold increases in standardized uptake value (p < 0.05) by the study endpoint, respectively. In vivo bioluminescent assay showed that systemically delivered PEDF inhibited growth of primary osteosarcoma. DISCUSSION: Application of [(18)F]-Fluoride-PET and [(18)F]-FDG-PET to an established murine model of orthotopic osteosarcoma has improved the assessment of disease. The use of targeted imaging should prove beneficial for the evaluation of new approaches to osteosarcoma therapy.

Outcomes of dual modular cementless femoral stems in revision hip arthroplasty.

With an increasing number of primary hip replacements being performed every year, the burden of revision hip arthroplasty, for septic and aseptic loosening, recurrent dislocation or periprosthetic fracture, is also increasing. In recent years, different approaches to revising the femoral prosthesis have emerged; including both cemented and cementless techniques. With a stable cement mantle and good bone quality, or through the use of impaction bone grafting when bone stock is lacking, it is possible to re-cement a femoral prosthesis. Alternatively, a cementless modular femoral prosthesis may be used, providing the surgeon with further options for restoring leg length, hip offset, anteversion and stability. Studies evaluating the use of modular cementless prostheses have so far been limited to midterm studies, with results comparable to primary hip arthroplasty. There are some concerns, however, regarding tribological complications such as stem fracture, corrosion, and failure, and long-term studies are required to further evaluate these concerns. This review outlines the current evidence for the use of both cemented and cementless modular femoral prostheses in the setting of revision hip arthroplasty. Results of prospective and retrospective studies will be outlined, along with results obtained from national joint registries.

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.

Microarray: an instrument for cancer surgeons of the future?

Microarray enables the study of thousands of genes simultaneously. While still in its infancy as a technique and with a number of barriers to be overcome, microarray is allowing scientists to thoroughly examine the molecular pathways of cancer pathogenesis. However, the adoption of microarray as a clinically applicable technique has been slow coming. Current literature suggests roles in the diagnosis of tumours of unknown origin, in the evaluation of prognostic markers, and in guiding treatment for recurrent and resistant malignancy. This review outlines the science of microarray and draws on clinical examples, including osteosarcoma, breast, prostate and pancreatic carcinomas, to highlight the potential of microarray as a technique of surgical importance.

In vitro and in vivo biological activity of PEDF against a range of tumors.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is an emerging anti-cancer agent that targets both tumor tissue and its supporting vasculature. These direct and indirect effects of PEDF have been examined in vitro and in vivo for a range of malignancies. OBJECTIVE: This review seeks to present PEDF as a potential anti-cancer agent with applications across multiple malignancies. We refer closely to experimental methodology whilst still highlighting the clinical significance of PEDF in cancer, drawing on biological findings in vitro and in vivo. METHODS: A Pubmed database search was performed limiting the scope of this discussion paper mainly to PEDF's biological role in cancer, specifically lung, breast, prostatic, ovarian and pancreatic carcinomas, melanoma, glioma and osteosarcoma. CONCLUSIONS: The biological roles of PEDF are diverse and multidimensional. As an anti-cancer agent, PEDF has great potential as a focused anti-neoplastic therapy against a variety of tumor types.

Outcomes of total knee arthroplasty in English- versus non-English-speaking patients.

PURPOSE: To compare outcomes of total knee arthroplasty (TKA) in English- versus non-English-speaking patients. METHODS: 193 women and 85 men (mean age, 72 years) underwent 117 left and 161 right primary TKAs. 237 and 41 patients were English and non-English speaking, respectively. Interpretation was provided. Pre- and post-operative functional outcomes were measured using the International Knee Society (IKS) score. RESULTS: Most non-English-speaking patients were female (38 vs 3 of 41, p<0.001). The mean body mass index of non-English-speaking patients was significantly higher (34 vs 31 kg/m[2], p=0.003). 14 foreign languages were spoken among the 41 non-English-speaking patients, of which Greek and Italian were the most common. Non-English-speaking patients had significantly worse IKS scores both preoperatively and at the 12-month follow-up. The proportions of poor postoperative IKS scores were significantly higher in non-English-speaking patients (58% vs 27%, p<0.001), in whom pain was also significantly worse (p=0.017). In a multiple logistic regression analysis, being non-English speaking was the only predictor of poor functional outcome at the 12-month follow-up (odds ratio=2.77, confidence interval=1.25-6.14, p=0.012). CONCLUSION: The non-English-speaking background of a patient is a predictor of less favourable functional outcome after TKA.

Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy.

Pigment epithelium-derived factor (PEDF) has roles in antiangiogenesis and antitumourigenesis that are intimately entwined and is showing promise as a potential anticancer agent. However, the function of PEDF in the deregulated apoptotic pathways of malignant cells must first be fully characterized. Here, we review the currently known apoptotic pathways that are relevant to PEDF and cancer. Recently, a pathway that includes the PEDF receptor, PPARgamma and p53 has emerged. It is hoped that further characterization of this and other pathways involved in cancer will bring to light potential new therapeutic targets and approaches, which due to their specificity might be free of the morbidity associated with conventional chemotherapy.