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

The Utility of Outcome Measures in Total Knee Replacement Surgery

Total knee replacement (TKR) is the mainstay of treatment for people with end-stage knee OA among suitably “fit” candidates. As a high cost, high volume procedure with a worldwide demand that continues to grow it has become increasingly popular to measure response to surgery. While the majority who undergo TKR report improvements in pain and function following surgery, a significant proportion of patients report dissatisfaction with surgery as a result of ongoing pain or poor function. Poor outcomes of TKR require care that imposes on already overburdened health systems. Accurate and meaningful capture and interpretation of outcome data are imperative for appropriate patient selection, informing those at risk, and for developing strategies to mitigate the risk of poor results and dissatisfaction. The ways in which TKR outcomes are captured and analysed, the level of follow-up, the types of outcome measures used, and the timing of their application vary considerably within the literature. With this in mind, we reviewed four of the most commonly used joint specific outcome measures in TKR. We report on the utility, strengths, and limitations of the Oxford knee score (OKS), knee injury and osteoarthritis outcome score (KOOS), Western Ontario and McMaster Universities osteoarthritis index (WOMAC), and knee society clinical rating system (KSS)

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

Addressing obesity in the management of knee and hip osteoarthritis - weighing in from an economic perspective

BACKGROUND: Obesity is one of the only modifiable risk factors for both incidence and progression of Osteoarthritis (OA). So there is increasing interest from a public health perspective in addressing obesity in the management of OA. While evidence of the efficacy of intereventions designed to address obesity in OA populations continues to grow, little is known about their economic credentials. The aim of this study is to conduct a scoping review of: (i) the published economic evidence assessing the economic impact of obesity in OA populations; (ii) economic evaluations of interventions designed to explicitly address obesity in the prevention and management of OA in order to determine which represent value for money. Besides describing the current state of the literature, the study highlights research gaps and identifies future research priorities. METHODS: In July 2014, a search of the peer reviewed literature, published in English, was undertaken for the period January 1975 - July 2014 using Medline Complete (Ebscohost), Embase, Econlit, Global Health, Health Economics Evaluation Database (HEED), all Cochrane Library databases as well as the grey literature using Google and reference lists of relevant studies. A combination of key search terms was used to identify papers assessing the economic impact of obesity in OA or economic evaluations conducted to assess the efficiency of obesity interventions for the prevention or management of OA. RESULTS: 14 studes were identified; 13 were cost burden studies assessing the impact of obesity as a predictor for higher costs in Total Joint Arthroplasty (TJA) patients and one a cost-effectiveness study of an intervention designed to address obesity in the managment of mild to moderate OA patients. CONCLUSION: The majority of the economic studies conducted are cost burden studies. While there is some evidence of the association between severe obesity and excess hospital costs for TJA patients, heterogeneity in studies precludes definitive statements about the strength of the association. With only one economic evaluation to inform policy and practice, there is a need for future research into the cost-effectiveness of obesity interventions designed both for prevention or management of OA along the disease spectrum and over the life course

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

Mortality, patient-reported outcome measures, and the health economic burden of prosthetic joint infection

Prosthetic joint infection (PJI) is one of the most devastating complications for a patient following arthroplasty. This scoping review aims to evaluate the burden of PJI on individual patients and the healthcare system regarding the mortality rate, patient-reported quality of life, and healthcare resource utilisation. Patients with PJI have up to a five-fold higher mortality rate than those who have undergone an uninfected primary arthroplasty. There is an increased use of ambulatory aids and reduced joint function scores in patients with PJI. Global quality of life is poorer, specifically measured by the EQ-5D. Direct hospitalisation costs are two- to five-fold higher, attributed to surgery and prostheses, antibiotics, and a prolonged inpatient stay. There is an immense clinical and health economic burden secondary to PJI worldwide. This is expected to rise exponentially due to the increasing number of primary procedures and an ageing population with comorbidities • Improving preventative and treatment strategies is imperative for patients and the healthcare system

Handheld Co-Axial Bioprinting: Application to in situ surgical cartilage repair

Three-dimensional (3D) bioprinting is driving major innovations in the area of cartilage tissue engineering. Extrusion-based 3D bioprinting necessitates a phase change from a liquid bioink to a semi-solid crosslinked network achieved by a photo-initiated free radical polymerization reaction that is known to be cytotoxic. Therefore, the choice of the photocuring conditions has to be carefully addressed to generate a structure stiff enough to withstand the forces phisiologically applied on articular cartilage, while ensuring adequate cell survival for functional chondral repair. We recently developed a handheld 3D printer called Biopen . To progress towards translating this freeform biofabrication tool into clinical practice, we aimed to define the ideal bioprinting conditions that would deliver a scaffold with high cell viability and structural stiffness relevant for chondral repair. To fulfill those criteria, free radical cytotoxicity was confined by a co-axial Core/Shell separation. This system allowed the generation of Core/Shell GelMa/HAMa bioscaffolds with stiffness of 200KPa, achieved after only 10seconds of exposure to 700mW/cm2 of 365nm UV-A, containing \u3e90% viable stem cells that retained proliferative capacity. Overall, the Core/Shell handheld 3D bioprinting strategy enabled rapid generation of high modulus bioscaffolds with high cell viability, with potential for in situ surgical cartilage engineering

Combined mRNA expression levels of members of the urokinase plasminogen activator (uPA) system correlate with disease-associated survival of soft-tissue sarcoma patients

<p>Abstract</p> <p>Background</p> <p>Members of the urokinase-type plasminogen activator (uPA) system are up-regulated in various solid malignant tumors. High antigen levels of uPA, its inhibitor PAI-1 and its receptor uPAR have recently been shown to be associated with poor prognosis in soft-tissue sarcoma (STS) patients. However, the mRNA expression of uPA system components has not yet been comprehensively investigated in STS patients.</p> <p>Methods</p> <p>The mRNA expression level of uPA, PAI-1, uPAR and an uPAR splice variant, uPAR-del4/5, was analyzed in tumor tissue from 78 STS patients by quantitative PCR.</p> <p>Results</p> <p>Elevated mRNA expression levels of PAI-1 and uPAR-del4/5 were significantly associated with clinical parameters such as histological subtype (<it>P </it>= 0.037 and <it>P </it>< 0.001, respectively) and higher tumor grade (<it>P </it>= 0.017 and <it>P </it>= 0.003, respectively). In addition, high uPAR-del4/5 mRNA values were significantly related to higher tumor stage of STS patients (<it>P </it>= 0.031). On the other hand, mRNA expression of uPA system components was not significantly associated with patients' survival. However, in STS patients with complete tumor resection (R0), high PAI-1 and uPAR-del4/5 mRNA levels were associated with a distinctly increased risk of tumor-related death (RR = 6.55, <it>P </it>= 0.054 and RR = 6.00, <it>P </it>= 0.088, respectively). Strikingly, R0 patients with both high PAI-1 and uPAR-del4/5 mRNA expression levels showed a significant, 19-fold increased risk of tumor-related death (<it>P </it>= 0.044) compared to the low expression group.</p> <p>Conclusion</p> <p>Our results suggest that PAI-1 and uPAR-del4/5 mRNA levels may add prognostic information in STS patients with R0 status and distinguish a subgroup of R0 patients with low PAI-1 and/or low uPAR-del4/5 values who have a better outcome compared to patients with high marker levels.</p