Osteosarcoma: From Molecular Biology to Mesenchymal Stem Cells

Osteosarcoma is the most common primary malignant tumour of bone. Currently, despite treatment with multi-agent chemotherapy and limb salvage surgery, the five-year survival rate for osteosarcoma remains at 70%. The pathogenesis of osteosarcoma is complex and involves alterations in cellular apoptosis, adhesion, migration, invasion and molecular signalling. Research most recently has focused on the molecular basis of the disease with the goal of identifying novel therapeutic targets. To this end, mesenchymal stem cells (MSCs) have been identified to play a role in sarcomagenesis. MSC transformation may give rise to tumours, whereas interactions of MSCs with osteosarcoma cells in the tumour microenvironment may cause increased cell proliferation. This is in stark contrast to the role of MSCs as a promising source for tissue repair and regeneration. In order to utilize MSCs for biological reconstruction in the setting of osteosarcoma, further research is necessary to delineate the role of MSCs in osteosarcoma transformation and progression

Arthroplasty of a Charcot knee

The Charcot knee - or neuropathic arthropathy - presents a considerable challenge to the orthopaedic surgeon. Caused by a combination of sensory, motor and autonomic neuropathy, it was originally described as an arthritic sequelae of neurosyphilis. In today's western orthopaedics it is more often caused by diabetes. A Charcot knee is often symptomatically painful and unstable. Traditional management has usually been conservative or arthrodesis, with limited success. Arthroplasty of a Charcot joint has commonly been avoided at all costs. However, in the right patient, using the right technique, arthroplasty can significantly improve the symptoms of a Charcot joint. This article explores the evidence surrounding the role of arthroplasty in the management of a Charcot knee. Arthroplasty is compared to other forms of treatment and specific patient demographics and surgical techniques are explored in an attempt to define the role of arthroplasty in the management of a Charcot knee

Three-dimensional printed calcaneal prosthesis following total calcanectomy

Introduction: The majority of patients with extremity sarcoma can be surgically treated without amputation. However, limb-salvage surgery for foot sarcomas including the calcaneus remains challenging. Presentation of case: A 71-year-old man presented with a 5-year history of right heel persistent pain. Imaging studies revealed an osteolytic, destructive and highly metabolic lesion in the right calcaneus. Computed tomography guided core needle biopsy confirmed the diagnosis of grade 2 chondrosarcoma. A total calcanectomy was performed, and the defect was reconstructed with a patient matched three-dimensional printed titanium calcaneal prosthesis. Intra-operatively, ligaments including the Achilles tendon, and plantar fascia were reattached. The post-operative course was uneventful, and at the 5-month clinical follow-up, the patient was fully weightbearing, with a mobile ankle without pain. Discussion: This case is the first to use additive manufacturing to create a prosthetic calcaneus. The complex peri-calcaneal articular surfaces and reattachment of tendinous structures facilitate efforts to stabilize the prosthesis in situ. Conclusion: Three-dimensional-printed prosthesis of the calcaneus is a viable alternative to amputation

Bim-targeted cancer therapy: a link between drug action and underlying molecular changes

In the past few years, the pro-apoptotic molecule Bim has attracted increasing attention as a plausible target for tumor therapy. A variety of normal and pathological systems regulated by Bim, dependent on cell type, apoptotic stimulation, and chemotherapeutic agents, have been documented. Bim promotes anoikis of many tumor cells, such as lung cancer, breast cancer, osteosarcoma, and melanoma. Various chemotherapeutic agents use Bim as a mediating executioner of cell death. Hence, Bim suppression supports metastasis and chemoresistance. Imatinib, gefitinib, bortezomib, and Bim protein itself are spotlighted as current and future Bim-targeting therapeutic agents. The potential benefits of Bim-targeted therapies are selectivity of treatment for tumor cells and reduction in tumorassociated phenomena such as chemoresistance and metastasis. Thus, Bim-targeting therapies may provide more effective and unique tumor management modalities in future. This review article discusses all these issues

The Impact of Sex on the Outcomes of Prosthetic Joint Infection Treatment with Debridement, Antibiotics and Implant Retention: A Systematic Review and Individual Patient Data Meta-analysis

BACKGROUND: The influence of sex on the failure of débridement antibiotics and implant retention (DAIR) for treating prosthetic joint infection (PJI) is important for decision-making, patient counseling, and equitable health care. However, very few studies in the orthopaedic literature conduct sex-specific analyses. AIM: The primary aim was to determine whether sex influences treatment success after DAIR. METHODS: A systematic review and individual patient data (IPD) meta-analysis was conducted. MEDLINE (Ovid), EMBASE (Ovid), Web of Science, and Google Scholar were searched, and IPD was requested via e-mail. Patients who underwent DAIR after developing PJI within 12 months of a primary total hip or knee arthroplasty were included in the analysis. Treatment failure was defined by the Delphi International Consensus criteria. Adjusted odds ratios for treatment failure were calculated using a mixed-effects logistic regression. RESULTS: The study collected and analyzed IPD of 1,116 patients from 21 cohorts. The odds of treatment failure were 29% lower in women (odds ratio, 0.71; 95% CI 0.54 to 0.017; P = 0.017), after adjusting for duration of symptoms >7 days and Staphylococcus aureus infection (methicillin-susceptible Staphylococcus aureus or any infection with S aureus). None of the 64 studies included in the systematic review conducted a sex-specific analysis. CONCLUSION: For patients who developed a PJI within 1 year postsurgery, females have lower odds of DAIR failure than males. Other factors also have varying effects on outcome for men and women. It is essential to implement sex-specific analysis in orthopaedic research

Placebo Surgery Controlled Trials : Do They Achieve What They Set Out To Do? A Systematic Review

OBJECTIVE: To explore whether placebo surgery controlled trials achieve what they set out to do by investigating discrepancy between projected and actual design aspects of trials identified through systematic review methods. SUMMARY BACKGROUND: Interest in placebo surgery controlled trials is growing in response to concerns regarding unnecessary surgery and the societal cost of low-value healthcare. As questions about the justifiability of using placebo controls in surgery have been addressed, attention is now being paid to more practical concerns. METHODS: Six databases were searched from inception - May 2020 (MEDLINE, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library). Placebo surgery controlled trials with a published protocol were included. Three authors extracted "projected" design aspects from protocols and "actual" design aspects from main findings papers. Absolute and relative difference between projected and actual design aspects were presented for each trial. Trials were grouped according to whether they met their target sample size ("completed") and were concluded in a timely fashion. Pairs of authors assessed risk of bias. RESULTS: Of 24 trials with data available to analyse; 3 were completed and concluded within target timeframe; 10 were completed and concluded outside the target timeline; 4 were completed without clear target timeframes; 2 were incomplete and concluded within the target framework; 5 were incomplete and concluded outside the target timeline. Trials which reached the recruitment target underestimated trial duration by 88% and number of recruitment sites by 87%. CONCLUSIONS: Trialists need to factor additional time and sites into future placebo surgery controlled trials. A robust reporting framework of projected and actual trial design is imperative for trialists to learn from their predecessors. REVIEW REGISTRATION: PROSPERO (CRD42019133296)

Applying advanced imaging techniques to a murine model of orthotopic osteosarcoma

IntroductionReliable 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 methodsIntra-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, [18F]-Fluoride-PET and [18F]-FDG-PET. Results[18F]-Fluoride-PET was more sensitive than [18F]-FDG-PET for detecting early disease. Both [18F]-Fluoride-PET and [18F]-FDG-PET showed progressive disease in the model, with 4-fold and 2-fold increases in SUV (p<0.05) by the study endpoint, respectively. In vivo bioluminescent assay showed that systemically delivered PEDF inhibited growth of primary osteosarcoma.DiscussionApplication of [18F]-Fluoride-PET and [18F]-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

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Background:Sarcomas are rare and heterogeneous cancers. We assessed the contribution of DICER1 mutations to sarcoma development.Methods:The coding region of DICER1 was sequenced in 67 sarcomas using a custom Fluidigm Access Array. The RNase III domains were Sanger sequenced in six additional sarcomas to identify hotspot DICER1 variants.Results:The median age of sarcoma diagnosis was 45.7 years (range: 3 months to 87.4 years). A recurrent embryonal rhabdomyosarcoma (ERMS) of the broad ligament, first diagnosed at age 23 years, harboured biallelic pathogenic somatic DICER1 variants (1 truncating and 1 RNase IIIb missense). We identified nine other DICER1 variants. One somatic variant (p.L1070V) identified in a pleomorphic sarcoma and one germline variant (c.2257-7A>G) may be pathogenic, but the others are considered to be benign.Conclusions:We show that deleterious DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, in particular ERMS of the urogenital tract