Benign aggressive tumors are common and can be debilitating for patients especially if they are in peri-articular regions or cause pathological fracture as is common for giant cell tumor of bone (GCT). Although GCT rarely metastasize, the literature reports many series with high rates of local recurrence, and evidence about which risk factors influence recurrence is lacking. This study aims to evaluate the recurrence rate and identify local recurrence risk factors by reviewing patient data from a single high-volume orthopedic oncology center. A retrospective analysis of all patients treated for GCT at a tertiary orthopedic oncology center was conducted. In total 413 patients were treated for GCT between 1989 and 2017. Multiple patient and tumour characteristics were analysed to determine if they influenced local recurrence including: age, gender, anatomical site, Campanacci stage, soft tissue extension, presence of metastasis, pathologic fractures, and prior local recurrence. Additional variables that were analysed included type of treatment (en bloc resection or aggressive intralesional curettage) and use of local adjuvants. The main outcome parameters were local recurrence- free survival, metastasis-free survival and complications. Patients treated with Denosumab were excluded from analysis given its recently documented association with high rates of local recurrence. “There were 63/413 local recurrences (15.3%) at a mean follow-up of 30.5 months. The metastatic rate was 2.2% at a mean 50.6 months follow-up and did not vary based on type of treatment. Overall complication rate of 14.3% was not related to treatment modality. Local recurrence was higher (p=0.019) following curettage (55/310; 17.7%) compared to resection (8/103; 7.8%) however, joint salvage was possible in 87% of patients (270/310) in the curettage group. Use of adjuvant therapy including liquid nitrogen, peroxide, phenol, water versus none did not show any effect on local recurrence rates (p= 0.104). Pathological fracture did not affect local recurrence rates regardless of treatment modality (p= 0.260). Local recurrence at presentation was present in 16.3% (58/356) patients and did not show any significance for further local recurrence (p= 0.396). Gender was not associated with local recurrence (p=0.508) but younger patient age, below 20 years (p = 0.047) or below 30 years (p = 0.015) was associated with higher local recurrence rates. GCT in distal radius demonstrated the highest rate of local recurrence at 31.6% compared to other sites, although this was not significant (p=0.098). In addition, Campanacci stage and soft tissue extension were not risk factors for recurrence. The overall GCT local recurrence rate was 15.3%, but varied based on the type of resection: 17.7% following joint sparing curettage compared to 7.8% following resection. Local recurrence was also higher with younger patient age (30 years or less) and in distal radius lesions. In addition, neither Campanacci stage, soft tissue extension or presence of a pathologic fracture affected local recurrence. Most patients with GCT can undergo successful curettage and joint sparing, while only a minority require resection +/− prosthetic reconstruction. Even in the presence of soft tissue extension or a pathologic fracture, most joints can be salvaged with curettage

Giant cell tumors of bone (GCTs) are locally aggressive tumors with recurrence potential that represent up to 10% of primary tumors of the bone. GCTs pathogenesis is driven by neoplastic mononuclear stromal cells that overexpress receptor activator of nuclear factor kappa-B/ligand (RANKL). Treatment with specific anti-RANKL antibody (denosumab) was recently introduced, used either as a neo-adjuvant in resectable tumors or as a stand-alone treatment in unresectable tumors. While denosumab has been increasingly used, a percentage of patients do not improve after treatment. Here, we aim to determine molecular and histological patterns that would help predicting GCTs response to denosumab to improve personalized treatment. Nine pre-treatment biopsies of patients with spinal GCT were collected at 2 centres. In 4 patients denosumab was used as a neo-adjuvant, 3 as a stand-alone and 2 received denosumab as adjuvant treatment. Clinical data was extracted retrospectively. Total mRNA was extracted by using a formalin-fixed paraffin-embedded extraction kit and we determined the transcript profile of 730 immune-oncology related genes by using the Pan Cancer Immune Profiling panel (Nanostring). The gene expression was compared between patients with good and poor response to Denosumab treatment by using the nSolver Analysis Software (Nanostring). Immunohistochemistry was performed in the tissue slides to characterize cell populations and immune response in CGTs. Two out of 9 patients showed poor clinical response with tumor progression and metastasis. Our analysis using unsupervised hierarchical clustering determined differences in gene expression between poor responders and good responders before denosumab treatment. Poor responding lesions are characterized by increased expression of inflammatory cytokines as IL8, IL1, interferon a and g, among a myriad of cytokines and chemokines (CCL25, IL5, IL26, IL25, IL13, CCL20, IL24, IL22, etc.), while good responders are characterized by elevated expression of platelets (CD31 and PECAM), coagulation (CD74, F13A1), and complement classic pathway (C1QB, C1R, C1QBP, C1S, C2) markers, together with extracellular matrix proteins (COL3A1, FN1,. Interestingly the T-cell response is also different between groups. Poor responding lesions have increased Th1 and Th2 component, but good responders have an increased Th17 component. Interestingly, the checkpoint inhibitor of the immune response PD1 (PDCD1) is increased ~10 fold in poor responders. This preliminary study using a novel experimental approach revealed differences in the immune response in GCTs associated with clinical response to denosumab. The increased activity of checkpoint inhibitor PD1 in poor responders to denosumab treatment may have implications for therapy, raising the potential to investigate immunotherapy as is currently used in other neoplasms. Further validation using a larger independent cohort will be required but these results could potentially identify the patients who would most benefit from denosumab therapy

Implant-associated infection is a major source of morbidity in orthopaedic surgery. There has been extensive research into the development of materials that prevent biofilm formation, and hence, reduce the risk of infection. Silver nanoparticle technology is receiving much interest in the field of orthopaedics for its antimicrobial properties, and the results of studies to date are encouraging. Antimicrobial effects have been seen when silver nanoparticles are used in trauma implants, tumour prostheses, bone cement, and also when combined with hydroxyapatite coatings. Although there are promising results with in vitro and in vivo studies, the number of clinical studies remains small. Future studies will be required to explore further the possible side effects associated with silver nanoparticles, to ensure their use in an effective and biocompatible manner. Here we present a review of the current literature relating to the production of nanosilver for medical use, and its orthopaedic applications. Cite this article: Bone Joint J 2015; 97-B:582–9

Aim. Optimal strategies for surgical and antimicrobial management of Candida periprosthetic joint infections (PJI) are unclear. We present a retrospective case series of patients diagnosed with PJI caused by Candida spp. Method. Patients treated at our institution with Candida PJI from 01/2017 to 04/2018 were retrospectively included with isolation of Candida spp. in synovial fluid, intraoperative tissue or sonication fluid culture. PJI was defined by the proposed European Bone and Joint Infection Society (EBJIS) criteria. Treatment failure was defined as relapse or persistence of infection. Results. We included 9 patients (4 men and 5 women, mean age 75 years) involving 4 knee and 5 hip joint prosthesis. Risk factors for Candida PJI were prior PJI (n=4), diabetes mellitus (n=3), chronic kidney disease (n=3), obesity (n=3), negative-pressure wound therapy (n=3), rheumatoid arthritis (n=1) and chronic decubitus (n=1). Two patients had no risk factors for Candida PJI identified. Infection was acquired postoperatively (n=7), hematogenously (n=1) or contiguously through communicating vesico-articular sinus (n=1). The causative pathogen was C. albicans in 5, C. parapsilosis in 3, C. tropicalis in 1 patient, isolated from periprosthetic tissue samples (n=7), sonication fluid (n=3) and blood cultures (n=2); bacterial co-pathogens were isolated in 8 patients. Histopathological analysis revealed low-grade inflammation in all 6 patients, in whom it was performed. All patients were treated with oral fluconazole for 3 months, two initially received intravenous caspofungin and three received suppression with oral fluconazole for additional 9 months (total treatment 12 months). Liposomal amphotericin B (300–700 mg per 40 g bone cement) was admixed to spacer cement in 3 patients. Debridement and prosthesis retention was performed in one patient with tumor prosthesis after bone resection due to osteochondrosarcoma. In the remaining 8 patients the prosthesis was removed, with one-stage reimplantation in 1 patient and two-stage reimplantation in 3 patients (after 6 weeks, 3 months and 7 months); two patients are currently awaiting reimplantation, one died due to reason not related to PJI and another underwent knee arthrodesis. Among 5 patients with prosthesis in place, relapse occurred in one patient with prosthesis retention. Another patient experienced new PJI of the exchanged prosthesis caused by Staphylococcus aureus. Conclusions. All Candida PJI presented as chronic infection with low-grade inflammation. Treatment with prostheses retention failed, whereas in 4 patients who underwent two-stage exchange and long-term antifungal suppression, no relapse or persistence of infection was observed. All patients received oral fluconazole for ≥3 months

Aim. The induced membrane technique (IMT) or Masquelet technique is a two-step surgical procedure used to treat bony defects (traumatic or resulting from tumoral resections) and pseudo arthroses, even caused by infections. The relatively small case series reported, sometimes with variants to the original technique, make it difficult to assess the real value of the technique. Aim of this study was then to undertake a systematic review of the literature with a particular focus on bone union, infection eradication and complication rates. Method. A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Patient Data (PRISMA-IPD) guidelines. PubMed and other medical databases were searched using “Masquelet technique” and “induced membrane technique” keywords. English, French or Italian written articles were included if dealing with IMT employed to long bones in adults and reporting at least 5 cases with a 12 months minimum follow-up. Clinical and bone defect features, aetiology, surgical data, complications, re-interventions, union and infection eradication rates were recorded into a database. Fischer's exact test and unpaired t-test were used for the statistical analysis on the individual patient's data. Results. Ten papers met the inclusion criteria (312 patients), but only 5 reported individual patients data (65 cases). IMT was used for acute bone loss (53%), septic (47%) and aseptic (7%) pseudo arthroses and tumour resections (2%). Bone defect length ranged from 0.6 to 26 cm. Overall, union rate was achieved in 88% of the cases and infection cured in 93%. Complication rate was 53%. Surgical variants included the use of antibiotic-loaded spacers (59.9%), internal fixation during the first step (62.1%), use of Reamer-Irrigator-Aspirator technique (40.1%) instead of iliac crest (63.1%) grafting, bone substitutes (18.3%) and growth factors addition (41%). No statistical differences were found comparing patient-related factors or surgical variants in achieving the two outcomes. Conclusions. IMT is effective to achieve bone union and infection eradication, but is associated with a high rate of complications and re-interventions. This should be taken into consideration by the surgeons and be a part of the informed consent. This systematic review was limited by the few studies meeting the inclusion criteria and their high variability in data reporting, making a meta-analysis impossible to undertake. Further studies are needed to demonstrate the role the patients’ clinical features and IMT variants with respect to bone union and infection eradication

Purpose of the study. To review the primary bone tumours of the spine treated at our unit. Description of methods. Retrospective review of folders and x-rays of all the patients with primary bone tumours of the spine treated at our unit between 2005 and 2012. All haematological tumours were excluded. Summary of results. We treated 15 cases during this period. The median age at presentation was 36 years (8–65). There was a significant delay from onset of symptoms to diagnosis in most cases (median 7 months). Histological diagnoses included:. -Benign tumours.  Active. Hemangioma. 3. Osteoid osteoma. 1. Eosinophilic granuloma. 1.  Aggressive. Osteoblastoma. 1. Giant cell tumours. 2. Aneurysmal bone cysts. 4. -Malignant tumours.  Osteosarcomas. 2.  Leiomyosarcoma of bone. 1. A variety of definitive surgical methods were utilised. Seven patients had a debulking or intralesional resection of the tumour. Eight patients had an attempted marginal excision. This was achieved through anterior surgery only in 1 case, posterior only surgery in 6 cases and combination anterior and posterior surgery in 8 cases. The anterior and posterior surgery was performed in a single sitting in 5 cases and in a staged fashion in 3 cases. Adjuvant radiotherapy and chemotherapy were used where indicated. Three cases presented with significant neurological impairment. Of these 2 made a significant recovery. There were no cases of neurological deterioration following surgery. All 3 patients with malignant tumours died in the follow up period. We had 1 case of hardware failure due to chronic sepsis. Conclusion. Primary bone tumours of the spine are associated with a significant delay in diagnosis. Surgical treatment options and adjuvant therapy should be tailor made for each case depending on the diagnosis. Acceptable results with minimal complications can be achieved with this approach

Over 80% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Although thought to involve a complex cascade of cell-cell interactions, the factors controlling the development of bone metastases are still poorly understood. Osteoblasts may have an important role in mediating homing and proliferation of breast cancer cells to the bony environment. This study aimed to examine the potential role osteoblasts have in the migration of circulating tumour cells to bone and the factors involved in this attraction. Culture of osteoblasts and MDA-MB-231 breast cancer cells was performed. Breast cancer cell migration in response to osteoblasts was measured using Transwell Migration Inserts. Potential mediators of cell migration were detected using ChemiArray & ELISA assays. A luminometer based Vialight assay was used to measure breast cancer cell proliferation in response to factors secreted by osteoblasts. There was a 3-4 fold increase of MDA-MB-231 migration in response to osteoblasts. ChemiArray analysis of osteoblast-conditioned medium revealed a range of secreted chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. Initially, MCP-1 was quantified at 282 pg/ml, but rose to over 9000 pg/ml when osteoprogenitor cells were differentiated into mature osteoblasts. Inclusion of a monoclonal antibody to MCP-1 in osteoblast-conditioned medium resulted in a significant decrease in breast cancer cell migration to osteoblasts. There was no significant change in proliferation of MDA-MB 231 cells when exposed to osteoblast-conditioned medium. Osteoblasts are capable of inducing breast cancer cell migration mediated at least in part by chemokine secretion. MCP-1 produced by the osteoblasts was shown to play a central role in mediating homing of the breast cancer cells. Increased understanding of the pathways involved in the development of bone metastases may provide new targets for therapeutic intervention

Chondrosarcoma responds poorly to adjuvant therapy and therefore, new targeted therapy is required. Animal models have been utilised to test therapeutic candidates, however clinically relevant, orthotopic models are lacking. The aim of this study was to develop such a model. In vitro: two human chondrosarcoma cell lines, JJ012 and FS090, were compared with respect to proliferation, colony formation, invasion, MMP-2 and MMP-9 secretion, osteoclastogenesis, endothelial tube stimulation, and expression of the angiogenic factor VEGF, and the anti-angiogenic factor RECK on western blotting. In vivo: 20,000 cells (JJ012 or FS090) were injected either into the intramedullary canal of the mouse tibia (n=5 for each cell line), or into the tibial periosteum (n=5 for each cell line). Animals were measured, and x-rayed weekly. Once euthanised, tibias and lungs were preserved, embedded and sectioned to determine the presence of tumour and lung metastases. In vitro: compared with FS090, JJ012 demonstrated significantly higher proliferative capacity at both day two and day four (p=0.017, and p=0.01). JJ012 had a significantly greater ability to invade Matrigel with an average number of 812.5 invading cells, versus 140.8 FS090 cells (p=0.0005). JJ012 readily formed colonies in collagen I, while FS090 formed none. JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium. In vivo: tumours formed in the intratibial and periosteal groups injected with JJ012, whilst no mice injected with FS090 cells developed discernable tumours on physical inspection, caliper measurement or histological section. Periosteal tumours grew to three times the non-injected limb size by seven weeks, whereas intratibial injected limbs required 10 weeks to achieve the same extent of tumour growth. All JJ012 periosteal tumours resulted in lung micrometastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases. Lung metastases stained positive with Von Kossa and alizarin red stains, indicating a tendency for calcification, which is similar to metastases in the human disease. Sectioned tumour tissue demonstrated features of grade II-III chondrosarcoma. Similarities with the human disease were also noted on the X-ray, including endosteal scalloping, and cortical thickening. Both intratibial and periosteal JJ012 models replicate the site, morphology, and many behavioural characteristics of human chondrosarcoma. Local tumour invasion of bone and spontaneous lung metastasis offer valuable assessment tools to test the potential of novel agents for future chondrosarcoma therapy

Purpose. Maintenance of vertebral mechanical stability is of paramount importance to prevent pathologic fractures and resultant neurologic compromise in individuals with spinal metastases. Current non-surgical treatments for vertebral metastases (i.e. chemotherapy, bisphophonates (BP) and radiation) yield variable responses in the tumour and surrounding bone. Photodynamic therapy (PDT) is a novel, minimally-invasive technology that utilizes a drug activated by light at a specific non-thermal wavelength to locally destroy tumour cells. Previously, we observed that PDT can ablate cancer cells within bone and yield short-term (1-week) improvements in vertebral architecture and biomechanical strength, particularly when combined with BP therapy. This study aims to evaluate the effects of PDT in vertebral bone over a longer (6-week) time period, alone and combined with previous BP treatment, to determine if improvements in skeletal architecture and strength are maintained. Method. Fourty healthy rnu/rnu rats were randomly assigned to four treatment groups: (i) untreated control, (ii) BP only, (iii) PDT only and (iv) PDT following BP. BP treatments were administered on day 0 via subcutaneous injection of zoledronic acid. PDT was administered on day 7 via an intravenous injection of BPD-MA photosensitizer. A flat-cut optical fiber was inserted percutaneously adjacent to lumbar vertebra L2. After a 15-minute drug-light interval, 75J of light energy was delivered from a 690nm laser. Six weeks later, animals were euthanized. Structural properties of excised L2 vertebral bodies were quantified through semi-automated analysis of micro-CT images. In of the specimens, mechanical properties were evaluated by loading the L2 vertebral body to failure in axial compression. The remaining L2 vertebrae were analyzed for morphology, osteoid formation and osteoclast activity using histological methods. Results. Combined PDT+BP treatment yielded the largest increases in bone volume fraction (31%), trabecular thickness (45%) and vBMD (37%) and decreases in trabecular number (14%) and separation (26%) compared to untreated controls (n=10, all p<0.05). The cortical shell mass fraction was significantly lower than that of controls (24%) indicating increases in bone structure were primarily due to trabecular changes. Mechanically, PDT+BP treatment demonstrated a trend towards an increase in ultimate force compared to controls (n=5, p=0.176). BP-only and PDT-only treatments demonstrated similar trends to the combined treatment, but with a lower magnitude of effect. Qualitatively, histological analysis suggested more osteoid formation in groups receiving PDT, and a higher proportion of bone in BP-treated groups. Conclusion. PDT has a sustained positive effect on the mechanical and structural integrity of bone, particularly in combination with BP treatment. By ablating tumour tissue and strengthening bone, combined PDT+BP treatment presents as an attractive adjuvant minimally-invasive therapy for spinal metastasis

We evaluated the top 13 journals in trauma and orthopaedics by impact factor and looked at the longer-term effect regarding citations of their papers.

All 4951 papers published in these journals during 2007 and 2008 were reviewed and categorised by their type, subspecialty and super-specialty. All citations indexed through Google Scholar were reviewed to establish the rate of citation per paper at two, four and five years post-publication. The top five journals published a total of 1986 papers. Only three (0.15%) were on operative orthopaedic surgery and none were on trauma. Most (n = 1084, 54.5%) were about experimental basic science. Surgical papers had a lower rate of citation (2.18) at two years than basic science or clinical medical papers (4.68). However, by four years the rates were similar (26.57 for surgery, 30.35 for basic science/medical), which suggests that there is a considerable time lag before clinical surgical research has an impact.

We conclude that high impact journals do not address clinical research in surgery and when they do, there is a delay before such papers are cited. We suggest that a rate of citation at five years post-publication might be a more appropriate indicator of importance for papers in our specialty.

Cite this article: Bone Joint J 2014;96-B:414–19.