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Aims: A growing number of fractures progress to delayed or nonunion, causing significant morbidity and socioeconomic impact. Localized delivery of stem cells and subcutaneous parathyroid hormone (PTH) has been shown individually to accelerate bony regeneration. This study aimed to combine the therapies with the aim of upregulating fracture healing., Methods: A 1.5 mm femoral osteotomy (delayed union model) was created in 48 female juvenile Wistar rats, aged six to nine months, and stabilized using an external fixator. At day 0, animals were treated with intrafracture injections of 1 × 10 6 cells/kg bone marrow mesenchymal stem cells (MSCs) suspended in fibrin, daily subcutaneous injections of high (100 μg/kg) or low (25 μg/kg) dose PTH 1-34, or a combination of PTH and MSCs. A group with an empty gap served as a control. Five weeks post-surgery, the femur was excised for radiological, histomorphometric, micro-CT, and mechanical analysis., Results: Combination therapy treatment led to increased callus formation compared to controls. In the high-dose combination group there was significantly greater mineralized tissue volume and trabecular parameters compared to controls (p = 0.039). This translated to significantly improved stiffness (and ultimate load to failure (p = 0.049). The high-dose combination therapy group had the most significant improvement in mean modified Radiographic Union Score for Tibia fractures (RUST) compared to controls (13.8 (SD 1.3) vs 5.8 (SD 0.5)). All groups demonstrated significant increases in the radiological scores - RUST and Allen score - histologically compared to controls., Conclusion: We demonstrate the beneficial effect of localized MSC injections on fracture healing combined with low- or high-dose teriparatide, with efficacy dependent on PTH dose. Cite this article: Bone Joint Res  2021;10(10):659-667.

Background: Partial ablation of the prostate using high-intensity focussed ultrasound (HIFU-PA) is a treatment option for localised prostate cancer. When local recurrence occurs, salvage robot-assisted radical prostatectomy is a treatment option for selected patients, but there is a paucity of data on the peri-operative safety, functional and oncologic outcomes of sRARP.. The objective of this study was therefore to describe peri-operative safety, functional and early oncologic outcomes following salvage robot-assisted radical prostatectomy (sRARP) for local recurrence after HIFU-PA., Methods: Retrospective analysis of a prospective database of 53 consecutive men who underwent sRARP after HIFU-PA from 2012 to 2018. Continence and erectile-function were reported pre-HIFU, pre-sRARP, 3-months post-sRARP and 12-months post-sRARP. Complications, PSMs and need for subsequent ADT/radiotherapy were assessed., Results: 45 men were suitable for inclusion and had sufficient data for analyses. Median duration from HIFU to sRARP was 30.0 months and median follow-up post-sRARP was 17.7 months. Median age, PSA and ISUP group were 63.0 yrs., 7.2 ng/mL and 2; 88.9% were cT2. Median operative-console time, blood loss and hospital stay were 140 min, 200 ml and 1 day respectively. Clavien-Dindo grade 1, 2 and 3 complications < 90 days occurred in 8.9, 6.7 and 2.2%; late (>90d) complications occurred in 13.2%. At sRARP pathology, ISUP 3-5 occurred in 51.1%, pT3a/b in 64.5%, and PSMs in 44.4% (37.5% for pT2, 48.3% for pT3). Of men with > 3-months follow-up after sRARP, 26.3% underwent adjuvant radiotherapy/ADT for residual disease or adverse pathologic features; 5.3% experienced BCR requiring salvage ADT/radiotherapy. Freedom from ADT/radiotherapy was 66.7% at 12-months. Pad-free rates were 100% pre-HIFU, 95.3% post-HIFU, 29.4% 3-months post-sRARP, and 65.5% 12-months post-sRARP. Median IIEF-5 scores pre-HIFU, post-HIFU, 3- and 12-months post-sRARP were 23.5, 16, 5 and 5, respectively. Potency rates were 81.8, 65.5, 0 and 0%, respectively. Bilateral/unilateral nerve sparing were feasible in 7%/22%., Conclusion: Salvage RARP was safe with acceptable but sub-optimal continence and poor sexual-function and poor oncologic outcomes. One in three men required additional treatment within 12-months. This information may aid men and urologists with treatment selection and counselling regarding primary HIFU-PA vs primary RARP and when considering salvage RARP.

Periprosthetic joint infection (PJI) is associated with high patient morbidity and a large financial cost. This study investigated Photodynamic Therapy (PDT) as a means of eradicating bacteria that cause PJI, using a laser with a 665-nm wavelength and methylene blue (MB) as the photosensitizer. The effectiveness of MB concentration on the growth inhibition of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Acinetobacter baumannii was investigated. The effect of laser dose was also investigated and the optimized PDT method was used to investigate its bactericidal effect on species within planktonic culture and following the formation of a biofilm on polished titanium and hydroxyapatite coated titanium discs. Results showed that Staphylococci were eradicated at the lowest concentration of 0.1 mM methylene blue (MB). With P. aeruginosa and A. baumannii, increasing the MB concentration improved the bactericidal effect. When the laser dose was increased, results showed that the higher the power of the laser the more bacteria were eradicated with a laser power ≥ 35 J/cm 2 and an irradiance of 35 mW/cm 2 , eradicating all S. epidermidis. The optimized PDT method had a significant bactericidal effect against planktonic MRSA and S. epidermidis compared to MB alone, laser alone, or control (no treatment). When biofilms were formed, PDT treatment had a significantly higher bactericidal effect than MB alone and laser alone for all species of bacteria investigated on the polished disc surfaces. P. aeruginosa grown in a biofilm was shown to be less sensitive to PDT when compared to Staphylococci, and a HA-coated surface reduced the effectiveness of PDT. This study demonstrated that PDT is effective for killing bacteria that cause PJI.

Background: Robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) is an attractive option to open cystectomy, but the benefit in terms of improved outcomes is not established., Objective: To evaluate the early postoperative morbidity and mortality of patients undergoing iRARC and conduct a critical analysis of complications using standardised reporting criteria as stratified according to urinary diversion., Design, Setting, and Participants: A total of 134 patients underwent iRARC for bladder cancer at a single centre between June 2011 and July 2015., Intervention: Radical cystectomy with iRARC., Outcome Measurements and Statistical Analysis: Patient demographics, pathologic data, and 90-d perioperative mortality and complications were recorded. Complications were reported according to the Clavien-Dindo (CD) classification and stratified according to urinary diversion type and either surgical or medical complications. The chi-square test and t test were used for categorical and continuous variables respectively. Multivariable logistic regression was performed on variables with significance in univariate analysis., Results and Limitations: The 90-d all complication rate following ileal conduit and continent diversion was 68% and 82.4%, and major complications were 21.0% and 20.6% respectively. The 90-d mortality was 3% and 2.9% for ileal conduit and continent diversion patients, respectively. On multivariate analysis, the blood transfusion requirement was independently associated with major complications (p=0.002) and all 30-d (p=0.002) and 90-d (p=0.012) major complications. Male patients were associated with 90-d major complications (p=0.015). Critical analysis identified that surgical complications were responsible for 39.4% of all 90-d major complications. The incidence of surgical complications did not decline with increasing number of iRARC cases performed (p=0.742, r=0.31). Limitations of this study include its retrospective nature, limited sample size, and limited multivariate analysis due to the low number of major complications events., Conclusions: Although complications following iRARC are common, most are low grade. A critical analysis identified surgical complications as a cause of major complications. Addressing this issue could have a significant impact on lowering the morbidity associated with iRARC., Patient Summary: We looked at the surgical outcomes in bladder cancer patients treated with minimally invasive robotic surgery. We found that surgical complications account for most major complications and previous surgical experience may be a confounding factor when interpreting results from a different centre even in a randomised trial setting., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Congenital indifference to pain with anhidrosis (CIPA) is a rare hereditary neuropathy, which is associated with defective sensation to noxious stimuli and autonomic dysfunction. The objective of the study was to report on the orthopaedic manifestations of this condition and provide an evidence-based approach for management., Methods: Retrospective review of 14 consecutive patients with CIPA referred to a single tertiary centre. Mean age of diagnosis was 2.5 years (range 0.5 to 11 years)., Results: Patients presented with a range of orthopaedic problems including fractures, infections, growth disturbance, joint subluxation and Charcot joints affecting the limbs and spine. Conservative treatment with closed reduction and cast immobilisation was satisfactory for stress fractures of the lower extremity and Charcot joints. Posterior instrumented correction of scoliosis was associated with a high-risk of infection requiring reoperation for debridement and removal of posterior instrumentation. Growth disturbance leading to leg-length discrepancies were managed with shoe raises and corrective osteotomies. Aspiration and cultures may be used to differentiate between acute fracture and infection., Conclusions: Preventative treatment strategies with appropriately padded shoe-wear, gait and posture modification, parental education regarding environmental thermoregulation, and behavioural support are essential for improving prognosis and reducing long-term complications., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: From 1998 to 2008, 1000 skeletally mature patients underwent autologous chondrocyte implantation for an osteochondral defect of the knee. We evaluated the functional outcomes in 827 of 869 patients who had undergone autologous chondrocyte implantation with Chondron or periosteum (ACI-C/ACI-P) or matrix-assisted chondrocyte implantation (MACI) and attempted to identify factors that influenced outcome., Methods: The age of the patient, the size and site of the osteochondral lesion, previous surgery, and the presence of early osteoarthritis were assessed for their influence on outcomes. Each factor was evaluated in a separate Cox proportional hazards model with use of hazard ratios (HRs), with 95% confidence intervals (CIs), describing the likelihood of failure for that particular factor. Outcomes were assessed with use of the modified Cincinnati score, visual analog scale pain score, and Stanmore functional score., Results: The mean duration of follow-up was 6.2 years (range, two to twelve years). The mean age was thirty-four years (range, fourteen to fifty-six years), with 493 males and 334 females. The average size of the defect was 409 mm2 (range, 64 to 2075 mm2). Four hundred and twenty-one procedures (51%) were performed on the medial femoral condyle; 109 (13%), on the lateral femoral condyle; 200 (24%), on the patella; and fifty (6%), on the trochlea. Kaplan-Meier survival analysis revealed that the unadjusted graft survival rate was 78.2% at five years and 50.7% and ten years for the entire cohort. No difference was found between the survival rates of the ACI-C/ACI-P and MACI techniques (HR = 0.948, 95% CI = 0.738 to 1.219, p = 0.678). There was a significant postoperative improvement in the function and pain scores of all three outcome measures (p &lt; 0.002). Survivorship in the group with a previous cartilage regenerative procedure was inferior to that in patients with a previously untreated lesion, with failure five times more likely in the former group (HR = 4.718, standard error [SE] = 0.742, 95% CI = 3.466 to 6.420, p &lt; 0.001). Degenerative change in any compartment had a significant detrimental effect on survivorship, with survivorship worsening as the osteoarthritis grade increased (Grade 1: HR = 2.077, 95% CI = 1.299 to 3.322, p = 0.002; Grade 2: HR = 3.450, 95% CI = 2.646 to 4.498, p &lt; 0.001; and Grade 3: HR = 3.820, 95% CI = 2.185 to 6.677, p &lt; 0.001)., Conclusions: Our study demonstrated an overall graft survival of 78% at five years and 51% beyond ten years following both autologous chondrocyte implantation techniques. Despite study limitations, our results demonstrate that autologous chondrocyte implantation for the treatment of osteochondral defects of the knee can achieve good results., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: Controversies still exist regarding the optimal diagnostic and therapeutic strategies in patients with prosthetic joint infections (PJI)., Questions/purposes: How effective are preoperative and intraoperative cultures in isolating organisms and how do these culture results compare to one another? What are the results of surgical treatment of PJI in the hip and knee in an international, tertiary referral center cohort?, Patients and Methods: One hundred sixteen patients (N = 59 hip PJI, N = 57 knee PJI) were recruited prospectively to registries at three international, tertiary referral centers between December 2008 to November 2011. Retrospective review of prospective registry data including demographics, microbiology results, and operative reports was performed., Results: Preoperative synovial fluid aspiration yielded an organism in only 45.2% and 44.4% of cases, respectively, for knee and hip PJI. False-negative rates of preoperative aspiration relative to intraoperative culture were 56% and 46% in hip and knee PJI, respectively, with discordance rates of 25% and 21.4%, respectively. Rates of negative intraoperative cultures were 15% in hip PJI and 20.7% in knee PJI. Open debridement with prosthetic retention was the most common initial revision procedure performed (48.3% of hip PJI and 63.8% of knee PJI). This method of revision was successful in 41.3% of hip PJI and 59.4% of knee PJI. Initial failure rates for prosthetic revision was lower than debridement with prosthetic retention but remained substantial in both hip PJI (initial success of one-stage exchange 60% and two-stage exchange 70%) and knee PJI (initial success of one-stage exchange 80% and two-stage exchange 75%)., Conclusion: Diagnosis and treatment of PJI remains challenging with difficulty in isolating the offending organism and with high rates of prosthetic revision and initial treatment failures. Future advances in organism isolation and international standardization of treatment protocols may improve patient outcomes.

Periprosthetic femoral fractures with long stem implants, poor bone stock and loosening pose a considerable surgical challenge. We describe a reconstruction technique using a custom-made mega-prosthesis, cement-linked to the femoral stem of a well-fixed existing implant. Clinical and radiological outcomes were assessed at our tertiary referral centre. There were 15 patients with a periprosthetic femoral fracture: 5 proximal and 10 distal femoral arthroplasties linked to existing femoral stems. The survival rate was 93.3% at a mean follow-up of 5.3 years (0.5-19.3) with 1 revision. We present a salvage technique with good intermediate-term outcomes for highly selected patients with complex periprosthetic femoral fractures, as another option to conventional fixation methods. Specifically, it allows immediate weight bearing and avoids some of the morbidity of total femoral arthroplasty or amputation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Knee arthrodesis is most commonly performed for failed total knee arthroplasty. Conventional arthrodesis techniques are associated with a high incidence of complications and are unsuitable in cases with extensive bone loss. We report our medium-term results using a custom-made cemented knee arthrodesis prosthesis in 10 patients with a mean follow-up of 56.4 months (range, 15-199 months). The prosthesis was implanted as a 1- or 2-stage procedure for infected revision knee arthroplasty or tumor endoprosthesis in 9 patients and as a primary procedure in 1 patient with angiosarcoma involving the knee extensor mechanism. The average combined femoral and tibial bone deficit was 170 mm (range, 56-220 mm). Implant survivorship was 90%. All patients with retained prosthesis had no evidence of residual infection or loosening and were able to mobilize independently. One prosthesis was revised though retained following a prosthetic fracture, and 1 patient underwent above-knee amputation for uncontrolled infection. We conclude that the Stanmore knee arthrodesis prosthesis provides reliable fusion in an otherwise difficult-to-treat group of patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The optimal reconstructive method following segmental resection of malignant tumours in the humeral diaphysis is unknown as there are no prospective long-term studies comparing biologic with endoprosthetic reconstruction. This is a retrospective review of 13 patients who, between 1995 and 2010, had undergone limb salvage at our institution using a custom-made humeral diaphyseal endoprosthetic replacement following excision of malignant bone disease. There were 9 males and 4 females with a mean age of 35 years at the time of surgery (range: 10 to 78). Mean follow-up was 56.8 months (range: 5 to 148). Cumulative patient survival was 75% at 10 years. Implant survival, with removal of the endoprosthesis or part of it for any reason as an end point, was 47% at 10 years. Seven patients required revision (54%). Complications included metastases in four, aseptic loosening in four, peri-prosthetic fracture in two and local recurrence in two. Mean MSTS and TESS scores were 23 (18 to 27) and 67% (52-80) respectively. Custom-made humeral diaphyseal replacement following resection of malignant bone tumours provided functional results superior to amputation, without an obvious compromise in patient survival. There was a relatively high revision rate for aseptic loosening and peri-prosthetic fracture and patients should be counselled about this preoperatively.

Addressing severe proximal femoral bone loss in revision hip surgery is a challenging reconstructive problem. The use of modular proximal femoral megaprostheses is one of many available options to address this. This is a retrospective review of 15 patients who had undergone limb salvage at our institution using a modular proximal femoral replacement. There were 8 males and 7 females with a mean age of 67 years (34 to 85) and a mean follow-up of 60 months (1 to 99). Indications included re-implantation for deep infection in nine patients, aseptic loosening in three, periprosthetic fracture in two and painful excision arthroplasty in one. Mean Harris hip score increased from 28 (13 to 49) pre-operatively to 69 (39 to 85) at final follow-up (paired t-test, p < 0.0001) and mean Toronto Extremity Salvage score increased from 26% (14 to 40) to 71% (35 to 82) (paired t-test, p < 0.0001). Prosthesis survival with revision as the endpoint was 87% at 5 years. There were two dislocations (14%) and there was failure to eradicate deep infection in two. Modular proximal femoral replacement provided good function and versatility with an acceptable complication rate for patients with severe proximal femoral bone loss with or without infection.

Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2alpha), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

The aim of this study was to compare accuracy of an image guided percutaneous core needle biopsy (PCNB), using ultrasound or computed tomography, to PCNB without image guidance in the diagnosis of palpable soft tissue tumours. One hundred forty patients with a suspected soft tissue sarcoma underwent a percutaneous core needle biopsy with or without image guidance. One hundred eleven patients had subsequent surgical excision. The accuracy of guided PCNB and blind PCNB was calculated by comparing the histological results of the needle biopsy to the surgical specimen. The diagnostic accuracy of blind percutaneous core needle biopsy was 78% (36 of 46 biopsies) and was significantly lower (p < or = 0.025) in comparison to image guided percutaneous core needle biopsy, which was 95% (62 of 65 biopsies). We suggest that image guidance improves the diagnostic accuracy of PCNB especially for small-size deep sited suspected soft tissue tumours.

Metal-on-metal (MoM) hip bearings are being inserted into ever-younger patients. The effects on the immune system of chronic exposure are unknown. We investigated the immune response of patients with MoM hip bearings. In patients with MoM implants, the expression of antigen-presenting cell (APC) surface molecules (CD86 and HLA-DR) was seen to be significantly higher (P < .05) than control group. High levels of APC surface molecules suggest an activated state and attempts to propagate an immune response. However, in the same group, the expression of T-cell markers (CD3 and CD28) was low, indicating a small T-cell population. This suggests, despite the activation of APCs, that T cells down-regulate immune responses in MoM articulations. Conversely, in metal-on-polyethylene articulations, expression of T-cell molecules was elevated and expression of APC molecules lowered.

We treated three patients with aneurysmal bone cysts and seven with giant cell tumours who presented with a large osteolytic lesion in peri-articular areas of the knee. The patients age ranged from 8 to 49 years (mean 25 years). The average tumour volume was measured at 39.8 cm(3) (range 18 to 65 cm(3)). The tumour cavities were treated with curettage, phenolisation and application of a composite bone graft substitute containing 35% calcium-sulphate hemihydrate and 65% hydroxyapatite granules. All patients were followed up for 4.0 to 5.2 years (mean 4.5 years). Tumour recurrence was noted in two cases. In the remaining patients consolidation of the lesion was considered complete at a mean of 4.5 months (3-6.5 months). During follow-up no deformities developed and no radiological signs of joint degeneration were noted. All patients regained close to normal function, with a mean Musculoskeletal Tumour Society Rating Score of 95.1%. Due to their good osteoconductive abilities, composite synthetic bone graft substitute combining porous hydroxyapatite with calcium-sulphate appears to be an effective alternative to autologous cancellous bone graft in the treatment of large osteolytic lesions in peri-articular areas around the knee joint. They bear major advantages through ubiquitous availability and the avoidance of morbidity associated with iliac crest harvest. Concerns remain as the radio-opaque appearance of the bone graft substitute may potentially delay the detection of tumour recurrence.

Limited research has analysed paediatric shoulder girdle aneurysmal bone cyst management and outcomes. This study analysed locations affected, investigations, treatments and recurrence in children treated at the London Bone Tumour Unit between 1998 and 2004 and in English and French literature between 1956 and 2004. The proximal humerus and clavicle are most frequently affected whereas scapula involvement is rare. Radiographs, computed tomography and MRI are valuable. Sole curettage of clavicle and scapula lesions has low recurrence rates. Proximal humerus lesions recur most frequently. Curettage alone or with cementation are the most appealing treatments but are associated with significant recurrence.

Osteoblast progenitor cells (OBPCs) isolated from bone marrow have the ability to differentiate into osteoblasts and thus potential therapeutic use to tissue-engineer bone. In order for OBPCs to be available for clinical use a means of storing viable cells is necessary. The aim of this study was to determine whether a simple method of cryopreservation had an effect on osteogenic differentiation or growth of OBPCs isolated from fresh human bone marrow. Stro-1 was used to identify the isolated OBPCs. The osteoblastic potential of the marrow cells was confirmed as culture with osteogenic supplements (OS) significantly increased osteoblastic protein production (alkaline phosphatase (ALP), osteopontin and osteocalcin) compared with standard conditions (P less than 0.05). Ten further marrow aspirates were harvested; each was halved for either cryopreservation or control culture. Primary cultures from both populations formed colonies with recognised OBPC morphology. OS stimulated both cryopreserved and control populations to produce significantly more osteoblastic proteins (P less than 0.05) and there was no significant difference between the increase in osteogenic proteins when cultured with OS (P great than 0.2). The proliferation rate after 5 days in culture was not significantly affected by cryopreservation (P greater than 0.05). It has been suggested that OBPCs are immuno-privileged; so allogenic cells could be implanted into patients for tissue engineering bone without causing a hypersensitivity reaction. Our study demonstrates a method of storage, which allows OBPCs to be available for use without affecting osteoblastic potential or viability.