Aims. Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro. Methods. MG63 and U2OS cells were treated with benzamil for 24 hours. Cell viability was evaluated with the MTS/PMS assay, colony formation assay, and flow cytometry (forward/side scatter). Chromosome condensation, the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cleavage of poly-ADP ribose polymerase (PARP) and caspase-7, and FITC annexin V/PI double staining were monitored as indicators of apoptosis. Intracellular calcium was detected by flow cytometry with Fluo-4 AM. The phosphorylation and activation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) were measured by western blot. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), SOD1, and SOD2 were also assessed by western blot. Mitochondrial status was assessed with tetramethylrhodamine, ethyl ester (TMRE), and intracellular adenosine triphosphate (ATP) was measured with BioTracker ATP-Red Live Cell Dye. Total cellular integrin levels were evaluated by western blot, and the expression of cell surface integrins was assessed using fluorescent-labelled antibodies and flow cytometry. Results. Benzamil suppressed growth of osteosarcoma cells by inducing apoptosis. Benzamil reduced the expression of cell surface integrins α5, αV, and β1 in MG63 cells, while it only reduced the expression of αV in U2OS cells. Benzamil suppressed the phosphorylation and activation of FAK and STAT3. In addition, mitochondrial function and ATP production were compromised by benzamil. The levels of anti-apoptotic proteins XIAP, Bcl-2, and Bcl-xL were reduced by benzamil. Correspondingly, benzamil potentiated cisplatin- and methotrexate-induced apoptosis in osteosarcoma cells. Conclusion. Benzamil exerts anti-osteosarcoma activity by inducing apoptosis. In terms of mechanism, benzamil appears to inhibit integrin/FAK/STAT3 signalling, which triggers mitochondrial dysfunction and ATP depletion. Cite this article: Bone Joint Res 2024;13(4):157–168

Aims. The proximal tibia (PT) is the anatomical site most frequently affected by primary bone tumours after the distal femur. Reconstruction of the PT remains challenging because of the poor soft-tissue cover and the need to reconstruct the extensor mechanism. Reconstructive techniques include implantation of massive endoprosthesis (megaprosthesis), osteoarticular allografts (OAs), or allograft-prosthesis composites (APCs). Methods. This was a retrospective analysis of clinical data relating to patients who underwent proximal tibial arthroplasty in our regional bone tumour centre from 2010 to 2018. Results. A total of 76 patients fulfilled the inclusion criteria and were included in the study. Mean age at surgery was 43.2 years (12 to 86 (SD 21)). The mean follow-up period was 60.1 months (5.4 to 353). In total 21 failures were identified, giving an overall failure rate of 27.6%. Prosthesis survival at five years was 75.5%, and at ten years was 59%. At last follow-up, mean knee flexion was 89.8° (SD 36°) with a mean extensor lag of 18.1° (SD 24°). In univariate analysis, factors associated with better survival of the prosthesis were a malignant or metastatic cancer diagnosis (versus benign), with a five- and ten-year survival of 78.9% and 65.7% versus 37.5% (p = 0.045), while in-hospital length of stay longer than nine days was also associated with better prognosis with five- and ten-year survival rates at 84% and 84% versus 60% and 16% (p < 0.001). In multivariate analysis, only in-hospital length of stay was associated with longer survival (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.08 to 0.66). Conclusion. We have shown that proximal tibial arthroplasty with endoprosthesis is a safe and reliable method for reconstruction in patients treated for orthopaedic oncological conditions. Either modular or custom implants in this series performed well. Cite this article: Bone Jt Open 2022;3(9):733–740

Aims. Bone metastasis ultimately occurs due to a complex multistep process, during which the interactions between cancer cells and bone microenvironment play important roles. Prior to colonization of the bone, cancer cells must succeed through a series of steps that will allow them to gain migratory and invasive properties; epithelial-to-mesenchymal transition (EMT) is known to be integral here. The aim of this study was to determine the effects of G protein subunit alpha Q (GNAQ) on the mechanisms underlying bone metastasis through EMT pathway. Methods. A total of 80 tissue samples from patients who were surgically treated during January 2012 to December 2014 were used in the present study. Comparative gene analysis revealed that the GNAQ was more frequently altered in metastatic bone lesions than in primary tumour sites in lung cancer patients. We investigated the effects of GNAQ on cell proliferation, migration, EMT, and stem cell transformation using lung cancer cells with GNAQ-knockdown. A xenograft mouse model tested the effect of GNAQ using micro-CT analyses and histological analyses. Results. GNAQ-knockdown showed down-regulation of tumour growth through mitogen-activated protein kinase (MAPK) signalling in lung cancer cells, but not increased apoptosis. We found that GNAQ-knockdown induced EMT and promoted invasiveness. GNAQ-knockdown cells injected into the bone marrow of murine tibia induced tumour growth and bone-to-lung metastasis, whereas it did not in control mice. Moreover, the knockdown of GNAQ enhanced cancer stem cell-like properties in lung cancer cells, which resulted in the development of resistance to chemotherapy. Conclusion. The present study reveals that the GNAQ-knockdown induced cancer stem cell-like properties. Cite this article: Bone Joint Res 2021;10(5):310–320

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Treatment of high-grade limb bone sarcoma that invades a joint requires en bloc extra-articular excision. MRI can demonstrate joint invasion but is frequently inconclusive, and its predictive value is unknown. We evaluated the diagnostic accuracy of direct and indirect radiological signs of intra-articular tumour extension and the performance characteristics of MRI findings of intra-articular tumour extension.

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The present study investigated receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), and Runt-related transcription factor 2 (RUNX2) gene expressions in giant cell tumour of bone (GCTB) patients in relationship with tumour recurrence. We also aimed to investigate the influence of CpG methylation on the transcriptional levels of RANKL and OPG.

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We first sought to compare survival for patients treated surgically for solitary and multiple metastases in the appendicular skeleton, and second, to explore the role of complete and incomplete resection (R0 and R1/R2) in patients with a solitary bony metastasis in the appendicular skeleton.

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Radiotherapy is a well-known local treatment for spinal metastases. However, in the presence of postoperative systemic therapy, the efficacy of radiotherapy on local control (LC) and overall survival (OS) in patients with spinal metastases remains unknown. This study aimed to evaluate the clinical outcomes of post-surgical radiotherapy for spinal metastatic non-small-cell lung cancer (NSCLC) patients, and to identify factors correlated with LC and OS.

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Acridine orange (AO) demonstrates several biological activities. When exposed to low doses of X-ray radiation, AO increases the production of reactive radicals (radiodynamic therapy (AO-RDT)). We elucidated the efficacy of AO-RDT in breast and prostate cancer cell lines, which are likely to develop bone metastases.

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The aim of this study was to determine the prevalence and impact of tourniquet use in patients undergoing limb salvage surgery with endoprosthetic reconstruction for a tumour around the knee.

Aims. The aim of this study was to evaluate the prosthesis characteristics and associated conditions that may modify the survival of total femoral endoprosthetic replacements (TFEPR). Patients and Methods. In all, 81 patients treated with TFEPR from 1976 to 2017 were retrospectively evaluated and failures were categorized according to the Henderson classification. There were 38 female patients (47%) and 43 male patients (53%) with a mean age at diagnosis of 43 years (12 to 86). The mean follow-up time was 10.3 years (0 to 31.7). A survival analysis was performed followed by univariate and multivariate Cox regression to identify independent implant survival factors. Results. The revision-free survival of the implant was 71% at five years and 63.3% at ten years. Three prostheses reached 15 years without revision. The mean Musculoskeletal Tumor Society score in the group was 26 (23 to 28). The mechanisms of failure were infection in 18%, structural failures in 6%, tumour progression in 5%, aseptic loosening in 2%, and soft-tissue failures in 1%. Prostheses used for primary reconstruction after oncological resections had lower infection rates than revision implants (8% vs 25%; p = 0.001). The rates of infection in silver-coated and non-silver-coated prosthesis were similar (17.4% vs 19.%; p = 0.869). The incidence of hip dislocation was 10%. Rotating hinge prosthesis had a lower failure rate than fixed hinge prosthesis (5.3% vs 11%). After Cox regression, the independent factors associated with failures were the history of previous operations (hazard ratio (HR) 3.7; p = 0.041), and the associated arthroplasty of the proximal tibia (HR 3.8; p = 0.034). At last follow-up, 11 patients (13%) required amputation. Conclusion. TFEPR offers a reliable reconstruction option for massive bone loss of the femur, with a good survival when the prosthesis is used as a primary implant. The use of a rotating hinge at the knee and dual mobility bearing at the hip may be adequate to reduce the risk of mechanical and soft-tissue failures. Infection remains the main concern and there is insufficient evidence to support the routine use of silver-coated endoprosthesis. Cite this article: Bone Joint J 2019;101-B:522–528

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The modified Glasgow Prognostic Score (mGPS) uses preoperative CRP and albumin to calculate a score from 0 to 2 (2 being associated with poor outcomes). mGPS is validated in multiple carcinomas. To date, its use in soft-tissue sarcoma (STS) is limited, with only small cohorts reporting that increased mGPS scores correlates with decreased survival in STS patients.

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Rotating-hinge knee prostheses are commonly used to reconstruct the distal femur after resection of a tumour, despite the projected long-term burden of reoperation due to complications. Few studies have examined the factors that influence their failure and none, to our knowledge, have used competing risk models to do so. The purpose of this study was to determine the risk factors for failure of a rotating-hinge knee distal femoral arthroplasty using the Fine-Gray competing risk model.

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We have previously reported cryoablation-assisted joint-sparing surgery for osteosarcoma with epiphyseal involvement. However, it is not clear whether this is a comparable alternative to conventional joint arthroplasty in terms of oncological and functional outcomes.

Aims. To assess complications and failure mechanisms of osteoarticular allograft reconstructions for primary bone tumours. Patients and Methods. We retrospectively evaluated 38 patients (28 men, 74%) who were treated at our institution with osteoarticular allograft reconstruction between 1989 and 2010. Median age was 19 years (interquartile range 14 to 32). Median follow-up was 19.5 years (95% confidence interval (CI) 13.0 to 26.1) when 26 patients (68%) were alive. In addition, we systematically searched the literature for clinical studies on osteoarticular allografts, finding 31 studies suitable for analysis. Results of papers that reported on one site exclusively were pooled for comparison. Results. A total of 20 patients (53%) experienced graft failure, including 15 due to mechanical complications (39%) and three (9%) due to infection. In the systematic review, 514 reconstructions were analysed (distal femur, n = 184, 36%; proximal tibia, n = 136, 26%; distal radius, n = 99, 19%; proximal humerus, n = 95, 18%). Overall rates of failure, fracture and infection were 27%, 20%, and 10% respectively. With the distal femur as the reference, fractures were more common in the humerus (odds ratio (OR) 4.1, 95% CI 2.2 to 7.7) and tibia (OR 2.2, 95% CI 1.3 to 4.4); infections occurred more often in the tibia (OR 2.2, 95% CI 1.3 to 4.4) and less often in the radius (OR 0.1, 95% CI 0.0 to 0.8). Conclusion. Osteoarticular allograft reconstructions are associated with high rates of mechanical complications. Although comparative studies with alternative techniques are scarce, the risk of mechanical failure in our opinion does not justify routine employment of osteoarticular allografts for reconstruction of large joints after tumour resection. Cite this article: Bone Joint J 2017;99-B:522–30

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We have evaluated the survivorship, outcomes, and failures of an interlocking, reconstruction-mode stem-sideplate implant used to preserve the native hip joint and achieve proximal fixation when there is little residual femur during large endoprosthetic reconstruction of the distal femur.

Expandable prostheses were designed to allow progressive growth after tumour resection in children. The aim of this study was to report the late results of the non-invasive growing prostheses designed by A Soubeyran (Phenix prosthesis or Wright Repiphysis). From 1994 to January 2006, 27 children aged 4 to 12 (mean 8.5), underwent a resection of the knee for a bone tumour, with reconstruction by a non invasive expandable prosthesis. There were 16 boys and 11 girls. The tumours were 25 osteosarcomas and 2 Ewing tumours. All patients received pre and post-operative chemotherapy. There were 18 distal femur, 7 proximal tibia, and 2 femur + tibia resections. There were different successive designs based on the same electro-magnetic growing mechanism using a pre bent spring, released by eating in an induction coil. After, 7.2 years mean follow-up (4 months to 15 years), 20 patients had no evidence of disease and 7 were deceased. Two with a local recurrence were amputated. Mean lengthening was 5.1 centimeters (0 to 8), after 3 to 11 lengthening procedures. Mean limb-length discrepancy was 1.8 cm. Two patients had a secondary infection. Eleven had a revision for arthrofibrosis. All surviving patients were revised to a conventional hinged prosthesis. The mean MSTS functional score of the definitive prosthesis was 82% (63 to 96%). Theses prostheses showed many mechanical complications as loosening, fracture of the growing mechanism, and arthrofibrosis. The positive outcome was the possibility to perform a progressive lengthening, without surgery limiting the risk of infection. Theses prostheses should be considered as temporary until reconstruction with a conventional hinged prosthesis. Patients with multiple revisions had a tendency to show less favourable late functional results than with primary implanted hinged prosthesis

Chondrosarcomas are malignant hyaline cartilage tumours of bone. They are clinically resistant to conventional chemo- and radiotherapy and the underlying mechanism is poorly studied. Chemoresistance is a multifactorial process and the inaccessibility due to abundant hyaline cartilaginous matrix surrounding the cells, presence of multi-drug resistance pumps, and expression of anti-apoptotic proteins such as BCL2, have been suggested. Our aim was to study chemoresistance mechanisms in chondrosarcoma. We first studied the sensitivity of chondrosarcoma cell lines (SW1353, CH2879, JJ012, OUMS27) and 2 primary cultures for doxorubicin and cisplatin. We used a 3D pellet model of CH2879 to study doxorubicin incorporation. To investigate whether chondrosarcoma cells could be resensitised to chemotherapy we tested the BH3 mimetic ABT737 inhibiting anti-apoptotic BCL2 family proteins. Cell viability was assessed using a WST assay for mitochondrial activity. Dose response curves showed that chondrosarcoma cell lines and cultures are partially resistant to doxorubicin, while primary cultures were completely resistant to cisplatin. In 3D cell pellets, with morphology strongly resembling high grade chondrosarcoma, doxorubicin incorporation was confirmed. Chondrosarcoma cells responded to ABT737 with a >60% reduction in cell viability at high concentrations (25μM). Combination treatment allowing 2 days between ABT737 and chemotherapy addition led to a complete reduction of cell viability in all cell cultures. In conclusion, chondrosarcoma cell lines show a partial response to doxorubicin and less response to cisplatin. The incorporation of doxorubicin in the cells in a 3D pellet model indicates that resistance is not caused by inaccessibility of the cells for the drugs nor by multi-drug resistance pump activity. By combining BCL2 inhibition with Doxorubicin treatment, a complete reduction of cell viability was obtained. This suggests that BCL2 overexpression plays an important role in chemoresistance of chondrosarcoma, and turning on the apoptotic machinery by BCL 2 inhibition can render them chemosensitive

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There is a lack of evidence about the risk factors for local recurrence of a giant cell tumour (GCT) of the sacrum treated with nerve-sparing surgery, probably because of the rarity of the disease. This study aimed to answer two questions: first, what is the rate of local recurrence of sacral GCT treated with nerve-sparing surgery and second, what are the risk factors for its local recurrence?

We retrospectively studied 14 patients with proximal and diaphyseal tumours and disappearing bone (Gorham’s) disease of the humerus treated with wide resection and reconstruction using an allograft-resurfacing composite (ARC). There were ten women and four men, with a mean age of 35 years (8 to 69). At a mean follow-up of 25 months (10 to 89), two patients had a fracture of the allograft. In one of these it was revised with a similar ARC and in the other with an intercalary prosthesis. A further patient had an infection and a fracture of the allograft that was revised with a megaprosthesis. In all patients with an ARC, healing of the ARC-host bone interface was observed. One patient had failure of the locking mechanism of the total elbow replacement. The mean post-operative Musculoskeletal Tumor Society score for the upper extremity was 77% (46.7% to 86.7%), which represents good and excellent results; one patient had a poor result (46.7%). In the short term ARC effectively relieves pain and restores shoulder function in patients with wide resection of the proximal humerus. Fracture and infection remain significant complications

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We aimed to examine the long-term mechanical survivorship, describe the modes of all-cause failure, and identify risk factors for mechanical failure of all-polyethylene tibial components in endoprosthetic reconstruction.