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Bone & Joint Research
Vol. 13, Issue 2 | Pages 83 - 90
19 Feb 2024
Amri R Chelly A Ayedi M Rebaii MA Aifa S Masmoudi S Keskes H

Aims. 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. Methods. A total of 32 GCTB tissue samples were analyzed, and the expression of RANKL, OPG, and RUNX2 was evaluated by quantitative polymerase chain reaction (qPCR). The methylation status of RANKL and OPG was also evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). Results. We found that RANKL and RUNX2 gene expression was upregulated more in recurrent than in non-recurrent GCTB tissues, while OPG gene expression was downregulated more in recurrent than in non-recurrent GCTB tissues. Additionally, we proved that changes in DNA methylation contribute to upregulating the expression of RANKL and downregulating the expression of OPG, which are critical for bone homeostasis and GCTB development. Conclusion. Our results suggest that the overexpression of RANKL/RUNX2 and the lower expression of OPG are associated with recurrence in GCTB patients. Cite this article: Bone Joint Res 2024;13(2):84–91


Bone & Joint Research
Vol. 10, Issue 5 | Pages 310 - 320
3 May 2021
Choi J Lee YS Shim DM Lee YK Seo SW

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


Bone & Joint Research
Vol. 9, Issue 11 | Pages 821 - 826
1 Nov 2020
Hagi T Nakamura T Kita K Iino T Asanuma K Sudo A

Aims. Tocilizumab, an interleukin-6 (IL-6) receptor (IL-6R) targeting antibody, enhances the anti-tumour effect of conventional chemotherapy in preclinical models of cancer. We investigated the anti-tumour effect of tocilizumab in osteosarcoma (OS) cell lines. Methods. We used the 143B, HOS, and Saos-2 human OS cell lines. We first analyzed the IL-6 gene expression and IL-6Rα protein expression in OS cells using reverse transcription real time quantitative-polymerase chain reaction (RT-qPCR) analysis and western blotting, respectively. We also assessed the effect of tocilizumab on OS cells using proliferation and invasion assay. Results. The OS cell lines 143B, HOS, and Saos-2 expressed IL-6R. Recombinant human IL-6 treatment increased proliferation of 143B and HOS cells. Tocilizumab treatment decreased proliferation and invasion of 143B, HOS, and Saos-2. Conclusion. In conclusion, we confirmed the production of IL-6 and the expression of IL-6R in OS cells and demonstrated that tocilizumab inhibits proliferation and invasion in OS cells. Cite this article: Bone Joint Res 2020;9(11):821–826


Bone & Joint Research
Vol. 6, Issue 3 | Pages 186 - 193
1 Mar 2017
Choi YJ Lee YS Lee HW Shim DM Seo SW

Objectives. Eukaryotic translation initiation factor 3 (eIF3) is a multi-subunit complex that plays a critical role in translation initiation. Expression levels of eIF3 subunits are elevated or decreased in various cancers, suggesting a role for eIF3 in tumorigenesis. Recent studies have shown that the expression of the eIF3b subunit is elevated in bladder and prostate cancer, and eIF3b silencing inhibited glioblastoma growth and induced cellular apoptosis. In this study, we investigated the role of eIF3b in the survival of osteosarcoma cells. Methods. To investigate the effect of eIF3b on cell viability and apoptosis in osteosarcoma cells, we first examined the silencing effect of eIF3b in U2OS cells. Cell viability and apoptosis were examined by the Cell Counting Kit-8 (CCK-8) assay and Western blot, respectively. We also performed gene profiling to identify genes affected by eIF3b silencing. Finally, the effect of eIF3b on cell viability and apoptosis was confirmed in multiple osteosarcoma cell lines. Results. eIF3b silencing decreased cell viability and induced apoptosis in U2OS cells, and by using gene profiling we discovered that eIF3b silencing also resulted in the upregulation of tumour necrosis factor receptor superfamily member 21 (TNFRSF21). We found that TNFRSF21 overexpression induced cell death in U2OS cells, and we confirmed that eIF3b silencing completely suppressed cell growth in multiple osteosarcoma cell lines. However, eIF3b silencing failed to suppress cell growth completely in normal fibroblast cells. Conclusion. Our data led us to conclude that eIF3b may be required for osteosarcoma cell proliferation by regulating TNFRSF21 expression. Cite this article: Y. J. Choi, Y. S. Lee, H. W. Lee, D. M. Shim, S. W. Seo. Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells. Bone Joint Res 2017;6:186–193. DOI: 10.1302/2046-3758.63.BJR-2016-0151.R2


The Bone & Joint Journal
Vol. 105-B, Issue 11 | Pages 1216 - 1225
1 Nov 2023
Fujiwara T Kunisada T Nakata E Mitsuhashi T Ozaki T Kawai A

Aims

Clear cell sarcoma (CCS) of soft-tissue is a rare melanocytic subtype of mesenchymal malignancy. The aim of this study was to investigate the clinical and therapeutic factors associated with increased survival, stratified by clinical stage, in order to determine the optimal treatment.

Methods

The study was a retrospective analysis involving 117 patients with histologically confirmed CCS, between July 2016 and November 2017, who were enrolled in the Bone and Soft Tissue Tumour Registry in Japan.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XIV | Pages 60 - 60
1 Apr 2012
Wolahan B D'Arcy P Maruwge W Brodin B
Full Access

SSX was initially identified as a melanoma associated tumour antigen MEL2 and in the SS18/SSX fusion gene of synovial sarcoma. It consists of a family of nine, highly homologous X chromosome genes, being SSX1, SSX2 and SSX4 the most commonly expressed in tumours. In normal tissue, SSX expression is restricted to germ cells, trophoblasts, and mesenchymal stem cells. In malignant cells, SSX expression is over-represented in sarcomas. SSX expression is epigenetically regulated by methylation and histone deacetylation. Aim. To investigate the oncogenic properties of SSX. Validate it as tumour target and identify lead compounds. Methods. RNAi system for conditional silencing of SSX expression, Protein analysis and Mass Spec, PCR arrays, tumour xenographs and drug library screening. Results. SSX expression peaks at the G1/S phase of the cell cycle where it interacts with histone H3, H4 and β-catenin. This interaction promotes the phosphorylation of β-catenin at tyrosine residues and the transactivation of β-catenin genes MMP2 and cyclin D1. The association of SSX and MMP2 expression resulted in an increased invasion capacity of tumour cells. In vivo, silencing of SSX in tumour xenographs significantly affected the tumour growth. These tumours were characterized by large necrotic areas, impaired vascularization and cytoplasmic β-catenin. In contrast, tumour xenographs expressing SSX were highly proliferative, vascularized and exibited nuclear β-catenin. We further screened a chemical library and have identified lead compounds that target SSX. Conclusion. Our results demonstrate that SSX is a tumour target for drug development. We hypothesise that drugs targeting of SSX could affect functions related with the mesenchymal cell phenotype having potential cytostatic effect in sarcomas and/or epithelial tumour cells that undergo a epithelial-to-mesenchymal transition prior to metastasis


Bone & Joint Research
Vol. 10, Issue 9 | Pages 602 - 610
24 Sep 2021
Tsoi KM Gokgoz N Darville-O'Quinn P Prochazka P Malekoltojari A Griffin AM Ferguson PC Wunder JS Andrulis IL

Aims

Cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) are used for prognostication and monitoring in patients with carcinomas, but their utility is unclear in sarcomas. The objectives of this pilot study were to explore the prognostic significance of cfDNA and investigate whether tumour-specific alterations can be detected in the circulation of sarcoma patients.

Methods

Matched tumour and blood were collected from 64 sarcoma patients (n = 70 samples) prior to resection of the primary tumour (n = 57) or disease recurrence (n = 7). DNA was isolated from plasma, quantified, and analyzed for cfDNA. A subset of cases (n = 6) underwent whole exome sequencing to identify tumour-specific alterations used to detect ctDNA using digital droplet polymerase chain reaction (ddPCR).


Bone & Joint Research
Vol. 9, Issue 7 | Pages 333 - 340
1 Jul 2020
Mumith A Coathup M Edwards TC Gikas P Aston W Blunn G

Aims

Limb salvage in bone tumour patients replaces the bone with massive segmental prostheses where achieving bone integration at the shoulder of the implant through extracortical bone growth has been shown to prevent loosening. This study investigates the effect of multidrug chemotherapy on extracortical bone growth and early radiological signs of aseptic loosening in patients with massive distal femoral prostheses.

Methods

A retrospective radiological analysis was performed on adult patients with distal femoral arthroplasties. In all, 16 patients were included in the chemotherapy group with 18 patients in the non-chemotherapy control group. Annual radiographs were analyzed for three years postoperatively. Dimensions of the bony pedicle, osseointegration of the hydroxyapatite (HA) collar surface, bone resorption at the implant shoulder, and radiolucent line (RLL) formation around the cemented component were analyzed.


The Bone & Joint Journal
Vol. 102-B, Issue 2 | Pages 186 - 190
1 Feb 2020
Puri A Hegde P Gulia A Parikh M

Aims

The aim of this study was to analyze the complications and outcomes of treatment in a series of previously untreated patients with a primary aneurysmal bone cyst (ABC) who had been treated by percutaneous sclerosant therapy using polidocanol.

Methods

Between January 2010 and December 2016, 56 patients were treated primarily with serial intralesional sclerosant injections. Their mean age was 20 years (1 to 54). The sites involved were clavicle (n = 3), humeri (n = 11), radius (n = 1), ulna (n = 3), hand (n = 2), pelvis (n = 12), femur (n = 7), tibia (n = 13), fibula (n = 3), and foot (n = 1). After histopathological confirmation of the diagnosis, 3% polidocanol (hydroxypolyaethoxydodecan) was injected into the lesion under image intensifier guidance. Patients were evaluated clinically and radiologically every six to eight weeks. In the absence of clinical and/or radiological response, a repeat sclerosant injection was given after eight to 12 weeks and repeated at similar intervals if necessary.


The Bone & Joint Journal
Vol. 99-B, Issue 4 | Pages 516 - 521
1 Apr 2017
Willeumier JJ van der Hoeven NMA Bollen L Willems LNA Fiocco M van der Linden YM Dijkstra PDS

Aims

This study aims to assess first, whether mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (kRAS) genes are associated with overall survival (OS) in patients who present with symptomatic bone metastases from non-small cell lung cancer (NSCLC) and secondly, whether mutation status should be incorporated into prognostic models that are used when deciding on the appropriate palliative treatment for symptomatic bone metastases.

Patients and Methods

We studied 139 patients with NSCLC treated between 2007 and 2014 for symptomatic bone metastases and whose mutation status was known. The association between mutation status and overall survival was analysed and the results applied to a recently published prognostic model to determine whether including the mutation status would improve its discriminatory power.


The Bone & Joint Journal
Vol. 96-B, Issue 5 | Pages 673 - 676
1 May 2014
Han I Choi ES Kim H

Monostotic fibrous dysplasia of the proximal femur has a variable clinical course, despite its reported limited tendency to progress.

We investigated the natural history and predisposing factors for progression of dysplasia in a group of 76 patients with a mean follow-up of 8.5 years (2.0 to 15.2). Of these, 31 (41%) presented with an asymptomatic incidental lesion while 45 (59%) presented with pain or a pathological fracture. A group of 23 patients (30%) underwent early operative treatment for pain (19: 25%) or pathological fracture (4: 5%).

Of the 53 patients who were initially treated non-operatively, 45 (85%) remained asymptomatic but eight (15%) needed surgery because of pain or fracture. The progression-free survival of the observation group was 81% (sd 6.4%) at five-years follow-up. An initial presentation of pain (p < 0.001), a limp (p < 0.001), radiological evidence of microfracture (p = 0.001) and younger age (< 17 years) (p = 0.016) were significant predisposing factors for disease progression.

The risk of experiencing pain or pathological fracture is considerable in monostotic fibrous dysplasia of the proximal femur. Patients presenting with pain, a limp or radiological evidence of microfracture have a high chance of needing surgical treatment.

Cite this article: Bone Joint J 2014;96-B:673–6.


The Bone & Joint Journal
Vol. 95-B, Issue 12 | Pages 1708 - 1713
1 Dec 2013
Salem KH Brockert A Mertens R Drescher W

Avascular necrosis (AVN) is a serious complication of high-dose chemotherapy for haematological malignancy in childhood. In order to describe its incidence and main risk factors and to evaluate the current treatment options, we reviewed 105 children with a mean age of 8.25 years (1 to 17.8) who had acute lymphoblastic or acute myeloid leukaemia, or a non-Hodgkin’s lymphoma. Overall, eight children (7.6%) developed AVN after a mean of 16.8 months (8 to 49). There were four boys and four girls with a mean age of 14.4 years (9.8 to 16.8) and a total of 18 involved sites, 12 of which were in the femoral head. All these children were aged > nine years (p < 0.001). All had received steroid treatment with a mean cumulative dose of prednisone of 5967 mg (4425 to 9599) compared with a mean of 3943 mg (0 to 18 585) for patients without AVN (p = 0.005). No difference existed between genders and no thrombophilic disorders were identified. Their initial treatment included 11 core decompressions and two bipolar hip replacements. Later, two salvage osteotomies were done and three patients (four hips) eventually needed a total joint replacement. We conclude that AVN mostly affects the weight-bearing epiphyses. Its risk increases with age and higher steroid doses. These high-risk patients may benefit from early screening for AVN.

Cite this article: Bone Joint J 2013;95-B:1708–13.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 7 | Pages 882 - 888
1 Jul 2012
van der Heijden L Gibbons CLMH Dijkstra PDS Kroep JR van Rijswijk CSP Nout RA Bradley KM Athanasou NA Hogendoorn PCW van de Sande MAJ

Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT.

Although arthroscopic synovectomy through several portals has been advocated as an alternative to arthrotomy, there is a significant risk of inadequate excision and recurrence, particularly in the posterior compartment of the knee. For local disease partial arthroscopic synovectomy may be sufficient, at the risk of recurrence. For both local and diffuse intra-articular disease open surgery is advised for recurrent disease. Marginal excision with focal disease will suffice, not dissimilar to the treatment of GCT of tendon sheath. For recurrent and extra-articular soft-tissue disease adjuvant therapy, including intra-articular radioactive colloid or moderate-dose external beam radiotherapy, should be considered.


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 6 | Pages 808 - 813
1 Jun 2007
Kalra S Grimer RJ Spooner D Carter SR Tillman RM Abudu A

We identified 42 patients who presented to our unit over a 27-year period with a secondary radiation-induced sarcoma of bone. We reviewed patient, tumour and treatment factors to identify those that affected outcome. The mean age of the patients at presentation was 45.6 years (10 to 84) and the mean latent interval between radiotherapy and diagnosis of the sarcoma was 17 years (4 to 50). The median dose of radiotherapy given was estimated at 50 Gy (mean 49; 20 to 66). There was no correlation between radiation dose and the time to development of a sarcoma. The pelvis was the most commonly affected site (14 patients (33%)). Breast cancer was the most common primary tumour (eight patients; 19%). Metastases were present at diagnosis of the sarcoma in nine patients (21.4%). Osteosarcoma was the most common diagnosis and occurred in 30 cases (71.4%). Treatment was by surgery and chemotherapy when indicated: 30 patients (71.4%) were treated with the intention to cure. The survival rate was 41% at five years for those treated with the intention to cure but in those treated palliatively the mean survival was only 8.8 months (2 to 22), and all had died by two years. The only factor found to be significant for survival was the ability to completely resect the tumour. Limb sarcomas had a better prognosis (66% survival at five years) than central ones (12% survival at five years) (p = 0.009).

Radiation-induced sarcoma is a rare complication of radiotherapy. Both surgical and oncological treatment is likely to be compromised by the treatment received previously by the patient.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 11 | Pages 1580 - 1585
1 Nov 2010
Wu P Chen W Lee OK Chen C Huang C Chen T

We evaluated the long-term outcome of patients with an osteosarcoma who had undergone prior manipulative therapy, a popular treatment in Asia, and investigated its effects on several prognostic factors. Of the 134 patients in this study, 70 (52%) patients had manipulative therapy and 64 (48%) did not. The age, location, and size of tumour were not significantly different between the groups. The five-year overall survival rate was 58% and 92% in the groups with and without manipulative therapy (p = 0.004). Both the primary and overall rates of lung metastasis were significantly higher in the manipulative group (primary: 32% vs 3%, p = 0.003; overall lung metastasis rate: 51.4% vs 18.8%, p < 0.001). Patients who had manipulative therapy had higher local recurrence rates in comparison to patients who did not (29% vs 6%, p = 0.011). The prognosis for patients with osteosarcoma who had manipulative therapy was significantly poorer than those who had not. Manipulative therapy was an independent factor for survival.

This form of therapy may serve as a mechanism to accelerate the spread of tumour cells, and therefore must be avoided in order to improve the outcome for patients with an osteosarcoma.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 2 | Pages 262 - 266
1 Feb 2010
Parratt MTR Donaldson JR Flanagan AM Saifuddin A Pollock RC Skinner JA Cannon SR Briggs TWR

Elastofibroma dorsi is an uncommon, benign, slow-growing soft-tissue tumour of uncertain aetiology. It classically presents as an ill-defined mass at the inferior pole of the scapula with symptoms which include swelling, discomfort, snapping, stiffness and occasionally pain.

We report the symptoms, function and outcome after treatment of 21 elastofibromas in 15 patients. All were diagnosed by MRI and early in the series four also underwent CT-guided biopsy to confirm the diagnosis. In all, 18 tumours were excised and three were observed. After excision, the mean visual analogue score for pain decreased from 4.6 (0 to 10) pre-operatively to 2.4 (0 to 8) post-operatively (p = 0.04). The mean shoulder function, at a mean follow-up of 4.2 years (3 months to 16 years), was 78.1% (30 to 100) using the Stanmore percentage of normal shoulder assessment scoring system. The mean range of forward flexion improved from 135° (70° to 180°) to 166° (100° to 180°) after excision (p = 0.005). In four patients a post-operative haematoma formed; one required evacuation. Three patients developed a post-operative seroma requiring needle aspiration and one developed a superficial infection which was treated with antibiotics.

Our findings support previous reports suggesting that a pre-operative tissue diagnosis is not necessary in most cases since the lesion can be confidently diagnosed by MRI, when interpreted in the light of appropriate clinical findings. Surgical excision in symptomatic patients, is helpful.

It has been suggested that elastofibroma is caused by a local tissue reaction and is not a true neoplastic process. A strong association has been noted between elastofibroma and repetitive use of the shoulder, which is supported by our findings.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 3 | Pages 364 - 370
1 Mar 2008
Kubo T Sugita T Shimose S Matsuo T Arihiro K Ochi M

We investigated the use of hypoxia-inducible factor (HIF) proteins as prognostic markers in chondrosarcoma and the relationship of HIF to the biological characteristics of cartilage tumours. The expression of HIF-1α, HIF-2α, proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) were measured immunohistochemically in 29 specimens of cartilage tumour.

There was no HIF-1α and HIF-2α staining in any of the nine benign cartilage tumours. In 20 specimens of chondrosarcoma, the rate of HIF-1α and HIF-2α expression was 40% and 25%, respectively. The tumour size (≥ 8 cm), histological grade (grade 2 and grade 3) surgical margin (marginal and intralesional) and HIF-1α expression (positive) correlated significantly with a shorter disease-free survival. There was a significant association between HIF-1α and the MVD and a strong trend towards a correlation between HIF-1α and the PCNA index or histological grade.

Our findings suggest that HIF-1α protein may be a useful objective marker in the assessment of the prognosis in chondrosarcoma, since it plays an important role in tumour angiogenesis and cell proliferation.


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 9 | Pages 1229 - 1233
1 Sep 2007
Bacci G Balladelli A Forni C Longhi A Serra M Fabbri N Alberghini M Ferrari S Benassi MS Picci P

Despite local treatment with systemic chemotherapy in Ewing’s sarcoma family tumours (ESFT), patients with detectable metastases at presentation have a markedly worse prognosis than those with apparently localised disease. We investigated the clinical, pathological and laboratory differences in 888 patients with ESFT, 702 with localised disease and 186 with overt metastases at presentation, seen at our institution between 1983 and 2006.

Multivariate analyses showed that location in the pelvis, a high level of serum lactic dehydrogenase, the presence of fever and a short interval between the onset of symptoms and diagnosis were indicative of metastatic disease. The rate of overt metastases at presentation was 10% without these four risk factors, 22.7% with one, 31.4% with two, and 50% for those with three or four factors. We concluded that in ESFT the site, the serum level of lactic dehydrogenase, fever, and the interval between the onset of symptoms and diagnosis are indicators of tumours having a particularly aggressive metastatic behaviour.