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Bone & Joint Research
Vol. 13, Issue 4 | Pages 157 - 168
4 Apr 2024
Lin M Chen G Yu H Hsu P Lee C Cheng C Wu S Pan B Su B

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


Bone & Joint Open
Vol. 2, Issue 2 | Pages 125 - 133
1 Feb 2021
Bavan L Wijendra A Kothari A

Aims. Aneurysmal bone cysts (ABCs) are locally aggressive lesions typically found in the long bones of children and adolescents. A variety of management strategies have been reported to be effective in the treatment of these lesions. The purpose of this review was to assess the effectiveness of current strategies for the management of primary ABCs of the long bones. Methods. A systematic review of the published literature was performed to identify all articles relating to the management of primary ABCs. Studies required a minimum 12-month follow-up and case series reporting on under ten participants were not included. Results. A total of 28 articles meeting the eligibility criteria were included in this review, and all but one were retrospective in design. Due to heterogeneity in study design, treatment, and outcome reporting, data synthesis and group comparison was not possible. The most common treatment option reported on was surgical curettage with or without a form of adjuvant therapy, followed by injection-based therapies. Of the 594 patients treated with curettage across 17 studies, 86 (14.4%) failed to heal or experienced a recurrence. Similar outcomes were reported for 57 (14.70%) of the 387 patients treated with injection therapy across 12 studies. Only one study directly compared curettage with injection therapy (polidocanol), randomizing 94 patients into both treatment groups. This study was at risk of bias and provided low-quality evidence of a lack of difference between the two interventions, reporting success rates of 93.3% and 84.8% for injection and surgical treatment groups, respectively. Conclusion. While both surgery and sclerotherapy are widely implemented for treatment of ABCs, there is currently no good quality evidence to support the use of one option over the other. There is a need for prospective multicentre randomized controlled trials (RCTs) on interventions for the treatment of ABCs. Cite this article: Bone Jt Open 2021;2(2):125–133


The Bone & Joint Journal
Vol. 102-B, Issue 6 | Pages 772 - 778
1 Jun 2020
Kim Y Jang WY Park JW Park YK Cho HS Han I Kim H

Aims. For paediatric and adolescent patients with growth potential, preservation of the physiological joint by transepiphyseal resection (TER) of the femur confers definite advantages over arthroplasty procedures. We hypothesized that the extent of the tumour and changes in its extent after neoadjuvant chemotherapy are essential factors in the selection of this procedure, and can be assessed with MRI. The oncological and functional outcomes of the procedure were reviewed to confirm its safety and efficacy. Methods. We retrospectively reviewed 16 patients (seven male and nine female, mean age 12.2 years (7 to 16)) with osteosarcoma of the knee who had been treated by TER. We evaluated the MRI scans before and after neoadjuvant chemotherapy for all patients to assess the extent of the disease and the response to treatment. Results. The mean follow-up period was 64.3 months (25 to 148) after surgery and no patients were lost to follow-up. On MRI evaluation, 13 tumours were near but not in contact with the physes and three tumours were partially in contact with the physes before neoadjuvant chemotherapy. Bone oedema in the epiphysis was observed in eight patients. After neoadjuvant chemotherapy, bone oedema in the epiphysis disappeared in all patients. In total, 11 tumours were not in contact and five tumours were in partial contact with the physes. The postoperative pathological margin was negative in all patients. At the last follow-up, 12 patients were continuously disease-free and three had no evidence of disease. One patient died due to the disease. Functionally, the patients with retained allograft or recycled autograft had a mean knee range of flexion of 126° (90° to 150°). The mean Musculoskeletal Tumor Society functional score was 27.6 (23 to 30). Conclusion. TER is an effective limb-salvage technique for treating malignant metaphyseal bone tumours in paediatric and young osteosarcoma patients with open physes when a good response to chemotherapy and no progression of the tumour to the epiphysis have been confirmed by MRI. Cite this article: Bone Joint J 2020;102-B(6):772–778


The Bone & Joint Journal
Vol. 106-B, Issue 2 | Pages 195 - 202
1 Feb 2024
Jamshidi K Kargar Shooroki K Ammar W Mirzaei A

Aims

The epiphyseal approach to a chondroblastoma of the intercondylar notch of a child’s distal femur does not provide adequate exposure, thereby necessitating the removal of a substantial amount of unaffected bone to expose the lesion. In this study, we compared the functional outcomes, local recurrence, and surgical complications of treating a chondroblastoma of the distal femoral epiphysis by either an intercondylar or an epiphyseal approach.

Methods

A total of 30 children with a chondroblastoma of the distal femur who had been treated by intraregional curettage and bone grafting were retrospectively reviewed. An intercondylar approach was used in 16 patients (group A) and an epiphyseal approach in 14 (group B). Limb function was assessed using the Musculoskeletal Tumor Society (MSTS) scoring system and Sailhan’s functional criteria.


The Bone & Joint Journal
Vol. 103-B, Issue 9 | Pages 1541 - 1549
1 Sep 2021
Fujiwara T Evans S Stevenson J Tsuda Y Gregory J Grimer RJ Abudu S

Aims

While a centralized system for the care of patients with a sarcoma has been advocated for decades, regional variations in survival remain unclear. The aim of this study was to investigate regional variations in survival and the impact of national policies in patients with a soft-tissue sarcoma (STS) in the UK.

Methods

The study included 1,775 patients with a STS who were referred to a tertiary sarcoma centre. The geographical variations in survival were evaluated according to the periods before and after the issue of guidance by the National Institute for Health and Care Excellence (NICE) in 2006 and the relevant evolution of regional management.


The Bone & Joint Journal
Vol. 103-B, Issue 3 | Pages 569 - 577
1 Mar 2021
Fujiwara T Grimer RJ Evans S Medellin Rincon MR Tsuda Y Le Nail L Abudu S

Aims

Urgent referral to a specialist centre for patients with a soft-tissue sarcoma (STS) has been recommended by the National Institute for Health and Care Excellence (NICE) in the UK since 2006. However, the impact of this recommendation on the prognosis for these patients remains unclear. We aimed to determine the impact of the NICE guidelines on the disease-specific survival (DSS) of patients with an STS.

Methods

A total of 2,427 patients with an STS referred to a supraregional centre in the ten-year periods before (n = 1,386) and after (n = 1,041) the issue of the NICE guidelines were evaluated.


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.


The Bone & Joint Journal
Vol. 99-B, Issue 3 | Pages 409 - 416
1 Mar 2017
Scholfield DW Sadozai Z Ghali C Sumathi V Douis H Gaston L Grimer RJ Jeys L

Aims

The aim of this study was to identify any progression between benign osteofibrous dysplasia (OFD), OFD-like adamantinoma and malignant adamantinoma, and to investigate the rates of local recurrence, metastases and survival, in order to develop treatment algorithms for each.

Patients and Methods

A single institution retrospective review of all patients presenting with OFD, OFD-like adamantinoma and adamantinoma between 1973 and 2012 was undertaken. Complete data were available for 73 patients (42 with OFD; ten with an OFD-like adamantinoma and 21 with an adamantinoma). The mean follow-up was 10.3 years (3 to 25) for OFD, 9.2 years (3.0 to 26.3) for OFD-like and 11.6 years (0.25 to 33) for adamantinoma.


The Bone & Joint Journal
Vol. 97-B, Issue 2 | Pages 258 - 264
1 Feb 2015
Young PS Bell SW Mahendra A

We report our experience of using a computer navigation system to aid resection of malignant musculoskeletal tumours of the pelvis and limbs and, where appropriate, their subsequent reconstruction. We also highlight circumstances in which navigation should be used with caution.

We resected a musculoskeletal tumour from 18 patients (15 male, three female, mean age of 30 years (13 to 75) using commercially available computer navigation software (Orthomap 3D) and assessed its impact on the accuracy of our surgery. Of nine pelvic tumours, three had a biological reconstruction with extracorporeal irradiation, four underwent endoprosthetic replacement (EPR) and two required no bony reconstruction. There were eight tumours of the bones of the limbs. Four diaphyseal tumours underwent biological reconstruction. Two patients with a sarcoma of the proximal femur and two with a sarcoma of the proximal humerus underwent extra-articular resection and, where appropriate, EPR. One soft-tissue sarcoma of the adductor compartment which involved the femur was resected and reconstructed using an EPR. Computer navigation was used to aid reconstruction in eight patients.

Histological examination of the resected specimens revealed tumour-free margins in all patients. Post-operative radiographs and CT showed that the resection and reconstruction had been carried out as planned in all patients where navigation was used. In two patients, computer navigation had to be abandoned and the operation was completed under CT and radiological control.

The use of computer navigation in musculoskeletal oncology allows accurate identification of the local anatomy and can define the extent of the tumour and proposed resection margins. Furthermore, it helps in reconstruction of limb length, rotation and overall alignment after resection of an appendicular tumour.

Cite this article: Bone Joint J 2015;97-B:258–64.


The Bone & Joint Journal
Vol. 96-B, Issue 11 | Pages 1436 - 1440
1 Nov 2014
Henderson ER O’Connor MI Ruggieri P Windhager R Funovics PT Gibbons CL Guo W Hornicek FJ Temple HT Letson GD

Previous classification systems of failure of limb salvage focused primarily on endoprosthetic failures and lacked sufficient depth for the effective study of the causes of failure. In order to address these inadequacies, the International Society of Limb Salvage (ISOLS) formed a committee to recommend revisions of the previous systems. The purpose of this study was to report on their recommendations. The modifications were prepared using an earlier, evidence-based model with subclassification based on the existing medical literature. Subclassification for all five primary types of failure of limb salvage following endoprosthetic reconstruction were formulated and a complementary system was derived for the failure of biological reconstruction. An additional classification of failure in paediatric patients was also described.

Limb salvage surgery presents a complex array of potential mechanisms of failure, and a complete and precise classification of types of failure is required. Earlier classification systems lacked specificity, and the evidence-based system outlined here is designed to correct these weaknesses and to provide a means of reporting failures of limb salvage in order to allow the interpretation of outcome following reconstructive surgery.

Cite this article: Bone Joint J 2014;96-B:1436–40.


Bone & Joint 360
Vol. 1, Issue 4 | Pages 36 - 36
1 Aug 2012
Carey Smith R Wood D


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 6 | Pages 836 - 841
1 Jun 2012
Frisoni T Cevolani L Giorgini A Dozza B Donati DM

We retrospectively reviewed 101 consecutive patients with 114 femoral tumours treated by massive bone allograft at our institution between 1986 and 2005. There were 49 females and 52 males with a mean age of 20 years (4 to 74). At a median follow-up of 9.3 years (2 to 19.8), 36 reconstructions (31.5%) had failed. The allograft itself failed in 27 reconstructions (24%).

Mechanical complications such as delayed union, fracture and failure of fixation were studied. The most adverse factor on the outcome was the use of intramedullary nails, followed by post-operative chemotherapy, resection length > 17 cm and age > 18 years at the time of intervention. The simultaneous use of a vascularised fibular graft to protect the allograft from mechanical complications improved the outcome, but the use of intramedullary cementing was not as successful.

In order to improve the strength of the reconstruction and to advance the biology of host–graft integration, we suggest avoiding the use of intramedullary nails and titanium plates, but instead using stainless steel plates, as these gave better results. The use of a supplementary vascularised fibular graft should be strongly considered in adult patients with resection > 17 cm and in those who require post-operative chemotherapy.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 3 | Pages 419 - 424
1 Mar 2012
Masrouha KZ Khattab R Tawil A Abdallah A Saghieh S Haidar R Abboud M Khoury NJ

There are eight reported cases in the literature of osteosarcomas secreting β-hCG. Our primary aim was to investigate the rate of β-hCG expression in osteosarcoma and attempt to understand the characteristics of osteosarcomas that secrete β-hCG. We reviewed 37 histopathology slides (14 biopsies and 23 surgical specimens) from 32 patients with osteosarcoma. The slides were retrospectively stained for β-hCG expression. Patient and tumour characteristics, including age, gender, tumour location, subtype, proportion of necrosis, presence of metastases and recurrence were recorded. A total of five of the 32 tumours were found to be positive for β-hCG expression (one strongly and four weakly). This incidence of this expression was found in tumours with poor histological response to neoadjuvant chemotherapy.

The use of β-hCG expression as a diagnostic, prognostic or follow-up marker is questionable and needs further investigation with a larger sample size.


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. 93-B, Issue 7 | Pages 980 - 983
1 Jul 2011
Malhas AM Grimer RJ Abudu A Carter SR Tillman RM Jeys L

We investigated the eventual diagnosis in patients referred to a tertiary centre with a possible diagnosis of a primary bone malignancy.

We reviewed our database from between 1986 and 2010, during which time 5922 patients referred with a suspicious bone lesion had a confirmed diagnosis. This included bone sarcoma in 2205 patients (37%), benign bone tumour in 1309 (22%), orthopaedic conditions in 992 (17%), metastatic disease in 533 (9%), infection in 289 (5%) and haematological disease in 303 (5%). There was a similar frequency of all diagnoses at different ages except for metastatic disease. Only 0.6% of patients (17 of 2913) under the age of 35 years had metastatic disease compared with 17.1% (516 of 3009) of those over 35 years (p < 0.0001). Of the 17 patients under 35 years with metastatic disease, only four presented with an isolated lesion, had no past history of cancer and were systematically well.

Patients under the age of 35 years should have suitable focal imaging (plain radiography, CT or MRI) and simple systemic studies (blood tests and chest radiography). Reduction of the time to biopsy can be achieved by avoiding an unnecessary investigation for a primary tumour to rule out metastatic disease.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 4 | Pages 537 - 541
1 Apr 2011
Song WS Kong C Jeon D Cho WH Kim JR Lee S

The use of allografts for the treatment of bone tumours in children is limited by nonunion and the difficulty of finding a suitable graft. Furthermore, appositional growth can’t be expected of an allograft.

We used an overlapping allograft in 11 children, with a mean age of ten years (4 to 15), with a mean follow-up of 24.1 months (20 to 33). There were five intercalary and six intra-articular resections, and the tumours were in the femur in six cases and the humerus in five. Rates of union, times to union, remodelling patterns and allograft-associated complications were evaluated.

No allograft was removed due to a complication. Of the 16 junctional sites, 15 (94%) showed union at a mean of 3.1 months (2 to 5). Remodelling between host and allograft was seen at 14 junctions at a mean of five months (4 to 7). The mean Musculoskeletal Tumor Society score was 26.5 of 30 (88.3%). One case of nonunion and another with screw protrusion required re-operation.

Overlapping allografts have the potential to shorten time to union, decrease rates of nonunion and have positive appositional growth effect.


The Journal of Bone & Joint Surgery British Volume
Vol. 91-B, Issue 9 | Pages 1227 - 1231
1 Sep 2009
Abuhassan FO Shannak AO

We describe the treatment by subperiosteal resection of an aneurysmal bone cyst in the distal fibula in eight patients and highlight the role of the periosteum in the regeneration of bone defects. The mean age of the patients was 13.5 years (12 to 17). Seven had an open growth plate. The mean size of the resected specimen was 5.12 cm (3.5 to 8.0). None of the patients received instillation of bone marrow, autogenous bone graft, allograft or any synthetic bone substitutes.

All had complete regeneration of the bone defect within three to nine months, with no joint instability or recurrence.

The mean length of follow-up was 11.5 years (2 to 18). At the final follow-up there was no difference in the range of movement, alignment or stability of the ankle when compared with the opposite side. The periosteum played a major role in the complete filling of the bone defects and avoided the morbidity of other techniques.


The Journal of Bone & Joint Surgery British Volume
Vol. 91-B, Issue 3 | Pages 395 - 400
1 Mar 2009
Krieg AH Mani M Speth BM Stalley PD

We review the treatment of pelvic Ewing’s sarcoma by the implantation of extracorporeally-irradiated (ECI) autografts and compare the outcome with that of other reported methods.

We treated 13 patients with ECI autografts between 1994 and 2004. There were seven males and six females with a median age of 15.7 years (interquartile range (IQR) 12.2 to 21.7). At a median follow-up of five years (IQR 1.8 to 7.4), the disease-free survival was 69% overall, and 75% if one patient with local recurrence after initial treatment elsewhere was excluded. Four patients died from distant metastases at a mean of 17 months (13 to 23). There were three complications which required operative intervention; one was a deep infection which required removal of the graft. The functional results gave a mean Musculoskeletal Tumor Society score of 85% (60% to 97%), a mean Toronto extremity salvage score of 86% (69% to 100%) and a mean Harris hip score of 92 (67 to 100).

We conclude that ECI grafting is a suitable form of treatment for localised and resectable pelvic Ewing’s sarcoma.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 9 | Pages 1222 - 1227
1 Sep 2008
Jaiswal PK Aston WJS Grimer RJ Abudu A Carter S Blunn G Briggs TWR Cannon S

We treated 98 patients with peri-acetabular tumours by resection and reconstruction with a custom-made pelvic endoprosthesis. The overall survival of the patients was 67% at five years, 54% at ten years and 51% at 30 years. One or more complications occurred in 58.1% of patients (54), of which infection was the most common, affecting 30% (28 patients). The rate of local recurrence was 31% (29 patients) after a mean follow-up of 71 months (11 to 147). Dislocation occurred in 20% of patients (19). Before 1996 the rate was 40.5% (17 patients) but this was reduced to 3.9% (two patients) with the introduction of a larger femoral head. There were six cases of palsy of the femoral nerve with recovery in only two. Revision or excision arthroplasty was performed in 23.7% of patients (22), principally for uncontrolled infection or aseptic loosening. Higher rates of death, infection and revision occurred in men.

This method of treatment is still associated with high morbidity. Patients should be carefully selected and informed of this pre-operatively.


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 9 | Pages 1234 - 1238
1 Sep 2007
Foster L Dall GF Reid R Wallace WH Porter DE

We have reviewed the data from our regional Bone Tumour Registry on patients with osteosarcoma diagnosed between 1933 and 2004 in order to investigate the relationship between survival and changes in treatment. There were 184 patients with non-metastatic appendicular osteosarcoma diagnosed at the age of 18 or under. Survival was calculated using Kaplan-Meier curves, and multivariate analysis was performed using the Cox regression proportional hazards model.

The five-year survival improved from 21% between 1933 and 1959, to 62% between 1990 and 1999. During this time, a multi-disciplinary organisation was gradually developed to manage treatment. The most significant variable affecting outcome was the date of diagnosis, with trends in improved survival mirroring the introduction of increasingly effective chemotherapy. Our experience suggests that the guidelines of the National Institute for Clinical Excellence on the minimum throughput of centres for treatment should be enforced flexibly in those that can demonstrate that their historical and contemporary results are comparable to those published nationally and internationally.