We have treated 50 patients with bony malignancy by en bloc resection, extracorporeal irradiation (ECI) with 50Gy and re-implantation of the bone segment as a method of limb salvage. Mean survivor follow-up is 38 months (12–92). 42 patients remain alive without disease. 4 recurrences occurred. Functional results were generally good: Mankin grades 17 excellent, 13 good, 9 fair, 3 failures; MSTS mean 77 (20–100); TESS mean 81 (40–100). Solid bony union was the norm, however bone resorption was seen in some cases. The dose of radiation is theoretically lethal to all cells and produces a dead autogenous bone graft of perfect fit. ECI is a useful technique of limb salvage where there is a reasonable residual bone stock. It allows effective re-attachment of muscle tendons, and produces a lasting biological reconstruction. The risk from the re-implanted bone of both local recurrence and of late radiotherapy induced malignancy should be nil.

In this paper, a retrospective review was undertaken of a large musculoskeletal tumour database to identify patients who presented with tumours of the foot and ankle. Soft tissue tumours occurred more frequently than bone tumours, and were also more frequently malignant than bone tumours. In contrast to the more recent trend towards limb-preserving surgery in other anatomic areas, malignant tumours of the foot and ankle were frequently unresectable and were treated with amputation. Although the majority of extremity tumours that present to the orthopaedic surgeon are found in the proximal limbs or around the knee, tumours of the ankle and foot are also relatively common. The purpose of this study is to identify the frequency with which benign and malignant bone and soft tissue tumours occur in the foot and ankle and the oncologic and surgical outcomes of these patients. A retrospective review of a large musculoskeletal tumor database in a tertiary referral center from the years 1986–2002 was undertaken. For oncologic outcomes, a minimum two-year follow up was considered. A total of one hundred and sixteen bone and one hundred and seventy-one soft tissue tumours were identified. Seventy-seven bone tumours were benign and thirty-nine were malignant. Sixty-six soft tissue tumours were benign and one hundred and five were malignant. The most common benign bone tumour was giant cell tumour and osteosarcoma was the most common malignancy. Malignant fibrous histiocytoma was common in the distal leg but synovial sarcoma and clear cell sarcoma were more common in the foot. Twenty patients with bone malignancies (51%) and twenty-four with soft tissue sarcomas (23%) had amputation as definitive surgical management. Death from metastases occurred in 25% of patients with bone malignancies and 10% of soft tissue sarcomas. At this center, the majority of bone tumours treated are benign but the majority of soft tissue tumours are malignant. Limb salvage is often not possible and amputation for local tumour control is necessary far more often than in other anatomic sites

Osteosarcoma (OS) is an aggressive bone malignancy with a high relapse rate despite combined treatment with surgery and multiagent chemotherapy. As for other cancers, OS-associated microenvironment may contribute to tumor initiation, growth, and metastasis. We consider mesenchymal stromal cells (MSC) as a relevant cellular component of OS microenvironment, and have previously found that the interaction between MSC and tumor cells is bidirectional: tumor cells can modulate their peripheral environment that in turn becomes more favourable to tumor growth through metabolic reprogramming (1). Stem-like cells were derived from HOS osteosarcoma cell line by using the spherogenic system (2). CSC isolated from HOS (HOS-CSC) were co-coltured with MSC isolated from bone marrow. Cell lysates and supernatants were collected for the analysis of RNA expression and of secreted cytokines, by Q-RT-PCR and specific ELISA assays, respectively. Here, we determined the effects of MSC on OS stemness and migration, two major features associated with recurrence and chemoresistance. Recruitment of MSC to the tumor environment leads to enhanced proliferation of OS stem cells, which increase the expression levels of TGFβ1. The latter, in turn, could be responsible for the activation of NF-kB genes and IL-6 secretion by MSC. Pro-tumorigenic effects of MSC, via IL-6, including induction of HOS-CSC migration and sphere growth, can be counteracted by IL-6 neutralizing antibody. The presence of MSC is also responsible for increased expression of adhesion molecules involved in intra- or extra-vasation. Stromal cells in combination with OS spheres exploit a vicious cycle where the presence of CSC stimulates mesenchymal cytokine secretion, which in turn increases stemness, proliferation, migration, and metastatic potential of CSC. Furthermore, for the first time we identified a novel OS stem cell marker, the Met proto-oncogene, that is frequently overexpressed and is pathogenetically relevant in OS (2 and 3). Altogether, our data corroborates the concept that a comprehensive knowledge of the interplay between tumor and stroma that also includes the stem-like fraction of tumor cells is needed to develop novel and effective anti-cancer therapies

Introduction. Bone tumours of the foot are rare, representing 3–6% of all bone tumours. Of these 15–25% are thought to be malignant. Obtaining clear surgical margins remains an important factor in improving outcome from tumours. However, the anatomical complexity of the foot can lead to an inadequate resection, particularly if the operating surgeon is attempting to preserve function. The aim of this paper is to identify the clinical course of patients suffering from malignant bone tumours of the foot. Method. A prospective tumour registry over a 30 yr period was used to identify patients with a malignant bone tumour of the foot. Patient demographics along with the site of primary malignancy, region of the foot involved and clinical management were recorded. Results. 70 patients with a malignant foot tumour were identified. 25(35%) were chondrosarcomas, 20 Ewings Sarcoma, 10 Osteosarcoma and 15 were metastatic lesions. Of those diagnosed with a primary bone tumour, 8(14.5%) were referred following a “whoops” procedure. The median length of symptoms prior to diagnosis was 52 weeks. The most common regions affected were the 1. st. Ray (31%) and Calcaneus (22%). The mainstay of treatment involved either Ray or Below Knee Amputation in 70% of cases. 11 patients developed either local recurrence or metastatic disease. Conclusion. We present the largest single centre review of malignant bone tumours affecting the foot. Our series confirms that patients often have to suffer with protracted symptoms prior to the establishment of the correct diagnosis. The variety of differential diagnoses may explain the long delay in diagnosis. Worryingly, 14.5% of the primary bone malignancies in our series underwent a “whoops” procedure. This highlights further that physicians need to maintain a high index of suspicion when treating a patient with foot symptoms, even when the symptoms may be protracted

Summary Statement. In this study we suggested a possible role of prion proteins genes in osteosarcoma. Therefore, the inhibition of prion proteins expression must be tested because it could represent a new approach to the molecular treatment of osteosarcoma. Introduction. Although osteosarcoma is the most common bone malignancy, the molecular and cellular mechanisms influencing its pathogenesis have remained elusive. Prion proteins (PRNP and PRND), known mostly for its involvement in neurodegenerative spongiform encephalopathies, have been recently demonstrated to be involved in resistance to apoptosis, tumorigenesis, proliferation and metastasis. Patients & Methods. The main aim of research was to study whether prion proteins were over-expressed in human osteosarcoma, and if prion proteins could have a role also in osteosarcomas. We evaluated differential gene expression between 22 cases of osteosarcoma and 40 cases of normal bone specimens through cDNA microarray analysis spanning a substantial fraction of the human genome. Results. PRNP and PRND are significantly over-expressed in osteosarcoma. PRNP and PRND appear involved with some important genes related to tumorigenesis and apoptosis. PRNP is linked to PTK2, RBBP9 and TGFB1 while PRND is linked to TNFSF10, BCL2A1, NFKB2 and TP53RK. Discussion/Conclusion. Increased expression on Affymetrix arrays of prion proteins seems to be associated with the development of osteosarcoma. Prions seem to induce a negative regulation of apoptosis, thus promoting osteosarcoma development and progression. Osteosarcoma is a very aggressive tumor and even after modern chemotherapy and excision of tumors efforts are needed to improve clinical outcome. Since Prion proteins seem to be related to osteosarcoma development, their inhibition could represent a new approach to the molecular treatment of osteosarcoma

Introduction:. Skeletal involvement in non-Hodgkin lymphoma in HIV/AIDS is rarely reported. The bone lesions can have a spectrum of radiological features. Aims:. The aim of the study was to review the radiological features of non-Hodgkin lymphoma (NHL) involving the bone in HIV positive patients. Methodology:. All cases of NHL involving bone in HIV positive patients diagnosed histopathologically were recorded retrospectively between September 2002 and December 2013. Clinical manifestations, radiological features and haematological investigations were analysed from the patients' records. Histopathological subtypes were analysed from slides. Results:. 105 Cases of lymphoma involving bone were recorded. Of these, 46 patients met the criteria of being HIV positive and diagnosed with NHL involving bone. The male to female ratio was equal, the age ranged from 14 to 51 years (average 35 years), the absolute CD 4 count ranged from 17 to 307 (average 100). The sites of involvement were:- vertebrae (22), ribs (8), pelvis (6), femur (3), mandible (3), humerus (2), sternum (1) and clavicle (1). Vertebral involvement was multifocal with a large extradural soft tissue mass in 17 cases and solitary in 5 cases. Pathological fractures were seen in 4 cases of long bone involvement. Most patients presented with a high grade large B cell non-Hodgkin lymphoma with CD20 immunopositivity. Conclusion:. Primary bone lymphoma is a rare disease, accounting for approximately 3% of all primary bone malignancies and 4% to 7% of all extranodal lymphomas in the general population. The prevalence of primary and secondary bone lymphoma is very high in HIV positive patients. The disease is very aggressive, presenting in patients with low CD 4 count and the prognosis is poor. The radiologic patterns can be lytic, blastic or subtle changes, solitary or multifocal. The diagnosis of skeletal NHL is made on histopathology

Aim. To estimate the risk of bone malignancy arising in premalignant conditions. Methods. There are quite a number of possible premalignant conditions with considerable uncertainty about the actual risk of a bone sarcoma developing. The incidence of these malignant conditions was identified from a prospective database containing 3000 primary bone sarcomas. Results. 178 of the 3000 patients with newly diagnosed bone sarcomas had a pre-exiting condition which in all probability led to the sarcoma. These included 50 with previous radiotherapy treatment and 47 with Paget's disease. 31 patients developed malignancy in HME, 8 with neurofibromatosis and 7 each with Ollier's disease and retinoblastoma. There were 4 malignancies in patients with Mafucci's syndrome, 3 in patients with fibrous dysplasia, 3 in patients with synovial chondromatosis and 2 in patients with Rothmund-Thomson syndrome. Given that the incidence of bone sarcomas is 9/million population per year, our 3000 patients represent 333 million population years. When the incidence of a condition is known in the population this allows an estimation of the risk of malignancy compared with the normal population. Retinoblastoma for instance is known to arise in 1 in 16000 births. The 7 malignancies we saw thus represents a risk to individuals with retinoblastoma of 336/million/yr - a figure 37 times the risk of the normal population. Approximate figures of risk have been calculated for other entities. Conclusion. Data from a supra-regional register allows an approximate estimate of the increased risk of bone tumours in premalignant conditions

Aim: To estimate the risk of bone malignancy arising in premalignant conditions. Methods: There are quite a number of possible premalignant conditions with considerable uncertainty about the actual risk of a bone sarcoma developing. The incidence of these malignant conditions was identified from a prospective database containing 3000 primary bone sarcomas. Results: 178 of the 3000 patients with newly diagnosed bone sarcomas had a pre-exiting condition which in all probability led to the sarcoma. These included 50 with previous radiotherapy treatment and 47 with Paget’s disease. 31 patients developed malignancy in HME, 8 with neurofibromatosis and 7 each with Ollier’s disease and retinoblastoma. There were 4 malignancies in patients with Mafucci’s syndrome, 3 in patients with fibrous dysplasia, 3 in patients with synovial chondromatosis and 2 in patients with Rothmund-Thomson syndrome. Given that the incidence of bone sarcomas is 9/million population per year, our 3000 patients represent 333 million population years. When the incidence of a condition is known in the population this allows an estimation of the risk of malignancy compared with the normal population. Retinoblastoma for instance is known to arise in 1 in 16000 births. The 7 malignancies we saw thus represents a risk to individuals with retinoblastoma of 336/million/yr – a figure 37 times the risk of the normal population. Approximate figures of risk have been calculated for other entities. Conclusion: Data from a supra-regional register allows an approximate estimate of the increased risk of bone tumours in premalignant conditions

The rising incidence of atraumatic fractures in patients either with Ewing's sarcoma or osteosarcoma years after chemotherapy revealed a growing population of childhood cancer survivors with a decreased bone mineral density (BMD) possibly due to a long-term effect of the chemotherapy. Therefore we started to screen our patients below 50y of age who were treated for bone malignancies between 1994 and 2009. The first series of measurements included 15 patients – eight Ewing's sarcoma, three female and five male, with a mean age of 18y (±13SD), and seven osteosarcoma, two female and five male, with a mean age of 19y(±9SD). We screened the patients for deficits in their bone status using DEXA (dual-energy-x-ray-absorptiometry) to gain the T-and Z-Scores of the proximal femur and the lumbal spine. Additionally we took blood samples for endocrinological analysis and utilised a questionnaire to scan the patient's liefestyle. The mean time between diagnosis and investigation was 95months (±79SD) in Ewing's sarcoma and 105months (±54 SD) in osteosarcoma. The results of the age and gender matched lumbal measurement (Z-Score) of the Ewing's sarcoma patients showed a reduction of the BMD in six cases (6/8), including three times osteopenia (3/8) and two times osteoporosis (2/8). The osteosarcoma patients presented a BMD-decline in four cases (4/7) with two times osteopenia (2/7) and one osteoporosis (1/7). In the proximal femur six Ewing's sarcoma (6/8) and six osteosarcoma patients (6/7) showed a BMD-decrease including three osteopenic (3/8) and one osteoporotic (1/8) Ewing's sarcoma and four osteopenic osteosarcoma (4/7). We found two cases of pathologic fractures (2/15), one Ewing's sarcoma 29 months after diagnosis with a fracture of the distal femur and the proximal Tibia (1/8) and one osteosarcoma with a fractured distal femur after 72 months (1/7). As presented in our case series osteoporosis after chemotherapy is an underestimated long-term effect of the chemotherapeutic treatment. In our series BMD-reduction seems to be independent of tumour-type and chemotherapeutic agent like MTX

High-dose methothrexate, a standard agent in the therapy protocols for osteosarcoma, has long been suspected to have a negative long-term effect on bone metabolism and bone mineral density, especially in children and young adults. Recent literature questioned this association as also the BMD of Ewing‘s sarcoma patients treated without methothrexate is known to be decreased. We therefore wanted to screen our patients treated for Ewing‘s sarcoma and osteosarcoma for osteopenia/osteoporosis-associated fractures. Between 1994 and 2008 107 patients below 50y of age were treated for bone malignancies including 51 Ewing’s sarcomas – 31 male and 20 female – with a mean age at diagnosis of 17y(±11SD) and 56 osteosarcomas – 36 male and 20 female – with a mean age of 23y(±12SD). We screened the patients‘ files for fractures after chemotherapy. We found five patients with not trauma-associated fractures – one Ewing‘s sarcoma(1/51;2%) and four osteosarcoma patients(4/56;7%). They presented one fracture of the proximal femur 107 months after tumour diagnosis, three fractures of the distal femur after 29, 51, and 72 months and two fractures of the proximal tibia after 29 and 32 months (one patient suffered from fractures affecting both – the distal femur and the proximal tibia). As presented in our case series fractures due to an osteoporotic process after chemotherapy for bone sarcomas are well known late effects. Although described in several studies therapeutic recommendations for pro-phylaxis are sparse. Furthermore the fact that fractures occurred in both types of sarcoma casts MTX as the main cause of chemotherapy-induced osteoporosis into doubt. Additionally we estimate a high number of unreported cases of premature osteoporosis because sarcoma patients are usually not tested for their BMD-levels. Therefore further studies using DEXA (dual-energy-x-ray-absorptiometry) to measure the patients BMDs after chemotherapy are needed

Salvage procedures for complications following revision arthroplasty are becoming an increasingly necessary intervention. Total femoral replacement (TFR), initially developed for limb salvage in the management of bone malignancy is the most extreme example of this. Over the last 25 years, 14 patients have undergone TFR at the author’s institution following complications of revision arthroplasty surgery. We have retrospectively reviewed the medical records and radiographs on this patient group (in terms of operative indication, morbidity and mortality). The clinical outcome has been evaluated using the International Symposium of Limb salvage (ISOLS) criteria. 14 patients, 9 male 5 female were treated with TFR between 1978 and 2003. The average age was 64 years (range 44–79 years). The duration of symptoms from primary intervention to total femoral replacement was on average 8 years (range 1–15 years) and during this period the number of revision procedures undertaken ranged from 1– 4. In 86 % of cases the operative indication for TFR was for the management of deep sepsis. Other indications include non-union and periprosthetic fracture with massive bone loss. The post operative course was varied with 4 patients experiencing no significant complications, 2 needing further surgery as a consequence of infection, 5 needed surgery for dislocation with 2 of these patients being left with a permanently dislocated hip. As all patients had undergone some form of limb salvage procedure prior to TFR their level of function was assessed pre-operatively by the ISOLS criteria. This showed a range 0 – 33% (poor function). Clinical outcome following TFR measured by the same ISOLS criteria showed a range 36 – 80% (poor to good function). Total femoral replacement has a definite role in the management of complex problems arising following hip and knee revision arthroplasty surgery. Pain can be controlled to an acceptable level and independence can be maintained

Proximal humerus is the common site for primary bone malignancies that surgical treatment consists of wide excision of the tumor and reconstruction with tumor resection prosthesis or allograft. The ultimate function of the shoulder depends on the degree of sacrification of adjacent structures. Thirty-two patients with primary malignancies have been treated by wide excision and endoprosthetic replacement by senior author between 1989–2005 12 patients were female, 20 patients were male, mean age was 26,6 years (range 7–69 years). Histological diagnosis was 14 osteosarcoma, 4 Ewing’s sarcoma, 4 chondrosarcoma, 3 parosteal sarcoma, 4 giant cell tumor, 1 aneurysmal bone cyst, 2 synovial sarcoma. Synovial sarcoma, osteosarcoma and Ewing’s sarcoma patients received neoadjuvant chemotherapy prior to excision. Mean follow-up was 50,4 months (range 6–153 months). Oncologic results were 20 patients NED (no evidence of disease), 2 patients AWD (alive with disease), 10 patients DOD (died of disease). Functional outcome was scored according to Musculo-Skeletal System Tumor Society (MSTS) rating scale, 7 patients were excellent, 22 patients were good and 3 patients were poor. Regarding complications 2 patients developed local recurrence, 2 patients had superficial infection. Infected cases were treated by systemic antibiotic treatment. All patients had dexterity of the hand and elbow. Regarding shoulder abduction and forward flexion, 7 patients whose deltoid muscle and axillary nerve could be spared got nearly normal shoulder function but even the patients with loss of deltoid had limited abduction owing to elevation of scapula by shrugging. Elongation of the newly formed shoulder capsule was seen in patients that artificial mesh augmentation was not used. Prolene mesh was used to create a new substitute instead of resected shoulder joint capsule. These patients did not show any elongation at long-term follow-up. All arthroplasties was hemi-type without glenoid reconstruction. Hemiarthroplasty by a modular tumor resection prosthesis system after wide excision of proximal humerus seems to be an effective method of treatment after shoulder malignancies. The main determinant of the function is the status of deltoid axillary nerve and rotator cuff but the patients deprived of structures had a functional upper limb with a good command of the elbow and the hand

Sarcoma is a malignancy of mesenchymal and neuroectodermal tissue, and as such, may arise in any location in the body. It is a rare tumour accounting for less than 1 in 1000 cancers and occurs with an incidence of 1.7–2 per 100000 head of population. Disease free survival following treatment of sarcoma has increased significantly over the last 20–30 years and five year survival for primary bone malignancies is approximately 75–80% and that for soft tissue sarcomas is approximately 70%. Early attempts at limb sparing surgery was characterised by surgery with narrow margins, complicated incisions and substantial soft tissue bruising. Not surprisingly, the risk of local recurrence was high, but this was attributed to the nature of sarcoma rather than technique, and amputation became the treatment of choice for sarcoma. In the mid 1970’s, the importance of surgical margins was recognised and guidelines were established for achieving oncologic surgical margins. Intralesional and marginal margins alone were regarded as inadequate, while wide and radical margins were acceptable for achieving local control of disease. The advent of magnetic resonance imaging improved the level of tumour delineation and allowed more accurate preoperative planning. This together with modern chemotherapy and radiotherapy increased the potential for limb sparing surgery. Reconstruction following tumour resection is an exciting opportunity to protect the function of the limb and the mobility and independence of the patient. There have been a variety of techniques described and these involve either biological, prosthetic or a combination of these options. Reconstructions may be mobile or rigid. Mobile reconstructions frequently utilise prosthetic joints, but at other times pseudarthroses may function similarly, e.g. hip, shoulder. Osteoarticular allografts are also used to maintain joint function following tumour resection. Prosthetic joints incorporate advances in articulation and fixation to improve longevity as many of these devices are implanted into younger patients than normally anticipated for arthroplasty, and these joints are thus, exposed to an increased risk of wear and loosening. Osteoarticular allografts are prone to degenerative changes as well as graft disintegration and infection. Allograft prosthetic composites aim to reduce the articulation problems and may also assist in fixation of the construct. Biologic reconstructions using vascularised or non-vascularised bone are a useful technique for bridging defects and for replenishing bone stock. Adequate soft tissue coverage is vital following reconstruction. The future of limb sparing surgery will depend on our ability to characterise the biological behaviour of the tumour because this will provide more information on the response of the tumour to treatment, the potential grade of the lesion and thus, its capacity to grown and spread. By understanding the process of tumour progression, we will be able to develop better strategies for treatment. Functional nuclear scanning using isotopes that are metabolised by tumours is a technique that is currently being evaluated as a complementary form of imaging. Chemotherapy has been the cornerstone in the treatment of bone sarcomas, but remains surprisingly disappointing when used for soft tissue sarcomas. Recent meta-analyses have demonstrated only a minimal improvement in disease–free survival with chemotherapy. Novel techniques or agents are required to improve the systemic role of chemotherapy. Patient selection is important and this may relate to their risk of developing systemic spread. Prognostic factors are therefore, important for identifying patients who may be candidates for novel or intensive chemotherapy. Molecular biology is providing an avenue for characterising these tumours but despite the identification of a multitude of distinctive chromosomal abnormalities with their associated gene products, only 2 abnormalities have been shown to be of prognostic significance (19p+ in MFH, and SSX/SYT in synovial sarcoma). Surgeon education is an area where significant advances may be made. Constant reiteration is required to ensure that the principles of proper diagnosis and referral are known. Successful treatment is dependent on knowledge of the criteria for and technique of biopsy, and the principle that the team that will be providing definitive treatment should perform the biopsy. Up to 30% of limbs are sacrificed each year because of inappropriate biopsy or surgery. This figure may be improved upon with greater understanding of the behaviour of sarcomas. A regimented, multidisciplinary approach to the management of bone and soft tissue sarcomas is likely to improve the local and systemic control of this disease

Aims: Limb sparing surgery, for selected cases of long bone primary malignancy, may be accomplished with the use of large prostheses. Conventional joint implants are known to release metal ions by corrosion or wear. The aim of this study was to determine if a specialist group of patients had elevated serum metal levels. Methods: Over a 12 month period, 20 patients who had undergone previous surgery were recruited from a bone tumour clinic. A 10ml venous blood sample was obtained and analysed for trace metals using a previously published mass-spectrometry technique. Results: Eight children (mean age 14.5 years) and 12 adults (mean age 46.5 years) were recruited a mean of 54 months and 86 months following surgery, respectively. Trace metal (aluminium, titanium, cobalt) elevation was observed in 5/8 (63%) paediatric cases and 6/12 (50%) adult cases. Three of the adults had signiþcantly raised levels, (≤ 50 times), and had undergone revision surgery for loosening. There was no observed implant loosening in the paediatric group. Conclusions: This small sample has demonstrated that many patients with long-term large tumour implants have trace metal levels below laboratory detection. Signiþcant elevation of metal levels in adults was associated with loosening or wear of implants. A signiþcant proportion of paediatric cases had slight elevations, but the signiþcance of this is unknown at present