Aims. A recent report from France suggested an association between the use of cobalt-chrome (CoCr) femoral heads in total hip arthroplasties (THAs) and an increased risk of dilated cardiomyopathy and heart failure. CoCr is a commonly used material in orthopaedic implants. If the reported association is causal, the consequences would be significant given the millions of joint arthroplasties and other orthopaedic procedures in which CoCr is used annually. We examined whether CoCr-containing THAs were associated with an increased risk of all-cause mortality, heart outcomes, cancer, and neurodegenerative disorders in a large national database. Methods. Data from the National Joint Registry was linked to NHS English hospital inpatient episodes for 374,359 primary THAs with up to 14.5 years' follow-up. We excluded any patients with bilateral THAs, knee arthroplasties, indications other than osteoarthritis, aged under 55 years, and diagnosis of one or more outcome of interest before THA. Implants were grouped as either containing CoCr or not containing CoCr. The association between implant construct and the risk of all-cause mortality and incident heart failure, cancer, and neurodegenerative disorders was examined. Results. There were 158,677 individuals (42.4%) with an implant containing CoCr. There were 47,963 deaths, 27,332 heart outcomes, 35,720 cancers, and 22,025 neurodegenerative disorders. There was no evidence of an association between patients with CoCr implants and higher rates of any of the outcomes. Conclusion. CoCr-containing THAs did not have an increased risk of all-cause mortality, or clinically meaningful heart outcomes, cancer, or neurodegenerative disorders into the second decade post-implantation. Our findings will help reassure clinicians and the increasing number of patients receiving primary THA worldwide that the use of CoCr-containing implants is not associated with significant adverse systemic effects. Cite this article: Bone Joint J 2022;104-B(3):359–367

Bone metastases are common and severe complications of cancers. It is estimated to occur in 65–75% of breast and prostate cancer patients and cause 80% of breast cancer-related deaths. Metastasised cancer cells have devastating impacts on bone due to their ability to alter bone remodeling by interacting with osteoblasts and osteoclasts. Exercise, often used as an intervention for cancer patients, regulates bone remodeling via osteocytes. Therefore, we hypothesise that bone mechanical loading may regulate bone metastases via osteocytes. This provides novel insights into the impact of exercises on bone metastases. It will assist in designing cancer intervention programs that lowers the risk for bone metastases. Investigating the mechanisms for the observed effects may also identify potential drug targets. MLO-Y4 osteocyte-like cells (gift of Dr. Bonewald, University of Missouri-Kansas City) on glass slides were placed in flow chambers and subjected to oscillatory fluid flow (1Pa; 1Hz; 2 hours). Media were extracted (conditioned media; CM) post-flow. RAW264.7 osteoclast precursors were conditioned in MLO-Y4 CM for 7 days. Migration of MDA-MB-231 breast cancer cells and PC3 prostate cancer cells towards CM was assayed using Transwell. Viability, apoptosis, and proliferation of the cancer cells in the CM were measured with Fixable Viability Dye eFluor 450, APOPercentage, and BrDu, respectively. P-values were calculated using Student's t-test. Significantly more MDA-MB-231 and PC3 cells migrated towards the CM from MLO-Y4 cells with exposure to flow in comparison to CM from MLO-Y4 cells not exposed to flow. The preferential migration is abolished with anti-VEGF antibodies. MDA-MB-231 cells apoptosis rate was slightly lower in CM from MLO-Y4 cells exposed to flow, while proliferation rate was slightly higher. The current data showed no difference in cancer cells viability and adhesion to collagen between any two groups. On the other hand, it was observed that less MDA-MB-231 cells migrated towards CM from RAW264.7 cells conditioned in CM from MLO-Y4 cells stimulated with flow in comparison to those conditioned in CM from MLO-Y4 cells not stimulated with flow. TRAP staining results confirmed that there were less differentiated osteoclasts when RAW264.7 cells were cultured in CM from MLO-Y4 cells exposed to flow. Overall, this study suggests that when only osteocytes and cancer cells are involved, osteocytes subjected to mechanical loading can promote metastases due to the increased secretion of VEGF. However, with the incorporation of osteoclasts, mechanical loading on osteocytes seems to reduce MDA-MB-231 cell migration. This is likely because osteocytes reduce osteoclastogenesis in response to mechanical stimulation, and osteoclasts have been shown to support cancer cells. Animal studies will also be conducted to verify the pro- or anti-metastatic effect of mechanical loading that is observed in the in vitro part of this study

Aims. Breast cancer survivors have known risk factors that might influence the results of total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study evaluated clinical outcomes of patients with breast cancer history after primary THA and TKA. Methods. Our total joint registry identified patients with breast cancer history undergoing primary THA (n = 423) and TKA (n = 540). Patients were matched 1:1 based upon age, sex, BMI, procedure (hip or knee), and surgical year to non-breast cancer controls. Mortality, implant survival, and complications were assessed via Kaplan-Meier methods. Clinical outcomes were evaluated via Harris Hip Scores (HHSs) or Knee Society Scores (KSSs). Mean follow-up was six years (2 to 15). Results. Breast cancer patient survival at five years was 92% (95% confidence interval (CI) 89% to 95%) after THA and 94% (95% CI 92% to 97%) after TKA. Breast and non-breast cancer patients had similar five-year implant survival free of any reoperation or revision after THA (p ≥ 0.412) and TKA (p ≥ 0.271). Breast cancer patients demonstrated significantly lower survival free of any complications after THA (91% vs 96%, respectively; hazard ratio = 2 (95% CI 1.1 to 3.4); p = 0.017). Specifically, the rate of intraoperative fracture was 2.4% vs 1.4%, and venous thromboembolism (VTE) was 1.4% and 0.5% for breast cancer and controls, respectively, after THA. No significant difference was noted in any complications after TKA (p ≥ 0.323). Both breast and non-breast cancer patients experienced similar improvements in HHSs (p = 0.514) and KSSs (p = 0.132). Conclusion. Breast cancer survivors did not have a significantly increased risk of mortality or reoperation after primary THA and TKA. However, there was a two-fold increased risk of complications after THA, including intraoperative fracture and VTE. Cite this article: Bone Joint J 2024;106-B(4):365–371

Background: About 60% of all cancer patients survive at least 5 years, and therefore have a risk to develop long-term effects after cancer treatment. Most research, the later years, on long-term effects after cancer treatment, has focused on cardiovascular side effects and side effects in the pelvic region. On the other hand, hardly any focus has been on possible side effects on the musclo-skeletal system, though there are multiple reasons that surviving cancer patients may develop such problems. Aim: To determine whether cancer patients have an increased risk for receiving a total hip replacement compared to the population of Norway. Analyses are based on a linkage between The Cancer Register of Norway and The Norwegian Arthroplasty Register. Materials and Methods: By linking these two registers we have connected all cancer diagnosis, all total hip arthroplasties and information about time of death for each patient. Data refers to 741,901 patients, divided into three groups; 652,197 patients with at least one cancer diagnose but none hip arthroplasties. 72,469 patients with at least one hip arthroplasty but no cancer diagnose. The last group of 17,235 patients have at least one cancer diagnose and at least one hip arthroplasty. From the last group 8,629 patients received a cancer diagnoses first and a total hip arthroplasty second. Statistical methods in this study were the Kaplan-Meier method, Cox regression and Standardized Incidence Ratio (SIR). Results: Cancer patients had a slight increased risk to receive a total hip arthroplasty compared to the Norwegian population (SIR=1.13 (95% CI, 1.10–1.15)). For cancer located proximal to the pelvic area there were no significant increase in risk for hip arthroplasty, except for breast cancer (SIR=1.12 (95% CI 1.07–1.17)). Cancer located to the pelvic area (SIR=1.18 (95% CI 1.14–1.22)), lymphoma (SIR=1.29 (95% CI 1.14–1.45)) and leukaemia (SIR=1.16 (95% CI 1.17–1.31)) had an increased risk for receiving a total hip arthroplasty. Conclusion: We found a small increase in risk for receiving total hip arthroplasty after cancer diagnose. Treatment type may affect these results. Radiation dose to the pelvic area may affect the bone structure and increase the need of arthroplasty. Future studies on effect of radiation doses and risk of receiving hip arthroplasty are planed

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

Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening. Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival. In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed. Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required

Cancer is a major health problem for teenagers and young adults (TYA’s). However, many young people are often late to receive a cancer diagnosis. Young people may not recognize symptoms as serious and delay seeking help. Furthermore, there is evidence to suggest that once a young person does seek help from a general practitioner (GP), significant delay can still occur. During the annual Find Your Sense of Tumour (FYSOT) conference 2007; a group of 200 TYA’s with cancer participated in a survey regarding their diagnostic experience; the cohort included 22 patients with bone tumours. Following the onset of symptoms; nearly half of the TYA’s with a bone tumour (46%) reported 4 or more visits to their G.P before being referred to a specialist. However, 91% of bone tumour patients had multiple, ‘classic’ cancer symptoms and the majority (77%) sought help from the G.P within 4 weeks of noticing symptoms. The ‘Christie Crew’ (CC) are a group of TYA’s who have been treated for cancer and work on various projects to improve cancer services. The Christie Crew wanted to empower young people with the knowledge that TYA’s do get cancer and to raise awareness of the signs and symptoms of cancer and have produced a DVD and education pack that has been launched across 80 schools and throughout the North West. The DVD is highlights individual’s stories of diagnosis. There is also a poster campaign highlighting signs and symptoms of cancer being displayed in large public venues across the Manchester area. The aim is to roll out the project nationally as part of the health awareness (Healthy Schools) initiative. By highlighting that young people get cancer it is hoped that more young people will recognise the signs and symptoms and be empowered to go to their GP if they have persistent problems

Aims. Receptor activator of nuclear factor-κB ligand (RANKL) is a key molecule that is expressed in bone stromal cells and is associated with metastasis and poor prognosis in many cancers. However, cancer cells that directly express RANKL have yet to be unveiled. The current study sought to evaluate how a single subunit of G protein, guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), transforms cancer cells into RANKL-expressing cancer cells. Methods. We investigated the specific role of GNAQ using GNAQ wild-type cell lines (non-small-cell lung cancer cell lines; A549 cell lines), GNAQ knockdown cell lines, and patient-derived cancer cells. We evaluated GNAQ, RANKL, macrophage colony-stimulating factor (M-CSF), nuclear transcription factor-κB (NF-κB), inhibitor of NF-κB (IκB), and protein kinase B (Akt) signalling in the GNAQ wild-type and the GNAQ-knockdown cells. Osteoclastogenesis was also evaluated in both cell lines. Results. In the GNAQ-knockdown cells, RANKL expression was significantly upregulated (p < 0.001). The expression levels of M-CSF were also significantly increased in the GNAQ-knockdown cells compared with control cells (p < 0.001). GNAQ knockdown cells were highly sensitive to tumour necrosis factor alpha (TNF-α) and showed significant activation of the NF-κB pathway. The expression levels of RANKL were markedly increased in GNAQ mutant compared with GNAQ wild-type in patient-derived tumour tissues. Conclusion. The present study reveals that the alterations of GNAQ activate NF-κB pathway in cancers, which increase RANKL and M-CSF expression and induce osteoclastogenesis in cancers. Cite this article:Bone Joint Res. 2020;9(1):29–35

Aims. 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. Methods. We used the mouse osteosarcoma cell line LM8, the human breast cancer cell line MDA-MB-231, and the human prostate cancer cell line PC-3. Cultured cells were exposed to AO and radiation at various concentrations followed by various doses of irradiation. The cell viability was then measured. In vivo, each cell was inoculated subcutaneously into the backs of mice. In the AO-RDT group, AO (1.0 μg) was locally administered subcutaneously around the tumour followed by 5 Gy of irradiation. In the radiation group, 5 Gy of irradiation alone was administered after macroscopic tumour formation. The mice were killed on the 14th day after treatment. The change in tumour volume by AO-RDT was primarily evaluated. Results. The viability of LM8, MDA-MB-231, and PC-3 cells strongly decreased at AO concentration of 1.0 μg/ml and a radiation dose of 5 Gy. In xenograft mouse model, the AO-RDT also showed a strong cytocidal effect on tumour at the backside in osteosarcoma, breast cancer, and prostate cancer. AO-RDT treatment was more effective for tumour control than radiotherapy in breast cancer. Conclusion. AO-RDT was effective in preventing the proliferation of osteosarcoma, breast cancer, and prostate cancer cell lines in vitro. The reduction in tumour volume by AO-RDT was also confirmed in vivo. Cite this article: Bone Joint Res 2022;11(10):715–722

Metastatic bone disease (MBD) is a significant contributor to diminished quality of life in cancer patients, often leading to pathologic fractures, hypercalcaemia, intractable bone pain, and reduced functional independence. Standard of care management for MBD patients undergoing orthopaedic surgery is multi-disciplinary, includes regular surgical follow-up, case by case assessment for use of bone protective medications, and post-operative radiation therapy to the operative site. The number of patients in southern Alberta receiving standard of care post-operative management is currently unclear. Our aim is to develop a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD and to assess for deficiencies and opportunities to ensure standard of care for this complex patient population. Patients were identified for database inclusion by a search query of the Alberta Cancer Registry of all patients with a diagnosis of metastatic cancer who underwent surgery for an impending or pathologic fracture in the Calgary, South and Central Alberta Zones. Demographic information, primary cancer history, previous local and systemic treatments, anatomical location of MBD event(s), surgical fixation techniques, and post-operative care details were collected. The rate of standard of care post-operative treatment was evaluated. A comparison of outcomes between tertiary urban centres and rural centres was also completed. Survival was calculated from time of first operation to date of death. Univariate and multivariate analyses were performed to identify the impact of post-operative care variables on survival amongst patients surviving longer than one month. We identified 402 patients who have undergone surgical treatment for MBD in southern Alberta from 2006-2018. Median age at time of surgery was 66.3 years and 52.7% of patients were female. Breast, lung, prostate, renal cell and multiple myeloma were the most common primary malignancies (n=328, 81.6%). Median post-operative survival was 6.8 months (95%CI: 5.7-8.3). 203 patients (52.5%) were treated with post-operative radiotherapy and 159 patients (50.8%) had post-operative surgical follow-up. Only 39 patients (11.3%) received bone protective agents in the peri-operative period. On multivariate survival analysis, post-operative surgical follow-up was associated with improved survival (p<0.001). Patients were treated at nine hospitals across southern Alberta with most patients treated in an urban center (65.9%). Post-operative survival was significantly longer amongst patients treated in an urban center (9.0 months, 95%CI: 6.9-12.3 versus 4.3 months, 95%CI: 3.4-5.6, p<0.001). The burden of MBD is significant and increasing. With treatment occurring at multiple provincial sites, there is a need for standardized, primary disease-specific peri- and post-operative protocols to ensure quality and efficacious patient care. To provide evidence informed treatment recommendations, we have developed a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD. Our results demonstrate that many patients were not treated according to post-operative standard of care recommendations. Notably, half of the included patients did not have documented surgical follow-up, post-operative radiation treatment was low and only 11% were actively treated with bone protective agents. This data justifies the need for established surgical MBD care pathways and provides reference data to benchmark prospective QA and QI outcomes in this patient population

Lung cancer is the most common cancer diagnosed, the leading cause of cancer-related deaths, and bone metastases occurs in 20–40% of lung cancer patients. They often present symptomatically with pain or skeletal related events (SREs), which are independently associated with decreased survival. Bone modifying agents (BMAs) such as Denosumab or bisphosphonates are routinely used, however no specific guidelines exist from the National Comprehensive Cancer Center or the European Society of Medical Oncologists. Perhaps preventing the formation of guidelines is the lack of a high-quality quantitative synthesis of randomized controlled trial (RCT) data to determine the optimal treatment for the patient important outcomes of 1) Overall survival (OS), 2) Time to SRE, 3) SRE incidence, and 4) Pain Resolution. The objective of this study was to perform the first systematic review and network meta-analysis (NMA) to assess the best BMA for treatment of metastatic lung cancer to bone. We conducted our study in accordance to the PRISMA protocol. We performed a librarian assisted search of MEDLINE, PubMed, EMBASE, and Cochrane Library and Chinese databases including CNKI and Wanfang Data. We included studies that are RCTs reporting outcomes specifically for lung cancer patients treated with a bisphosphonate or Denosumab. Screening, data extraction, risk of bias and GRADE were performed in duplicate. The NMA was performed using a Bayesian probability model with R. Results are reported as relative risks, odds ratios or mean differences, and the I2 value is reported for heterogeneity. We assessed all included articles for risk of bias and applied the novel GRADE framework for NMAs to rate the quality of evidence supporting each outcome. We included 132 RCTs comprising 11,161 patients with skeletal metastases from lung cancer. For OS, denosumab was ranked above zoledronic acid (ZA) and estimated to confer an average of 3.7 months (95%CI: −0.5 – 7.6) increased survival compared to untreated patients. For time to SRE, denosumab was ranked first with an average of 9.1 additional SRE-free months (95%CI: 4.0 – 14.0) compared to untreated patients, while ZA conferred an additional 4.8 SRE-free months (2.4 – 7.0). Patients treated with the combination of Ibandronate and systemic therapy were 2.3 times (95%CI: 1.7 – 3.2) more likely to obtain successful pain resolution, compared to untreated. Meta-regression showed no effect of heterogeneity length of follow-up or pain scales on the observed treatment effects. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for SRE incidence, and low for pain resolution. While a generally high risk of bias was observed across studies, whether they were from Western or Chinese databases. The overall GRADE for the evidence underlying our results is High for Pain control and SRE incidence, and Moderate for OS and time to SRE. This study represents the most comprehensive synthesis of the best available evidence guiding pharmacological treatment of bone metastases from lung cancer. Denosumab is ranked above ZA for both overall survival and time to SRE, but both treatments are superior to no treatment. ZA was first among all bisphosphonates assessed for odds of reducing SRE incidence, while the combination of Ibandronate and radionuclide therapy was most effective at significantly reducing pain from metastases. Clinicians and policy makers may use this synthesis of all available RCT data as support for the use of a BMA in MBD for lung cancer

The initiation and progression of malignant tumors are supported by their microenvironment: cancer cells per se cannot explain growth and formation of the primary or metastasis, and a combination of proliferating tumor cells, cancer stem cells, immune cells, mesenchymal stromal cells and/or cancer-associated fibroblasts all contribute to the tumor bulk. The interaction between these multiple players, under different microenvironmental conditions of biochemical and physical stimuli (i.e. oxygen tension, pH, matrix mechanics), regulates the production and biological activity of several soluble factors, extracellular matrix components, and extracellular vesicles that are needed for growth, maintenance, chemoresistance and metastatization of cancer. Both in osteosarcoma and bone metastases from carcinomas this aspect has been only recently explored. In this lecture, I will discuss the role of tumor microenvironment, with a particular focus on the mesenchymal stroma, contributing to bone tumor progression through inherent. The most recent advances in the molecular cues triggered by cytokines, soluble factors, and metabolites that are partially beginning to unravel the axis between stromal elements of mesenchymal origin and bone cancer cells, under different microenvironmental conditions, will be reviewed providing insights likely to be used for novel therapeutic approaches

Breast and other cancers commonly metastasize to bone to cause bone destruction, pain, fractures hypercalcemia and muscle weakness. Recently, we described a specific molecular mechanism by which bone-derived transforming growth factor (TGF)-beta, released as a consequence of tumor-induced bone destruction causes muscle dysfunction, before the loss of muscle mass. Circulating TGF-beta induces oxidation of the ryanodine receptor (RYR1) on the sarcoplasmic reticulum of skeletal muscle to induce calcium leak and muscle weakness. Blocking TGF-beta, or its release from bone (with bisphosphonates), preventing oxidation of or stabilizing RyR1 all prevented muscle weakness in mouse models of breast cancer bone metastases. In addition to these effects on skeletal muscle, circulating TGF-beta may act on beta cells of the pancreas to impair insulin secretion and result in glucose intolerance. These and other potential systemic effects of TGF-beta released from the tumor-bone microenvironment or from cancer treatment-induced bone destruction implicate bone as a major source of systemic effects of cancer and cancer treatment. Therapy to block the systemic effects of the bone microenvironment will improve morbidity associated with bone metastases and cancer treatment

A recent French report suggested that cobalt metal ions released from total hip replacements (THRs) were associated with an increased risk of dilated cardiomyopathy and heart failure. If the association is causal the consequences would be significant given the millions of Orthopaedic procedures in which cobalt-chrome is used annually. We examined whether cobalt-chrome containing THRs were associated with an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders. Data from the National Joint Registry was linked to NHS English hospital inpatient episodes for 375,067 primary THRs with up to 14·5 years follow-up. Implants were grouped as either containing cobalt-chrome or not containing cobalt-chrome. The association between implant construct and the risk of all-cause mortality and incident heart failure, cancer, and neurodegenerative disorders was examined. There were 132,119 individuals (35·2%) with an implant containing cobalt-chrome. There were 48,106 deaths, 27,406 heart outcomes, 35,823 cancers, and 22,097 neurodegenerative disorders. There was no evidence of an association that patients with cobalt-chrome implants had higher rates of any of the outcomes. For all-cause mortality there was a very small survival advantage for patients having a cobalt-chrome implant (restricted mean survival time 13·8=days, 95% CI=6·8-20·9). Cobalt-chrome containing THRs did not have an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders into the second decade post-implantation. Our findings will reassure clinicians and patients that primary THR is not associated with systemic implant effects

Breast cancer is generally managed surgically with adjuvant agents which include hormone therapy, chemotherapy, radiotherapy and bisphosphonate therapy. However, some of these adjuvant therapies may cause adverse events, including wound infection, neutropenia, bone marrow suppression and fever. The simultaneous presentation of osteonecrosis and osteomyelitis has not previously been described in patients with breast cancer undergoing hormone therapy and chemotherapy. We report a patient with breast cancer who developed bone infarcts in both legs as well as osteomyelitis in the right distal tibia after treatment which included a modified radical mastectomy, hormone therapy and chemotherapy. Simultaneous osteonecrosis and osteomyelitis should be considered in patients with breast cancer who are receiving chemotherapy and hormone therapy who present with severe bone pain, especially if there have been infective episodes during treatment

The burden of metastatic disease presenting with axial skeleton lesions is exponentially rising predominantly due to advances in oncological therapies. A large proportion is these lesions are located in the proximal femora, which given its unique biomechanical architecture is problematic. These patients are frequently comorbid and require prompt and concise decision making regarding their orthopaedic care in line with recent British Orthopaedic Association guidelines. We present data detailing the outcomes for patients with proximal femoral metastatic disease referred and treated over a three year period in an Regional Cancer Centre. We retrospectively reviewed a prospectively maintained database of all patients referred for discussion at MDT with axial skeletal metastatic disease. From this we isolated patients with femoral disease. Demographic data along with primary tumour and metastatic disease site were assessed. Treatment regimens were analysed and compared. Finally predicted and actual mortality data was collated. 331 patients were referred over the analysed time period, of which 99 had femoral disease. 66% of patients were managed conservatively with serial monitoring while 34% underwent operative treatment. 65% of those received an intramedullary fixation while 35% had arthroplasty performed. There was a 51:49 split male to female with Prostate, Lung and Breast being the predominant primary tumours. Concurrent spinal metastatic disease was noted in 62% of patients while visceral mets were seen in 37%. Mortality rate was 65% with an average prognosis of 388 days (1.06years) while average mortality was noted within 291 days (0.8 years). Proximal femoral metastatic disease accounts for a large volume of the overall mets burden. There is an overall tendency towards conservative management and of those requiring surgery IM nailing was the treatment of choice. The data would indicate that outcomes for these patients are guarded and on average worse than those predicted

One out of nine Canadian males would suffer prostate cancer (PC) during his lifetime. Life expectancy of males with PC has increased with modern therapy and 90% live >10 years. However, 20% of PC-affected males would develop incurable metastatic diseases. Bone metastases (BM) are present in ~80% of metastatic PC patients, and are the most severe complication of PC, generating severe pain, fractures, spinal cord compression, and death. Interestingly, PC-BMs are mostly osteoblastic. However, the structure of this newly formed bone and how it relates to pain and fracture are unknown. Due to androgen antagonist treatment, different PC phenotypes develop with differential dependency on androgen receptor (AR) signaling: androgen-dependent (AR+), double negative (AR-) and neuroendocrine. How these phenotypes are related to changes in bone structure has not been studied. Here we show a state-of-the-art structural characterization of PCBM and how PC phenotypes are associated to abnormal bone formation in PCBM. Cadaveric samples (n=14) obtained from metastases of PC in thoracic or lumbar vertebrae (mean age 74yo) were used to analyze bone structure. We used micro-computed tomography (mCT) to analyze the three-dimensional structure of the bone samples. After imaging, the samples were sectioned and one 3mm thick section was embedded in epoxy-resin, ground and polished. Scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and quantitative backscattering electron (qBSE) imaging were used to determine mineral morphology and composition. Another section was used for histological analysis of the PC-affected bone. Collagen structure, fibril orientation and extracellular matrix composition were characterized using histochemistry. Additionally, we obtained biopsies of 3 PCBM patients undergoing emergency decompression surgery following vertebral fracture and used them for immunohistological characterization. By using mCT, we observed three dysmorphic bone patterns: osteolytic pattern with thinned trabecula of otherwise well-organized structures, osteoblastic pattern defined as accumulation of disorganized matrix deposited on pre-existing trabecula, and osteoblastic pattern with minimum residual trabecula and bone space dominated by accumulation of disorganized mineralized matrix. Comparing mCT data with patho/clinical parameters revealed a trend for higher bone density in males with larger PSA increase. Through histological sections, we observed that PC-affected bone, lacks collagen alignment structure, have a higher number of lacunae and increased amount of proteoglycans as decorin. Immunohistochemistry of biopsies revealed that PC-cells inside bone organize into two manners: i) glandular-like structures where cells maintain their polarization in the expression of prostate markers, ii) diffuse infiltrate that spreads along bone surfaces, with loss of cell polarity. These cells take direct contact with osteoblasts in the surface of trabecula. We define that PCBM are mostly composed by AR+ with some double negative cells. We did not observe neuroendocrine phenotype cells. PCBMs generate predominantly osteoblastic lesions that are characterized by high lacunar density, lack of collagen organization and elevated proteoglycan content. These structural changes are associated with the infiltration of PC cells that are mostly androgen-dependent but have lost their polarization and contact directly with osteoblasts, perhaps altering their function. These changes could be associated with lower mechanical properties that led to fracture and weakness of the PCBM affected bone

Aims. 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. Methods. A retrospective, single-centre review was conducted of patients with spinal metastases from NSCLC who underwent surgery followed by systemic therapy at our institution from January 2018 to September 2022. Kaplan-Meier analysis and log-rank tests were used to compare the LC and OS between groups. Associated factors for LC and OS were assessed using Cox proportional hazards regression analysis. Results. Overall, 123 patients with 127 spinal metastases from NSCLC who underwent decompression surgery followed by postoperative systemic therapy were included. A total of 43 lesions were treated with stereotactic body radiotherapy (SBRT) after surgery and 84 lesions were not. Survival rate at one, two, and three years was 83.4%, 58.9%, and 48.2%, respectively, and LC rate was 87.8%, 78.8%, and 78.8%, respectively. Histological type was the only significant associated factor for both LC (p = 0.007) and OS (p < 0.001). Treatment with targeted therapy was significantly associated with longer survival (p = 0.039). The risk factors associated with worse survival were abnormal laboratory data (p = 0.021), lesions located in the thoracic spine (p = 0.047), and lumbar spine (p = 0.044). This study also revealed that postoperative radiotherapy had little effect in improving OS or LC. Conclusion. Tumour histological type was significantly associated with the prognosis in spinal NSCLC metastasis patients. In the presence of post-surgical systemic therapy, radiotherapy appeared to be less effective in improving LC, OS, or quality of life in spinal NSCLC metastasis patients. Cite this article: Bone Jt Open 2024;5(4):350–360

Aims. Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma. Methods. We reviewed 4,739 patients diagnosed with primary bone sarcomas from the Surveillance, Epidemiology and End Results (SEER) registry between 2007 and 2015. We examined the impact of race and insurance status associated with the presence of metastatic disease at diagnosis, treatment outcome, and overall survival (OS). Results. Patients with Medicaid (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.15 to 1.72) and uninsured patients (OR 1.90; 95% CI 1.26 to 2.86) had higher risks of metastatic disease at diagnosis compared to patients with health insurance. Compared to White patients, Black (OR 0.63, 95% CI 0.47 to 0.85) and Asian/Pacific Islander (OR 0.65, 95% CI 0.46 to 0.91) were less likely to undergo surgery. In addition, Black patients were less likely to receive chemotherapy (OR 0.67, 95% CI 0.49 to 0.91) compared to White patients. In patients with chondrosarcoma, those with Medicaid had worse OS compared to patients with insurance (hazard ratio (HR) 1.65, 95% CI 1.06 to 2.56). Conclusion. In patients with a bone sarcoma, the cancer stage at diagnosis varied based on insurance status, and racial disparities were identified in treatment. Further studies are needed to identify modifiable factors which can mitigate socioeconomic and racial disparities found in patients with bone sarcomas. Cite this article: Bone Joint Res 2022;11(5):278–291

Purpose of study: Osteonecrosis is a potentially devastating condition which requires early diagnosis before articular collapse occurs. We have become aware of an increase in the number of childhood cancer survivors presenting to us with osteonecrosis. This is recognised in the literature among leukaemia survivors, particularly those treated in adolescence. In the majority of cases the hips have been affected, but shoulders, knees and ankles also appear susceptible. The presentation to orthopaedics is often late with subchondral fracture or collapse of the articular surface, which precludes any salvage of the joint. We wished to assess the extent of the problem throughout Britain. Method: A postal questionnaire was sent to all BSCOS members. Members were asked to note their unit’s experience of childhood cancer survivors with osteonecrosis, current management strategies and if they were willing to participate in a detailed national survey of cases. Results: 58% of respondents work in units where children with childhood cancer are treated. 37% of respondents, or their colleagues, had seen survivors of childhood cancer with osteonecrosis in the last twelve months. Most units had seen less than 5 cases per year. Of the respondents who had treated cases of osteonecrosis (n =30), management included restricted weight-bearing (29), core decompression (9) and bisphosphonates (6). Other treatment modalities used were joint distraction (2), fibular grafting (2), bone marrow injection (1), fusion (1) and arthroplasty (4). Conclusions: We have shown that a large number of units are each seeing small numbers of cases of osteonecrosis in childhood cancer survivors. The study establishes an estimate of the problem nationally and a network of centres to continue a more detailed analysis of cases

Introduction: Within a study group of 102 consecutive patients diagnosed with chondrosarcoma of the femur, tibia or humerus, an association with previously treated breast cancer was noted. We researched this proposed relationship. Methods: We retrospectively reviewed the records of all patients diagnosed histologically with chondrosarcoma of the femur, tibia or humerus over a six-year period at a supra-regional bone tumour unit. We identified those patients who had previously been treated for breast cancer. Results: There were 58 female and 44 male patients. The study group contained six females (10%, mean age 53 years) who had previously been treated for breast cancer, a higher proportion than would be expected. They were referred following identification of a solitary area of increased activity on routine screening with isotope bone scan, presumed to be a solitary bony metastasis. Most (86%) of this breast carcinoma sub-group had developed low-grade bone chondrosarcoma (Trojani grade 0.5-I) and only one case (14%) had developed high-grade chondrosarcoma (Trojani grade II–III). Discussion: A suspicious long bone lesion on bone scan in a patient with a past medical history of breast cancer must, therefore, not be assumed to be a metastasis without further investigation; the possibility of a chondral lesion should be considered. It is important that patients receive a full multidisciplinary team investigation prior to treatment in order to obtain the correct tissue diagnosis, as the management of these conditions is often different. Our study suggests there may be a relationship between patients previously treated for breast cancer and the development of subsequent chondrosarcoma

Common cancer metastases in bone include those derived from the breast or prostate. Associated with such metastases is considerable pain for the patient, a high incidence of pathological fractures (breast cancer metastases), and complications of spinal cord compression and paraplegia. Attention has focussed on the properties of breast or prostate cancer cells that permit them to migrate from their primary site and to invade and grow in bone. Both breast and prostate cancer cell lines and primary cancers exhibit a number of phenotypic properties in common with bone cells, and it has been proposed that these properties may contribute to a breast cancer’s capacity to establish and grow in bone. Once established in bone, these cancers may induce an osteosceloritic or osteolytic lesion. Osteolysis is also noted in the establishment of an osteosclerotic lesion that is frequently associated with prostate cancers. Thus, paramount for a cancer to establish in bone is the requirement for limited bone destruction, and the magnitude of associated bone destruction is a function of the cancer cell. Although it has been postulated that bone destruction by cancer cells is mediated directly by tumor cells, evidence indicates that breast cancer-induced bone destruction is mediated by the osteoclast. Support for the latter include: 1) breast cancers express cytokines [such as IL-1, IL-6, LIF, prostaglandin tumor necrosis factor and parathyroid hormone-related protein (PTHrP)] which can influence osteoclast formation; 2) histologic analyses of osteolytic lesions reveal tumor adjacent to osteoclasts resorbing bone; 3) and use of bisphosphonates, potent inhibitors of osteoclastic bone resorption, in women with breast cancer metastases to bone results in reduced skeletal morbidity. The interaction of cytokines expressed by cancer cells in the bone microenvironment and their action on osteoblast/stromal cells to induce differentiation of haematopoietic cells of the macrophage / monocyte lineage into osteoclasts is now understood. The mechanisms involved in cancer metastasis, osteoclast formation, and ultimately bone destruction will be discussed, along with the potential new therapies to limit bone destruction

Over 80% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Although thought to involve a complex cascade of cell-cell interactions, the factors controlling the development of bone metastases are still poorly understood. Osteoblasts may have an important role in mediating homing and proliferation of breast cancer cells to the bony environment. This study aimed to examine the potential role osteoblasts have in the migration of circulating tumour cells to bone and the factors involved in this attraction. Culture of osteoblasts and MDA-MB-231 breast cancer cells was performed. Breast cancer cell migration in response to osteoblasts was measured using Transwell Migration Inserts. Potential mediators of cell migration were detected using ChemiArray & ELISA assays. A luminometer based Vialight assay was used to measure breast cancer cell proliferation in response to factors secreted by osteoblasts. There was a 3-4 fold increase of MDA-MB-231 migration in response to osteoblasts. ChemiArray analysis of osteoblast-conditioned medium revealed a range of secreted chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. Initially, MCP-1 was quantified at 282 pg/ml, but rose to over 9000 pg/ml when osteoprogenitor cells were differentiated into mature osteoblasts. Inclusion of a monoclonal antibody to MCP-1 in osteoblast-conditioned medium resulted in a significant decrease in breast cancer cell migration to osteoblasts. There was no significant change in proliferation of MDA-MB 231 cells when exposed to osteoblast-conditioned medium. Osteoblasts are capable of inducing breast cancer cell migration mediated at least in part by chemokine secretion. MCP-1 produced by the osteoblasts was shown to play a central role in mediating homing of the breast cancer cells. Increased understanding of the pathways involved in the development of bone metastases may provide new targets for therapeutic intervention

The incidence of cancer after hip replacement was studied in the 1.6 million inhabitants of Stockholm County, Sweden. A cohort of 10,785 individuals who had had hip replacement between 1974 and 1988 was followed from the date of operation to the first malignant tumour, to death, or to the end of 1989. The follow-up was based on 58,437 person-years at risk as calculated from information obtained by record-linkage with the National Cancer Registry and the National Cause-of-Death Register. The Standardised Morbidity Ratio (SMR) for all cancer sites, disregarding the length of follow-up, was 0.96 (95% CI 0.90 to 1.03). For lymphoma and leukaemia the corresponding SMR was 0.89 (0.68 to 1.14). Our results do not support previous suggestions of an increased incidence of leukaemia and lymphoma after total hip replacement

Introduction: Total hip replacement in one of the most commonly performed operation in orthopaedics in the UK with similar numbers being operated in other parts of the world (2). The main reasons for this magnitude are marked improvement in function and the quality of life. The hip prosthesis has evolved significantly over half a century and better prostheses are available today. These newer implants are required to have a survival of 90% for a minimum of 10 years. The improved survival of the implant tends to have effect on the quality of life as well as the life expectancy. There has been a continuous attempt to quantify this increased life expectancy and survival following total hip arthroplasty. Materials and Methods: We compared the mortality figures of 3947 patients who had hip resurfacing arthroplasty with the national mortality figures of the UK. The cause of death was determined by telephone call to the next of kin and from the national death register. Results: The average standardized mortality ratio of hip resurfacing patients compared to national figures over the nine year period was 0.524(99 percent C.I. 0.39 to 0.69). Individual SMR for each year is shown in Table. The number of observed deaths were 86 as compared to the expected deaths number 164. Out of the total 86 deaths over a nine year period, 36 deaths were due to cancer, 25 due to cardiovascular causes, eight due to respiratory conditions, four following accidents and 13 due to other causes such as suicide, old age. In the cancer group 7 patients died of lung cancer and 8 died of blood cell neoplasms. National figures for year 2007 were not yet compiled so SIR for cancer was not calculated. Conclusion: The results of this study are comparable to other follow up studies on mortality following total hip replacement. This indicates that increased activity following hip resurfacing may help the patients maintain better fitness. The incidence of cancer needs to be interpreted with caution and can only be ascertained by a prospective study

Purpose. Versican is a member of the large aggregating chondroitin sulfate proteoglycan family. Structurally, it is made up of an N-terminal G1 domain, a glycosamingoglycan attachment region, and a C-terminus containing a selectin-like (G3) domain. Versican is highly expressed in the interstitial tissues at the invasive margins of breast carcinoma and predictive of relapse and overall survival. The purpose of the study to investigate the role of of versican G3 domain in breast cancer bone metastasis. Method. Mouse mammary tumor cell lines 66c14, 4T07 and 4T1, and human breast cancer cell lines MT-1, MDA-MB-468 and MDA-MB-231 were stably transfected with versican G3. Effects of expression of versican G3 on cell proliferation, migration, invasion, cell cycle progression, and EGFR signaling were observed. The effects of G3 on cell viability in the conditional media of serum free, apoptotic agent C2-ceramide, and chemotherapeutic agents, including Docetaxel, Doxorubicin, Epirubicin were investigated. Colony formation assay and mammosphere formation assay were performed. A syngeneic orthotopic animal model was used to do the in vivo study. Results. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and bone metastasis in vivo. Versican G3 domain enhanced tumor cell resistance to apoptosis in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P), and promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhanced expression of pSAPK/JNK and decreased GSK-3β (S9P). Versican expresses highly in the breast cancer mammosphere progenitor cells. Expression of versican G3 enhanced breast cancer self-renewal in vitro and in vivo. Conclusion. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents indicate a potential mechanism for breast cancer cell sensitivity or resistance to chemotherapy and EGFR therapy. GSK-3β (S9P) works as a key check point for the balance of apoptosis and anti-apoptosis. Over-expression of versican G3 domain enhanced breast cancer self-renewal, and resistant to chemo-drug treatments. Strategies designed to target versican mediated breast cancer self-renewal or GSK-3β (S9P) may lead to an effective therapy benefiting advanced breast cancer patients

The aim of this study was to produce estimates of specificity and predictive value of presenting symptoms and signs of paediatric bone cancer, a rare and frequently misdiagnosed condition, to aid clinical decision-making in primary care. A systematic literature review plus questionnaire to primary care physicians were carried out to determine frequency of bone cancer symptoms in both cancer and the benign conditions as which cancer is misdiagnosed. Literature sources – Ovid MEDLINE (1950-May 2008), EMBASE (1980-May 2008) and AMED (Allied and Alternative Medicine) (1985-May 2008). Literature review methods – We included systematic reviews, cohort studies or case series (where n ≥ 10), reporting frequency of symptoms and signs at initial presentation, as originally recorded in case notes or observed by the authors, in subjects aged 0–18 years. Disease incidence data was taken from retrospective and prospective studies from 1980 onwards which recorded incidence over a defined time period, in a large pre-defined population within Europe, North America or Australia. Questionnaire respondents – 32 general practitioners and paediatric Accident & Emergency physicians throughout Scotland and England. Positive predictive values (PPVs) for bone cancer symptoms range from 0.003 to 0.034% (percentage of children presenting with symptom who have cancer). Specificity (percentage of children without cancer who do not have the symptom) varies considerably between symptoms and ranges from 24% (tenderness) to 95% (weight loss). Specificity can be improved by looking for combinations of symptoms. Weight loss and fever are the features with both highest specificity and highest PPV. Bone cancer symptoms, even those with high specificity for cancer, have low positive predictive value. We suggest that diagnosis based on initial presentation to primary care is intrinsically difficult and that delay in diagnosis is not unreasonable if it is to make use of time as a diagnostic aid

Aims. 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. Methods. We conducted a retrospective study on a population-based cohort of all adult patients treated surgically for bony metastases of the appendicular skeleton between January 2014 and December 2019. We excluded patients in whom the status of bone metastases and resection margin was unknown. Patients were followed until the end of the study or to their death. We had no loss to follow-up. We used Kaplan-Meier analysis (with log-rank test) to evaluate patient survival. We identified 506 operations in 459 patients. A total of 120 operations (in 116 patients) were for solitary metastases and 386 (in 345 patients) for multiple metastases. Of the 120 operations, 70 (in 69 patients) had no/an unknown status of visceral metastases (solitary group) and 50 (in 49 patients) had visceral metastases. In the solitary group, 45 operations (in 44 patients) were R0 (resections for cure or complete remission) and 25 (in 25 patients) were R1/R2 (resections leaving microscopic or macroscopic tumour, respectively). The most common types of cancer in the solitary group were kidney (n = 27), lung (n = 25), and breast (n = 20). Results. The one-year patient survival was 47% (95% confidence interval (CI) 38 to 57) for the solitary bony metastases and 34% (95% CI 29 to 39) for multiple bone metastases (p < 0.001). The one-year patient survival was 64% (95% CI 52 to 75) for solitary bony metastases without/with unknown visceral metastases and 23% (95% CI 11 to 36) for solitary bony metastases with visceral metastases (p < 0.001). The one-year patient survival was 75% (95% CI 62 to 89) for a solitary bony metastasis after R0 surgery and 42% (95% CI 22 to 61) for a solitary bony metastasis with R1/R2 surgery (p < 0.001). Conclusion. Our study suggests that the surgical treatment of patients with a solitary bony metastasis to the appendicular skeleton results in better survival than for patients with multiple bony metastases. Furthermore, aggressive treatment of a solitary bony metastasis with R0 surgery may improve patient survival. Cite this article: Bone Joint J 2023;105-B(11):1206–1215

Within a study group of 102 consecutive patients diagnosed at a supra-regional bone tumour unit with chondrosarcoma of the femur, tibia or humerus, an association with previously treated breast cancer was noted. There were 58 female patients and 44 male patients. The study group contained six females (10%, mean age 53 years) who had previously been treated for breast cancer, a higher proportion than would be expected. They were referred following identification of a solitary area of increased activity on routine screening with isotope bone scan, presumed to be a solitary bony metastasis. Most (86%) of this breast carcinoma sub-group had developed low-grade bone chondrosarcoma (Trojani grade 0.5-I) and only one case (14%) had developed high-grade chondrosarcoma (Trojani grade II-III). A suspicious long bone lesion on bone scan in a patient with a past medical history of breast cancer must, therefore, not be assumed to be a metastasis without further investigation; the possibility of a chondral lesion should be considered. It is important that patients receive a full multidisciplinary team investigation prior to treatment in order to obtain the correct tissue diagnosis, as the management of these conditions is often different. Our study suggests there may be a relationshipbetween patients previously treated for breast cancer and the development of subsequent chondrosarcoma

Patients with cancer and bone metastases can have an increased risk of fracturing their femur. Treatment is based on the impending fracture risk: patients with a high fracture risk are considered for prophylactic surgery, whereas low fracture risk patients are treated conservatively with radiotherapy to decrease pain. Current clinical guidelines suggest to determine fracture risk based on axial cortical involvement of the lesion on conventional radiographs, but that appears to be difficult. Therefore, we developed a patient-specific finite element (FE) computer model that has shown to be able to predict fracture risk in an experimental setting and in patients. The goal of this study was to determine whether patient-specific finite element (FE) computer models are better at predicting fracture risk for femoral bone metastases compared to clinical assessments based on axial cortical involvement on conventional radiographs, as described in current clinical guidelines. 45 patients (50 affected femurs) affected with predominantly lytic bone metastases who were treated with palliative radiotherapy for pain were included. CT scans were made and patients were followed for six months to determine whether or not they fractured their femur. Non-linear isotropic FE models were created with the patient-specific geometry and bone density obtained from the CT scans. Subsequently, an axial load was simulated on the models mimicking stance. Failure loads normalized for bodyweight (BW) were calculated for each femur. High and low fracture risks were determined using a failure load of 7.5 × BW as a threshold. Experienced assessors measured axial cortical involvement on conventional radiographs. Following clinical guidelines, patients with lesions larger than 30 mm were identified as having a high fracture risk. FE predictions were compared to clinical assessments by means of diagnostic accuracy values (sensitivity, specificity and positive (PPV) and negative predictive values (NPV)). Seven femurs (14%) fractured during follow-up. Median time to fracture was 8 weeks. FE models were better at predicting fracture risk in comparison to clinical assessments based on axial cortical involvement (sensitivity 100% vs. 86%, specificity 74% vs. 42%, PPV 39% vs. 19%, and NPV 100% vs. 95%, for the FE computer model vs. axial cortical involvement, respectively). We concluded that patient-specific FE computer models improve fracture risk predictions of femoral bone metastases in advanced cancer patients compared to clinical assessments based on axial cortical involvement, which is currently used in clinical guidelines. Therefore, we are initiating a pilot for clinical implementation of the FE model

A patient with a chronic discharging sinus or an extensive adherent scar is never safe from the risk of malignant change. Examples are still occurring more than thirty years after the end of the first world war. The possibility should be kept in mind by those concerned with the long-term treatment of wounds of this kind. Reasonable prophylactic measures would be: excision of adherent or unstable scars with, if necessary, their replacement by suitable pedicle flaps having a good blood supply; and earlier amputation if a osteomyelitic sinus persists for several years and does not yield to treatment. Supervision of doubtful cases should be frequent and should not be relaxed with the passage of the years. Warty changes or indolent ulceration of scars should be regarded with grave suspicion and investigated by biopsy. Any increase in pain or discharge in association with a sinus should receive prompt attention. Finally, if malignant change supervenes, treatment should be as speedy and as radical as with any other cancer. At least thirteen of our twenty-four patients have died of cancer

Introduction. Degenerative spondylosis (DS) represents a challenging condition to diagnose and treat. There are multiple modalities to investigate DS including X-ray, MRI and CT, but symptoms may not be equivocal to DS to support the clinical findings. The investigation of metastases commonly utilises SPECT/CT for identification of areas of increased osteoblastic activity to denote disease. The aim of the study was to analyse the prevalence of asymptomatic DS in a consecutive hospital cohort of oncology patients who had SPECT/CT for investigation of metastases. Methods. Oncology patients who underwent SPECT/CT at St. George's Hospital were analysed between 2015–2019. Exclusion criteria: back pain, inflammatory disorders, metastases, trauma, infection. Radiology reports were examined for DS and anatomical distribution of tracer uptake. Results. A total of 1182 patients had a Whole-Body SPECT CT used for the spinal analysis. After exclusions (age >80 [n=260], non-cancer [n=318], back pain [n=72]), 522 reports with cancer were utilised. Mean age was 65 (4–80). Age and distribution of DS are given in the table. Conclusion. The prevalence of radiological asymptomatic DS is prevalent in large proportions of patients without back pain, and its incidence increases with age. Approximately 60% of 60 year old and 70% of 70 years old patients have asymptomatic DS in the lumbosarcal region. We conclude that SPECT/CT will detect radiographic degenerative spondylosis in an asymptomatic hospital cohort and this prevalence increase with age. Therefore, this modality of imaging must be utilised with caution when investigating potential pain generators. For any figures or tables, please contact the authors directly

Bone is the preferred site of metastases in women with breast cancer, which can cause skeletal-related events (SRE¡¦s) such as pathologic fractures. Bisphosphonates are the current standard of care for treatment of meta-static bone disease by preventing further bone destruction. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for malignancies. In PDT, light is delivered to a tumour after the administration of a photosensitiser. Earlier pre-clinical studies in a metastatic rat model have shown that PDT reduced the tumour burden in the vertebrae. The goal of this investigation was to study the effect of PDT on bisphosphonate pre-treated cancer in-vitro. Human breast cancer cells, MT-1, were cultured until confluent. The following groups were formed: no treatment; incubation with zoledronic acid (24h; 10 ƒÝmol) only; PDT treatment only and incubation with zoledronic acid and PDT treatment. Prior to light application 1 microg/ml of the photosensitiser BPD-MA was added. PDT was performed with a light dose of 1J and 10 J. The cells were stained with a live/dead stain and analyzed by fluorescence microscope and flowcytometry. Incubation of the MT-1 carcinoma cells with bisphosphonate zoledronic acid resulted in a significantly higher number of dying cells following PDT treatment when compared cells that were not treated by zoledronic acid (p< 0.05). When comparing cell groups that did not undergo PDT treatment the incubation with zoledronic acid alone did not have a statistically significant effect on cell survival twenty-four hours following zoledronic acid administration. In-vitro, breast cancer cells appear more susceptible to PDT after they have been incubated with the zoledronic acid. Zoledronic acid, a potent bisphosphonate, inhibits farsenylpyrophosphate (FPP) which is involved in farsenylation of cell membrane proteins. The inhibition of FPP may cause a reduced effect of PDT on cell rescue. The treatment with bisphosphonates seems to have a synergistic effect with PDT treatment. As such, light dosimetry in PDT treatment may need to take into account potential therapeutic interactions between PDT and current medical therapies in the treatment of skeletal metastatic burden

Aims: Nationwide, computer-based survey of all total joint arthroplasties performed in Finland has been carried out since January 1980. From these records a cohort of 9,443 patients, with 80,734 person-years, after primary operation with a total polyethylene-on-metal knee arthroplasty (TKA) has been followed up for cancer. In 1999 we published the material until December 31, 1996. The standardized incidence ratio (SIR) for all cancers was 0.98. The SIRs for non-Hodgkin lymphoma (1.40), Hodgkinñs disease (1.24), multiple myeloma (1.54) and prostate cancer (1.49) were increased, but only that of non-Hodgkin lymhoma was statistically signiþcant 3 to 10 years after the operation. The overall cancer risk after TKA done for primary osteoarthrosis appeared to be negligible. Material and methods: Follow-up for cancer was undertaken using the þles in the population-based, nationwide Finnish Cancer Registry, employing personal identiþcation numbers. Follow-up for cancer started at the date of þrst knee replacement and ended on emigration, death, or 31 December 2000, whichever occurred þrst. No subject was lost to follow-up. Standardized incidence ratios (SIRs) were calculated by dividing observed numbers of cases by expected numbers. Results: There were 2,001 men and 7,442 women left in the cohort to be followed-up. Numbers of person-years are now 15,679 and 650,552, respectively. The mean duration of follow-up per person was therefore 8,5 years. During the 21-year follow-up period, 358 cases of cancer occurred in the male subjects. The expected number was 349. In the female subjects 801 cases of cancer were observed vs. 804 expected. Combining data for men and women, the SIR for cancer at all sites was 1.00. SIRs were signiþ-cantly lower in relation to cancers of the lung (0.69), and colon (0.77). The incidence of risk of colon cancer was lower than would have been expected only in women (SIR 0.70). As far as cancers of the urinary organs is concerned, the SIR was within unity (SIR 1,03). The overall incidence of non-Hodgkin lymphoma (extranodal sites included) was elevated, but without any statistical signiþ-cance (SIR 1.22). The SIR values for multiple myeloma and leucemia have reduced to 0.80 and 0.53. Conclusions: We conclude, that this large nation-wide material could not establish any association between TKA and the all-over incidence of remote or adjacent cancers; on the contrary incidences of certain cancers were in fact lower than those reported in the formed material with four years less follow-up. All the alarming SIRs in the former material, especially those with non-Hodgin lym-phoma, urinary tract cancers and leucemia, have now reduced and are less than unity

Summary. Starting from human musculoskeletal sarcomas, we isolated a subset of cells that display cancer stem cell properties. The control of culture conditions is crucial to enhance the isolation of this cell population. Introduction. Cancer stem cells (CSCs) have emerged as the real responsible for the development, chemoresistance, and metastatic spread of different human cancers, including musculoskeletal sarcomas. However, unlike most leukemias and solid tumors, so far, data on musculoskeletal sarcomas refer to CSCs obtained from established cell lines, and only a few authors have reported on the isolation of CSCs from tissue samples [1-7]. Reasonably due to some peculiar features of mesenchymal tumors, including the lack of unique surface markers that identify tumor progenitors, there are still partial clues on the existence of a CSC population in these cancers. Here, we report the identification of putative CSCs in musculoskeletal sarcomas using the most general accepted isolation method, the sphere culture system. Accordingly to recent reports, we also analyzed the effects of reduced oxygen availability on the behavior of sarcoma CSCs. Patients & Methods. Between 2009 and 2012, we collected fresh tissue samples from 49 patients (25 males and 24 females, age 6–85 yr) with musculoskeletal sarcomas. Cells obtained from samples were cultured in anchorage-independent serum-starved conditions, in the presence of adequate growth factors, until the formation of floating spheres, here called ‘sarcospheres’. To obtain parental tumor cell cultures, single cells obtained from biopsies were in parallel seeded in anchorage-dependent conditions, in the presence of fetal bovine serum until the formation of cell monolayers. The obtained sarcospheres were characterised in terms of gene expression and in vivo tumorigenic potential. We then exposed sarcospheres obtained from a rhabdomyosarcoma model (RD cells) to a hypoxic environment (1% O. 2. ), and analyzed their growth and gene expression to that of sarcospheres grown at standard 21% O. 2. . Results. Using a sphere-forming assay, we established sphere cultures in 5 out of 49 cases (10.2 %). All sarcosphere cultures expressed consistent mRNA levels for OCT3/4, Nanog, and SOX2. CSCs from a chondrosarcoma and from a rhabdomyosarcoma also showed the ability to recapitulate the original tumor morphology in a mouse model. Finally, we observed that hypoxia induced a significant increase of the number and size of CSCs from RD. Discussion/Conclusion. Starting from human sarcoma biopsies and established cell lines, we were able to characterise the CSC subset of musculoskeletal sarcomas, that were isolated through the sphere system assay. These cells had stem-like properties, and showed in vivo tumorigenic ability. We also observed that exposure of CSCs to low oxygen conditions increased the number and size of spheres and the expression of stem cell-related markers, suggesting that the culture in hypoxic conditions could improve the yield of the isolation method here used, and that the oxygen availability is a crucial element in the physiological maintenance of CSCs of musculoskeletal sarcomas

We studied the pedigrees of 17 index patients with osteosarcoma, recording malignant disease and cause of death for first- and second-degree relatives. There were seven cancers and five cancer deaths per 2151.5 person-years in first-degree relatives of osteosarcoma patients under the age of 50 years, a significantly greater incidence than in an age- and sex-matched population group (p < 0.001). This excess of malignancy was largely due to two families which fulfilled the criteria for the Li-Fraumeni cancer family syndrome. Both of these families were shown to have the genetic alterations in the p53 gene which have been implicated in this syndrome. Our study suggests that orthopaedic surgeons seeing new cases of osteosarcoma should arrange screening for familial malignancy

Corrosion and wear of total hip (THA) and knee (TKA) prostheses extricate metallic particles and soluble metallic compounds. The oncogenic risk of these products should be known. Material and methods: Three Nordic cohorts of total hip (THA) and total knee arthroplasty (TKA) patients operated on for primary osteoarthrosis during 1967–1995 were combined for meta-analysis. The number of THA patients was 49,000 and TKA patients 24,000 totaling 497,000 person years. The mean follow-up time was 6.8 years. Standardized incidence ratios (SIRs) with 95% conþdence intervals (95% CI) were calculated for the observed and expected number of cancers. The expected numbers were based on national incidence rates. Results: The allover SIRs as well as the site-speciþc cancer incidences were similar for the THA and TKA patients. The observed number of all site cancers was 7639 and 8202 expected (SIR 0.93, 95% CI 0.91–0.95). The SIR for lung cancer (0.69, 0.64–0.75) was reduced. The incidence was also low for cancers of the stomach (SIR 0.76, 0.67–0.84), colon (SIR 0.86, 0.79–0.93) and rectum (SIR 0.89, 0.80–0.98). Slightly elevated SIRs were seen among TKA patients in cancer of the endometrium and prostate and among both THA and TKA patients in skin melanoma. Conclusions: Total cancer risk was signiþcantly reduced among THA and TKA patients due to decrease of respiratory and gastrointestinal cancers. The present results do not suggest any oncogenic risk of the components of hip and knee prostheses and their degradation products

Activated leukocyte cell adhesion molecule (ALCAM) has been shown to be involved in cell migration and in both homotypic/homophilic adhesion and heterotypic/heterophilic adhesion. It has been shown that a decreased level of ALCAM expression in human breast cancer tissue correlated with a significantly poor prognosis. Aim: Previous studies have looked at nodal and general metastasis; in this analysis using an expanded tumour cohort, we, for the first time, specifically identified patients who went on to develop skeletal metastasis. Primary breast cancer tissues (n=234) and non-neoplastic mammary tissue (n=34) were collected and patients were routinely followed up clinically after surgery. The immunohistochemical distribution and location of ALCAM was assessed in the normal breast tissue and carcinoma and the level of ALCAM transcripts in the frozen tissue was determined using real-time quantitative PCR. The results were analysed against the clinical data looking principally at the levels in patients with skeletal metastasis but also in relation to the nodal involvement, ER status, Nottingham Prognostic Index and survival. The immunohistochemical staining intensity shows that the cytoplasmic staining in normal breast tissue is significantly stronger than that in breast cancer tissue (p=0.023) and also the breast cancer tissue from patients who went onto develop skeletal metastasis (p=0.048). The ALCAM transcript levels were the lowest in patient with skeletal metastasis (p=0.0048) compared to those who were disease free. Significantly lower transcript levels were also found the patients who developed local recurrence (p=0.040), and who died from breast cancer (p= 0.0075). Other indicators of poor prognosis show a significant difference: patients with moderate and poor NPI prognosis lower levels than those with a good prognosis (p=0.05, p=0.0089 respectively); and lower in patients with a positive ER status than those ER negative patients (p=0.043). This study has for the first time shown that the patient who went on to develop skeletal metastasis tended to have the lowest levels of ALCAM transcript in their breast cancers. This fact could be used to provide patient with a more accurate prognosis and identify those who may benefit enhanced monitoring and early medical and orthopaedic treatment

Purpose: To identify local and systemic risk factors for the development of pathologic fractures and determine the value of the Tokuhashi Score in patients with known asymptomatic lytic spinal metastases secondary to breast cancer. Method: A prospective cohort study was carried out on 51 patients with lytic spinal metastases secondary to breast cancer identified as having either purely lytic or mixed disease. The Tokuhashi Score, developed to estimate life expectancy for patients with symptomatic spinal metastases being considered for surgery, was calculated for each of the 51 patients. The score consists of six parameters each of which is rated from 0–2. Initial and follow up CT images and pain and function data were obtained every four months for one year. A final review of patient charts was performed two years later to determine if each patient was still alive. Results: Tumour burden was predominantly blastic and mixed rather than lytic. There was no progression of lytic tumour burden over the 12-month period, however there was progression of blastic tumour load. Eleven compression fractures occurred in seven patients; no burst fractures occurred during the study. No correlation between tumour burden (lytic, blastic or both) and risk of fracture was found. A weak correlation between bone mineral density and length of time elapsed from diagnosis of metastatic disease and fracture risk was found. Pain and functional data results were not related to tumour load. Tokuhashi score did correlate with survival, however actual survival in our population was far longer than that found in previous studies. Negative progesterone status was found to be negatively associated with life expectancy. Conclusion: Metastatic vertebral disease in breast cancer patients has a predominantly blastic and mixed appearance with current pharmacologic therapies. Pathologic fracture risk appears to be more related to bone mineral density than tumour burden in this population. Tokuhashi score does correlate with life expectancy in patients with relatively asymptomatic spinal metastases. Having a progesterone receptor negative tumour has a significantly negative impact on life expectancy

The CONnective TIssue CAncers NETwork to integrate European Experience in Adults and Children (CONTICANET) is dedicated to improve the outcome of connective tissue cancers in adults, adolescents and children. Funded by the European Commission’s Sixth Framework Program (FP6-018806), this Network of Excellence kicked off in February 2006 for a five-year period. Ten work packages are grouped around the themes of “Integration” “Common research programme” and “Dissemination of excellence”. A consortium of 24 different organisations – cancer centres, academic institutions, patient advocacy groups and private enterprises – hailing from 9 countries (Belgium, France, Germany, Ireland, Italy, the Netherlands, Spain, Slovenia, UK), including > 250 researchers, is involved in collaborative research efforts that will help propagate excellence in the field. Improving the management of these tumours will come out the following outputs of the network activities:. Epidemiology. Molecular characterisation and nosological classification. Understanding the deviations of medical practices and initiating corrective strategies. Identifying new molecular targets and targeted treatments. Promoting clinical research on very rare subtypes. Addressing specific age (paediatrics, adolescents) or condition (Recklinghausen) group issues. Organisation of the collection and storage of biological samples. Standardisation of their management. Identification of centres of excellence for pathological and biological management and clinical management, and the scientific promotion of shared and multidisciplinary research programs. In addition, CONTICANET will integrate the expertise from other networks through collaborations, such as clinical research networks (EORTC, National sarcoma groups), other networks (EUROBONET, networks on rare tumors and paediatric/adolescent tumors). Afyer 5 years a legal entity will continue to spread excellence in several directions: enlarging the network with academic and private organisations; continuing to enhance relations with EMEA, health authorities, patients advocacy groups, cancer leagues. Together, we aim to a European research foundation able to support integrated research actions and make available new treatments in these diseases

Background. Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Methods. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. Results. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949-1988 developed angiosarcomas in edematous arms (Stewart-Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980-2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16 %. Conclusions. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer

Aims: In 1999 we published a cohort of 24,638 polyethylene-on-metal total hip arthroplasty (THA) patients followed up for cancer, using Finnish Cancer Registry data, from 1980 to 1995. The number of person-years was then 173,022 (until 31st Dec, 1996). During follow-up, there were statistically significantly fewer cancers among the THA patients (standardized incidence ratio [SIR], 0.91; 95% confidence interval [Cl], 0.87–0.94). There was no significantly increased risk at any site, and for certain cancers that was even below the unity (lung and stomach). On the longer run, however, certain tendency for increased risk for cancer of the urinary bladder, myeloma, and leukemia could be observed; SIRs were greater than unity with the THA patients followed up 3 to 9 years. Further follow-up of the cohort is therefore needed. Methods: The follow-up of the same cohort, originally identified in the National Register of Arthroplasties, maintained by the National Agency for Medicines (primary THA with primary arthritis as the indication) was expanded with a four year period (from 1st of Jan 1997 to 31st of Dec 2000). Follow-up for cancer was undertaken using the files in the population-based, nationwide Finnish Cancer Registry, employing personal identification numbers. Follow-up for cancer started at the date of first hip replacement and ended on emigration, death, or December 31, 2001, whichever occurred first. Multiple cancers were taken account of in similar ways in relation to observed and expected numbers of cases. Results: After excluding revision and infective or systemic disease as indications for operation, there were 9,479 men and 15,157 women in the cohort followed. The updated numbers for person-years were 89,295 for males and 153,759 for females. The mean duration of follow-up was now 9,9 years. The total risk for cancer was now 0.93 (95%Cl 0.90–0.96) and that for stomach 0.89, for colon 0.90, lung 0.64, for urinary organs 1.01, and for connective tissues 0.88. The SIRs for non-Hogkin lymphoma, myeloma and leucemia were all under the untity, 0.88, 1.09 and 0.73, respectively, without any tendency for increased risk in the follow-up of plus ten years. Conclusions: These findings indicate that the risk of hematopoietic cancers is not increased after THA using polyethylene-on-metal prostheses. Expanding of the follow-up with four years did not markedly change the profile of the SIRs at any specific site, and contrary to our earlier report there were increased risk left of myeloma and leucemia with increased follow-up time. The SIRs associated with soft tissue cancers and bone sarcomas were not significantly different from unity. No sarcomas developed at the site of a prosthesis

We have studied the incidence of tumours at remote sites following total hip replacement: 1,358 individuals have been followed up for 14,286 person-years after operation. In the decade following implantation the incidence of tumours of the lymphatic and haemopoietic systems was significantly greater, and that of cancer of the breast, colon, and rectum, significantly less than expected. Whilst the association might be due in part to an effect of the prosthetic implants, other mechanisms, particularly drug therapy, require consideration

Childhood cancer survival has increased dramatically over the last 30 years. Childhood Cancer Survivor Study- SG was established to evaluate the outcome and toxicities experienced by long term childhood cancer survivors in Singapore. There were 429 cases of hematological malignancies (HM) and 342 cases of solid tumors (ST) diagnosed and treated at National University Hospital (NUH) Singapore from May 1981 to December 2007. There were seven long term survivors for Osteosarcoma (OS) out of 26 patients seen during the study period. Median age at diagnosis was 13.8 (range, 6.4–15.8 years) and median follow-up was 7.9 (range, 2.6 – 13.2 years). Cumulative doses of chemotherapy received included: cisplatin (240 – 800 mg/m2); doxorubicin 150 – 450 mg/m2); methotrexate (16 – 144 Grams/m2); ifosfamide (27–80 mg/m2); and etoposide (1000 – 3300 mg/ m2). According to the NCI Criteria for Toxicity (CTC version 2.0), three patients experiences grade 2 sensorineural hearing loss; three cases of grade 1 cardiomyopathy; three cases of grade 1 renal tubulopathy; and six cases of post surgical complications (infection-3, length discrepancy-3, poor fitting prosthesis-2). Many of the patients did not have baseline pre-treatment evaluations such as audiograms, renal function, echocardiograms and similar proportion were not adequately followed-up post treatment. This is the first analysis and report in the country on treatment related outcome and toxicity in long-term survivors of childhood cancers such as osteosarcoma and other solid tumors. Authors recommend that future treatment protocols for childhood cancer in Singapore should incorporate pre- and post-treatment evaluations and close follow-up of young survivors with establishment of a multi-disciplinary late effects clinic

Purpose: Bony metastases in vertebrae secondary to breast cancer can result in osteolysis and an increase in skeletal related events. Bisphosphonates (BP) are the current standard of care for breast cancer patients with skeletal disease. Photodynamic therapy (PDT) is a non-radiative treatment, which has been successfully applied to various malignancies and shown to successfully ablate vertebral human breast cancer (MT1) metastases in a murine model. Previous in-vitro study has shown that pre-treatment of MT-1 cells with the BP zoledronic acid (Zometa. ®. ) renders them more susceptible to PDT. The aim of this study was to evaluate the influence of pre-treatment with BPs on the effect of PDT treatment on tumour ablation in metastatically involved vertebrae in vivo. Method: Metastases were induced in fourteen 5–6 weeks old female athymic rats (Hsd:RH-Foxn1rnu) by intra-cardiac injection of 2x10^6 MT-1 cells. Four groups were formed:. control, no treatment;. BP only;. PDT only;. BP and PDT combined. Seven days after MT-1 injection 60 μg/kg of zoledronic acid was injected. PDT treatment was administered on day 14 using the photosensitizer BPD-MA (1.0 mg/kg; Visudyne). Fifteen minutes later, laser-light (690nm; 75J) was administered to the lumbar vertebrae. The rats were euthanized 7 days after PDT treatment. A total of 45 vertebrae were evaluated using a histomorphometric program (GENIE™, Aperio) to assess tumour burden. Statistical analyses were performed using a one-way ANOVA with a Tukey post hoc test. A p-value p< .05 was considered to be statistically significant. Results: The total The total tumour burden within vertebrae of rats pre-treated with BP and/or PDT was significantly lower compared to the control rats (p< .001). In addition, the PDT alone treated group demonstrated significantly less tumour burden than the combined BP+PDT group. In the control and BP-only groups, large tumours were found to include regions of necrosis. The PDT treatment groups (PDT and BP+PDT) exhibited areas of necrosis throughout the entire vertebral bodies with adjacent formation of granulation tissue. Conclusion: BP, PDT and combined BP+PDT treatments resulted in a lower overall tumour burden at day 21 post MT-1 cell injection compared to control rats. A surprising increased level of tumour burden was found in comparing the combined treatment group to the PDT-only group. These findings are in contrast to previous in-vitro results, where the pre-treatment with BPs made the cells more susceptible to PDT. Pre-treatment with BP affects both the bone and tumour cells, and as such may induce different cellular pathways in response to PDT treatment. However, the ability of PDT applied at day 14 to cause a similar reduction in tumour burden compared to BP treatment at day 7, suggests its ability to rapidly and effectively ablate the tumour within the bone, even in the presence of BP

Introduction: Breast cancer is the most frequently diagnosed cancer in western countries and bone metastases of breast cancer cause significant morbidity. Tumor growth and progression requires the formation of new blood vessels, a process called angiogenesis. Angiogenesis is a complex multifactorial process involving a variety of proangiogenic and proteolytic enzyme activators and inhibitors. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF), which is overexpressed in several tumor tissues. The single nucleotide polymorphism 1498 C/T of VEGF was associated with increased plasma levels of VEGF. In this case controlled study, we analyzed the role of this polymorphism in bone metastasis of breast cancer. Material and Methods: We genotyped 839 female breast cancer patients. The study was performed according to the Austrian Gene Technology Act and has been approved by the Ethical Committee of the Medical University Graz. According to breast cancer staging, patients were divided in three groups, representing patients without metastases (n = 708), those with metastases other than bone (n = 69), and those with bone metastasis (n = 62). Results: Frequency of the 1498 CC genotype of VEGF was significantly lower among patients with bone metastases (6.5%) than among those with other metastases (23.2%; p=0.005) or no metastases (23.4%; p=0.002). Odds ratio of the CC genotype for bone metastases was 0.22 (95% CI 0.08 – 0.61; p = 0.004). Conclusion: We conclude that the homozygous 1498 C genotype of VEGF may be protective against development of bone metastasis in breast cancer patients

Cementoplasty, like vertebroplasty, is a technique whereby Polymetylmethacrylate is placed into a bone lesion either percutaneouly or by surgery under image intensifier guidance. Although there have been few studies with regard to cementoplasty percutaneously, there is no series in the literature to support the open surgical technique as a palliative procedure. In our series we describe four patients (1male and 3 females, age range 63-83) with metastatic bone cancer who have benefited from an open surgical procedure. The four patients presented to our hospital between January 2004 and December 2006. They all had gradually worsening hip pain at the time of presentation and pelvic radiographs revealed osteolytic lesions in the acetabulum. A 5 centimetre longitudinal incision proximal to the greater trochanter was made and the malignant lesion identified using the image intensifier. The malignant tissue was curetted and sent for microscopy, culture, sensitivity and histopathology and the remaining void filled with bone cement (via a gun or by hand) under x-ray control. Radiographs were taken in all patients post-operatively and were referred for adjuvant radiotherapy. All patients had immediate relief of pain and were able to mobilise within 48 hours. Two patients died within 6 weeks post-operatively due to complications from their primary malignancy (lung). One patient died at three months due to unknown primary. One patient remained pain free and fully ambulatory at one and a half years post surgery (breast primary). This procedure can be recommended for patients with metastatic bone disease as it provides adequate pain control and improves the quality of life in this group of patients. These patients need a multi-disciplinary approach to their care, but as orthopaedic surgeons, we can make a significant impact to such patients and their families

Summary. Photodynamic therapy with ICG lactosome and near-infrared light has phototoxic effects on human breast cancer cells. With the same total energy, phototoxic effects depend on output of irradiation light rather than irradiation time. Introduction. The phototoxic effects of indocyanine green (ICG) and near-infrared light have been studied in various fields. Plasma proteins bind strongly to ICG, which is followed by rapid clearance by the liver, resulting in no tumor selectivity after systemic administration. We have proposed a novel nanocarrier labeled with ICG (ICG lactosome) that has tumor selectivity due to its enhanced permeation and retention (EPR) effect. The aim of this study was to investigate in vitro phototoxic effects and to optimise the irradiation conditions by changing the output and time of near-infrared light as excitation light. Materials and Methods. MDA-MB-231 human breast cancer cells were seeded (2 × 10. 4. cells per well) into 96-well plates. The plates were divided (16 wells/treatment) into the following groups: control/untreated, only ICG lactosome administration (ICG lactosome), only laser irradiation (laser), and ICG lactosome administration plus laser irradiation (photodynamic therapy: PDT). Cells in the control, laser, and PDT groups were incubated in 100 μl medium for 24 h. Cells in the ICG lactosome group were incubated in 100μl medium containing 1 mg ICG lactosome for 24 h. The following day, laser group samples with 100 μl phosphate buffer solution (PBS) and PDT group samples with PBS containing 1 mg ICG lactosome were treated with laser irradiation using a near-infrared medical diode laser (λ = 810 ± 20 nm). Irradiation conditions were set to low output-/-long time (31 mW/cm. 2. -/-600 sec) and high output-/-short time (235 mW/cm. 2. -/-80 sec). The total energy density of both was 18.8 J/cm. 2. The media in these irradiated wells was replaced with fresh medium every 24 h post-irradiation. The control and ICG lactosome group wells received fresh medium every 24 h. Cells in all groups were incubated for 96 h post-treatment. Microscopic examination was performed, and cell viability was measured using a WST-1 assay every 24 h after treatment for 96 h. Mean absorbance in the WST-1 assay (an indicator of cell viability) was analyzed using the Tukey-Kramer test for comparison of multiple groups. Results. Cell viability in the high output-/-short time PDT group was significantly lower than that in the low output-/-long time PDT group at 96 h after treatment. Cell viability in the two PDT groups was significantly lower than that in the other 3 groups at each time point. Irradiation increased the temperature by 25.5°C, 11.1°C, 8.1°C, and 7.1°C in the high output-/-short time PDT, low output-/-long time PDT, high output-/-short time laser, and low output-/-long time laser groups, respectively. Discussion/Conclusion. PDT with ICG can penetrate deeper into tissue than that with Photofrin (the most widely used photosensitizer in clinical PDT), because ICG absorbs light at longer wavelengths than Photofrin. With the same total energy, inhibition of cell viability depended on irradiation output rather than irradiation time. It is reported that hyperthermia may contribute to the PDT effect if the surface irradiance exceeds 200 mW/cm. 2. We therefore believe that photodynamic and hyperthermal effects occurred in the high output-/-short time PDT group, and conclude that excitation light output rather than irradiation time may affect the photodynamic effect

To identify if disease severity and cancer-risk might depend on genotype in Hereditary Multiple Exostoses (HME). The discovery that the EXT family of tumour suppressor genes is responsible for Hereditary Multiple Exostoses (HME) now enables correlation of clinical features with genetic defects. Genetic epidemiological studies, such as this, may provide additional data of use to the clinician. In most population-based HME cohorts, the incidence of sarcomatous degeneration has been estimated as 1–5%. This is not high, but occurs at a younger age (on average 2–3 decades younger) than chondrosarcoma in the general population. Genetic stratification might allow a very high-risk subgroup to be identified, within which surveillance for neoplastic change in osteochondromas could be concentrated. In a pilot study, 29 affected individuals from 17 families with HME were screened for EXT mutation, with mutations identified in 12 families. Pedigrees were obtained and a complete assessment of disease severity made. We have since expanded this cohort; a further 71 affected individuals from 34 families with HME have provided detailed pedigree data and undergone a simple clinical examination to assess number of palpable osteo-chondromas. EXT mutation was assessed by means of fluorescent single-strand conformational polymorphism (f-SSCP) screening, followed by sequencing analysis. Validation of clinical examination : In those who underwent radiographic examination for clinical purposes, number of palpable osteochondromas correlated strongly with number seen on radiographs at 146 anatomical sites (r= 0.814, p< 0.001), validating the usefulness of clinical examination in a population analysis, and negating the need for a radiographic skeletal survey in individuals at risk from malignant change. EXT mutation : EXT mutation detection rates for f-SSCP were calculated to be 93%. As suggested in the pilot study, most (84%) were loss-of-function mutations. 60% had not previously been reported in the literature. There were 42 individuals with EXT1 and 29 with EXT2 mutations. Disease severity and EXT mutation: In the pilot study, median number of palpable osteochondromas were about twice as frequent in the 7 families with EXT1 mutation than in the 5 families with EXT2 mutation (p< 0.05). This was also reflected in overall disease severity scores. In the larger follow-up study, individuals with EXT1 mutation had a median number of 32 osteochondromas, compared with 16 osteochondromas in those with EXT2 mutation (Wilcoxon rank sum test p< 0.0005). Cancer risk: Six chondrosarcomas occurred, and were only found in individuals with EXT1 mutation. The observation that osteochondromas are more frequent in patients with EXT1 than EXT2 mutations is an important message in genetic counselling. If disease severity and cancer risk is greater in individuals with EXT1 mutation, screening for neoplastic change might be targeted on this group, in which lifetime risk of malignant change in osteochondromas could be increased to between 5% and 10%

Background. 70% of breast cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self-renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. Aim. To investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases. Methods. MSCs harvested from the iliac crest of healthy volunteers were grown for collection of conditioned medium (CM), containing all factors secreted by the cells. Breast cancer cell lines (T47D, SK-BR-3, MDA-MB-231) were then cultured in MSC CM +/− antibodies to TGFβ, VEGF, MCP-1 and CCL5 for 72hrs. Cell proliferation was assessed using an Apoglow. (r). assay and RNA harvested for analysis of changes in Epithelial Mesenchymal Transition specific gene expression : N-Cadherin, E-Cadherin, Vimentin, Twist, Snail. Results. A significant down regulation of breast cancer cell proliferation in the presence of MSC secreted factors was observed (p< 0.05). There was a dramatic increase in expression of EMT specific genes in both cell lines following exposure to MSC-secreted factors. Inclusion of antibodies to TGF, VEGF, MCP-1 and CCL5 inhibited the effect seen, suggesting these paracrine factors played a role in the elevated expression levels. Conclusion. MSCs clearly have a distinct paracrine effect on breast cancer epithelial cells, mediated at least in part through secretion of growth factors and chemokines. These factors play an important role in the metastatic cascade and may represent potential therapeutic targets to inhibit MSC-breast cancer interactions, helping to prevent the formation of bone metastases in cancer

Background. 70% of Breast Cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. Aims. The aim of this study was to investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases. Methods. MSCs harvested from the iliac crest of healthy volunteers were grown for collection of conditioned medium (CM), containing all factors secreted by the cells. Breast cancer cell lines (T47D, SK-BR-3, MDA-MB-231) were then cultured in MSC CM +/− antibodies to TGFβ, VEGF, MCP-1 and CCL5 for 72hrs. Cell proliferation was assessed using an Apoglow(r) assay and RNA harvested for analysis of changes in Epithelial Mesenchymal Transition specific gene expression : N-Cadherin, E-Cadherin, Vimentin, Twist, Snail. Results. A significant down regulation of breast cancer cell proliferation in the presence of MSC secreted factors was observed (p<0.05). There was a dramatic increase in expression of EMT specific genes in both cell lines following exposure to MSC-secreted factors. Inclusion of antibodies to TGF, VEGF, MCP-1 and CCL5 inhibited the effect seen, suggesting these paracrine factors played a role in the elevated expression levels. Conclusion. MSCs clearly have a distinct paracrine effect on breast cancer epithelial cells, mediated at least in part through secretion of growth factors and chemokines. These factors play an important role in the metastatic cascade and may represent potential therapeutic targets to inhibit MSC-breast cancer interactions, helping to prevent the formation of bone metastases in cancer

In 2008 The Christie was chosen by Manchester United Football Club to form a unique partnership. This funded a specialist Physiotherapist and Occupational Therapist to work exclusively on the Young Oncology Unit, creating the first posts of their kind in the UK. The YOU treats patients between 16–24 years old with a diagnosis of cancer, sarcoma being one of the most common in this age group. All patients attending the YOU now receive a fully comprehensive Physiotherapy and Occupational Therapy service to address their rehabilitation needs. The NICE guidelines (2005) indicate that cancer care for young adults needs to be age specific, age appropriate and undertaken by appropriately trained staff; hence the importance of having specialist therapists on the YOU. The needs of teenagers and young adults with cancer, both physically and psychologically, are more critical than at any other time in life. During their treatment patients will experience stressful events, such as alopecia, weight loss or gain, altered physical appearance, fatigue, nausea and vomiting, absence from education, and reduced contact with peers. The Physiotherapy and Occupational Therapy roles are essential in enabling young adults to adapt to their diagnosis and learn coping strategies to deal with the stressful events they encounter through their cancer experience. During this presentation we will describe the unique role of Physiotherapy and Occupational Therapy with teenagers and young adults, using case studies to illustrate the benefits of having dedicated YOU therapists. We will also share with you the innovative ways in which the Manchester United training facilities have been used for different initiatives that have greatly benefitted and motivated our patients and their families. The partnership between two local organisations, one of the biggest football clubs in the world and a world class Cancer Centre has been a unique and positive liaison

Tumour cells induce osteolysis by producing multiple cytokines that indirectly activate osteoclasts; this process is dependent upon surface expression of a protein known as “receptor activator of nuclear factor kB ligand (RANK-L)” on osteoblasts (OB), and subsequent osteoclast (OC) interaction via surface expressed RANK. Harnessing this RANK-RANK-L interaction has potential for reducing cancer osteolysis. The aim of this study is to prevent tumour-induced osteolysis by ablating osteoclast activation. A monocyte cell line (RAW 264.7) was grown in vitro in the presence of RANK-L and recombinant mouse macrophage colony stimulating factor (rmM-CSF) to produce osteoclasts. Tumour-associated cytokines IL-1a, TNF-a, and IL-6, and the regulatory cytokine osteoprotegerin (OPG) were added to assess osteoclast cell number (cytospin analysis with TRAP staining) and function (resorption pit number on dentine slices). Short interfering sequence of RNA directed towards RANK receptor (RANK RNAi) was used to assess the effect of abrogating RANK-RANK-L signaling in this pathway. Tumour-associated cytokines failed to significantly alter OC cell number or function in the model tested. When TNF-a, IL-1a, and IL-6 were added together, the effect on OC function was variable, without a clear trend towards OC activation. The addition of the cytokine OPG revealed a trend towards reducing OC function, but this did not reach statistical significance. RANK RNAi also revealed a trend towards reducing OC function in the presence and absence of tumour-associated cytokines. Tumour associated cytokines failed to enhance OC function using the monocyte cell line RAW 264.7. Both OPG and RANK RNAi revealed a trend towards reducing OC function, although further testing is required to confirm this observation. Future direction with include analysis of fresh bone marrow-derived OC, which may be more appropriate for this model

ITCC was created in 2003 as a European network to support the introduction of new therapies into the paediatric cancer population. There are two core arms to the network. Firstly a biology programme to evaluate new compounds in a preclinical setting with the aim of prioritising drugs for further clinical evaluation. Secondly a network of clinical centres in Europe able to deliver high quality Phase I and II clinical trials. To date nine research laboratories are participating in the biology programme linked by a consortium agreement. These laboratories include specialist units focusing on rhabdomyodsarcoma, Ewings sarcoma and osteosacrcoma. A large biological resource of tumour samples, cell lines and gene profile data is available through this network. The clinical trials programme has identified and accredited 36 centres in six EU Member States to conduct clinical trials. ITCC has become recognised as the major academic network for drug development in paediatric cancer in Europe. Strong collaborations have been forged with the pharmaceutical industry, and regulatory authorities to capitalise on the emerging EU legislation facilitating the development of drugs for children. We are also in a strong position to advise and partner with the major disease-specific groups developing Phase III trials in a range of tumours such that new therapies can be introduced appropriately into front-line treatment

Summary. Methotrexate chemotherapy (commonly used in treating cancers and rheumatoid arthritis) creates an inflammatory condition in bone, decreasing osteogenesis, enhancing adipogenesis, increasing osteoclastogenesis, leading to bone loss and marrow adiposity; treatment with fish oil or folinic acid counteracts these negative effects and prevents bone loss. Introduction. Chemotherapy with anti-metabolite methotrexate (MTX) is commonly used in treating cancers and rheumatoid arthritis; however it is known to cause bone loss for which currently there are no adjunct preventative treatments. Methods and Materials. Using a rat model, this study investigated the damaging effects in bones caused by daily MTX injections (0.75mg/kg) for 5 consecutive days (mimicking induction phase treatment for childhood leukaemia) and also the potential protective benefits of omega-3 fatty acid-rich fish oil at different doses (0.25, 0.5 or 0.75 mL/100g BW) in comparison to antidote folinic acid (given i.p at 0.75mg/kg 6 hours post MTX, which is clinically used to reduce MTX toxicities in soft tissues). Results. Histological analysis showed that MTX significantly reduced primary spongiosa bone height and metaphyseal trabecular bone volume. MTX also significantly reduced density of osteoblasts at the secondary spongiosa. Ex vivo differentiation assays with bone marrow stromal cell populations of treated rats revealed a significant reduction in osteogenic differentiation but an increase in adipogenesis. Consistently, RT-PCR gene expression study within the stromal cell population revealed a lower expression of osteogenic transcription factors Runx2 and Osx and bone matrix protein osteocalcin but a significantly upregulated adipogenesis-related genes FABP4 and PPARγ, indicating that MTX chemotherapy induces a switch in the differentiation potential towards adipogenesis at the expense of osteogenesis. MTX increased the density of osteoclasts within the metaphyseal bone as revealed by histological analysis and osteoclast precursor cell pool as shown by ex vivo osteoclastogenesis assay with bone marrow samples. Consistently, mRNA expression of proinflammatory and osteoclastogenic cytokines IL-1, IL-6, TNF-α, and the RANKL/OPG ratio were significantly upregulated by MTX. Supplementary treatment with fish oil (0.5mL/100g BW) or folinic acid significantly preserved metaphyseal trabecular bone volume, osteoblast density, and bone marrow stromal cell osteogenic differentiation and suppressed MTX-induced adipogenesis. These supplements also prevented MTX-induced increased osteoclast density, osteoclastogenesis, and expression of proinflammatory and osteoclastogenic cytokines. Conclusion. These results suggest that MTX chemotherapy creates an inflammatory condition in bone resulting in increased osteoclast formation and decreased osteoblast formation thus leading to bone loss, and that supplementary treatment with fish oil at 0.5mL/100g BW or folinic acid counteract these negative effects, helping to conserve bone formation, suppress bone resorption and bone marrow adiposity, and thus prevent bone loss during MTX chemotherapy

The treatment of deep prosthetic infection in cancer patients with tumour prostheses remains the major complication to be dealt with in this population. The Vienna Bone Tumour Registry includes information of more than 6500 patients of a period of 36 years. 145 patients with malignant proximal femoral tumors had resection and limb salvage with an uncemented Kotz modular femoral and tibial reconstruction megaprosthesis (KMFTR). There were twenty osteosarcomas, thirteen Ewing’s sarcomas, six chondrosarcomas, six plasmozytomas, three fibrosarcomas, three liposacomas and others. Thirteen patients (7 males, 6 females with an average age of 45 years, range 10 to 75 years) suffered from deep prosthetic infection within an average of 44 months after primary implantation, representing an infection rate of 8,97 percent. Average follow-up was 109 months, range 7 to 339 months. Two patients with only mild signs of infection were treated by a conservative antibiotic regimen. Nine patients were treated by one-stage revision. One of the remaining two patients with severe infection underwent exarticulation of the hip as primary intervention, the other patient died due to general sepsis on the fourth post-operative day. Six patients showed no further signs of infection. Six patients, however, required one or more reoperations due to recurrent prosthetic infection. Among these four patients have successfully been treated by repeated one-stage revision, in two patients the prosthesis had to be removed permanently. Deep prosthetic infection around modular tumour prostheses of the proximal femur and hip seems to be less common compared to distal femur, knee or tibia. However, the treatment of this complication has a higher failure rate due to multiply recurrent infection

Aims

Advances in treatment have extended the life expectancy of patients with metastatic bone disease (MBD). Patients could experience more skeletal-related events (SREs) as a result of this progress. Those who have already experienced a SRE could encounter another local management for a subsequent SRE, which is not part of the treatment for the initial SRE. However, there is a noted gap in research on the rate and characteristics of subsequent SREs requiring further localized treatment, obligating clinicians to extrapolate from experiences with initial SREs when confronting subsequent ones. This study aimed to investigate the proportion of MBD patients developing subsequent SREs requiring local treatment, examine if there are prognostic differences at the initial treatment between those with single versus subsequent SREs, and determine if clinical, oncological, and prognostic features differ between initial and subsequent SRE treatments.

Cite this article: Bone Joint Res 2023;12(5):311–312.

Aims

To determine whether side-bending films in scoliosis are assessed for adequacy in clinical practice; and to introduce a novel method for doing so.

The clinical records, radiographs and histopathological material of all forty-one patients recorded as suffering from fibrosarcoma of bone in the Swedish Cancer Registry for the years 1958 to 1968 have been analysed; in addition, four cases were found on histological review of a series of osteosarcomas. From this re-examination, twenty-four patients with genuine fibrosarcoma of bone were identified; twenty-two had primary neoplasms and two secondary. No sex or geographical differences were found. The tumours showed a prevalence for patients in the adult and older age groups. Half of the tumours arose from femoral or tibial metaphysial bone adjacent to a knee joint. All the tumours were of the medullary type. Almost one-third presented with a pathological fracture, and soft-tissue extension had occurred in all but three tumours. In contrast to previous reports, these tumours were more malignant than osteosarcomas and showed a five-year survival rate of only 4-2 per cent. In accessible sites, ablative surgery was used as the primary treatment, Fibrosarcoma of bone is a distinctive lesion and should be distinguished carefully from periosteal and soft-tissue fibrosarcomas because of differences in prognosis and treatment

Aims

Current literature suggests that survival outcomes and local recurrence rates of primary soft-tissue sarcoma diagnosed in the very elderly age range, (over 90 years), are comparable with those in patients diagnosed under the age of 75 years. Our aim is to quantify these outcomes with a view to rationalizing management and follow-up for very elderly patients.

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.

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.

Purpose of the study: Infection is the most severe orthopedic complication observed after conservative surgery. The purpose of this study was to ascertain the incidence and causes of such infection and analyze progress achieved over the last ten years.

Material and methods: From 1983 to 2004, surgical procedures were performed in more than 600 patients with bone sarcomas; 520 underwent reconstruction with a prosthesis and/or massive allow graft and were followed for at least six months. Age ranged from 4.5 to 82 years. Deep infections occurred in 47 patients requiring one or several revisions. Three other cases of infection, in patients initially given in other institutions, were included in the series. The study population thus included 50 deep infections after massive reconstruction. Forty-five of these patients had received chemotherapy and 20 radiotherapy. All patients were given adapted antibiotic therapy. Four patients required emergency amputation, and cleaning was attempted in 26. When the infection persisted, or when the infection became chronic, implanted material was removed systematically with insertion of an antibiotic-loaded spacer (gentamycin alon before 1990 then gentamycin+vancomycin). Reimplantation was attempted three to six weeks later when the laboratory results were satisfactory and the muscular and cutaneous situation was sufficient.

Results: Mean follow-up after infection was 8.5 years. At last follow-up, amputation had been necessary in 21 of the 50 patients. The limb was intact in the 29 others but the prosthesis could be reimplanted in only 27 after an average of 2.4 operations. The statistical analysis demonstrated that radiotherapy is a factor of poor prognosis (14 amputations in 20 radiotherapy patients versus 7 amputations in 30 patients without radiation) and that adjunction of vancomycin into the spacer cement has a beneficial effect (15 amputations in 23 patients without vancomycin versus 6 amputations in 27 patients with vancomycin.

Conclusion: Infection of a massive prosthesis is the most serious orthopedic complication because limb survival is compromised. Preventive treatment is crucial: radiotherapy should be avoided and duration of aplasia limited by the use of hematopoietic growth factors. Curative treatment can be achieved with early removal of implanted material, surgical cover with a muscle flap, and adjunction of vancomycin to the spacer cement. The role of prolonged systemic antibiotics remains controversial.

An 86-year-old male presented with a loose total hip replacement (THR) ten years after implantation. At revision for anticipated aseptic loosening, watery pus was found in the joint and Bacille-Calmette-Guérin (BCG) was seen on culture. The bacterial strain was identified and was identical to the BCG used in the intravesicular treatment of superficial bladder carcinoma in this patient ten months earlier. After revision he received a full course of antituberculous treatment.

The clinical and radiological results were excellent after follow-up for 30 months with his uncemented THR showing satisfactory incorporation. His inflammatory markers were normal and his Harris hip score was 95 points.

The diagnosis of a tuberculous infection can be easily missed, but must be considered, especially if sterile pus is encountered.

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.

Introduction: Due to an increase in survival skeletal metastasis becomes a significant factor on life quality in carcinoma patients. Also shown in publications of the last years the surgical approach and the expected prognosis are very much based on the primary. Especially patients with breast carcinoma show very long survival times, which must be considered in choosing the adequate surgical approach. Aim of this study was to proof that on a large collective of consecutively treated patients.

Methods: Between 1980 and 2005 115 patients with metastatic disease to the bone due to breast carcinoma had been surgically treated. In 112 female and 3 male the mean age at surgery was 58 years (17–84 years). Retrospectively location and extension of the disease, symptoms, surgical approaches, complications, recurrencies and survival time had been evaluated.

Results: The most often peformed procedure was a decompression with or without stabilisation of the spine in 42 cases. Four vertebroplasties had been additionally performed. The proximal femur had to be reconstructed with an endoprotsthetic device in 24 cases, an endoprostehtic reconstruction of the humerus was necessary in 2 patients, of the pelvis in one case. One diaphyseal prothesis was implanted. Two resctions/amputation without any reconstruction had to be performed. In 20 cases a compound osteosynthesis, in 19 cases a biopsy only was done. In most of the cases postsurgical radiation was administered in some cases preoperative radiation had been applied. Follow-up was done 1 to 26 years after surgery (average 11.7 years).

Many pateints showed an extented survival despite disseminated disease with a high and quality of life. Radical resection as tried in a few patients did not proof to be beneficial regarding the prognsotic effect.

Conclusions: Patients with skeletal manifestations of breast carcinoma showed long survival times despite extented disease. The intralesional surgical approach including radiation therapy showed a better functional outcome in comparison to radical procedures with no disadvantage in survival time or local recurrencies.

Background

Bone lesions in Ewing's sarcoma (ES/PNET) have been traditionally diagnosed with bone Scan. PET-scan is emerging as a promising investigative modality for detection of metastatic lesions. In this prospective study, we compare the utility of both to detect the metastatic sites.

Breast cancer is the most frequent malignancy in women with an estimation of 2.1 million new diagnoses in 2018. Even though primary tumours are usually efficiently removed by surgery, 20–40% of patients will develop metastases in distant organs. Bone is one of the most frequent site of metastases from advanced breast cancer, accounting from 55 to 58% of all metastases. Currently, none of the therapeutic strategies used to manage breast cancer bone metastasis are really curative. Tailoring a suitable model to study and evaluate the disease pathophysiology and novel advanced therapies is one of the major challenges that will predict more effectively and efficiently the clinical response. Preclinical traditional models have been largely used as they can provide standardization and simplicity, moreover, further advancements have been made with 3D cultures, by spheroids and artificial matrices, patient derived xenografts and microfluidics. Despite these models recapitulate numerous aspects of tumour complexity, they do not completely mimic the clinical native microenvironment. Thus, to fulfil this need, in our study we developed a new, advanced and alternative model of human breast cancer bone metastasis as potential biologic assay for cancer research. The study involved breast cancer bone metastasis samples obtained from three female patients undergoing wide spinal decompression and stabilization through a posterior approach. Samples were cultured in a TubeSpin Bioreactor on a rolling apparatus under hypoxic conditions at time 0 and for up to 40 days and evaluated for viability by the Alamar Blue test, gene expression profile, histology and immunohistochemistry. Results showed the maintenance and preservation, at time 0 and after 40 days of culture, of the tissue viability, biological activity, as well as molecular markers, i.e. several key genes involved in the complex interactions between the tumour cells and bone able to drive cancer progression, cancer aggressiveness and metastasis to bone. A good tis sue morphological and microarchitectural preservation with the presence of lacunar osteolysis, fragmented trabeculae locally surrounded by osteoclast cells and malignant cells and an intense infiltration by tumour cells in bone marrow compartment in all examined samples. Histomorphometrical data on the levels of bone resorption and bone apposition parameters remained constant between T0 and T40 for all analysed patients. Additionally, immunohistochemistry showed homogeneous expression and location of CDH1, CDH2, KRT8, KRT18, Ki67, CASP3, ESR1, CD8 and CD68 between T0 and T40, thus further confirming the invasive behaviour of breast cancer cells and indicating the maintaining of the metastatic microenvironment. The novel tissue culture, set-up in this study, has significant advantages in comparison to the pre-existent 3D models: the tumour environment is the same of the clinical scenario, including all cell types as well as the native extracellular matrix; it can be quickly set-up employing only small samples of breast cancer bone metastasis tissue in a simple, ethically correct and cost-effective manner; it bypasses and/or decreases the necessity to use more complex preclinical model, thus reducing the ethical burden following the guiding principles aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes; it can allow the study of the interactions within the breast cancer bone metastasis tissue over a relatively long period of up to 40 days, preserving the tumour morphology and architecture and allowing also the evaluation of different biological factors, parameters and activities. Therefore, the study provides for the first time the feasibility and rationale for the use of a human-derived advanced alternative model for cancer research and testing of drugs and innovative strategies, taking into account patient individual characteristics and specific tumour subtypes so predicting patient specific responses

Aims. This study aimed to compare the performance of survival prediction models for bone metastases of the extremities (BM-E) with pathological fractures in an Asian cohort, and investigate patient characteristics associated with survival. Methods. This retrospective cohort study included 469 patients, who underwent surgery for BM-E between January 2009 and March 2022 at a tertiary hospital in South Korea. Postoperative survival was calculated using the PATHFx3.0, SPRING13, OPTIModel, SORG, and IOR models. Model performance was assessed with area under the curve (AUC), calibration curve, Brier score, and decision curve analysis. Cox regression analyses were performed to evaluate the factors contributing to survival. Results. The SORG model demonstrated the highest discriminatory accuracy with AUC (0.80 (95% confidence interval (CI) 0.76 to 0.85)) at 12 months. In calibration analysis, the PATHfx3.0 and OPTIModel models underestimated survival, while the SPRING13 and IOR models overestimated survival. The SORG model exhibited excellent calibration with intercepts of 0.10 (95% CI -0.13 to 0.33) at 12 months. The SORG model also had lower Brier scores than the null score at three and 12 months, indicating good overall performance. Decision curve analysis showed that all five survival prediction models provided greater net benefit than the default strategy of operating on either all or no patients. Rapid growth cancer and low serum albumin levels were associated with three-, six-, and 12-month survival. Conclusion. State-of-art survival prediction models for BM-E (PATHFx3.0, SPRING13, OPTIModel, SORG, and IOR models) are useful clinical tools for orthopaedic surgeons in the decision-making process for the treatment in Asian patients, with SORG models offering the best predictive performance. Rapid growth cancer and serum albumin level are independent, statistically significant factors contributing to survival following surgery of BM-E. Further refinement of survival prediction models will bring about informed and patient-specific treatment of BM-E. Cite this article: Bone Joint J 2024;106-B(2):203–211

Aims. The standard of surgical treatment for lower limb neoplasms had been characterized by highly interventional techniques, leading to severe kinetic impairment of the patients and incidences of phantom pain. Rotationplasty had arisen as a potent limb salvage treatment option for young cancer patients with lower limb bone tumours, but its impact on the gait through comparative studies still remains unclear several years after the introduction of the procedure. The aim of this study is to assess the effect of rotationplasty on gait parameters measured by gait analysis compared to healthy individuals. Methods. The MEDLINE, Scopus, and Cochrane databases were systematically searched without time restriction until 10 January 2022 for eligible studies. Gait parameters measured by gait analysis were the outcomes of interest. Results. Three studies were eligible for analyses. Compared to healthy individuals, rotationplasty significantly decreased gait velocity (-1.45 cm/sec; 95% confidence interval (CI) -1.98 to -0.93; p < 0.001), stride length (-1.20 cm; 95% CI -2.31 to -0.09; p < 0.001), cadence (-0.83 stride/min; 95% (CI -1.29 to -0.36; p < 0.001), and non-significantly increased cycle time (0.54 sec; 95% CI -0.42 to 1.51; p = 0.184). Conclusion. Rotationplasty is a valid option for the management of lower limb bone tumours in young cancer patients. Larger studies, with high patient accrual, refined surgical techniques, and well planned rehabilitation strategies, are required to further improve the reported outcomes of this procedure. Cite this article: Bone Jt Open 2023;4(11):817–824

Surgical management for acute or impending pathologic fractures in metastatic bone disease (MBD) places patients at high-risk for post-operative venous thromboembolism (VTE). Due to the combination of malignancy, systemic cancer treatment, and surgical treatment, VTE-risk is increased 7-fold in patients with MBD compared to non-cancer patients undergoing the same procedure. The extent and duration of post-operative hypercoagulability in patients with MBD remains unknown and thromboprophylaxis guidelines were developed for non-cancer patients, limiting their applicability to address the elevated VTE-risk in cancer patients. Thrombelastography (TEG) analysis is a point-of-care test that measures clot formation, stabilization, and lysis in whole blood samples. The TEG parameter, maximal amplitude (MA), indicates clot strength and the threshold of ≥65 mm has been used to define hypercoagulability and predict VTE events in non-cancer patients requiring orthopaedic surgery. Therefore, this study aims to quantify the extent and duration of post-operative hypercoagulability in patients with MBD using serial TEG analysis. Consecutive adults (≥18 years) with MBD who required orthopaedic surgery for acute or impending pathologic fractures were enrolled into this single-centre, prospective cohort study. Serial TEG analysis was performed onsite using a TEG®6s haemostasis analyzer (Haemonetics Corporation, Boston, MA) on whole blood samples collected at seven timepoints: pre-operatively; on post-operative day (POD) 1, 3, and 5; and at 2-, 6-, and 12-weeks post-operatively. Hypercoagulability was defined as MA ≥65 mm. Participants received standardized thromboprophylaxis for four weeks and patient-reported compliance with thromboprophylaxis was recorded. VTE was defined as symptomatic DVT or PE, or asymptomatic proximal DVT, and all participants underwent a screening post-operative lower extremity Doppler ultrasound on POD3. Descriptive statistics were performed and difference between pre-operative MA values of participants with VTE versus no VTE was evaluated using Student's t-test (p≤0.05). Twenty-one participants (10 female; 47.6%) with a mean age of 70 ± 12 years were enrolled. Nine different primary cancers were identified amongst participants, with breast (23.8%), colorectal (19.0%), and lung cancer (14.3%) most frequently reported. Most participants (57.1%) were hypercoagulable pre-operatively, and nearly half remained hypercoagulable at 6- and 12-weeks post-operatively (47.1 and 46.7%, respectively). VTE occurred in 5 patients (23.8%) and mean MA was 68.1 ± 4.6 mm at the time of diagnosis. Mean pre-operative MA values were significantly higher (p=0.02) in patients who experienced VTE (68.9 ± 3.5 mm) compared to those who did not (62.7 ± 6.5 mm). VTE incidence was highest in the first week post-operatively, during which time four VTE events (80%) occurred. The proportion of patients in a hypercoagulable state increased at three consecutive timepoints, beginning on POD3 (85.0%), increasing on POD5 (87.5%), and peaking at 2-weeks post-operatively (88.9%). Current thromboprophylaxis guidelines do not consider cancer-associated risk factors that contribute to increased VTE incidence and prescription duration may be inadequate to address prolonged post-operative hypercoagulability in patients with MBD. The high rate of VTE events observed and sustained hypercoagulable state indicate that thromboprophylaxis may be prematurely terminated while patients remain at high risk for VTE. Therefore, extending thromboprophylaxis duration beyond 4-weeks post-operatively in patients with MBD warrants further investigation

Bone turnover and microdamage are impacted by skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This study aimed to establish an understanding of microdamage accumulation and load to failure in healthy and osteolytic vertebrae following cancer treatment (stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX)). Forty-two 6-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo) were studied; 22 were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Animals were randomly assigned to four groups: untreated (healthy=5, osteolytic=6), SBRT on day 14 (healthy=6, osteolytic=6), ZA on day 7 (healthy=4, osteolytic=5), and DTX on day 14 (healthy=5, osteolytic=5). Animals were euthanized on day 21. L1-L3 motion segments were compression loaded to failure and force-displacement data recorded. T13 vertebrae were stained with BaSO. 4. and µCT imaged (90kVp, 44uA, 4.9µm) to visualize microdamage location and volume. Damage volume fraction (DV/BV) was calculated as the ratio of BaSO. 4. to bone volume. Differences in mean load-to-failure were compared using three-way ANOVA (disease status, treatment, cells injected). Differences in mean DV/BV between treatment groups were compared using one-way ANOVA. Treatment had a significant effect on load-to-failure (p=0.004) with ZA strengthening the healthy and osteolytic vertebrae. Reduced strength post SBRT seen in the metastatic (but not the healthy) group may be explained by greater tumor involvement secondary to higher cell injection concentrations. Untreated metastatic samples had higher DV/BV (16.25±2.54%) compared to all treatment groups (p<0.05) suggesting a benefit of treatment to bone quality. Focal and systemic cancer treatments were shown to effect load-to-failure and microdamage accumulation in healthy and osteolytic vertebrae. Developing a better understanding of how treatments effect bone quality and mechanical stability is critical for effective management of patients with spinal metastases

Aims. The incidence of bone metastases is between 20% to 75% depending on the type of cancer. As treatment improves, the number of patients who need surgical intervention is increasing. Identifying patients with a shorter life expectancy would allow surgical intervention with more durable reconstructions to be targeted to those most likely to benefit. While previous scoring systems have focused on surgical and oncological factors, there is a need to consider comorbidities and the physiological state of the patient, as these will also affect outcome. The primary aim of this study was to create a scoring system to estimate survival time in patients with bony metastases and to determine which factors may adversely affect this. Methods. This was a retrospective study which included all patients who had presented for surgery with metastatic bone disease. The data collected included patient, surgical, and oncological variables. Univariable and multivariable analysis identified which factors were associated with a survival time of less than six months and less than one year. A model to predict survival based on these factors was developed using Cox regression. Results. A total of 164 patients were included with a median survival time of 1.6 years (interquartile range 0.5 to 3.1) after surgery. On multivariable analysis, a higher American Society of Anesthesiologists grade (p < 0.001), a high white cell count (p = 0.002), hyponatraemia (p = 0.001), a preoperative resting heart rate of > 100 bpm (p = 0.052), and the type of primary cancer (p = 0.026) remained significant predictors of reduced survival time. The predictive model developed showed good discrimination and calibration to predict both six- and 12-month survival in patients with metastatic bone disease. Conclusion. In addition to surgical and oncological factors, the level of comorbidity and physiological state of the patient has a significant impact on survival in patients with metastatic bone disease. These factors should be considered when assessing the appropriateness of surgical intervention. This is the first study to examine other patient factors alongside surgical and oncological data to identify a relationship between these and survival. Cite this article: Bone Joint J 2021;103-B(11):1725–1730

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

The April 2024 Oncology Roundup. 360. looks at: Midterm outcomes of total hip arthroplasty after internal hemipelvectomy and iliofemoral arthrodesis; Intraosseous conventional central chondrosarcoma does not metastasize irrespective of grade in pelvis, scapula, and in long bone locations; Oncological and functional outcomes after resection of malignant tumours of the scapula; Reconstruction following oncological iliosacral resection – a comparison of techniques; Does primary tumour resection improve survival for patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at diagnosis?; Older patients with Ewing’s sarcoma: an analysis of the National Cancer Database; Diagnostic challenges in low-grade central osteosarcoma; Effect of radiotherapy on local recurrence, distant metastasis, and overall survival in 1,200 limb soft-tissue sarcoma patients: a retrospective analysis using inverse probability of treatment weighting-adjusted models

The June 2024 Spine Roundup. 360. looks at: Intraoperative navigation increases the projected lifetime cancer risk in patients undergoing surgery for adolescent idiopathic scoliosis; Intrawound vancomycin powder reduces delayed deep surgical site infections following posterior spinal fusion for adolescent idiopathic scoliosis; Characterizing negative online reviews of spine surgeons; Proximal junctional failure after surgical instrumentation in adult spinal deformity: biomechanical assessment of proximal instrumentation stiffness; Nutritional supplementation and wound healing: a randomized controlled trial

Introduction. Advanced practice physiotherapists (APPs) manage the national low back and radicular pain pathway across the UK. A novel spinal APP-led same-day emergency care (SDEC) pathway in Nottingham, manages patients referred from community services and the emergency department (ED). Patients may attend ED in the belief their pain is due to sinister or ‘red flag’ pathology. Little data exists on prevalence of spinal ‘red flag’ pathologies within a secondary care setting. This paper aims to review the number of ‘red flag’ pathology identified by APP's on a same-day emergency care pathway. Methods. Retrospective data from 1 year of routinely collected information was extracted and analysed by two APPs. Counts were reported as a percentage of total patients seen on the SDEC unit over a one-year period and compared to nationally reported figures. A total of 2042 patients were assessed on the unit in 2021, of which, 293 (14%) had serious pathology identified. Patients were classified into type of serious pathology: myelopathy (126, 6.1%), fractures (72, 3.5%), cauda equine compression (40, 1.9%), infection (37, 1.8%), cancers (28, 1.3%), neurological conditions (14, 0.6%) and other (16, 0.8%) serious pathology. Conclusion. APP's working within an emergency pathway are highly likely to see and diagnose serious spinal pathology. The most common include cord or cauda equina compression, fractures, infection and cancers. Figures reported are slightly higher than previously documented. Knowledge and training to identify ‘red flags’ and robust pathways of escalation are essential in support of APP roles and services. Conflict of interest: No conflicts of interest. Sources of funding: No sources of funding

Macrophages (Mφ) are immune cells that play a crucial role in both innate and adaptive immunity as they are involved in a wide range of physiological and pathological processes. Depending on the microenvironment and signals present, Mφ can polarize into either M1 or M2 phenotypes, with M1 macrophages exhibiting pro-inflammatory and cytotoxic effects, while M2 macrophages having immunosuppressive and tissue repair properties. Macrophages have been shown to play key roles in the development and progression or inhibition of various diseases, including cancer. For example, macrophages can stimulate tumor progression by promoting immunosuppression, angiogenesis, invasion, and metastasis. This work aimed to investigate the effect of extracellular vesicles (EVs)-derived from polarized macrophages on an osteosarcoma cell line. Monocytes were extracted from buffy coats and cultured in RPMI medium with platelet lysate or M-CSF. After 6 days of seeding, Mφ were differentiated into M1 and M2 with INF-γ/LPS and IL-4/IL-13, respectively. The medium with M1 or M2 derived EVs was collected and EVs were isolated by differential centrifugation and size exclusion chromatography and its morphology and size were characterized with SEM and NTA, respectively. The presence of typical EVs markers (CD9, CD63) was assessed by Western Blot. Finally, EVs from M1 or M2-polarized Mφ were added onto osteosarcoma cell cultures and their effect on cell viability and cell cycle, proliferation, and gene expression was assessed. The EVs showed the typical shape, size and surface markers of EVs. Overall, we observed that osteosarcoma cells responded differentially to EVs isolated from the M1 and M2-polarized Mφ. In summary, the use of Mφ-derived EVs for the treatment of osteosarcoma and other cancers deserves further study as it could benefit from interesting traits of EVs such as low immunogenicity, nontoxicity, and ability to pass through tissue barriers. Acknowledgements: Carlos III Health Institute and the European Social Fund for contract CP21/00136 and project PI22/01686

Aims. The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold. Methods. Female Sprague Dawley (SD) rats were used to establish a rat model of BCP, and the messenger RNA (mRNA) and protein expression of ionized calcium binding adaptor molecule 1 (IBA1) and cyclin D1 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot, respectively. The proliferation of spinal microglia was detected by immunohistochemistry. The pain behaviour test was assessed by quantification of spontaneous flinches, limb use, and guarding during forced ambulation, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. Results. IBA1 and cyclin D1 in the ipsilateral spinal horn increased in a time-dependent fashion. Spinal microglia proliferated in BCP rats. The microglia inhibitor minocycline attenuated the pain behaviour in BCP rats. The cyclin-dependent kinase inhibitor flavopiridol inhibited the proliferation of spinal microglia, and was associated with an improvement in pain behaviour in BCP rats. Conclusion. Our results revealed that the inhibition of spinal microglial proliferation was associated with a decrease in pain behaviour in a rat model of BCP. Cyclin D1 acts as a key regulator of the proliferation of spinal microglia in a rat model of BCP. Disruption of cyclin D1, the restriction-point control of cell cycle, inhibited the proliferation of microglia and attenuated the pain behaviours in BCP rats. Cyclin D1 and the proliferation of spinal microglia may be potential targets for the clinical treatment of BCP. Cite this article: Bone Joint Res 2022;11(11):803–813

Background. The advent of EOS imaging has offered clinicians the opportunity to image the whole skeleton in the anatomical standing position with a smaller radiation dose than standard spine roentgenograms. It is known as the fifth modality of imaging. Current NICE guidelines do not recommend EOS scans over x-rays citing: “The evidence indicated insufficient patient benefit in terms of radiation dose reduction and increased throughput to justify its cost”. Methods. We retrospectively reviewed 103 adult and 103 paediatric EOS scans of standing whole spines including shoulders and pelvis for those undergoing investigation for spinal deformity in a tertiary spinal centre in the UK. We matched this against a retrospective control group of 103 adults and 103 children who underwent traditional roentgenograms whole spine imaging at the same centre during the same timeframe. We aimed to compare the average radiation dose of AP and lateral images between the two modalities. We utilised a validated lifetime risk of cancer calculator (. www.xrayrisk.com. ) to estimate the additional mean risk per study. Results. In the Adult EOS Group (AEG) the mean estimated effective dose of AP was 0.08 mSv (0.04–0.15) and Lateral 0.06 mSv (0.03–0.14). Conversely in the Adult Roentgenograms Group (ARG) the mean AP was 0.49 mSv (0.15–1.88) and Lateral was 0.29 mSv (0.07–1.20). In the Paediatric EOS Group (PEG): the mean dose of AP was 0.07 mSv (0.02–0.21) and Lateral 0.04 mSv (0.02–0.11). Conversely Paediatric Roentgenograms Group (PRG) had a mean dose in AP of 0.37 mSv (0.03–5.92) and in lateral of 0.17 mSv (0.03–0.44). The percentage differences were: ARG:AES AP 613%, ARG:AES Lat 483%, PPG:PEG AP 529%, PRG:PEG Lat 425%. Mean difference 513%. The additional lifetime cancer risk for AEG was 1 in 176056 for males and 1 in 138696 for females, compared to ARG 1 in 31596 for males and 1 in 24894 for females. In PEG that was 1 in 58207 for boys and 1 in 33367 for girls, compared to PRG 1 in 11860 for boys and 1 in 6797 in girls. Differences in additional lifetime risk of cancer per scan: ARG:AES Male 557%, Female 557%, PRG:PEG Male 491%, Females 491%. Conclusion. Standard plain film imaging of the whole spine requires approximately five-times higher doses of radiation compared to dual planar EOS scans. This carries a significant impact when considering the need for repeat imaging on additional lifetime malignancy risk in both children and adults. There is approximately 5-fold increase in risk of cancer for all groups with roentgenograms over EOS. We directly challenge the NICE guidance and recommend EOS dual planar imaging in favour of plane roentgenograms for investigation of spinal deformity

Great strides have been made in the early detection and treatment of cancer which is resulting in improved survivability and more Canadians living with cancer. Approximately 80% of primary breast, lung, and prostate cancers metastasize to the spine. Poly-methyl methacrylate (PMMA) bone cement is one of the most commonly used bone substitutes in spine surgery. In clinical practice it can be loaded with various drugs, such as antibiotics or chemotheraputic drugs, as a means of local drug delivery. However, studies have shown that drugs loaded into PMMA cement tend to release in small bursts in the first 48–72 hours, and the remaining drug is trapped without any significant release over time. The objective of this study is to develop a nanoparticle-functionalized PMMA cement for use as a sustained doxorubicin delivery device. We hypothesize that PMMA cement containing mesoporous silica nanoparticles will release more doxorubicin than regular PMMA. High viscosity SmartSet ™ PMMA cement by DePuy Synthes was used in this study. The experimental group consisted of 3 replicates each containing 0.24 g of mesoporous silica nanoparticles, 1.76 g of cement powder, 1ml of liquid cement monomer and 1 mg of doxorubicin. The control group consisted 3 replicates each containing 2.0 g of cement powder, 1ml of liquid cement monomer and 1 mg of doxorubicin. The experimental group contained an average of 8.18 ± 0.008 % (W/W) mesoporous silica nanoparticles. Each replicate was casted into a cylindrical block and incubated in a PBS solution which was changed at predetermined intervals for 45 days. The concentration of eluted doxorubicin in each solution was measured using a florescent plate reader. The mechanical properties of cement were assessed by unconfined compression testing. The effect of the doxorubicin released from cement on prostate and breast tumor cell metabolic activity was assessed using the Alamar Blue test. After 45 days the experimental group released 3.24 ± 0.25 % of the initially loaded doxorubicin which was more than the 2.12 ± 0.005% released by the control group (p 0.03). There was no statistically significant difference in Young's elasticity modulus between groups (p 0.53). Nanoparticle functionalized PMMA suppressed the metabolic activity of prostate cancer by more than 50 percent but did not reach statistical significance. Nanoparticle functionalized PMMA suppressed the metabolic activity of breast cancer cells by 69 % (p < 0.05). Nanoparticle-functionalized PMMA cement can release up to 1.53 times more doxorubicin than the standard PMMA. The use of mesoporous silica nanoparticles to improve drug release from PMMA cement shows promise. In the future, in vivo experiments are required to test the efficacy of released doxorubicin on tumor cell growth

Aims. The aim of this study was to quantify the risk of developing cancer from the exposure to radiation associated with surgery to correct limb deformities in children. Patients and Methods. A total of 35 children were studied. There were 19 girls and 16 boys. Their mean age was 11.9 years (2 to 18) at the time of surgery. Details of the radiological examinations were recorded during gradual correction using a Taylor Spatial Frame. The dose area product for each radiograph was obtained from the Computerised Radiology Information System database. The effective dose in millisieverts (mSv) was calculated using conversion coefficients for the anatomical area. The lifetime risk of developing cancer was calculated using government-approved Health Protection Agency reports, accounting for the age and gender of the child. Results. Correction was undertaken in five femurs, 18 tibiae, and 12 feet. The median duration of treatment was 45 months (11 to 118). The mean effective dose was 0.31 mSv (0.05 to 0.64) for the femur, 0.29 mSv (0.01 to 0.97) for the tibia, and 0.027 mSv (0.001 to 0.161) for the foot. The cumulative exposure gave ‘negligible’ risk in 26 children and ‘minimal’ risk in nine children, according to Public Health England categories. These results are below the mean annual background radiation in the United Kingdom. Conclusion. The lifetime attributable risk of developing cancer from repeated exposure to radiation was negligible or minimal in all children. This is the first study to quantify the exposure to radiation from serial radiographs in children with limb deformities who are treated surgically using circular external fixation, linking this to the risk of developing cancer. Cite this article: Bone Joint J 2019;101-B:241–245

The poor prognosis of patients with soft-tissue sarcoma as not changed in the past several decades, highlighting the necessity for new therapeutic approaches. T-cell based immunotherapies are a promising alternative to traditional cancer treatments due to their ability to target only malignant cells, leaving benign cells unharmed. The development of successful immunotherapy requires the identification and characterization of targetable immunogenic tumor antigens. Cancer-testis antigens (CTA) are a group of highly immunogenic tumor-associated proteins that have emerged as potential targets for CD8+ T-cell recognition. In addition to identifying a targetable antigen, it is crucial to understand the tumor immune microenvironment. The level of immune infiltration and mechanisms of immune suppression within the tumor play important roles in the outcome of immunotherapy. The goal of this study is to identify targetable immunogenic antigens for T-cell based immunotherapy and to characterize the tumor immune microenvironment in human dedifferentiated liposarcoma (DDLS) by Nanostring and IHC. To assess the complexity of the human DDLS tumor immune microenvironment and to identify target antigens we used the nCounter NanoString platform to generate a gene expression profile for hundreds of genes from RNA obtained from 29 DDLS and 10 control fat FFPE samples. To classify inflammatory status of DDLS tumors, we performed hierarchical clustering based on expression levels of selected tumor inflammatory signature genes (CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-E, IDO1, LAG3, PDCDILG2, PSMB10, STAT1, TIGIT). To confirm protein expression and distribution of identified antigens, we performed immunohistochemistry on human tissue micro-arrays encompassing DDLPS tumor tissues and matched normal control tissue from 63 patients. IHC for the cancer testis antigens PBK, SPA17, MAGE-A3, NY-ESO-1 and SSX2 was performed, and the staining results were scored by two authors based on maximal staining intensity on a scale of zero to three (absent=0, weak=1, moderate=2, or strong=3) and the percentage of tumor cells that stained. Hierarchical clustering of DDLS tumors based on expression of tumor inflammation signature genes revealed two distinct groups, consisting of 15 inflamed tumor and 14 non-inflamed tumors, demonstrating tumor heterogeneity within the DDLS sarcoma subtype. All antigens were found to be expressed in DDLS at an mRNA level. SPA17 was expressed at the highest levels in DDLS, however, this antigen was expressed at high levels in normal fat. Notably, antigens PBK and TTK had the largest fold change increase in expression in DDLS compared to normal fat controls. Immunohistochemical analysis of selected antigens revealed that PBK was found to be expressed in 96% (52/54) of DDLS samples at high levels. Other antigens were absent or expressed at low levels in DDLS; MAGEA3 in 15.87% (10/63) NY-ESO-1 in 6.35% (4/62) and SSX2 in 12.7% (8/63) and SPA17 in 5.5% (3/54). This data shows considerable inter-tumoral heterogeneity of inflammation, which should be taken into consideration when designing an immunotherapy for DDLS. To date, these results show promising expression of PBK antigen in DDLS, which may be used as a target in the future development of an immunotherapy for sarcoma

Aims. In the last decade, perioperative advancements have expanded the use of outpatient primary total knee arthroplasty (TKA). Despite this, there remains limited data on expedited discharge after revision TKA. This study compared 30-day readmissions and reoperations in patients undergoing revision TKA with a hospital stay greater or less than 24 hours. The authors hypothesized that expedited discharge in select patients would not be associated with increased 30-day readmissions and reoperations. Methods. Aseptic revision TKAs in the National Surgical Quality Improvement Program database were reviewed from 2013 to 2020. TKAs were stratified by length of hospital stay (greater or less than 24 hours). Patient demographic details, medical comorbidities, American Society of Anesthesiologists (ASA) grade, operating time, components revised, 30-day readmissions, and reoperations were compared. Multivariate analysis evaluated predictors of discharge prior to 24 hours, 30-day readmission, and reoperation. Results. Of 21,610 aseptic revision TKAs evaluated, 530 were discharged within 24 hours. Short-stay patients were younger (63.1 years (49 to 78) vs 65.1 years (18 to 94)), with lower BMI (32.3 kg/m. 2. (17 to 47) vs 33.6 kg/m. 2. (19 to 54) and lower ASA grades. Diabetes, chronic obstructive pulmonary disease, hypertension, and cancer were all associated with a hospital stay over 24 hours. Single component revisions (56.8% (n = 301) vs 32.4% (n = 6,823)), and shorter mean operating time (89.7 minutes (25 to 275) vs 130.2 minutes (30 to 517)) were associated with accelerated discharge. Accelerated discharge was not associated with 30-day readmission and reoperation. Conclusion. Accelerated discharge after revision TKA did not increase short-term complications, readmissions, or reoperations. Further efforts to decrease hospital stays in this setting should be evaluated. Cite this article: Bone Joint J 2022;104-B(12):1323–1328

Aims. Total femoral arthroplasty (TFA) is a rare procedure used in cases of significant femoral bone loss, commonly from cancer, infection, and trauma. Low patient numbers have resulted in limited published work on long-term outcomes, and even less regarding TFA undertaken for non-oncological indications. The aim of this study was to evaluate the long-term clinical outcomes of all TFAs in our unit. Methods. Data were collected retrospectively from a large tertiary referral revision arthroplasty unit’s database. Inclusion criteria included all patients who underwent TFA in our unit. Preoperative demographics, operative factors, and short- and long-term outcomes were collected for analysis. Outcome was defined using the Musculoskeletal Infection Society (MSIS) outcome reporting tool. Results. Overall, 38 TFAs were identified. The mean age was 73 years (42 to 80). All patients underwent TFA for non-oncological indications, most commonly as a consequence of infection (53%) and periprosthetic fracture (26%). The mean follow-up time was ten years (0 to 26); 63% of TFAs were considered a success based upon the MSIS outcome reporting tool. The mean time between TFA and death was 8.5 years (0.2 to 19.2), with two patients dying within one year of surgery. Within the cohort, 66% suffered at least one complication, dislocation being most common (37%); 55% of the total cohort required at least one subsequent operation. In total, 70% of TFAs undertaken for infection were considered infection-free at time of final follow-up. The percentage of mobile patients improved from 52% to 65% between pre- and postoperation, with all patients being able to at least transfer from bed to chair at time of final review. Conclusion. This study is the largest in the UK assessing the use of TFA in patients with bone loss secondary to non-oncological conditions. It demonstrates that TFA has a significant complication profile, however it is favourable in terms of mortality and rehabilitation when compared to amputation and disarticulation. Cite this article: Bone Joint J 2023;105-B(8):888–894

In the past decades, a huge amount of effort has been devoted to translate evidence based on standard preclinical models of bone tumours to effective tools for clinical applications. Although cancer is a genetic disease, hence the emphasis on -omics approaches, the complexity of cancer tissue, a mix of competing clones of transformed elements that react differently to microenvironmental stimuli, may hardly be reproduced by standard approaches. Cost, biological differences and ethical concerns are increasingly recognized as weaknessess of animal models. To overcome these limitations and provide reliable, reproducible, and affordable tools for predicting the effectiveness of treatments, environmental-controlled 3D cultures and co-cultures (spheroids, organoids) coupled with microfluidics and advanced imaging have recently being considered as effective instrument to increase knowledge on the pathophysiology of bone tumours and define effective therapeutic solutions

Aims. The aims of this study were to determine the incidence and factors for developing periprosthetic joint infection (PJI) following hemiarthroplasty (HA) for hip fracture, and to evaluate treatment outcome and identify factors associated with treatment outcome. Methods. A retrospective review was performed of consecutive patients treated for HA PJI at a tertiary referral centre with a mean 4.5 years’ follow-up (1.6 weeks to 12.9 years). Surgeries performed included debridement, antibiotics, and implant retention (DAIR) and single-stage revision. The effect of different factors on developing infection and treatment outcome was determined. Results. A total of 1,984 HAs were performed during the study period, and 44 sustained a PJI (2.2%). Multiple logistic regression analysis revealed that a higher CCI score (odds ratio (OR) 1.56 (95% confidence interval (CI) 1.117 to 2.187); p = 0.003), peripheral vascular disease (OR 11.34 (95% CI 1.897 to 67.810); p = 0.008), cerebrovascular disease (OR 65.32 (95% CI 22.783 to 187.278); p < 0.001), diabetes (OR 4.82 (95% CI 1.903 to 12.218); p < 0.001), moderate-to-severe renal disease (OR 5.84 (95% CI 1.116 to 30.589); p = 0.037), cancer without metastasis (OR 6.42 (95% CI 1.643 to 25.006); p = 0.007), and metastatic solid tumour (OR 15.64 (95% CI 1.499 to 163.087); p = 0.022) were associated with increasing PJI risk. Upon final follow-up, 17 patients (38.6%) failed initial treatment and required further surgery for HA PJI. One-year mortality was 22.7%. Factors associated with treatment outcome included lower preoperative Hgb level (97.9 g/l (SD 11.4) vs 107.0 g/l (SD 16.1); p = 0.009), elevated CRP level (99.1 mg/l (SD 63.4) vs 56.6 mg/l (SD 47.1); p = 0.030), and type of surgery. There was lower chance of success with DAIR (42.3%) compared to revision HA (66.7%) or revision with conversion to total hip arthroplasty (100%). Early-onset PJI (≤ six weeks) was associated with a higher likelihood of treatment failure (OR 3.5 (95% CI 1.2 to 10.6); p = 0.007) along with patients treated by a non-arthroplasty surgeon (OR 2.5 (95% CI 1.2 to 5.3); p = 0.014). Conclusion. HA PJI initially treated with DAIR is associated with poor chances of success and its value is limited. We strongly recommend consideration of a single-stage revision arthroplasty with cemented components. Cite this article: Bone Jt Open 2022;3(12):924–932

The spine is one of the most common sites of bony metastasis, with 80% of prostate, lung, and breast cancers metastasizing to the vertebrae resulting in significant morbidity. Current treatment modalities are systemic chemotherapy, such as Doxorubicin (Dox), administered after resection to prevent cancer recurrence, and systemic antiresorptive medication, such as Zolendronate (Zol), to prevent tumor-induced bone destruction. The large systemic doses required to elicit an adequate effect in the spine often leads to significant side-effects by both drugs, limiting their prolonged use and effectiveness. Recently published work by our lab has shown that biocompatible 3D-printed porous polymer scaffolds are an effective way of delivering Dox locally over a sustained period while inhibiting tumor growth in vitro. Our lab has also generated promising results regarding antitumor properties of Zol in vitro. We aim to develop 3D-printed scaffolds to deliver a combination of Zol and Dox that can potentially allow for a synergistic antitumor activity while preventing concurrent bone loss locally at the site of a tumor, avoiding long systemic exposure to these drugs and decreasing side effects in the clinical setting. The PORO Lay polymer filaments are 3D-printed into 5mm diameter disks, washed with deionized water and loaded with Dox or Zol in aqueous buffer over 7 days. Dox or Zol-containing supernatant was collected daily and the drug release was analyzed over time in a fluorescence plate reader. The polymer-drug (Dox or Zol) release was tested in vitro on prostate and lung cancer cell lines and on prostate- or lung-induced bone metastases cells. Alternatively, direct drug treatment was also carried out on the same cells in vitro. Following treatment, all cells were subject to proliferation assay (MTT and alamar blue), viability assay (LIVE/DEAD), migration assay (Boyden chamber) and invasion assay (3D gel matrix). 3D-printed scaffolds loaded with both Dox and Zol will also be tested on cells. We have established an effective dose (EC50) for prostate and lung cancer cell lines and bone metastases cells with direct treatment with Zol or Dox. We have titrated the drug loading of scaffolds to allow for a release amount of Dox at the EC50 dose over 7 days. In ongoing experiments, we are testing the release of Zol. We have shown Dox releasing scaffolds inhibit cancer cell growth in a 2D culture over 7 days using the above cellular assays and testing the scaffolds with Zol is currently being analyzed. 3D-printed porous polymers like the PORO Lay series of products offer a novel and versatile opportunity for delivery of drugs in future clinical settings. They can decrease systemic exposure of drugs while at the same time concentrating the drugs effect at the site of tumors and consequently inhibit tumor proliferation. Their ability to be loaded with multiple drugs can allow for achieving multiple goals while taking advantage of synergistic effects of different drugs. The ability to 3D-print these polymers can allow for production of custom implants that offer better structural support for bone growth

Aims. The purpose of this study was to identify prognostic indicators of outcome at presentation to the orthopaedic surgeon, in patients with metastatic prostate cancer. Our aim was to use this information in a pragmatic, clinic-based approach so that surgical decision making could be optimized to benefit the patient in their remaining lifetime. Patients and Methods. A cohort analysis was undertaken of all patients with metastatic disease of the prostate who presented to a regional orthopaedic centre in the United Kingdom between 2003 and 2016. Biochemical data were collected in addition to disease and demographic data. These included: prostate-specific antigen (PSA) at orthopaedic presentation; haemoglobin (Hb); platelets (plt); alkaline phosphatase (ALP); albumin (Alb); and corrected calcium (CaC). Statistical analysis included Kaplan–Meier survival analysis, and a Cox proportional hazards model was fitted to the data. Results. From the departmental database, 137 episodes were identified in 136 patients with a median age at presentation of 72 years (interquartile range (IQR) 66 to 78). Most patients had stage IV disease (n = 98, 72%), and most did not undergo surgical intervention. At one-year follow-up, 50% of patients had died. Biomarkers found to be independently associated with poor survival were: low Hb, low Alb, relatively low PSA (< 30 mmol/l), and a raised ALP. Patients who needed surgical intervention had a poorer survival rate than patients who were managed nonoperatively. Conclusion. The study findings are important for orthopaedic clinical practice in the management of patients with metastatic prostate cancer. The interpretation of routine blood tests can help to predict survival in patients who present with orthopaedic manifestations of prostate cancer. A lower PSA is not necessarily a good prognostic sign. We believe that simple blood testing should be carried out routinely when assessing a patient, guiding potential surgical management and palliative care in the future