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

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

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

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%