High grade sarcoma present a systemic metastatic progression in approximaly 50% of cases. The effectiveness of palliative chemotherapy as a treatment of systemic metastases is still controversed. The main objectif of this study is to assess disease progression and survival of patients diagnosed with metastatic soft tissue sarcomas treated with palliative chemotherapy, analyse chemotherapy treatment patterns and response to different lines of treatment. Retrospective chart review of 75 patients treated with palliative chemotherapy for metastatic soft tissue sarcomas between 2003 and 2013 at Maisonneuve-Rosemont Hospital. Data for control group of 40 patients with metastatic soft tissue sarcomas not treated with chemotherapy was collected retrospectively. Collected data include demographic data, overall survival, time free survival, type of chemotherapy treatment, surgical treatment and adverse reaction to palliative chemotherapy. Overall survival was analysed with Kaplan-Meier test. Categorial variable were compared with Log-Rank test. Seventy-five patients (37% female; mean age 50.4 years) received minimally one line of chemotherapy for their metastatic sarcomas. The regimens most commonly used in first-line were doxorubicin (48%) and doxorubicin combined with ifosfamide (21.3%). Favorable response was achieved by 38.7% in first-line and 27.9% in second-line therapy. Median overall survival with chemotherapy treatments was more than two times overall survival without treatments. Median overall survival was 19 months with chemotherapy treatments and 7 months without chemotherapy (p<0.0001). There was no statistically significant difference between survivals for treated and untreated patients with chemotherapy when analysed in term of the histological subtype, age and monotherapy versus combined treatment. Event-free survival was statistically longer during the first year for the group of patients treated with combined chemotherapy (p=0.0125). Results have shown a significantly improved overall survival in all histological groups, resulting in an OS of 19 vs 7 months for the chemotherpy and non chemotherapy group respectively. Nevertheless, patients with favorable response to chemotherapy have poor outcomes. Additional treatment options are needed

Ewing sarcoma (ES) and Osteosarcoma (OS) are the 2 most common malignant primary bone tumors. A patient's response to neoadjuvant chemotherapy has important implications in subsequent patient management and prognosis, as a favourable response to chemotherapy allows orthopedic oncologists to be more aggressive in pursuing limb-sparing surgery. An accurate and non-invasive pre-operative marker of response would be ideal for planning surgical margins and as a prognostic tool. ES and OS have differing biological characterisitcs and respond differently to chemotherapy. We reviewed 18F-FDG PET imaging characteristics of ES and OS patients at baseline and following treatment to determine whether this biological variation is reflected in their imaging phenotype. A retrospective review of ES and OS patients treated with neoadjuvant chemotherapy and surgery was done, correlating PET results with histologic response to chemotherapy. Change in the maximum standardized Uptake Value (SUVmax) between baseline and post-treatment scanning was not significantly associated with histologic response for either ES or OS. Metabolic tumor volume (MTV) and the percentage of injected 18F-FDG dose (%ID) in the primary tumor were found to be different for ES and OS response subgroups. A 50% reduction in MTV (MTV2:1 < 0.5) was found to be significantly associated with histologic response in OS. Using the same criteria for ES incorrectly predicted good responders. Increasing the cut-offs for ES to a 90% reduction in MTV (MTV 2:1 < 0.1) resulted in association with histologic response. Response to neoadjuvant chemotherapy as reflected by changes in PET characteristics should be interpreted differently for ES and OS

We investigated the effect of adjuvant and neoadjuvant chemotherapy regimens on the tibial regenerate after removal of the external fixator in a rabbit model of distraction osteogenesis using New Zealand white rabbits. Forty rabbits were randomly distributed into two groups. In the neoadjuvant group, half of the rabbits received 1mg/kg cisplatinum & 2mg/kg adriamycin at eight weeks of age followed by 1mg/kg cisplatinum & 4mg/kg adriamycin at ten weeks of age. The remaining ten received an identical volume of normal saline using the same regimen. The adjuvant group differed only in the timing of the chemotherapy infusion. Half received the initial infusion ten days prior to the osteotomy, with the second infusion four days following the osteotomy. Again, the remaining ten rabbits received an identical volume of normal saline using the same regimen. This produced an identical interval between infusions and identical age at osteotomy in both groups. All rabbits underwent a tibial osteotomy at 12 weeks of age. Distraction started 24hours after osteotomy at a rate of 0.75mm a day for 10 days, followed by 18 days without correction to allow for consolidation of the regenerate. At week 16 there was no difference in Bone Mineral Density (BMD), Bone Mineral Content (BMC) or volumetric Bone Mineral Density (vBMD) in the adjuvant group. Neoadjuvant chemotherapy appears to have a significant detrimental effect on BMD, vBMD and BMC. Despite this there were no significant alterations in the mechanical properties of the regenerate. Histologically there was a trend for increased cortical thickness in the control groups compared to intervention however this did not prove statistically significant. In conclusion, adjuvant chemotherapy may be more beneficial for cases where distraction osteogenesis is being considered to replace segmental bone loss after tumour excision

Purpose. Ewings Sarcoma (ES) and Osteosarcoma (OS) behave and respond differently to chemotherapy and any interpretation of diagnostics tests to predict a patients response to treatment must consider this. We reviewed 18F-FDG PET imaging characteristics of consecutive series of ES and OS patients to determine if any differences in PET imaging existed between them. Method. A retrospective review was performed of 31 patients with ES and OS who received all their treatment by our group and who had pre- and post-chemotherapy 18F-FDG PET scans at the Peter MacCallum Cancer Centre from Jan 1, 1999 to December 1, 2009 (Table 1). Patients who did not have both their pre- and post-chemotherapy PET scans done at Peter MacCallum Cancer Centre were excluded from the study to remove bias from having different PET scanning protocols. Patients received neoadjuvant chemotherapy according to standard protocols, all starting within 2 weeks after the initial pre-chemotherapy PET scans (PET1). The PET scan taken after the last cycle of chemotherapy prior to surgery was considered as the post-chemotherapy scan (PET2). The ratio between pre and post-chemotherapy for each PET parameter was then associated with the histology response for both ES and OS, and positive (PPV) and negative predicting values (NPV) of each parameter were calculated. Results. Standardized Uptake Values (SUV) was not significantly associated with histologic response for both ES and OS. Metabolic tumor volume (MTV) and accumulation percentage of 18F-FDG (%ID) was found to be different for ES and OS. A 50% reduction in MTV (MTV2:1 < 0.5) was found to be significantly associated with histologic response in OS. Using the same criteria for ES incorrectly predicted good responders. Increasing the cut-offs for ES to a 90% reduction in MTV (MTV 2:1 < 0.1) resulted in association with histologic response. Conclusion. Response to neoadjuvant chemotherapy as reflected by changes in PET characteristics should be interpreted differently for ES and OS

Traditional staging systems for high grade osteosarcoma (Enneking, MSTS) are based largely on gross surgical margins and were developed before the widespread use of neoadjuvant chemotherapy. It is now well known that both microscopic margins and chemotherapy are predictors of local recurrence. However, neither of these variables are used in the traditional surgical staging and the precise safe margin distance is debated. Recently, a novel staging system utilizing a 2mm margin cutoff and incorporating precent necrosis was proposed and demonstrated improved prognostic value for local recurrence free survival (LRFS) when compared to the MSTS staging system. This staging system has not been validated beyond the original patient cohort. We propose to analyze this staging system in a cohort of patients with high-grade osteosarcoma, as well as evaluate the ability of additional variables to predict the risk of local recurrence and overall survival. A retrospective review of a prospectively collected database of all sarcoma patients between 1985 and 2020 at a tertiary sarcoma care center was performed. All patients with high-grade osteosarcoma receiving neo-adjuvant chemotherapy and with no evidence of metastatic disease on presentation were isolated and analyzed. A minimum of two year follow up was used for surviving patients. A total of 225 patients were identified meeting these criteria. Univariate analysis was performed to evaluate variable that were associated with LRFS. Multivariate analysis is used to further analyze factors associated with LRFS on univariate analysis. There were 20 patients (8.9%) who had locally recurrent disease. Five-year LRFS was significantly different for patients with surgical margins 2mm or less (77.6% v. 93.3%; p=0.006) and those with a central tumor location (67.9 v. 94.4; <0.001). A four-tiered staging system using 2mm surgical margins and a percent necrosis of 90% of greater was also a significant predictor of 5-year LRFS (p=0.019) in this cohort. Notably, percent necrosis in isolation was not a predictor of LRFS in this cohort (p=0.875). Tumor size, gender, and type of surgery (amputation v. limb salvage) were also analyzed and not associated with LRFS. The MSTS surgical margin staging system did not significantly stratify groups (0.066). A 2mm surgical margin cutoff was predictive of 5-year LRFS in this cohort of patients with localized high-grade osteosarcoma and a combination of a 2mm margin and percent necrosis outperformed the prognostic value of the traditional MSTS staging system. Utilization of this system may improve the ability of surgeons to stage thier patients. Additional variables may increase the value of this system and further validation is required

Abstract. Background. Extracorporeal radiation therapy (ECRT) has been reported as an oncologically safe and effective reconstruction technique for limb salvage in diaphyseal sarcomas with promising functional results. Factors affecting the ECRT graft-host bone incorporation have not been fully investigated. Methods. In our series of 51 patients of primary bone tumors treated with ECRT, we improvised this technique by using a modified V-shaped osteotomy, additional plates and intra-medullary fibula across the diaphyseal osteotomy in an attempt to increase the stability of fixation, augment graft strength and enhance union at the osteotomy sites. We analyzed our patients for various factors that affected union time and union rate at the osteotomy sites. Results. On univariate analysis, age <20 years, metaphyseal osteotomy site, V-shaped diaphyseal osteotomy, extramedullary plate fixation and use of additional plate at diaphyseal ostetomy had a significantly faster time to union while gender, tumor type, resection length, chemotherapy and use of intra-medullary fibula did not influence union time. In multivariate analysis, metaphyseal ostoeotomy, V-shaped diaphyseal osteotomy and use of additional plate at diaphyseal ostetomy were the independent factors with favourable time to union. Although the rate of union was higher with V-shaped diaphyseal osteotomy and use of additional plate and intra-medullary fibula at diaphyseal ostetomy, this difference could not be established statistically. None of the analyzed factors apparently affected the union rate in univariate analysis. Conclusion. Judicious choice of osteosynthesis and augmentation of ECRT graft can enhance incorporation with reduced complications and good functional outcome

Aim. Deep infection following endoprosthetic replacement (EPR) of long bones is a devastating complication occurring in 15% of musculoskeletal tumour patients. The recently published PARITY Trial demonstrated that extending antibiotic prophylaxis from 24 hours to 5 days does not reduce infection rates. However, questions remain about the optimal antibiotic choice and dose. Method. A 23-question multiple-choice questionnaire was designed and piloted through an iterative feedback process until the final version was agreed by all authors. Open and closed-ended questions were used to gather information on practice and Likert-type scale responses were used to grade responses to ascertain surgeon perceptions and preferences. The online survey was sent to all surgeon delegates of the 34th Annual Meeting of the European Musculo-Skeletal Oncology Society in London in October 2022. Results. Amongst 61 respondents, 43 were based in Europe and 18 outside of Europe. The majority (48/61) had been in clinical practice over 11 years. Antibiotic choice. 1st or 2nd generation cephalosporins were the first line choice practiced among 49 (80.3%) of respondents. Of these, 39 responded had a 2nd line protocol for beta-lactam allergy which was most commonly clindamycin (18), vancomycin (11) or a combination of a glycopeptide or clindamycin plus gentamicin (4). Respondents changed their first line regimen for radiotherapy in 6/61, chemotherapy in 8/61 and tumour site in 20/61. Re-dosing. Intraoperative re-dosing intervals of 1st and 2nd generation cephalosporins ranged from 2 to 8 hourly. Re-dosing for blood loss ranged from never to when 2 litres was lost. Of the 47 respondents, 24 said intraoperative re-dosing is always reliably administered. Duration. Six (10%) of 61 respondent routinely cover the intraoperative period only, whereas 30 (49%) give 24 hours, 16 (give 48 hours or longer and 8 continue until surgical drains are removed. 31 of 61 change duration depending on clinical situation. The most common reasons for changing were patient risk factors, soft tissue status and previous radiotherapy. 57/61 surgeons were aware of the PARITY Trial. When these respondents were asked whether they had changed practice based on PARITY, 12 said yes, 24 said no and 21 said they always give 24 hours anyway. Conclusions. Amongst an international cohort of orthopaedic oncology surgeons there was a wide variation in practice. Further research should focus on the optimum choice and re-dosing strategy, which have not been defined

Aim. Extraspinal osteoarticular tuberculosis (TOA-ER) is a rare form of extra-pulmonary tuberculosis. It remains a topical problem not only in underdeveloped countries but also in developed countries due to cases of immune deficiency. Through a study of 40 cases, we specify the current diagnostic aspects of TOA-ER and detail their therapeutic and evolutionary modalities. Method. The mean age of our patients was 40 years with a clear predominance of females observed (SR = 0.66). 76.31% of the cases were from a rural setting. The impairment was single-focal in 72.5%. Associated tuberculosis location was found in 59% of cases. Pain and swelling were the main clinical symptoms. Signs of tuberculous impregnation were found in less than half of the cases. The IDR was positive in 67%. All patients underwent an appropriate radiological exploration consisting of a standard x-ray (30 cases), CT (21 cases) and MRI (23 cases). technetium-99m bone scintigraphy, performed in 15 cases, detected 5 infra-clinical osteoarticular locations. 77.5% of patients had formal pathological and / or bacteriological confirmation of the diagnosis. All patients had adequate anti-tuberculosis chemotherapy with a mean duration of 18 months. 67% of patients had a surgical debridement procedure. Results. After a mean follow-up of 5 years, the outcome was favourable in 75.2% of cases. A microbiological cure at the cost of serious functional sequelae was noted in 12.8% of cases. The outcome was unfavourable with relapse observed in 4.8% of cases and death in 7.2% of cases. Conclusions. Extraspinal osteoarticular tuberculosis is a fairly common condition in our country. Its insidious clinical course is the cause of diagnostic and therapeutic delay. Its treatment is mainly medical. The surgery keeps some indications. Good therapeutic adherence and early diagnosis are the best guarantees of good therapeutic results

Sarcomas generally metastasize to the lung, while extra-pulmonary metastases are rare. However, they may occur more frequently in certain histological sub-types. Bone metastases from bone and soft tissue sarcomas account for a significant number of extra-pulmonary disease. Resection of lung metastases is widely accepted as therapeutic option to improve the survival of oligometastatic patients but there is currently no literature supporting curative surgical management of sarcoma bone metastases. Most are treated on a case-by-case basis, following multidisciplinary tumour boards recommendations. One study reported some success in controlling bone metastases using radiofrequency ablation. Our goal was to assess the impact of curative resection of bone metastases from soft tissue and bone sarcomas on oncologic outcomes. Extensive review of literature was done to evaluate epidemiological and outcomes of bone metastases in sarcoma. We examined our prospective database for all cases of bone metastases from sarcoma treated with surgical resection between 1990 and 2016. Epidemiology, pathology, metastatic status upon diagnosis, type of secondary relapses and their treatments were recorded. Overall survival and disease-free survival were calculated and compared to literature. Thirty-five patients were included (18 men, 17 women) with a mean age of 46 years. Fifteen were soft tissue (STS) and 20 were bone (BS) sarcomas. Most STS were fibrosarcomas, leiomyosarcomas or UPS while chondrosarcomas and osteosarcomas were the most frequent BS. Nine (60%) STS were grade 3, 4 (27%) grade 2 and one grade 1 (3%). Eight (23%) were metastatic upon diagnosis (6 lungs, 3 bone). Treatment of the primary tumour included wide excision with reconstruction and (neo)-adjuvant therapies as required. Margins were negative in 32 cases and micro-positive in 3 cases. Amputation occurred in 6 (17%) cases. Primary lung metastases were treated by thoracotomy and primary bone metastases by wide excision. First relapse occurred in bone in 19 cases (54%), lungs and bone in 7 cases, 5 in lungs and 4 in soft-tissues. Lung metastases were treated by thoracotomy and chemotherapy in 3 cases, chemotherapy alone in the remaining cases. Bone metastases were treated by wide resection-reconstruction in 24 cases, extensive curettage in 4. Soft tissue relapses were re-excised in 4 patients. Two amputations were required. All margins were negative except for the 4 treated by curettage. Fourteen second relapses occurred in bone, 7 were radically-excised and 2 curetted. At last follow-up, 6 patients were alive (overall survival of 17%), with a mean survival of 57 months, a median overall survival of 42.5 months and a median disease-free survival (DFS) of 17 months. Overall survival was 17%, compared to an 11% 10-year survival previously reported in metastatic sarcomas. Median disease-free survival was better in this study, compared to 10 months in literature, so as median OS (42.5 months vs 15). Three patients were alive with no evidence of disease. DFS, OS and median survival seemed to be improved by bone metastases wide excision and even if several recurrences occur, curative surgery with adjuvant therapies should be considered

Soft tissue sarcomas (STS) are rare, aggressive malignancies derived from connective tissues such as muscle and fat. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common STS in adults. UPS is an aggressive, highly metastatic sarcoma, and is resistant to chemotherapy. New therapies for UPS are desperately needed. STS have an immune desert tumour immune microenvironment (TIME), characterized by a paucity of tumour infiltrating lymphocytes and subsequent resistance to immunotherapies such as immune checkpoint inhibitors. Strategies capable of creating an immune-rich, inflamed TIME may improve immunotherapy efficacies for sarcoma. Activation of the STING (stimulator of interferon genes) receptor can induce potent innate and adaptive immune responses within immunogenic solid tumours. However, this approach has never been attempted in immune-inert sarcomas. Purpose: To determine the therapeutic anti-tumour effects of STING activation in UPS tumours. We have developed an inducible, immune-competent mouse model of UPS. We evaluated intra-tumoural injection of the murine STING receptor agonist, DMXAA, into UPS-bearing immune-competent mice. DMXAA was injected into palpable UPS tumours of the hindlimb. Tumour volume and bioluminescence imaging was recorded bi-weekly. DMXAA treated UPS tumours were also evaluated for necrosis and immune infiltration at defined time points. UPS tumours developed necrosis and lymphocytic infiltration 72 hours after DMXAA treatment. A single intra-tumoural dose of DMXAA into UPS tumours resulted in durable cure in 50% of mice. All survivors rejected a re-challenge of the UPS tumours in both the contralateral hindlimb and lung, suggesting adaptive immunity. The therapeutic effects of DMXAA were mitigated in lymphocyte deficient Rag2 knockout mice. STING therapy is a promising immunotherapeutic opportunity for immune-inert sarcomas. Our data warrants further preclinical investigations in other sarcoma models and in combination with other immune-based therapies

Dedifferentiated chondrosarcoma is a rare but highly malignant manifestation that can occasionally arise in patients with cartilage tumours. There remains uncertainty as to the best treatment for this condition and in particular whether chemotherapy may have a role in improving prognosis. Members of EMSOS were invited to contribute data on patients, tumours, treatment and outcomes of patients with dedifferentiated chondrosarcoma. Eight centres contributed data on 317 patients from 7 countries. The mean age was 59 (range 15 to 89) and the most common site was the femur (46%) followed by the pelvis (28%). 25% of patients presented with a pathological fracture and the most common high grade component identified was MFH. 23% had metastases at diagnosis and these patients had a median survival of 5 months. 30% of patients received chemotherapy, with 47% under 60 having chemotherapy compared with 10% over 60. One third of this group had neoadjuvant chemotherapy and the rest had adjuvant reatment. 88% had surgery with limb salvage in 80% of this group. The overall survival was 38% at 2 years and 24% at 5 years but in patients without metastases at diagnosis these figures were 44% and 28% respectively. Poor prognostic factors for survival were: metastases at diagnosis, amputation or no operation, local recurrence, age over 60 and pathological fracture at presentation. We were unable to identify any group in whom chemotherapy appeared to have a survival benefit. Dedifferentiated chondrosarcoma carries a dismal prognosis. Although 30% of patients received chemotherapy in this study we were not able to prove that it improved survival. Early diagnosis and complete surgical excision still offer the best prognosis for this condition

Ewing Sarcoma is the second most common primary bone sarcoma in young patients, however, there remains geographical variation in the treatment of these tumours. All patients receive neoadjuvant chemotherapy and, in most cases, the soft tissue mass diminishes significantly in volume. Controversy surrounds whether to then treat the pre- or post-chemotherapy tumour volume. Many centres advocate either (1) resection of the pre-chemotherapy volume or (2) treatment of the pre-chemotherapy volume with radiation followed by resection of the post-chemotherapy volume. These approaches increase both the short and long-term morbidity for this young patient population. In this study, we retrospectively reviewed our experience resecting only the post-chemotherapy volume without the use of (neo)adjuvant radiotherapy. A retrospective analysis of all patients with Ewing Sarcoma treated at a tertiary orthopaedic oncology centre was conducted. All patients were treated as per the consensus opinion of the multidisciplinary tumour board. Demographic and oncological variables were collected from our institutional database. Presentation and re-staging MRI scans were reviewed to evaluate pre- and post-chemotherapy tumour volumes. Operative and pathology reports were utilized to determine the extent of the surgical resection. Outcome variables included local recurrence free-, metastasis free- and overall survival. Sixty-five patients were identified in our institutional database of which 56 did not receive (neo)adjuvant radiotherapy. Median age at diagnosis was 24 years (range 13–64), 60% of patients were male and 67.6% of tumours were located in the appendicular skeleton. All 56 patients not treated with radiotherapy had resection of the post-chemotherapy tumour volume. There were 3 local recurrences in this group with a mean follow-up of 70.8 months (range 2 to 328). The median overall survival was 47 months and the mean of 70.8months. The rate of local recurrence is comparable to reports in the literature in which patients had their entire pre-chemotherapy tumour volume treated by radiation and/or surgery. Similarly, two-year overall survival for our patient cohort is not significantly different from previous studies in which more aggressive local control measures were employed. Resecting the post-chemotherapy tumour volume in Ewing Sarcoma without the use of (neo)adjuvant radiotherapy does not appear to increase the risk of local recurrence or negatively impact overall survival. This approach should be studied further as it reduces the risk of short and long-term complications for this patient population.”

Purpose. Evaluate the demographics, stages and outcomes in Myxoid (ML) and Round Cell liposarcoma (RCL). Establish the incidence of local recurrence and metastases. Outline the use and benefits of radiotherapy and chemotherapy. Provide guidelines for future management of these rare tumors. Method. Multicentric retrospective study of 421 cases of MRCLS primarily managed by multidisciplinary sarcoma teams in Canada. Data were collected in each centers through a standardized database and statistically analysed. Results. There were 247 males (59%) Age ranged from 14 to 88 years old (avg: 46 yrs) and the average follow-up was 5.9 yrs (range: 1 mo–21.3 yrs). Tumor volume averaged 745 cc (range: 1.5–14580 cc). The proximal lower limb, including the thigh, the buttock and the inguinal region, was the location in 314 cases (75%). Tumors were deep in 81%. On histology 305 patients were classified as pure myxoid liposarcoma, 87 had mixed myxoid/round cell histology (≥ 5% round cell content)and 19 were pure round cells only. AJCC staging were Ia: 44, Ib: 114, IIa: 115, IIb: 57, IIc: 2, III: 56, IV: 9, unknown: 24. Radiotherapy was given to 310 pts and chemotherapy to 26 pts as part of initial management. 419 underwent surgery (407 limb salvage and 12 amputations) Margins were R0 in 309, R1 in 94 and R2 in 15 patients. Overall 10 yrs local control rate was 92% and no differences were recorded between ML and RCL. Radiotherapy was significant in preventing local relapse (p= 0.03) but did not impact survival. Metastatic disease was recorded in 82 patients (19%). Chemotherapy did not prevent metastatic occurrence and survival was statistically worse for the chemotherapy group (p= 0.01). Location of first metastasis was often multiple (29), followed by lung or soft tissue (14 each), retroperitoneum (12) and bone (10). Thirty-four patients had bone involvement with spine involved in 27. The 5 and 10 yrs metastatic free survival were respectively 84 and 73% for ML and 73 and 49% for RCL (p= 0.003). Latest disease status were: 323 alive with no evidence of disease, 27 alive with disease, 8 alive with unknown status, 52 deadfrom tumor and 11 dead from other causes. Conclusion. Myxoid and Round cell Liposarcoma present different prognoses. Metastatic disease at the time of diagnosis is an unusual event. Local control is good but radiotherapy decreased the incidence of local relapse. The effectiveness of chemotherapy remains to be established for round cell liposarcoma. New staging stategies need to be identified to account for the unusual metastatic pattern of these sarcoma

Osteosarcoma (OS) is the most prevalent bone tumor in children and young adults. Most tumors arise from the metaphysis of the long bones and easily metastasize to the lungs. Current therapeutic strategies of osteosarcoma are routinely surgical resection and chemotherapy, which are limited to the patients suffering from metastatic recurrence. Therefore, to investigate molecular mechanisms that contribute to osteosarcoma progression is very important and may shed light on targeted therapeutic approach to improve the survival of patients with this disease. Several miRNAs have been found expressed differentially in osteosarcoma (OS), In this study, we found that miR-144 significantly suppresses osteosarcoma cell proliferation, migration andinvasion ability in vitro, and inhibited tumor growth and metastasisin vivo. The function and molecular mechanism of miR-144 in Osteosarcoma was further investigated. Tissue samples from fifty-one osteosarcoma patients were obtained from Shanghai Ninth People's Hospital. The in vitro function of miR-144 in Osteosarcoma was investigated by cell viability assay, wound healing assay, invasion assay, the molecular mechanism was identified by Biotin-coupled miRNA capture, Dual-luciferase reporter assays, etc. the in vivo function of miR-144 in osteosarcoma was confirmed by osteosarcoma animal model and miR-144−/− zebrafish model. Mechanically, we demonstrated that Ras homolog family member A (RhoA) and its pivotal downstream effector Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) were both identified as direct targets of miR-144. Moreover, the negative co-relation between downregulated miR-144 and upregulated ROCK1/RhoA was verified both in the osteosarcoma cell lines and clinical patients' specimens. Functionally, RhoA with or without ROCK1 co-overexpression resulted a rescue phenotype on the miR-144 inhibited cell growth, migration and invasion abilities, while individual overexpression of ROCK1 had no statistical significance compared with control in miR-144 transfected SAOS2 and U2-OS cells. This study demonstrates that miR-144 inhibited tumor growth and metastasis in osteosarcoma via dual-suppressing of RhoA and ROCK1, which could be a new therapeutic approach for the treatment ofosteosarcoma

The management of primary malignant bone tumors with metastatic disease at presentation remains a challenge. While surgical resection has been shown to improve overall survival among patients with non-metastatic malignant bone tumors, current evidence regarding the utility of surgery in improving overall survival in metastatic patients remains limited. The 2004–2016 National Cancer Database (NCDB) was queried using International Classification of Diseases 3rd Edition (ICD-O-3) topographical codes to identify patients with primary malignant bone tumors of the extremities (C40.0-C40.3, C40.8 and C40.9) and/or pelvis (C41.4). Patients with malignant bone tumors of the axial skeleton (head/skull, trunk and spinal column) were excluded, as these cases are not routinely encountered and/or managed by orthopaedic oncologists. Histological codes were used to categorize the tumors into the following groups - osteosarcomas, chondrosarcomas, and Ewing sarcomas. Patients who were classified as stage I, II or III, based on American Joint Commission of Cancer (AJCC) guidelines, were excluded. Only patients with metastatic disease at presentation were included in the final study sample. The study sample was divided into two distinct groups – those who underwent surgical resection of the primary tumors vs. those who did not receive any surgery of the primary tumor. Kaplan-Meier survival analysis was used to report unadjusted 5-year overall survival rates between patients who underwent surgical resection of the primary tumor, compared to those who did not. Multi-variate Cox regression analyses were used to assess whether undergoing surgical resection of the primary tumor was associated with improved overall survival, after controlling for differences in baseline demographics, tumor characteristics (grade, location, histological type and tumor size), and treatment patterns (underwent metastatectomy of distal and/or regional sites, positive vs. negative surgical margins, use of radiation therapy and/or chemotherapy). Additional sensitivity analyses, stratified by histologic type for osteosarcomas, chondrosarcomas and Ewing sarcomas, were used to assess prognostic factors for overall survival. A total of 2,288 primary malignant bone tumors (1,121 osteosarcomas, 345 chondrosarcomas, and 822 Ewing sarcomas) with metastatic disease at presentation were included – out of which 1,066 (46.0%) underwent a surgical resection of the primary site. Overall 5-year survival rates, on unadjusted Kaplan-Meier log-rank analysis, were significantly better for individuals who underwent surgical resection vs. those who did not receive any surgery (31.7% vs. 17.3%; p<0.001). After controlling for differences in baseline demographics, tumor characteristics and treatment patterns, undergoing surgical resection of primary site was associated with a reduced overall mortality (HR 0.42 [95% CI 0.36–0.49]; p<0.001). Undergoing metastectomy (HR 0.92 [95% CI 0.81–1.05]; p=0.235) was not associated with a significant improvement in overall survival. On stratified analysis, radiation therapy was associated with improved overall survival for Ewing Sarcoma (HR 0.71 [95% CI 0.57–0.88]; p=0.002), but not for osteosarcoma (HR 1.14 [95% CI 0.91–1.43]; p=0.643) or chondrosarcoma (HR 1.08 [95 % CI 0.78–1.50]; p=0.643). Chemotherapy was associated with improved overall survival for osteosarcoma (HR 0.50 [95% CI 0.39–0.64]; p<0.001) and chondrosarcoma (HR 0.62 [95% CI 0.45–0.85]; p=0.003), but not Ewing sarcoma (HR 0.79 [95% CI 0.46–1.35]; p=0.385). Surgical resection of the primary site significantly improves overall survival for primary malignant bone tumors with metastatic disease at presentation. Physicians should strongly consider surgical resection of the primary tumor, with adjunct systemic and/or radiation therapy (dependent on tumor histology), in patients presenting with metastatic disease at presentation

Background. Decisions about local treatment are important in osteosarcoma treatment. The purpose of this study was to review decisions about local treatment in one centre. Methods. This was a retrospective review of the records of all patients with high-grade extremity osteosarcoma presenting to our centre between 1997 and 2008. Particular attention was paid to local control decisions. Results. 54 patients were included, 37 were male. Median age was 18 (4.1 to 71.3 years). The anatomical location was distal femur in 33, tibia in 8, humerus in 7, ankle/foot in 3, fibula in 2 and clavicle in 1. 8 (14.8%) patients had metastases at presentation. 13 (24.1%) patients underwent primary amputation, predominantly in the early years of the series. The remaining 41 patients had limb-sparing surgery, 5 of whom had microscopically positive margins. 21 of 54 (38.8%) had >90% necrosis in the resected tumour. 3 patients had poor necrosis and positive margins. These were a 70 yo intolerant of chemotherapy, who refused amputation, developed LR and metastatic disease; a 15 yo with metastatic disease, who had a secondary amputation and metastatectomy and survived and a 43 yo who developed metastases and LR on chemotherapy. 4 further patients had local recurrence after LSS. All had poor necrosis after chemotherapy but adequate margins. All developed metastatic disease and 3 have died. Overall survival was 60%. 5-year survival without metastatic disease at presentation was 65%. Conclusion. Our series is similar to other centres. Challenges include older patients, poor response to chemotherapy and metastases

Lymph node metastasis are a rare occurrence in soft tissue sarcomas of the extremity, arising in less than 5% of patients. Few studies have evaluated the prognosis and survival of patients with a lymph node metastasis. Early reports compared lymph node involvement to lung metastasis, while others suggested a slightly better outcome. The purpose of this study was to evaluate the impact of lymph node metastasis on patient survival and to investigate the histologic and clinical features associated with lymph node involvement. A retrospective review was done of the prospectively collected soft tissue sarcoma database at our institution. Two thousand forty-five patients had surgery for soft tissue sarcoma of an extremity between January 1986 and August 2017. Included patients either presented with a synchronous lymph node metastasis or were diagnosed with a lymph node metastasis after their initial treatment. Demographic, treatment, and outcome data for patients with lymph node involvement were obtained from the clinical and radiographic records. Lymph node metastases were identified as palpable adenopathy by physical examination and were further characterized on cross-sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) scans. All cases were confirmed by pathologic examination of biopsy specimens. A pathologist with expertise in sarcoma determined the histologic type and graded tumors as 1, 2, or 3. One hundred eighteen patients with a mean age of 55.7 (SD=18.9) were included in our study. Seventy-two (61.3%) out of 119 patients were male. Thirty six patients (57.1%) had lymph node involvement at diagnosis. The mean follow-up from the date of the first surgery was 56.3 months. The most common histological diagnoses were Malignant fibrous histiocytoma (35) and liposarcoma (12). Ninety eight patients (89%) underwent surgical treatment of the lymph node metastasis while 21 (17.6%) were treated with chemotherapy and/or radiation therapy. The mean survival was 52.6 months (range 1–307). Our results suggest that patients with a lymph node metastasis have a better prognosis than previously described. Their overall survival is superior to patients diagnosed with lung metastasis. A signifant proportion of patients may expect long term survival after surgical excision of lymph node metastasis. Furthermore, our study also indicates that different histological subtypes such as liposarcoma or malignant peripheral nerve sheath tumor (MPNST) may also be responsible for lymph node metastasis. Additional studies to further improve the treatment of soft tissue sarcoma nodal metastasis are warranted

Introduction. Despite the advances in adjuvant chemotherapy and surgical techniques, the diagnosis of a bone tumour still carries with it a significant risk of mortality. This study investigates factors affecting survival, in patients treated for malignant tumours of bone using Endoprosthetic replacement (EPR). Methods. Our tertiary referral musculoskeletal tumour unit has taken referrals over 40 years. Electronic patient records have been prospectively kept on all patients seen since 1986 and data has been entered retrospectively for patients seen between 1966 and 1986. A consecutive series of 1264 patients underwent endoprosthetic reconstruction; after 158 patients were excluded, 1106 patients were left in the study group. Factors including diagnosis, size of tumour, surgical margins, percentage tumour necrosis following chemotherapy, tumour site, local recurrence, decade of reconstruction, fracture and post-operative deep infection were analysed. Results. Overall population survival was 58.4% at 5 years, 50.5% at 10 years and 44.6% at 20 years. Significant prognostic factors on cox-regression analysis included locally recurrent disease (p<0.001), metastatic disease (p<0.001), chemotherapy (p<0.001), percentage tumour necrosis after chemotherapy (p=0.001), tumour size (p<0.001), post-operative surgical margin (p<0.001), fracture (p<0.001) and post-operative deep infection (p=0.05). Univariate analysis showed proximal femoral site (p=0.01) and EPRs after 1991 (p=0.05) were significant factors. Patients diagnosed with a deep infection within 2.5 years from implantation had 63.2% 10 year survival, compared to 49.4% in the non infected group. When stratified by diagnosis this was significant in patients with myeloma (p=0.01) and a showed strong trend in those with osteosarcoma (p=0.1). Trends towards better survival with Staphylococcal infections (p=0.2) were not demonstrated with other organisms. Discussion and conclusion. Several known prognostic factors were demonstrated for malignant bone tumours but there was evidence for increased survival after deep post-operative infection. The authors feel the results of this study and other recent evidence warrant further investigation

Impaired bone healing biology secondary to soft tissue deficits and chemotherapy contribute to non-union, fracture and infection following limb salvage surgery in Osteosarcoma patients. Approved bone healing augments such as recombinant human bone morphogenetic protein-2 (rhBMP-2) have great potential to mitigate these complications. rhBMP-2 use in sarcoma surgery is limited, however, due to concerns of pro-oncogenic signalling within the tumour resection bed. To the contrary, recent pre-clinical studies demonstrate that BMP-2 may induce Osteosarcoma differentiation and limit tumour growth. Further pre-clinical studies evaluating the oncologic influences of BMP-2 in Osteosarcoma are needed. The purpose of this study is to evaluate how BMP-2 signalling affects Osteosarcoma cell proliferation and metastasis in an active tumour bed. Two Osteosarcoma cell lines (143b and SaOS-2) were assessed for proliferative capacity and invasion. 143b and SaOS-2 cells were engineered to upregulate BMP-2. In vitro proliferation was assessed using a cell viability assay, motility was assessed with a scratch wound healing assay, and degree of osteoblastic differentiation was assessed using qRT-PCR of Osteoblastic markers (CTGF, ALP, Runx-2 and Osx). For in vivo evaluation, Osteosarcoma cells were injected into the intramedullary proximal tibia of immunocompromised (NOD-SCID) mice and local tumour growth and metastases were assessed using weekly bioluminescence imaging (BLI) and tumour volume measurements for 4–6 weeks. At the experimental end point we assessed radiographic tumour burden using ex-vivo micro-CT, as well as tibial and pulmonary gross and histologic pathology. SaOS-2 was more differentiated than 143b, with increased expression of Runx-2 (p = 0.009), Osx (p = 0.004) and ALP (p = 0.035). BMP-2 upregulation did not stimulate an osteoblast differentiation response in 143b, but stimulated an increase in Osx expression in SaOS-2 (p = 0.002). BMP-2 upregulation in 143b cells resulted in increased proliferation in vitro (p = 0.014), faster in vitro wound healing (p = 0.03), significantly increased tumour volume (p = 0.001) with enhanced osteolysis detected on micro-CT, but did not affect rates of lung metastasis (67% vs. 71%, BMP-2 vs. Control). BMP-2 over-expression in SaOS-2 cells reduced in vitro proliferation when grown in partial osteogenic-differentiation media (p < 0.001), had no effect on in vitro wound healing (p = 0.28), reduced in vivo SaOS-2 tumour burden at 6 weeks (photon counts, p < 0.0001), decreased tumour-associated matrix deposition as assessed by trabecular thickness (p = 0.02), and did not affect rates of lung metastasis (0% vs. 0%). Our results indicate BMP-2 signalling incites a proliferative effect on a poorly differentiated Osteosarcoma cell line (143b), but conditionally reduces proliferative capacity and induces a partial differentiation response in a moderately-differentiated Osteosarcoma cell line (SaOS-2). This dichotomous effect may be due to the inherent ability for Osteosarcoma cells to undergo BMP-2 mediated terminal differentiation. Importantly, these results do not support the clinical application of BMP-2 in Osteosarcoma limb salvage surgery due to the potential for stimulating growth of poorly differentiated Osteosarcoma cells within the tumour bed. Additional studies assessing the effects of BMP-2 in an immune-competent mouse model are ongoing

Introduction. We conducted a retrospective study of 61 patients, suffering from osteosarcoma, who presented to the CMJAH tumour Unit between 2007 and 2011. Results. The average time to presentation to the unit, post-onset of symptoms, was 4.5 months. Most patients, 43/61 (70%), presented initially to a hospital or clinic; only 3/61patients (5%) presented first to traditional healers and 15/61 (25%) to a GP. 16 patients (26%) came from other South African provinces and 3 patients (5%) were international. 3 Patients (5%) presented with a pathological fracture. 3/61 (5%) patients were HIV positive, 8 unknown and the rest were HIV negative. A standard osteosarcoma work-up was performed. 4 patients (7%) were Enneking Stage 2A, 41 patients (67%) were Stage 2B and 16 patients (26%) presented with metastases (Stage 3). Biopsy was performed on average of 3 weeks post-presentation (delay largely due to MRI). Surgery was undertaken in 46 patients (75%), with the aim of achieving wide local resection margins: 13 (21%) limb salvage procedures and 33 (79%) limb ablations were performed. 4 patients refused further treatment. 54/57 patients (95%) underwent chemotherapy and, of these, 44 (81%) underwent a neo-adjuvant chemotherapy protocol and 2 patients (4%) received post-adjuvant chemotherapy only. 19/61 patients (31%) defaulted follow-up: of these 19 patients, 15 (79%) were amputees, 1 (5%) was a limb salvage patient and 4 (16%) were un-operated. Two patients developed local recurrence: 1 was treated with amputation & the other with further excision. Palliative Radiotherapy was administered to 2 patients. In March 2013, 41 patients were contactable. Of these, 17/41 (41%) were alive and of the surviving 17 patients, 9 (81%) were limb salvage patients and 6 (38%) were amputees. Of the 12 patients, who had initially presented with metastases, only I patient (8%) was alive. Only 1 of the 3 patients, who initially presented with pathological fracture, was traceable and alive. NO DISCLOSURES