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Osteosarcoma is a challenging disease requiring multidisciplinary management in expert centers for optimal outcome. There are no current international protocols or guidelines specific for pediatric and adolescent osteosarcoma. The European Standard Clinical Practice (ESCP) project is a collaboration between ERN PaedCan and SIOP Europe’s Clinical Trial Groups to develop approved clinical recommendations reflecting current best practice. This manuscript is a summary of the full ESCP guideline for patients with osteosarcoma. The manuscript provides evidence graded recommendations for diagnosis, staging, management, response evaluation and follow-up. The methodology as defined in the standard operating procedures of the European Society for Medical Oncology (ESMO) was applied. Experts of the Fight OsteoSarcoma Through European Research (FOSTER) consortium contributed. In summary, the ESCP provides guidance on low-grade, but has a focus on high-grade osteosarcoma. In high-grade osteosarcoma the outcomes of most recent trials for clinical subgroups (e.g., metastatic vs. non-metastatic, resectable vs. non-resectable) are discussed, for treatment-naïve as well as for recurrent/refractory disease. An overview of current evidence also highlights the need for further therapeutic development as patients with primary metastatic or recurrent/refractory high-grade osteosarcoma still have a poor prognosis. Intensified collaborative research is identified as a prerequisite to increase survival and to limit long-term toxicities.

Aim: Follow-up strategies for high-grade bone sarcomas have been optimized to facilitate early detection of local recurrence and distant metastasis. The ideology is that early detection enables early treatment presuming better survival. However, the clinical value for each individual patient remains questionable. This study aims to evaluate oncological events after initial treatment in order to assess current follow-up strategies for high-grade bone sarcomas in the Netherlands. Patients and Methods: A retrospective cohort study was conducted based on a national registry. All cases were retrieved from the Netherlands Cancer Registry. Our study consisted of 393 patients treated between 2007 and 2011 with complete follow-up data. Baseline characteristics were analysed for all entities. Local recurrence and distant metastasis was analysed along with overall survival for high-grade chondrosarcoma, high-grade osteosarcoma, Ewing sarcoma and chordoma. Results: Median follow-up was 8,3 years for high-grade chondrosarcoma, 4,9 for high-grade osteosarcoma, 3,8 for Ewing sarcoma and 7,5 for chordoma. Median time to local recurrence and distant metastasis was 1,2 years for high-grade osteosarcoma and 1,5 years for Ewing sarcoma. For high-grade osteosarcoma with localized disease at presentation, 0.09 new distant metastatic events per patient per year were seen after five years of follow-up with 11,1 patients needed to follow-up for any event. Five-year overall survival was 60,0% for high-grade chondrosarcoma, 50,0% for high-grade osteosarcoma, 45,3% for Ewing sarcoma and 71,4% for chordoma. Conclusions: This nationwide study shows a plateau in local recurrences and distant metastatic events after four years of treatment for patients with high-grade osteosarcoma and Ewing sarcoma. Due to a lack of reliable evidence however, we were not able to provide additional guidance on follow-up intervals and duration. Collaborative research with larger groups is needed in order to provide a solid scientific recommendation for follow-up in the heterogenous patient population with bone sarcoma.

Background: Local tissue and serum metal ions have been shown to be elevated in some metal-on-metal and metal-on-polyethylene joint replacements. Local elevations have been linked to adverse local tissue reactions in some patients, and systemic elevation has been less commonly implicated cardiac and neurologic issues. Using a prospective study design, we aimed to identify the changes in serum metal ion levels after hip or knee megaprosthesis reconstruction. Furthermore, we will evaluate the occurrence of adverse effects and complications, possibly linked to metal ion elevation. Methods: Fourteen consecutive patients receiving a Modular Universal Tumor Revision System megaprosthesis were enrolled. Blood samples were collected preoperatively and postoperatively to determine the serum ion concentrations of aluminum, chromium, cobalt, and silver. To evaluate the safety of the megaprostheses and the subsequently possible related (elevated) serum metal ion concentrations, all adverse effects and complications were registered until last outpatient clinic visit at the time of this study. Results: Compared to the preoperative median serum concentrations, the postoperative median serum concentrations of chromium, silver, and cobalt increased 11-fold, 62-fold, and 64-fold, respectively. The median serum concentration of aluminum increased with 16%. Elevations were primarily noted in patients with knee prostheses. Eight patients had no adverse effects or complications during the period between preoperative and postoperative blood sampling. One adverse effect directly related to the serum metal ion concentrations, namely argyria, was observed. Conclusions: This study documents significantly elevated concentrations of the metal ions, but only one adverse effect directly related to the metal ion concentrations was observed. Future studies are needed to further assess the impact of elevated metal ion levels after megaprostheses, specifically knee implants, which are metal-on-metal.

Summary: Background: Atypical cartilaginous tumour (ACT) and grade II chondrosarcoma (CS2) of long bones are respectively managed with watchful waiting or curettage and wide resection. Preoperatively, imaging diagnosis can be challenging due to interobserver variability and biopsy suffers from sample errors. The aim of this study is to determine diagnostic performance of MRI radiomics-based machine learning in differentiating ACT from CS2 of long bones. Methods: One-hundred-fifty-eight patients with surgically treated and histology-proven cartilaginous bone tumours were retrospectively included at two tertiary bone tumour centres. The training cohort consisted of 93 MRI scans from centre 1 (n=74 ACT; n=19 CS2). The external test cohort consisted of 65 MRI scans from centre 2 (n=45 ACT; n=20 CS2). Bidimensional segmentation was performed on T1-weighted MRI. Radiomic features were extracted. After dimensionality reduction and class balancing in centre 1, a machine-learning classifier (Extra Trees Classifier) was tuned on the training cohort using 10-fold cross-validation and tested on the external test cohort. In centre 2, its performance was compared with an experienced musculoskeletal oncology radiologist using McNemar's test. Findings: After tuning on the training cohort (AUC=0.88), the machine-learning classifier had 92% accuracy (60/65, AUC=0.94) in identifying the lesions in the external test cohort. Its accuracies in correctly classifying ACT and CS2 were 98% (44/45) and 80% (16/20), respectively. The radiologist had 98% accuracy (64/65) with no difference compared to the classifier (p=0.134). Interpretation: Machine learning showed high accuracy in classifying ACT and CS2 of long bones based on MRI radiomic features. Funding: ESSR Young Researchers Grant.

We present two patients with fibrous dysplasia who showed a decrease in lesional size and activity after denosumab therapy. Both patients also experienced a reduction in pain and bone turnover markers, which had not been accomplished during previous bisphosphonate therapy. These cases highlight the potential of denosumab to decrease lesional size in fibrous dysplasia. This finding has been reported in mice, but not in humans. Denosumab may be considered when bisphosphonates are not tolerated or not effective (enough), or in severe cases as neoadjuvant therapy to improve surgical possibilities and outcome. In addition, these results show that Na[18F]F PET-CT is suitable for detecting change in each fibrous dysplasia lesion distinctively.

Background: Prognostic nomograms for patients with extremity soft tissue sarcoma (eSTS) typically predict survival or the occurrence of local recurrence or distant metastasis at time of surgery. Our aim was to develop and externally validate a dynamic prognostic nomogram for overall survival in eSTS survivors for use during follow-up. Methods: All primary eSTS patients operated with curative intent between 1994 and 2013 at three European and one Canadian sarcoma centers formed the development cohort. Patients with Fédération Française des Centres de Lutte Contre le Cancer (FNCLCC) grade II and grade III eSTS operated between 2000 and 2016 at seven other European reference centers formed the external validation cohort. We used a landmark analysis approach and a multivariable Cox model to create a dynamic nomogram; the prediction window was fixed at five years. A backward procedure based on the Akaike Information Criterion was adopted for variable selection. We tested the nomogram performance in terms of calibration and discrimination. Findings: The development and validation cohorts included 3740 and 893 patients, respectively. The variables selected applying the backward procedure were patient's age, tumor size and its interaction with landmark time, tumor FNCLCC grade and its interaction with landmark time, histology, and both local recurrence and distant metastasis (as first event) indicator variables. The nomogram showed good calibration and discrimination. Harrell C indexes at different landmark times were between 0.776 (0.761–0.790) and 0.845 (0.823–0.862) in the development series and between 0.675 (0.643–0.704) and 0.810 (0.775–0.844) in the validation series. Interpretation: A new dynamic nomogram is available to predict 5-year overall survival at different times during the first three years of follow-up in patients operated for primary eSTS. This nomogram allows physicians to update the individual survival prediction during follow-up on the basis of baseline variables, time elapsed from surgery and first-event history. Keywords: Dynamic prediction, Landmark analysis, Prognostic nomogram, Sarcoma, Soft tissue sarcoma: Survivors