What’s New in Musculoskeletal Tumor Surgery

This past year, the musculoskeletal tumor surgery literature kept up with the rapidly increasing publication volume in the medical literature. Among the thousands of publications in our field, we highlight a chosen few in this Guest Editorial. We are excited to present remarkable collaborations and exciting innovations. Although the majority of research continues to be retrospective, unique approaches are being developed and international cohesion is apparent by the worldwide collaborations and sharing of prospective data sets. Molecular approaches to diagnosis and treatment have made incremental steps forward, and the use of machine learning in prognosis and diagnosis continues to make strides. Finally, surgical approaches to bone and soft-tissue tumors are becoming better understood through large case series. Soft-Tissue Sarcoma Prognostic Prediction Models Recent research has emphasized the crucial role of advanced diagnostic tools and methodologies in improving the prognosis and management of soft-tissue sarcomas. Marques et al. explored how magnetic resonance imaging (MRI) can predict the histological grade of soft-tissue sarcomas, suggesting that MRI features can provide valuable preoperative insights, potentially guiding treatment strategies1. Similarly, Kim et al. explored DNA methylation profiling as a means to classify histologic subtypes and grades in soft-tissue sarcomas2. Their findings indicate that this molecular approach can complement traditional histopathological evaluation, enhancing diagnostic accuracy and personalized treatment planning. Survival prediction models are also gaining attention. Yeramosu et al. developed a model to predict 5-year mortality in patients with soft-tissue sarcoma, emphasizing factors such as tumor size, patient age, and histological grade3. Kamalapathy et al. introduced a machine learning algorithm specifically for predicting 5-year survival in patients with soft-tissue leiomyosarcoma, highlighting the potential of artificial intelligence in clinical decision-making4. Additionally, Stauss et al. examined the impact of surgical resection margins on outcomes such as local recurrence, distant metastasis, and overall survival, underscoring the importance of achieving clear margins during the surgical procedure to improve patient prognosis5. Although the risk factors identified in these prediction model studies are not new, big data and the machine learning approach are important advancements. Specific Soft-Tissue Sarcoma Subtypes An increasing number of studies are approaching soft-tissue sarcoma subtypes as unique entities. In a Phase-2, international, open-label trial (SPEARHEAD-1), D’Angelo et al. investigated the efficacy of afamitresgene autoleucel in patients with advanced synovial sarcoma and myxoid round cell liposarcoma6. The study demonstrated promising results, with a notable percentage of patients experiencing tumor reduction and manageable safety profiles. This innovative therapy, which involves engineered T-cells targeting specific cancer antigens, showed potential in treating these aggressive sarcomas, offering hope for patients with limited treatment options, although improved survival was not proven. Atezolizumab, an immune checkpoint inhibitor, was evaluated for its effectiveness in treating advanced alveolar soft-part sarcoma in a study published in The New England Journal of Medicine7. The findings indicated that atezolizumab provided clinical benefits, including tumor shrinkage and prolonged progression-free survival for some patients. This study highlights the potential of immunotherapy in managing rare and difficult-to-treat sarcomas, underlining the importance of further research to optimize treatment protocols and patient selection. Additional studies have focused on other unique sarcoma subtypes and their management. Makris et al. provided insights into the natural history of undifferentiated pleomorphic sarcoma through the U.S. Sarcoma Collaborative, identifying factors influencing disease progression and outcomes8. Fujiwara et al. identified key survival factors in patients with clear cell sarcoma, emphasizing the importance of early detection and tailored treatment strategies9. Zhang et al. explored the optimal timing for reexcision in patients with synovial sarcoma, finding that immediate intervention postoperatively may improve outcomes compared with waiting for local recurrence10. Furthermore, Wahlig et al. assessed the clinical importance of bone marrow aspiration and biopsy in the initial staging of extraskeletal Ewing sarcoma, concluding that its routine use may not be necessary, thus potentially reducing patient burden without compromising diagnostic accuracy11. It is clear that a subtype-specific approach to the study and treatment of soft-tissue sarcoma will become increasingly more central to patient care. Wound Management Soft-tissue sarcoma surgery often results in wound complications. Therefore, ongoing research has focused on preventing and/or minimizing these complications. Mericli et al. introduced the Anderson SArcoma Risk of Complications (A-SARC) score, a novel tool designed to guide reconstructive decision-making in patients with extremity soft-tissue sarcoma12. This scoring system helps clinicians to determine when to opt for more complex reconstructive techniques over traditional methods by assessing the risk of complications. By considering various patient-specific factors, the A-SARC score emphasizes personalized treatment planning, ensuring that patients receive the most appropriate reconstructive strategy based on their individual risk profile. In another study, Gonzalez et al. analyzed the cost-effectiveness of wound vacuum-assisted closure temporization following tumor resection in patients with soft-tissue sarcoma13. By comparing propensity-score-matched patients, they demonstrated that vacuum-assisted closure temporization could be a cost-effective strategy, potentially reducing health-care expenses associated with prolonged hospital stays and additional surgical interventions, although vacuum-assisted closure temporization will not be necessary in all patients. Miwa et al. developed and validated a nomogram to predict the risk of surgical site infections after soft-tissue sarcoma resection14. This predictive tool allows clinicians to identify high-risk patients and implement targeted preventive measures, thereby minimizing the incidence of surgical site infections and improving postoperative outcomes. As further research clarifies the risks of wound complications and best practices for preventing wound complications, surgeons will be able to optimize surgical care and resource utilization in the management of soft-tissue sarcomas. Exploratory and Cutting-Edge Approaches Immunotherapy continues to be explored as a potential treatment approach for soft-tissue sarcoma. In a Phase-1 trial, Seo et al. investigated the combination of toll-like receptor 4 (TLR4) agonist injections with concurrent radiation therapy in patients with metastatic soft-tissue sarcoma15. The study demonstrated that this combination could be safe and potentially enhance the immune response against tumors. Meanwhile, Xu et al. conducted the ALTER-S006 trial, assessing anlotinib as a maintenance treatment for advanced soft-tissue sarcoma after chemotherapy16. The trial found that anlotinib could potentially prolong progression-free survival, offering a new therapeutic option for patients. Finally, a Phase-3 factorial trial of post-treatment surveillance for soft-tissue sarcoma, the Surveillance After Extremity Tumor Surgery (SAFETY) randomized controlled trial, completed the pilot study of 100 patients followed for 2 years with more or less intense clinical follow-up and thoracic imaging schedules17. The pilot phase confirmed the feasibility of enrollment, protocol adherence, and data quality. Full study enrollment was expected to be completed by the end of 2024. In support of the rationale for this trial, Priester et al. examined the utility of contrast-enhanced chest computed tomographic (CT) scans in the staging and surveillance of extremity sarcomas, finding that, although these scans can aid in detecting metastases, their routine use may not significantly impact patient outcomes18. The study suggested that a more selective approach to using contrast chest CT scans could optimize patient care and resource allocation. Tenosynovial Giant Cell Tumor (TGCT) Colony-stimulating factor 1 (CSF-1) inhibitors are a class of drugs designed to block the activity of CSF-1, a cytokine that regulates the production, differentiation, and function of macrophages. CSF-1 interacts with its receptor, CSF-1R (also known as CD115), which is expressed on the surface of macrophages and other cells of the mononuclear phagocyte system. By inhibiting the CSF-1/CSF-1R pathway, these drugs can reduce the number and activity of macrophages, which play a crucial role in various pathological processes. CSF-1 inhibitors have shown promise in the context of TGCTs. These inhibitors can decrease the recruitment and survival of tumor-associated macrophages (TAMs), which often promote tumor growth and suppress anti-tumor immune responses. Examples of CSF-1 inhibitors include pexidartinib and vimseltinib. The MOTION trial, conducted by Gelderblom et al., evaluated the efficacy of vimseltinib compared with placebo in patients with TGCTs through a multicenter, randomized, double-blinded, placebo-controlled Phase-3 study19. The trial demonstrated that vimseltinib significantly improved objective response rates in patients with TGCTs compared with placebo. Complementing this, van der Heijden et al. discussed the multimodal management of TGCTs, highlighting the integration of new druggable targets into treatment strategies20. These studies highlighted the evolving landscape of TGCT management, emphasizing the potential of targeted therapies. Prevention and Management of Thromboembolic Complications The patient population with musculoskeletal cancer is at high risk for thromboembolic and bleeding complications. Therefore, research into prevention and management is ongoing. LiBrizzi et al. used data from the PearlDiver database to evaluate the efficacy and safety of direct oral anticoagulants compared with low-molecular-weight heparin for venous thromboembolism prophylaxis in patients undergoing surgical resection of primary lower-extremity bone or soft-tissue sarcoma21. Their study concluded that direct oral anticoagulants are as effective as low-molecular-weight heparin in preventing venous thromboembolism in this patient population, with a similar safety profile with regard to bleeding complications. These findings suggested that direct oral anticoagulants could be a viable alternative to low-molecular-weight heparin for postoperative venous thromboembolism prophylaxis, potentially offering patients a more convenient oral administration route. In related research, Foster et al.22 performed a large, retrospective, single-center review that found the use of intravenous tranexamic acid during sarcoma resection to be associated with an increased risk of venous thromboembolism and pulmonary embolism. Despite the limitations of the retrospective study design, these findings nevertheless highlighted a critical consideration regarding the intraoperative management of patients with sarcoma—suggesting that, although tranexamic acid is effective in reducing blood loss, its potential risk of pulmonary embolism necessitates careful patient selection and monitoring. Additionally, in a secondary analysis of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) randomized controlled trial23, Sabharwal et al. investigated thromboembolism incidence and risk factors after endoprosthetic reconstruction in patients with musculoskeletal cancer24. Although relatively rare in the PARITY cohort (1.8%), thromboembolic events were more likely to occur in older patients and those receiving long-term prophylactic antibiotics. In contrast to the finding by Foster et al.22, intraoperative tranexamic acid and postoperative chemical thromboprophylaxis were not associated with a greater incidence of venous thromboembolism. International Collaboration, Consensus Work, and Data-Sharing The orthopaedic oncology community is coming together more to address and answer critical research questions in the field. An example of extraordinary collaboration is the attempt at international consensus on the diagnosis and management of chondrosarcoma and the prevention and management of surgical site infections in bone tumor reconstruction. The Birmingham Orthopaedic Oncology Consensus Meeting, organized by Jeys et al., explored the associated controversies in orthopaedic oncology25. The Birmingham Orthopaedic Oncology Consensus Meeting was held in January 2024 and aimed to establish global consensus on these issues by gathering >300 delegates from >50 countries. This meeting highlighted the ongoing debates and sought to generate consensus statements based on evidence and expert opinions from various regions. Finally, data-sharing by the PARITY trial team allowed for a greater understanding of the use of opioids in the orthopaedic oncology population. Gazendam et al. explored opioid consumption patterns and predictors of chronic opioid use in patients with musculoskeletal tumors undergoing limb-salvage surgery and endoprosthetic reconstruction26. Analyzing data from the PARITY trial revealed that 33.6% of patients consumed opioids preoperatively, dropping to 6.6% at 1 year postoperatively. Chronic opioid use was significantly associated only with surgical procedures for metastatic bone disease. Other factors such as preoperative opioid use, age, sex, operative time, reoperation rates, and country of origin were not predictive of chronic use. These findings highlight the need for specific opioid-prescribing guidelines for this patient group, as addiction and chronic use were uncommon. Bone Sarcoma Chondrosarcoma Chondrosarcoma continues to be a challenging entity, and the optimal diagnosis and management is an area of controversy. As noted above, the first-ever Birmingham Orthopaedic Oncology Consensus Meeting highlighted the most pressing issues, including the management of dedifferentiated and pelvic chondrosarcoma, the diagnostic utility of imaging modalities, and the management of atypical cartilaginous tumors25. This meeting of >300 specialists from >50 countries represented an important step forward in the understanding of this challenging disease. Recent literature on differentiating among atypical cartilaginous tumors has focused on utilized imaging modalities to create predictive models. Gitto et al. created a radiomics-based machine learning model utilizing cross-sectional imaging and radiographs to accurately differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma of the extremities27. Gundavda et al. developed a 9-parameter radiographic aggressiveness score utilizing radiographs and MRI to predict the grade of primary chondrosarcomas in the long bones28 The management of atypical cartilaginous tumors has also been controversial, with some groups advocating for wide resection, others for intralesional treatments, and still others for radiographic surveillance. The Leiden group reported on their experience with active radiographic surveillance for atypical cartilaginous tumors and demonstrated its safety in both the short and intermediate terms, with no malignant progression in 117 patients29. There has been an interest in the presence and implications of isocitrate dehydrogenase (IDH) mutations in patients with cartilaginous lesions. Trovarelli et al. found that the presence of IDH mutations was a negative prognostic factor in patients with chondrosarcoma30. Rey et al. examined the impact of IDH mutations in the preclinical setting and reported that, in cell lines with IDH2 mutations, enasidenib demonstrated profound antitumor effects31, although translation to clinical practice is far from ensured. Extremity Reconstruction There has been a renewed interest in the use of biologic reconstruction following extremity bone sarcoma resection. Bozzo et al. presented a prospective cohort analysis on the surgical, functional, and oncologic outcomes of distraction osteogenesis following bone sarcoma resection. They demonstrated that all patients achieved full bone-healing and independent at a of et al. reported on the outcomes of an reconstruction for short They found that reconstruction was associated with with no in et evaluated the efficacy of for patients with sarcoma. They demonstrated a reconstruction and utilizing the for patients or older patients with to be a for et reported on their experience utilizing for reconstruction following resection. They concluded that is a viable reconstruction option with an risk of postoperative complications including and et al. examined the utility of a reconstruction in combination with an in patients with a bone The use of a reconstruction allowed for and compared with reconstruction with an and Finally, et al. reported on their experience of utilizing for reconstruction and demonstrated outcomes and relatively is important to that these studies were retrospective in and to reconstruction continues to be a in limb-salvage after resection. et al. utilized the PARITY data to evaluate the rates and of early reoperation following lower-extremity endoprosthetic reconstruction. They demonstrated a reoperation of with the most of reoperation being and/or wound et al. reported on the Oncology experience with complications following They demonstrated that the most complications were at and rates at et al. utilized the PARITY trial data to and in lower-extremity endoprosthetic reconstruction. They demonstrated that was no in or rates between the 2 suggesting that both are viable in the appropriate patient et al. performed a single-center review of the utility of endoprosthetic reconstruction and found that function was associated with in of Finally, et al. compared outcomes of and patients undergoing lower-extremity endoprosthetic reconstruction and concluded that patients better outcomes at all postoperative although both groups showed similar from to 1 year of the most challenging clinical with high rates and postoperative et al. provided results of the from a They evaluated patients tumor resection and reconstruction and demonstrated a reoperation of most patients their primary and the concluded that this a viable reconstruction Zhang et al. presented an alternative reconstruction following tumor resection, utilizing a with using or They found that of patients were able to with by 2 et al. demonstrated that, of the of resection or was an independent risk factor for wound complications following pelvic sarcoma et al. demonstrated the learning associated with pelvic sarcoma They demonstrated a the utilization of or and team in rates of blood and local The role of reconstruction following sarcoma resection continues to be an area of controversy. et al. evaluated the role of reconstruction following resection at 2 They demonstrated that reconstruction was associated with blood and more with no in when compared with patients not a reconstruction. continues to be the of postoperative complications in patients undergoing a surgical procedure for a malignant bone tumor and was a of the Birmingham Orthopaedic Oncology Consensus This meeting highlighted the need for with to the surgical treatment for and the need to better the effectiveness of treatment used to the unique found in patients with number of PARITY trial secondary provided valuable insights into the predictors and impact of surgical site infections following lower-extremity endoprosthetic et al. demonstrated that operative was an independent risk factor for and that a prolonged of postoperative not the risk of in this high-risk LiBrizzi et al. demonstrated that prolonged was associated with following endoprosthetic the use of wound therapy not impact et al. highlighted the of infections following endoprosthetic with only of patients with a surgical site of the Finally, et al. the that postoperative may a survival in patients with finding that was associated with increased disease progression in the of patients with at an diagnosis in patients with bone sarcoma is as that patients receive and care. et al. analyzed international biopsy and their impact on surgical outcomes in patients with lower-extremity bone sarcoma and demonstrated that are more are more in the and Despite operative and more with no in rates or oncologic outcomes were central often has radiographic and pathological features that other bone its diagnosis and et al. analyzed patients with central that diagnosis was more with and that surgical to although local and distant were associated with resection is used to bone tumors with the although often results in outcomes. et al. evaluated the diagnostic accuracy of MRI in predicting in high-grade sarcoma finding that, although MRI can imaging findings such as with clinical such as disease in the or pathological diagnostic Bone Recent research in metastatic bone disease is our understanding and management of this complex in the and Management The Tumor with the of the of Orthopaedic developed a for managing metastatic There was evidence that the of may provide in and In patients to the was in to decrease and improve of These findings were by et al., performed a retrospective review and found that reconstruction in the setting of metastatic bone disease allowed for better of and less the findings of these retrospective studies and reconstruction be on a in patients with metastatic bone disease. studies examined the optimal surgical management of in the comparing outcomes for bone compared with bone et al. conducted a retrospective study on patients between and They found that patients with a a survival of significantly the for those with aggressive surgical resection of to a survival of compared with for less literature that and reconstruction can improve survival, for patients with cell with a bone the of such aggressive surgical approaches for other cancer such as and cancer metastases, studies suggested that aggressive surgical treatment of a can enhance patient survival, although the evidence by cancer Models Recent research in predictive models for extremity metastatic bone disease has made notable as by study conducted in compared the of survival prediction models among patients undergoing surgery for bone of the The study found that the Oncology model the its to predict survival et al. evaluated the effectiveness of the in predicting postoperative following of in patients with The other in predicting underscoring its in risk for surgical outcomes in this patient population. Furthermore, an international analysis of following treatment for metastatic bone disease revealed in survival over various cancer This highlights the evolving landscape of treatment by in both surgical techniques and medical the has focused on enhancing predictive the algorithm et al. validated its to predict survival in patients, and accuracy of survival rates of study investigated the with data by surgical from a cohort and found that, although the performed with up to without crucial factors such as and An tool was developed to these data to support more clinical for patients with metastasis, when surgical are

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