Zachary D. C. Burke

Patient‐reported outcome measures (PROMs) remain underutilized in musculoskeletal oncology, with only 4.9% of tumor‐focused articles incorporating them. This review synthesizes current PROM instruments—including Toronto Extremity Salvage Score, PROMIS, and emerging tools such as the Sarcoma Assessment Measure—and identifies barriers unique to this population, including psychological distress, workflow complexity, and disease heterogeneity. Future directions include flexible baseline collection, EHR‐integrated dashboards, national registry linkage, wearable technology, and AI‐driven processing to increase PROMs utilization.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite aggressive multimodal therapy, including surgery and chemotherapy with methotrexate, doxorubicin, and cisplatin (MAP), outcomes for patients with relapsed or refractory disease remain poor, with no standardized second-line regimen. We developed a clinically calibrated, temporally resolved in vitro model to examine how resistance and collateral drug responses evolve during treatment with methotrexate, doxorubicin, and cisplatin (MAP). We modeled the evolution of chemotherapy resistance in vitro by exposing an OS cell line, MG63.3, to clinically relevant cycles of MAP therapy. MAP resistance and collateral drug responses were quantified over time across five independent evolutionary replicates, and three solvent-treated replicates served as controls. We complemented this phenotypic screening with transcriptomic profiling to extract predictive biomarkers of collateral drug response that could be used to personalize second-line treatment in patients with refractory OS. MAP exposure produced progressive resistance to doxorubicin and methotrexate, whereas cisplatin sensitivity remained comparatively stable. Repeated temporal screening against 12 additional drugs and combinations revealed three broad patterns of collateral response: progressive resistance, progressive sensitivity, and non-linear or stochastic change. Etoposide resistance emerged consistently, while sensitivity developed toward palifosfamide-etoposide and gemcitabine-docetaxel. Transcriptomic profiling showed dynamic, replicate-specific evolutionary trajectories rather than a single uniform resistance state. To demonstrate one approach for how our large, paired dataset could be used to translate these findings into potentially actionable clinical tools, we extracted predictive gene expression signatures of collateral drug response. By applying a dynamic, clinically inspired model of chemotherapy resistance in OS, we generated a detailed temporal mapping of collateral drug responses that highlights potential therapeutic windows and can be used inform selection of second-line agents. This approach and the resulting dataset can ultimately support personalized medicine strategies for patients with relapsed or refractory OS.

The Area Deprivation Index (ADI) is a validated measure of neighborhood-level socioeconomic disadvantage. This study aimed to assess the association betwee

Aims: It remains unclear what factors differentiate patients who present with early rather than late pulmonary metastases after resection of a soft-tissue sarcoma, and how their outcomes differ. The purpose of this study was to compare the survival of patients with early and late sarcoma metastases in the lungs, and to compare the differences between the two groups. Methods: We carried out a retrospective review of a prospectively maintained database, between January 1992 and November 2020, for all patients with a soft-tissue sarcoma of the pelvis and limbs who developed pulmonary metastases after definitive resection. We compared patients with early and late metastatic disease, defined as presentation before or after two years, respectively. Results: A total of 584 patients developed pulmonary metastases after surgical treatment of a soft-tissue sarcoma of the limb or pelvis. Overall, 79% had metastases within two years of surgery. The median time to pulmonary metastasis was nine months (IQR 4 to 20). The five-year disease-specific survival (DSS) from presentation was significantly worse for patients who developed early pulmonary metastases compared with those with late pulmonary metastases (12.2% (95% CI 9.2 to 16.0) vs 27.5% (95% CI 19.2 to 37.7), respectively; p < 0.001). Among patients undergoing surgical excision of pulmonary metastases, the five-year DSS from presentation was significantly worse for patients who developed early pulmonary metastases (27.2% (95% CI 19.8 to 36.1) vs 48.7% (95% CI 32.8 to 64.9); p = 0.014). Multivariable analysis revealed that older age (hazard ratio (HR) 1.02 (95% CI 1.01 to 1.03); p = 0.001), larger tumour size (HR 1.1 (95% CI 1.04 to 1.13); p < 0.001), and higher tumour grade (HR 2.0 (95% CI 1.26 to 3.1); p = 0.002) were associated with an increased risk of early pulmonary metastases, whereas previous local recurrence was associated with an increased risk of late pulmonary metastases (HR 3.3 (95% CI 1.8 to 5.4); p < 0.001). Conclusion: DSS is poor after the development of pulmonary metastases from a treated limb or pelvic soft-tissue sarcoma, but survival is worse for patients who present early. Cite this article: Bone Joint J 2026;108-B(4):553–560.

A 40-year-old man presented with malignant giant cell tumor of bone of the left distal femur. Despite distal femur resection/replacement and adjuvant chemotherapy, he experienced local recurrence and lung metastases. Salvage radiation therapy was ineffective. Biopsy of the tumor showed a PD-L1 tumor proportion score of 40%. Pembrolizumab was initiated and resulted in a major partial response. However, the patient experienced radiation recall pneumonitis necessitating stoppage of pembrolizumab. The patient then experienced another local recurrence. PD-L1 blockade should be considered for MGCTB expressing PD-L1. Unfortunately, pembrolizumab was stopped, which likely allowed for tumor progression in this case.

Staphylococcus aureus bacteremia is typically treated empirically with vancomycin, with therapy later tailored based on susceptibility results. However, these tests occur before vancomycin exposure and do not account for adaptation during empiric treatment that can alter S. aureus ’ susceptibility to first-line drugs. To investigate these collateral drug responses, we experimentally evolved 18 methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations until they achieved intermediate resistance. Genomic sequencing revealed two distinct adaptive pathways characterized by mutations in the WalKR regulon, affecting cell wall metabolism, or rpsU , impacting translational stress responses. These pathways correlated with divergent collateral sensitivity profiles to first-line antibiotics. By developing a Collateral Response Score (CRS), we quantified the probability and magnitude of these responses, demonstrating that evolutionary dynamics critically influence resistance outcomes. Our findings suggest a probabilistic approach to antimicrobial therapy, advocating for rapid genomic diagnostics alongside susceptibility testing to better anticipate and respond to evolutionary changes.

Opinion Statement: Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are among the most common adult soft tissue sarcoma (STS) subtypes. Due to their high genetic complexity, heterogeneity, and lack of specific genetic alterations, no consistent molecular targets for targeted therapy have been identified for UPS and MFS. Recently, immune checkpoint inhibition (ICI) has emerged as a promising treatment modality for UPS and MFS. However, the efficacy of ICI in UPS and MFS remains far lower than in other cancers such as melanoma. Strategies to increase the efficacy of ICI, including selecting patients based on putative biomarkers and combining ICI with chemotherapy, targeted therapies, and/or radiation therapy, are currently in clinical development. In this review, we first summarize the clinical characteristics of UPS and MFS, examining the tumor microenvironment (TME) and its effect on the efficacy of ICI. We then review putative biomarkers of ICI response and highlight clinical trials testing ICI in patients with UPS and MFS. Finally, we discuss other forms of immunotherapy for UPS and MFS currently under preclinical investigation. The combination of ICI plus radiation therapy appears to have benefit for patients with localized UPS and MFS. ICI should be considered for patients with advanced or unresectable UPS and MFS, especially those with potential biomarkers of response such as tertiary lymphoid structures (TLS). However, singular biomarkers such as TLS may prove inadequate to predict ICI response; more accurate prediction will likely require a panel of biomarkers including TLS, immune cell infiltration, PD-L1 expression, and other TME components.

Background . Dedifferentiated liposarcoma (DDLPS) is an aggressive subtype of liposarcoma that can arise within an atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLs). The primary goal of treatment for DDLPS is wide-margin resection, but it remains unclear if ALT/WDLs surrounding DDLPS also necessitates wide-margin resection for optimal local control. Methods . Patients treated surgically for a biopsy showing DDLPS at a single institution were identified. Margin status for both DDLPS and ALT/WDLs were categorized into one of the following categories: wide, marginal or intralesional. All patients were categorized as either “wide throughout” or “wide on DDLPS, marginal on ALT/WDLs”. Chi-square tests were used to compare margin status and oncologic outcome. Results . Eighteen patients met the inclusion criteria for the study. Twelve patients had surgical margins wide on DDLPS/marginal on ALT/WDLs, and 6 patients had surgical margins wide throughout. Two patients with surgical margins wide on DDLPS/marginal on ALT/WDLs developed local recurrence compared with no patients with margins wide throughout ( P = .289). Six patients with surgical margins wide on DDLPS/marginal on ALT/WDLs developed metastases compared to 1 patient with margins wide throughout ( P = .289). Conclusions . Compared with patients with wide margins throughout, patients with margins wide on DDLPS/marginal on ALT/WDLs had more local recurrences, new metastases, and death from disease. While no statistically significant difference was found between subgroups for these comparisons, cohort size limits our ability to conclude that no clinical difference exists. This study forms the basis for a future, larger, multi-institutional study to improve external validity and power to identify clinically relevant differences.

Background: Despite the goal of an acceptable functional result, the surgical treatment of soft-tissue sarcoma can portend a prolonged course of recovery. More comprehensive data on the expected course of recovery following extremity sarcoma surgery are needed to help to inform physicians and patients. The purpose of the present study was to describe the typical course of functional recovery following limb-salvage resection of a soft-tissue sarcoma and to identify factors associated with a delayed postoperative course of recovery. Methods: A retrospective review of a prospectively maintained institutional database was performed for all patients undergoing surgical treatment with limb salvage of a soft-tissue sarcoma of the extremities or pelvis with at least 1 year of follow-up after the definitive surgical procedure. All patients were required to have preoperative functional outcomes recorded for either the Toronto Extremity Salvage Score (TESS) or the Musculoskeletal Tumor Society (MSTS) score and functional outcome measures at 1 year postoperatively. The primary outcome measures were time to recovery and maximal functional improvement. Results: In this study, 916 patients met inclusion criteria following surgical resection of a soft-tissue sarcoma of the extremities. The median follow-up was 74 months. Patients typically achieved a return to their baseline preoperative level of function for all functional outcome measures by 1 to 2 years and achieved maximal functional recovery by 2 years postoperatively. Older age, female sex, deep tumor location, larger tumor size, pelvic location, osseous resection, motor nerve resection, free and/or rotational soft-tissue coverage, and postoperative complications were independently associated with worse TESS and/or MSTS scores (p ≤ 0.05). Tumor recurrence was associated with worse functional outcomes scores. An analysis was performed to determine which patients had a prolonged course of recovery (i.e., were considered to still be recovering). Older age, female sex, larger tumor size, osseous resection, and motor nerve resection were associated with a delayed course of recovery (p ≤ 0.04). Complications and tumor recurrence were associated with delayed functional recovery across all domains. Conclusions: Most patients will achieve maximal recovery by 2 to 3 years following surgical resection for soft-tissue sarcoma of the extremities. Older age, female sex, larger tumor size, osseous resection, motor nerve resection, postoperative complications, and tumor recurrence portend poorer functional outcomes and a delayed course of recovery. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.