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Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma.In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy.Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response.Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Thromboelastography (TEG) is a point-of-care venipuncture test that measures the elasticity and strength of a clot formed from a patient's blood, providing a more comprehensive analysis of a patient's coagulation status than conventional measures of coagulation. TEG includes four primary markers: R-time, which measures the time to clot initiation and is a proxy for platelet function; K-value, which measures the time for said clot to reach an amplitude of 20 mm and is a proxy for fibrin cross-linking; maximum amplitude (MA), which measures the clot's maximum amplitude and is a proxy for platelet aggregation; and LY30, which measures the percentage of clot lysis 30 minutes after reaching the MA and is a proxy for fibrinolysis. Analysis of TEG-derived coagulation profiles may help surgeons identify patient-related and disease-related factors associated with hypercoagulability. TEG-derived coagulation profiles of patients with musculoskeletal oncology conditions have yet to be characterized.(1) What TEG coagulation profile markers are most frequently aberrant in patients with musculoskeletal oncology conditions presenting for surgery? (2) Among patients with musculoskeletal oncology conditions presenting for surgery, what factors are more common in those with TEG-defined hypercoagulability? (3) Do patients with musculoskeletal oncology conditions with preoperative TEG-defined hypercoagulability have a higher postoperative incidence of clinically symptomatic venous thromboembolism (VTE) than those with a normal TEG profile?In this retrospective, pilot study, we analyzed preoperatively drawn TEG assays on 52 patients with either primary bone sarcoma, soft tissue sarcoma, or metastatic disease to bone who were scheduled to undergo either tumor resection or nail stabilization. Between January 2020 and December 2021, our orthopaedic oncology service treated 410 patients in total. Of these, 13% (53 of 410 patients) had preoperatively drawn TEG assays. TEG assays were collected preincision as part of a division initiative to integrate the assay into a clinical care protocol for patients with primary bone or soft tissue sarcoma or metastatic disease to bone. Unfortunately, failures to adequately communicate this to our anesthesia colleagues on a consistent basis resulted in a low overall rate of assay draws from eligible patients. One patient on therapeutic anticoagulation preoperatively for the treatment of active VTE was excluded, leaving 52 patients eligible for analysis. We did not exclude patients taking prophylactic antiplatelet therapy preoperatively. All patients were followed for a minimum of 6 weeks postoperatively. We analyzed factors (age, sex, tumor location, presence of metastases, and soft tissue versus bony disease) in reference to hypercoagulability, defined as a TEG result indicating supranormal clot formation (for example, reduced R-time, reduced K-value, or increased MA). Patients with clinical concern for deep vein thrombosis (DVT) (typically painful swelling of the affected extremity) or pulmonary embolism (typically by dyspnea, tachycardia, and/or chest pain) underwent duplex ultrasonography or chest CT angiography, respectively, to confirm the diagnosis. Categorical variables were analyzed via a Pearson chi-square test and continuous variables were analyzed via t-test, with significance defined at α = 0.05.Overall, 60% (31 of 52) of patients had an abnormal preoperative TEG result. All abnormal TEG assay results demonstrated markers of hypercoagulability. The most frequent aberration was a reduced K-value (40% [21 of 52] of patients), followed by reduced R-time (35% [18 of 52] of patients) and increased MA (17% [9 of 52] of patients). The mean ± SD TEG markers were R-time: 4.3 ± 1.0, K-value: 1.2 ± 0.4, MA: 66.9 ± 7.7, and LY30: 1.0 ± 1.2. There was no association between hypercoagulability and tumor location or metastatic stage. The mean age of patients with TEG-defined hypercoagulability was higher than those with a normal TEG profile (44 ± 23 years versus 59 ± 17 years, mean difference 15 [95% confidence interval (CI) 4 to 26]; p = 0.01). In addition, female patients were more likely than male patients to demonstrate TEG-defined hypercoagulability (75% [18 of 24] of female patients versus 46% [13 of 28] of male patients, OR 3.5 [95% CI 1 to 11]; p = 0.04) as were those with soft tissue disease (as opposed to bony) (77% [20 of 26] of patients with soft tissue versus 42% [11 of 26] of patients with bony disease, OR 4.6 [95% CI 1 to 15]; p = 0.01). Postoperatively, symptomatic DVT developed in 10% (5 of 52; four proximal DVTs, one distal DVT) of patients, and no patients developed symptomatic pulmonary embolism. Patients with preoperative TEG-defined hypercoagulability were more likely to be diagnosed with symptomatic postoperative DVT than patients with normal TEG profiles (16% [5 of 31] of patients with TEG-defined hypercoagulability versus 0% [0 of 21] of patients with normal TEG profiles; p = 0.05). No patients with normal preoperative TEG profiles had clinically symptomatic VTE.Patients with musculoskeletal tumors are at high risk of hypercoagulability as determined by TEG. Patients who were older, female, and had soft tissue disease (as opposed to bony) were more likely to demonstrate TEG-defined hypercoagulability in our cohort. The postoperative VTE incidence was higher among patients with preoperative TEG-defined hypercoagulability. The findings in this pilot study warrant further investigation, perhaps through multicenter collaboration that can provide a sufficient cohort to power a robust, multivariable analysis, better characterizing patient and disease risk factors for hypercoagulability. Patients with TEG-defined hypercoagulability may warrant a higher index of suspicion for VTE and careful thought regarding their chemoprophylaxis regimen. Future work may also evaluate the effectiveness of TEG-guided chemoprophylaxis, as results of the assay may inform selection of antiplatelet versus anticoagulant agent.Level III, therapeutic study.

INTRODUCTION: The COVID-19 pandemic has highlighted significant racial and age-related health disparities. In response to pandemic-related restrictions, orthopedic surgery departments have expanded telemedicine use. We analyzed data from a tertiary care institute during the pandemic to understand potential racial and age-based disparities in access to care and telemedicine utilization. MATERIALS AND METHODS: Data on patient race and age, and numbers of telemedicine visits, in-person office visits, and types of telemedicine were extracted for time periods during and preceding the pandemic. We calculated odds ratios for visit occurrence and type across race and age groups. RESULTS: Patients ages 27–54 were 1.3 (95% confidence interval [CI] 1.1–1.4, p < 0.01) and 1.2 (95% CI 1.0–1.3, p < 0.05) times more likely to be seen than patients

Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES.

In the management of symptomatic bone metastases, current practice guidelines do not provide clear methodology for selecting palliative radiotherapy (RT) regimens based on specific patient and disease features. Decision support aids may offer an effective means for translating the complex data needed to render individualised treatment decisions, yet no such tools are available for use in this setting. Thus, we describe the development of the Bone Metastases Ensemble Trees for Survival-Decision Support Platform (BMETS-DSP), which aims to optimise selection of evidence-based, individualised palliative RT regimens.The Ottawa Decision Support Framework was used as the theoretical basis for development of BMETS-DSP. First, we utilised stakeholder input and review of the literature to assess determinants underlying the provider decision. Based on this assessment and iterative stakeholder feedback, we developed the web-based, provider-facing BMETS-DSP. Consistent with the underlying theoretical framework, our design also included assessment of decision quality using the International Patient Decision Aids Standards (IPDAS) certification checklist.Stakeholder input and review of 54 evidence-based publications identified the following determinants of the provider decision: estimated prognosis, characteristics of the target symptomatic lesion and the primary cancer type, consideration of alternative interventions, access to patient-specific recommendations, and patient preferences. Based on these determinants, we developed the BMETS-DSP that (1) collects patient-specific data, (2) displays an individualised predicted survival curve, and (3) provides case-specific, evidence-based recommendations regarding RT, open surgery, systemic therapy, and hospice referral to aid in the decision-making process. The finalised tool met IPDAS quality requirements. Preliminary results of a pilot assessment suggest impact of clinical outcomes.We describe the successful development of a provider-facing decision support platform to aid in the provision of palliative RT in better alignment with patient and disease features. Impact of the BMETS-DSP on decision outcomes will be further assessed in a randomised, controlled study.

Introduction Bone cement implantation syndrome (BCIS) occurs during and after cementation of implants and is associated with hypotension, hypoxia, and cardiovascular collapse. In this study, we aimed to identify risk factors and potential mitigating factors of BCIS in the oncologic adult cohort undergoing cemented arthroplasty. Methods We retrospectively reviewed oncologic patients aged 18 years or older who underwent cemented arthroplasty of either the hip or knee from 2015 to 2020. All implants were stemmed. We classified BCIS into three separate categories: (1) grade 1: intraoperative moderate hypoxia ( 20%; (2) grade 2: intraoperative severe hypoxia or drop in systolic blood pressure >40%; and (3) grade 3: cardiovascular collapse requiring cardiopulmonary resuscitation. Demographics, primary malignancy diagnosis, intraoperative factors including cement timing, development of BCIS, 30-day postoperative outcomes, and mortality up to 2 years postoperatively were evaluated. Bivariate analyses and multivariate logistic regression were performed. Results Sixty-seven patients met inclusion criteria. Of these, 31 patients (46%) developed BCIS. No difference was found in age (65.5 versus 60.9 years; P = 0.15) or body mass index (28.8 kg/m2 versus 29.3 kg/m2; P = 0.76), comorbidities, intraoperative factors, or postoperative surgical outcomes between those who developed BCIS and those who did not (all; P > 0.05). An association with the type of anesthesia administered and development of BCIS in patients receiving general anesthesia alone (17/24 patients, 71%), neuraxial and general (4/15 patients, 27%), and regional and general anesthesia (10/28 patients 36%, P = 0.01) was found. Compared With neuraxial and regional anesthesia, general anesthesia alone had 5.8 (P = 0.007) and 4.5 times (P = 0.006) greater odds of developing BCIS, respectively. No differences were noted in rates of BCIS between regional and neuraxial anesthesia (P = 0.81). Discussion Addition of regional or neuraxial anesthesia may be protective in reducing development of BCIS in the orthopaedic oncologic cohort undergoing hip and knee arthroplasty. Level of evidence III.

PURPOSE Benign, intermediate-grade and malignant tumors sometimes have overlapping imaging and clinical characteristics. The purpose of this study was to evaluate the added value of contrast-enhanced sequences (dynamic contrast enhancement (DCE)), diffusion-weighted imaging (DWI), and chemical shift imaging (CSI) to noncontrast MRI sequences for the characterization of indeterminate lipomatous tumors. MATERIALS AND METHODS Thirty-two consecutive patients with histologically proven peripheral lipomatous tumors were retrospectively evaluated. Two musculoskeletal radiologists recorded the MRI features in three sessions: (1) with noncontrast T1-weighted and fluid-sensitive sequences; (2) with addition of static pre- and post-contrast 3D volumetric T1-weighted sequences; and (3) with addition of DCE, DWI, and CSI. After each session, readers recorded a diagnosis (benign, intermediate/atypical lipomatous tumor (ALT), or malignant/dedifferentiated liposarcoma (DDL)). Categorical imaging features (presence of septations, nodules, contrast enhancement) and quantitative metrics (apparent diffusion coefficient values, CSI signal loss) were recorded. RESULTS For 32 tumors, the diagnostic accuracy of both readers did not improve with the addition of contrast-enhanced sequences, DWI, or CSI (53% (17/32) session 1; 50% (16/30) session 2; 53% (17/32) session 3). Noncontrast features, including thick septations (p = 0.025) and nodules ≥ 1 cm (p

Proximal femur anatomy and bone mineral density vary widely among individuals, precluding the use of one predefined finite element model to determine the stress field for all proximal femurs. This variability poses a challenge in current prosthetic hip design approach. Given the numerous options for generating computed tomography–based finite element models, selecting the best methods for defining the mechanical behavior of the proximal femur is difficult. In this study, a combination of computational and experimental approaches was used to explore the susceptibility of the predicted stress field of the proximal femur to different combinations of density-elasticity relationships, element type, element size, and calibration error. Our results suggest that finite element models with first-order voxelized elements generated by the Keyak and Falkinstein density-elasticity relationship or quadratic tetrahedral elements generated by the Morgan density-elasticity relationship lead to accurate estimations of the mechanical behavior of human femurs. Other combinations of element size, element type, and mathematical relationships produce less accurate results, especially in the cortical bone of the femoral neck and calcar region. The voxelized model was more susceptible to variation of element size and density-elasticity relationships than finite element models with quadratic tetrahedral elements. Regardless of element type, the stress fields predicted by the Keyak and Falkinstein and the Morgan relationships were the most robust to calibration error when deriving material density from computed tomography–generated Hounsfield data. These results provide insight into implementation of a robust platform for designing patient-specific implants capable of maintaining or modifying the stress in bones.

Background: Chordomas are malignant tumors originating from embryonic notochord remnants. Wide resection is challenging due to lack of intraoperative visualization, leading to unacceptably high recurrence rates. Known techniques using five-aminolevulinic acid (5-ALA) for tumor paint and photodynamic therapy (PDT) may improve outcomes but have not been well described for chordomas. The purpose of this study was to analyze chordoma cell response to 5-ALA tumor paint and PDT in vitro. Methods: Tumor Paint: Experiment 1: Human chordoma cells (MUG-Chor1) co-cultured with green fluorescence protein (GFP) rat adipose derived stromal cells (ADS) were observed 5 hours after 5-ALA exposure using emission filters showing GFP cells as green and 5-ALA positive cells as red. Experiment 2: GFP-ADS and MUG-Chor1 micromass pellets were co-cultured and observed 5 hours after 5-ALA exposure. Experiment 3: co-cultured human ADS and MUG-Chor1 cells were observed 5 hours after 5-ALA exposure. Photodynamic Therapy: MUG-Chor1 cells that had been exposed to 3 hours of 5-ALA were visualized at 10× with 405-nm excitation and emission at 603-738-nm. Time-lapse images of live cells were captured every second for 15 minutes and then visualized sequentially at 50× speed. Results: Tumor Paint: In the first experiment, chordoma cells displayed minimal red fluorescence while GFP-ADS cells appeared to fluoresce expectedly green. In the second experiment, chordoma cells fluoresced brightly red. As a micromass, the distinction between chordoma cells and GFP-ADS cells was clearly seen. The third experiment showed strong red fluorescence in high cellular density areas, yet minimal fluorescence in low cellular density areas. PDT: Initially, chordoma cells fluoresced red in response to the 405-nm excitation laser exposure. As time progressed, increased intracellular swelling occurred with concomitant rapid formation of multiple vesicles exiting from the cellular membrane. Conclusions: The results of these experiments demonstrate the effective in vitro application of 5-ALA tumor paint and PDT on chordoma cells. This will be the first time this phenomenon is documented visually using time-lapse photography for this tumor subtype, further validating prior research in this field. 5-ALA, with its double-edged applications of selective tumor identification and kill may lead to transformative change in the management of soft tissue sarcomas.

BACKGROUND: Checkpoint inhibitors and receptor tyrosine kinase inhibitors (RTKIs) have changed the standard of care for metastatic renal cell carcinoma (mRCC). Anecdotal evidence suggests these therapies may be less effective for treating bone than soft-tissue metastases. PURPOSE: We performed a retrospective review evaluating the relative clinical responses in soft-tissue and bone metastases in patients undergoing therapy using RTKIs and anti-programmed death-1 (PD-1) agents for mRCC. METHODS: Of the 2,212 patients in our institutional cancer registry with renal cell carcinoma (1997–2017), 68 (82 disease courses) were identified with measurable bone and soft-tissue metastases treated with RTKIs and/or PD-1s. Extent of metastasis was quantified at the time of therapy initiation (baseline) and at 3 months, 6 months, and 1 year. Changes in disease status were categorized as complete response, partial response, stable, mixed, or progression of disease according to RECIST v1.1 and MD Anderson criteria. These categories were further organized into “response to treatment” or “evidence of progression” to generate a generalized linear effects model with soft-tissue response as the independent variable and bone response as the dependent variable. Alpha = 0.05. RESULTS: Soft-tissue response correlated with bone response at 3 months (76 disease courses, p = 0.005) and 6 months (48 disease courses, p = 0.017). Of the patients with controlled soft-tissue disease, only 14 (19%) and 15 (32%) had progression in bone at 3 and 6 months, respectively. CONCLUSION: Contrary to anecdotal reports, osseous metastases do not appear to respond worse than soft-tissue metastases to treatment with these agents.

Background The overall rate of hip fractures not identified on radiographs but that require surgery (ie, surgical hip fractures) remains unclear in elderly patients who are suspected to have such fractures based on clinical findings. Moreover, the importance of advanced imaging in these patients has not been comprehensively assessed. Purpose To estimate the frequency of radiographically occult hip fracture in elderly patients, to define the higher-risk subpopulation, and to determine the diagnostic performance of CT and bone scanning in the detection of occult fractures by using MRI as the reference standard. Materials and Methods A literature search was performed to identify English-language observational studies published from inception to September 27, 2018. Studies were included if patients were clinically suspected to have hip fracture but there was no radiographic evidence of surgical hip fracture (including absence of any definite fracture or only presence of isolated greater trochanter [GT] fracture). The rate of surgical hip fracture was reported in each study in which MRI was used as the reference standard. The pooled rate of occult fracture, diagnostic performance of CT and bone scanning, and strength of evidence (SOE) were assessed. Results Thirty-five studies were identified (2992 patients; mean age, 76.8 years ± 6.0 [standard deviation]; 66% female). The frequency of radiographically occult surgical hip fracture was 39% (1110 of 2835 patients; 95% confidence interval [CI]: 35%, 43%) in studies of patients with no definite radiographic fracture and 92% (134 of 157 patients; 95% CI: 83%, 98%) in studies of patients with radiographic evidence of isolated GT fracture (moderate SOE). The frequency of occult fracture was higher in patients aged at least 80 years (44%, 529 of 1184), those with an equivocal radiographic report (58%, 71 of 126), and those with a history of trauma (41%, 977 of 2370) (moderate SOE). CT and bone scanning yielded comparable diagnostic performance in the detection of radiographically occult hip fracture (

Chondroblastoma is a rare benign tumor of immature cartilage cells that generally occurs in an epiphyseal location of skeletally immature individuals. However, a few studies have reported cases in older patients. The purpose of this study was to evaluate the clinical, radiographic, and pathologic features of chondroblastoma in an adult population. The pathology archives of our institution were searched for cases of chondroblastoma diagnosed in patients ≥25 years of age. Of 14 patients identified, 8 were male and 6 were female with a median age of 34 years (range = 29-54 years). Most lesions occurred in short bones of hands and feet (N = 7, 50%), followed by the long tubular bones (N = 4, 28%). All demonstrated typical histologic features of chondroblastoma, but more extensive calcification, necrosis, and degenerative changes were also seen. At follow-up (median = 73.5 months), 2 patients (17%) had local recurrence. None had metastasis. In summary, chondroblastoma in adults tends to involve the short bones of the hands and feet and demonstrate histologic changes associated with long-standing growth of a benign tumor.

Soft-tissue masses on the anterior ankle result from a broad range of underlying processes, often presenting a diagnostic challenge. Appropriate treatment of these tumors can be determined by using a combination of patient history, interpretation of pathologic findings, physical examination, and radiographic appearance. We present a case of an exceptionally rare malignant cutaneous adnexal tumor, highlighting the importance of adherence to fundamental biopsy principles for diagnosing and managing musculoskeletal lesions.

Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.

Surgical principles and techniques used during primary sarcoma excision focus on acquiring negative margins, reducing the risk of local recurrence, and minimizing contamination. These principles and techniques within orthopaedic oncology are not well documented in the literature. No standardized surgical hand-off or approach to education across disciplines on orthopaedic oncology principles and techniques has been published. Currently, education on intraoperative approaches is passed down by oral tradition.Our objective was to survey members of the Musculoskeletal Tumor Society (MSTS) to identify their core principles and practices in orthopaedic oncology. We aimed to 1) provide descriptive analyses of surgeon technique patterns; 2) determine correlations between individual practice patterns; and 3) identify distinct clusters of surgeons on the basis of common practice tendencies.A web-based, 16-question survey regarding orthopaedic oncology intraoperative principles and techniques was distributed online to all 349 members of the MSTS in 2021. There were 137 (39%) unique respondents, all of whom completed the entire survey. The 16 survey questions were grouped into 4 key aspects of sarcoma excision: pre-incision, exposure of the mass, delivery of the mass, and closure. The questions inquired about respondent preference on draping, back table setup, instrument use, and intraoperative decision making. These questions were selected on the basis of existing reports, as well as the senior author's experience. We analyzed the responses using 3 methods: 1) descriptive statistics, 2) correlations between question responses, and 3) clustering analysis. We used an artificial intelligence-based clustering algorithm to cluster respondents according to their practice patterns. The results of our correlation analyses are reported as Spearman's rho (ρ) correlation coefficients.Most respondents (mean, 71%; standard deviation, 22%) reported using the described surgical techniques "most of the time" or "in all cases." A strong positive correlation was found between respondents who answered "yes" to both of the following questions: "Do you change your surgical gloves after passing off the tumor specimen?" and "Does your entire surgical team change their gloves after passing off the tumor specimen?" (ρ = 0.88). A moderate positive correlation was found between those who answered "yes" to both of the following questions: "Do you change your surgical gloves after passing off the tumor specimen (i.e., prior to closure)?" and "Do you use new and/or unused surgical instruments for the final closure?" (ρ = 0.60). The cluster analysis identified 3 distinct clusters of respondents. The conservative technique cluster (N = 42) was more likely to answer "yes" to 9 of the 10 questions regarding incision management, consultant team communication, gloving, and instrument use, whereas the permissive technique cluster (N = 41) was more likely to answer "no" to questions regarding gloving, draping, and instrument use.Our findings indicate that most respondents perform the surveyed techniques, and there is homogeneity in the practice patterns of members of the MSTS; however, we identified distinct clusters of respondents who were significantly more likely to perform certain techniques. These results support establishing a standardized set of intraoperative techniques and formal surgical education regarding intraoperative principles and techniques in orthopaedic oncology.

BACKGROUND: PATHFx is a clinical decision-support tool based on machine learning capable of estimating the likelihood of survival after surgery for patients with skeletal metastases. The applicability of any machine-learning tool depends not only on successful external validation in unique patient populations but also on remaining relevant as more effective systemic treatments are introduced. With advancements in the treatment of metastatic disease, it is our responsibility to patients to ensure clinical support tools remain contemporary and accurate. QUESTION/PURPOSES: Therefore, we sought to (1) generate updated PATHFx models using recent data from patients treated at one large, urban tertiary referral center and (2) externally validate the models using two contemporary patient populations treated either surgically or nonsurgically with external-beam radiotherapy alone for symptomatic skeletal metastases for symptomatic lesions. METHODS: After obtaining institutional review board approval, we collected data on 208 patients undergoing surgical treatment for pathologic fractures at Memorial Sloan Kettering Cancer Center between 2015 and 2018. These data were combined with the original PATHFx training set (n = 189) to create the final training set (n = 397). We then created six Bayesian belief networks designed to estimate the likelihood of 1-month, 3-month, 6-month, 12-month, 18-month, and 24-month survival after treatment. Bayesian belief analysis is a statistical method that allows data-driven learning to arise from conditional probabilities by exploring relationships between variables to estimate the likelihood of an outcome using observed data. For external validation, we extracted the records of patients treated between 2016 and 2018 from the International Bone Metastasis Registry and records of patients treated nonoperatively with external-beam radiation therapy for symptomatic skeletal metastases from 2012 to 2016 using the Military Health System Data Repository (radiotherapy-only group). From each record, we collected the date of treatment, laboratory values at the time of treatment initiation, demographic data, details of diagnosis, and the date of death. All records reported sufficient follow-up to establish survival (yes/no) at 24-months after treatment. For external validation, we applied the data from each record to the new PATHFx models. We assessed calibration (calibration plots), accuracy (Brier score), discriminatory ability (area under the receiver operating characteristic curve [AUC]). RESULTS: The updated PATHFx version 3.0 models successfully classified survival at each time interval in both external validation sets and demonstrated appropriate discriminatory ability and model calibration. The Bayesian models were reasonably calibrated to the Memorial Sloan Kettering Cancer Center training set. External validation with 197 records from the International Bone Metastasis Registry and 192 records from the Military Health System Data Repository for analysis found Brier scores that were all less than 0.20, with upper bounds of the 95% confidence intervals all less than 0.25, both for the radiotherapy-only and International Bone Metastasis Registry groups. Additionally, AUC estimates were all greater than 0.70, with lower bounds of the 95% CI all greater than 0.68, except for the 1-month radiotherapy-only group. To complete external validation, decision curve analysis demonstrated clinical utility. This means it was better to use the PATHFx models when compared to the default assumption that all or no patients would survive at all time periods except for the 1-month models. We believe the favorable Brier scores (< 0.20) as well as DCA indicate these models are suitable for clinical use. CONCLUSIONS: We successfully updated PATHFx using contemporary data from patients undergoing either surgical or nonsurgical treatment for symptomatic skeletal metastases. These models have been incorporated for clinical use on PATHFx version 3.0 (https://www.pathfx.org). Clinically, external validation suggests it is better to use PATHFx version 3.0 for all time periods except when deciding whether to give radiotherapy to patients with the life expectancy of less than 1 month. This is partly because most patients survived 1-month after treatment. With the advancement of medical technology in treatment and diagnosis for patients with metastatic bone disease, part of our fiduciary responsibility is to the main current clinical support tools. LEVEL OF EVIDENCE: Level III, therapeutic study.

Purpose The purpose of this study was to characterize and evaluate the clinical significance of volume changes of soft tissue sarcomas during radiation therapy (RT), prior to definitive surgical resection. Materials and methods Patients with extremity or pelvis soft tissue sarcomas treated at our institution from 2013 to 2016 with RT prior to resection were identified retrospectively. Tumor volumes were measured using cone-beam computed tomography obtained daily during RT. Linear regression evaluated the linearity of volume changes. Kruskal-Wallis tests, Mann-Whitney U tests, and linear regression evaluated predictors of volume change. Logistic and Cox regression evaluated volume change as a predictor of resection margin status, histologic treatment response, and tumor recurrence. Results Thirty-three patients were evaluated. Twenty-nine tumors were high grade. Prior to RT, median tumor volume was 189 mL (range, 7.2 to 4,885 mL). Sixteen tumors demonstrated significant linear volume changes during RT. Of these, 5 tumors increased and 11 decreased in volume. Myxoid liposarcoma (n = 5, 15%) predicted decreasing tumor volume (p = 0.0002). Sequential chemoradiation (n = 4, 12%) predicted increasing tumor volume (p = 0.008) and corresponded to longer times from diagnosis to RT (p = 0.01). Resection margins were positive in three cases. Five patients experienced local recurrence, and 7 experienced distant recurrence, at median 8.9 and 6.9 months post-resection, respectively. Volume changes did not predict resection margin status, local recurrence, or distant recurrence. Conclusion Volume changes of pelvis and extremity soft tissue sarcomas followed linear trends during RT. Volume changes reflected histologic subtype and treatment characteristics but did not predict margin status or recurrence after resection.

Several treatment regimens for childhood malignancies have been associated with the development of osteonecrosis, including radiation therapy, glucocorticoid medications, immunotherapy (including anti-angiogenic agents), and several chemotherapeutic agents. Adolescents older than 10 years are at greatest risk of developing osteonecrosis within 1 year of initiating therapy. Screening with magnetic resonance imaging in this high-risk population may be a useful method for detecting osteonecrosis. Surgery may be required for lesions that have progressed substantially despite nonoperative interventions.

New evidence and systemic therapies demand an updated analysis of chemotherapy for soft tissue sarcoma. We completed a meta-analysis of chemotherapy in localized STS, assessing OS, PFS, and local and distant recurrence (local recurrence-free survival [LRFS] and distant recurrence-free survival [DRFS]). Ten studies, totaling 3157 patients, were included. A pooled analysis for 5-year OS, progression-free survival, LRFS, and DRFS showed no benefit of chemotherapy over locoregional therapy alone for all-comers or site-specific STS. We make recommendations to improve outcome reporting and quality indices.

Background Reconstructive surgery is often required following lower extremity soft tissue sarcoma resection. The relationship between the method of plastic surgery reconstruction and postoperative wound healing or functional oncologic outcomes in this patient population is poorly understood. Methods We performed a retrospective review on all adult patients that underwent soft tissue reconstruction following resection of lower extremity soft tissue sarcomas between 1996 and 2016 at our institution. Results One hundred and thirty-six patients were identified. Wound complications occurred within 6-months postoperatively in 72 patients (52.9%). Average time to heal was 13.0 weeks. Limb survival was 94.9%. 16.9% and 36.8% of patients had evidence of local recurrence or metastatic disease, respectively. There was no significant difference in the incidence of overall wound complications, time to heal, limb survival, local recurrence, or metastatic disease between the different reconstructive methods. Conclusions In our cohort, the utilization of different reconstructive techniques did not correlate with a difference in postoperative wound complications or oncologic outcomes. Local flaps can effectively reconstruct the majority of lower extremity sarcoma defects that cannot be closed primarily. However, alternative reconstructive techniques may be utilized when indicated without a significant increase in postoperative morbidity in this patient population.

BackgroundCurrent therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.Methods66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung ‘PM interface’ and ‘PM interior’ regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.ResultsIHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.ConclusionsOsteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.

Benign, intermediate-grade and malignant tumors sometimes have overlapping imaging and clinical characteristics. The purpose of this study was to evaluate the added value of contrast-enhanced sequences (dynamic contrast enhancement (DCE)), diffusion-weighted imaging (DWI), and chemical shift imaging (CSI) to noncontrast MRI sequences for the characterization of indeterminate lipomatous tumors.Thirty-two consecutive patients with histologically proven peripheral lipomatous tumors were retrospectively evaluated. Two musculoskeletal radiologists recorded the MRI features in three sessions: (1) with noncontrast T1-weighted and fluid-sensitive sequences; (2) with addition of static pre- and post-contrast 3D volumetric T1-weighted sequences; and (3) with addition of DCE, DWI, and CSI. After each session, readers recorded a diagnosis (benign, intermediate/atypical lipomatous tumor (ALT), or malignant/dedifferentiated liposarcoma (DDL)). Categorical imaging features (presence of septations, nodules, contrast enhancement) and quantitative metrics (apparent diffusion coefficient values, CSI signal loss) were recorded.For 32 tumors, the diagnostic accuracy of both readers did not improve with the addition of contrast-enhanced sequences, DWI, or CSI (53% (17/32) session 1; 50% (16/30) session 2; 53% (17/32) session 3). Noncontrast features, including thick septations (p = 0.025) and nodules ≥ 1 cm (p 0.001), were useful for differentiating benign tumors from ALTs and DDLs, as were DWI (p = 0.01) and CSI (p = 0.009) metrics.The addition of contrast-enhanced sequences (static, DCE), DWI, and CSI to a conventional, noncontrast MRI protocol did not improve diagnostic accuracy for differentiating benign, intermediate-grade, and malignant lipomatous tumors. However, we identified potentially useful imaging features by DCE, DWI, and CSI that may help distinguish these entities.

Background Racial disparities in outcomes after orthopaedic surgery have been well-documented in the fields of arthroplasty, trauma, and spine surgery; however, little research has assessed differences in outcomes after surgery for oncologic musculoskeletal disease. If racial disparities exist in the treatment of patients with pathologic long bone fractures, then they should be identified and addressed to promote equity in patient care. Questions/purposes (1) How do wait times between hospital admission and operative fixation for pathologic fractures of long bones differ between Black and non-Hispanic white patients, after controlling for confounding variables using propensity score matching? (2) How does the proportion of patients with 30-day postoperative complication differ between these groups after controlling for confounding variables using propensity score matching? Methods Using the National Surgical Quality Improvement Program database, we analyzed 828 patients who underwent fixation for pathologic fractures from 2012 to 2018. This database not only provides a large enough sample of pathologic long bone fracture patients to conduct the present study, but also it contains variables such as time from hospitalization to surgery that other national databases do not. After excluding patients with incomplete data (4% of the initial cohort), 775 patients were grouped by self-reported race as Black (12% [94]) or white (88% [681]). Propensity score matching using a 1:1 nearest-neighbor match was then used to match 94 Black patients with 94 white patients according to age, gender, BMI, American Society of Anesthesiologists physical status classification, anemia, endstage renal disease, independence in performing activities of daily living, congestive heart failure, and pulmonary disease. The primary outcome of interest was the number of days between hospital admission and operative fixation, which we assessed using a Poisson regression and report as an incidence risk ratio. The secondary outcomes were the occurrences of major 30-day postoperative adverse events (failure to wean off mechanical ventilation, cerebrovascular events, renal failure, cardiovascular events, reoperation, death), minor 30-day adverse events (reintubation, wound complications, pneumonia, and thromboembolic events), and any 30-day adverse events (defined as the pooling of all adverse events, including readmissions). These outcomes were analyzed using a bivariate analysis and logistic regression with robust estimates of variance and are reported as odds ratios. Because any results on disparities rely on rigorous control of other baseline demographics, we performed this multivariable approach to ensure we were controlling for confounding variables as much as possible. Results After controlling for potentially confounding variables such as age and gender, we found that Black patients had a longer mean wait time (incidence risk ratio 1.5 [95% CI 1.1 to 2.1]; p = 0.01) than white patients. After controlling for confounding variables, Black patients also had greater odds of having any postoperative adverse event (OR 2.1 [95% CI 1.1 to 3.8]; p = 0.02), including readmission (OR 3.3 [95% CI 1.5 to 7.6]; p = 0.004). Conclusion The racial disparities in pathologic long bone fracture care found in our study may be attributed to fundamental racial biases, as well as systemic socioeconomic disparities in the US healthcare system. Identifying and eliminating the racial, socioeconomic, and sociocultural biases that drive these disparities would improve care for patients with orthopaedic oncologic conditions. One possible way to reduce these disparities would be to implement standardized surgical care pathways for pathological long bone fractures across different institutions to minimize variation in important aspects of care, such as time to surgical fixation. Further insight is needed on the types of standardized care pathways and the implementation mechanisms that are most effective. Level of evidence Level III, therapeutic study.

Background. The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. Methods. The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan–Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. Results. In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size

Current mortality predictive tools, in the setting of completed or impending pathologic fractures, are nonspecific. Clinical decision making and mortality prediction in research would benefit from creation of a high-fidelity scoring system for calculating the risk of 30-day postoperative mortality. The purpose of this study is to develop a validated research and clinical tool that is superior to existing methods in estimating postoperative mortality risk after fixation of pathologic fractures.One thousand two hundred nineteen patients who underwent fixation for either completed or impending pathologic fractures in the National Surgical Quality Improvement Program (2012 to 2018) database were analyzed. Multivariable logistic regression with diagnostics was used to develop a predictive model in a derivation cohort and then validated in a validation cohort. Area under the curve (AUC) from receiver operator curve analysis was used to assess accuracy. A score was derived and compared with the American Society of Anesthesiologists classification and modified five-component frailty index (mF-I5). The score was validated in an exclusive cohort of patients who underwent fixation for pathologic fractures at a tertiary care center.Of 1,219, a total of 177 (15%) patients did not survive beyond 30 days postoperatively. AUC for our predictive model was 0.76 in the derivation and 0.75 in the validation National Surgical Quality Improvement Program cohorts. The derived Pathologic Fracture Morbidity Index included seven data points: anemia, alkaline phosphatase150 U/L, albumin3.5 mg/dL, pulmonary disease, recent weight loss, functional dependence, and white blood cell count12,000. The PFMI (AUC = 0.75) was more accurate than ASA (AUC = 0.60) or mF-5 (AUC = 0.58) (P0.01). The AUC for PFMI in predicting 30-day mortality in the exclusive cohort (N = 39) was 0.74.The PFMI is a validated tool that may be used for predicting postoperative 30-day mortality after fixation of pathologic fractures, with higher level of accuracy compared with ASA or mF-I5.

Background Patients with relapsed metastatic osteosarcoma have no effective treatments available to them,1 and immunotherapy thus far has not succeeded in improving outcomes.2–5 We aim to understand the immune architecture of the tumor microenvironment (TME) of osteosarcoma, with the goal of harnessing the immune system as a major therapeutic strategy for the treatment of patients with osteosarcoma. Methods 66 osteosarcoma tissue specimens were stained and analyzed by immunohistochemistry. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional multiparameter flow cytometry (MFC). Distinct regions from 16 pulmonary metastases (PMs) were microdissected, and RNA was extracted to perform comparative transcriptomic studies. Clinical follow-up (median 24 months) was available from resection. Results Digital image analysis of immunohistochemistry demonstrated significantly higher infiltrating immune cells in the PMs compared to primary bone tumors, concentrated at the tumor-normal lung ‘PM interface’ region, and elevated expression of multiple immune checkpoint molecules at the PM interface (figure 1). MFC confirmed the increased expression of the immune checkpoint molecules programmed cell death 1 (PD-1, p Conclusions In contrast to primary bone osteosarcoma ‘immune deserts,’ osteosarcoma PMs represent an ‘immune-excluded’ TME where immune cells are present but are halted at the PM interface. TILs can produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs that prevent TILs from penetrating into the PM interior, including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with PFS of patients, which could be potentially manipulated for successful immunotherapy. Ethics Approval This study was approved by Johns Hopkins University’s Ethics Board, approval number FWA00005752. References Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the surveillance, epidemiology, and end results program. Cancer 2009;115(7):1531–43. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017;18(11):1493–501. Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Liu X, et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol 2020;21(4):541–50. D’Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (alliance A091401): Two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 2018;19(3):416–26. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, et al. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res 2016;6:24.

We compared short-term outcomes after operative versus nonoperative treatment of pathologic humeral fractures. We hypothesized that patients who underwent operative fixation would heal faster and have better pain control. A retrospective review was conducted of 25 patients who underwent operative fixation and 6 who received nonoperative treatment from 2005-2017. Operative patients healed significantly earlier than nonoperative patients (p = 0.02). At 16-week follow-up, radiographs showed evidence of healing in 24 of 25 operatively treated patients and 2 of 6 nonoperatively treated patients (p0.01). Pain improved during the inpatient stay in 24 of 25 operatively treated patients and none of the nonoperatively treated patients (p0.01). All operatively treated patients returned to self-reported baseline motor function by final follow-up, whereas none of the nonoperatively treated patients returned to baseline (p = 0.01). Operative treatment was associated with earlier healing, pain control and return to function compared with nonoperative treatment of pathologic humeral fractures. Level of Evidence: 3. (Journal of Surgical Orthopaedic Advances 29(3):177-181, 2020).

Patients with fungating extremity soft-tissue sarcoma (STS) can develop lymphadenopathy, which can represent nodal metastasis or benign reactive adenopathy. In 1787 patients with STS, 67 (3.7%) had fungating extremity STS. In the 62 patients who met our inclusion criteria, we evaluated prevalence and histopathology of lymphadenopathy, factors associated with lymphadenopathy and nodal metastasis, and prevalence of and factors associated with lung metastasis and survival time from fungation. Logistic regression and Cox proportional-hazards models were used to analyze node pathology, lung metastasis, and survival duration with α = 0.05. Lymphadenopathy occurred in 11 of 62 patients (18%), 6 with nodal metastasis and 5 with reactive adenopathy. The only factor associated with lymphadenopathy was location of primary tumor in the upper extremity (p = 0.02). No tumor characteristics were associated with nodal metastasis. In all five patients with reactive adenopathy, the condition was recognized within 3 days after tumor fungation. Lymphadenopathy recognized more than 3 days after tumor fungation was likely to be nodal metastasis. Forty-one percent of patients developed lung metastasis, which was not associated with presence of lymphadenopathy or any patient or tumor characteristic. Age, tumor size, and Black and Asian race were independently associated with greater risk of death. Eighteen percent of patients with fungating extremity STS developed lymphadenopathy. Approximately half of cases represented nodal metastasis, and half represented reactive adenopathy. Lymphadenopathy that develops within 3 days after tumor fungation should increase suspicion for reactive adenopathy versus nodal metastasis.