Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

The efficacy and safety of direct oral anticoagulants compared with low-molecular-weight heparin for venous thromboembolism prophylaxis after surgical resection of primary lower extremity bone or soft-tissue sarcoma.

INTRODUCTION: The incidence of postoperative venous thromboembolism (VTE) and wound complications is greater after sarcoma resection. We sought to identify differences in postoperative VTE and bleeding complications with direct oral anticoagulants (DOACs) versus low-molecular-weight heparin (LMWH) following resection of lower extremity primary bone or soft tissue sarcoma. METHODS: We retrospectively identified 2083 patients from the PearlDiver database who underwent resection of primary bone or soft tissue sarcoma of the lower extremity from January 2010 to October 2021 and prescribed LMWH or DOAC within 90-days postoperatively. The primary outcomes were comparison of postoperative incidence and odds of deep venous thrombosis (DVT), pulmonary embolism (PE), and bleeding complications within 90-days following resection. RESULTS: Patients prescribed DOACs had a greater odds of DVT (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.06-2.41; p = 0.024) and PE (OR: 3.38; 95% CI: 1.96-5.86; p < 0.001) within 90-days following resection of bone sarcoma when compared with the LMWH cohort. Patients undergoing resection of soft tissue sarcomas also had greater odds DVT (OR: 1.65; 95% CI: 1.09-2.49; p = 0.016) and PE (OR: 2.62; 95% CI: 1.52-4.54; p < 0.001) in the DOAC cohort. There was no difference in the odds of bleeding complications. CONCLUSION: This study demonstrated an increased incidence and odds of VTE, but not bleeding complications, when using DOACs versus LMWH after primary bone or soft tissue sarcoma resection. LEVEL OF EVIDENCE: Level III.

The role of imaging in extremity sarcoma surgery.

The surgical management of extremity bone and soft tissue sarcomas has evolved significantly over the last 50 years. The introduction and refinement of high-resolution cross-sectional imaging has allowed accurate assessment of anatomy and tumor extent, and in the current era more than 90% of patients can successfully undergo limb-salvage surgery. Advances in imaging have also revolutionized the clinician's ability to assess treatment response, detect metastatic disease, and perform intraoperative surgical navigation. This review summarizes the broad and essential role radiology plays in caring for sarcoma patients from diagnosis to post-treatment surveillance. Present evidence-based imaging paradigms are highlighted along with key future directions.

Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sentinel Lymph Node Biopsy for Extremity and Truncal Soft Tissue Sarcomas: A Systematic Review of the Literature.

BACKGROUND: Regional lymph node metastasis (RLNM) occurs infrequently in patients with soft tissue sarcoma (STS), although certain STS subtypes have a higher propensity for RLNM. The identification of RLNM has significant implications for staging and prognosis; however, the precise impact of node-positive disease on patient survival remains a topic of controversy. Although the benefits of sentinel lymph node biopsy (SLNB) are well documented in patients with melanoma and breast cancer, whether this procedure offers a benefit in STS is controversial. METHODS: A systematic literature search was performed and articles reviewed to determine if SLNB in patients with extremity/truncal STS impacts disease-free or overall survival. RESULTS: Six studies were included. Rates of sentinel lymph node positivity were heterogeneous (range 4.3-50%). The impact of SLNB on patient outcomes remains unclear. The overall quality of available evidence was low, as assessed by the Grading of Recommendations, Assessment, Development, and Evaluation system. CONCLUSIONS: The literature addressing the impact of nodal basin evaluation on the staging and management of patients with extremity/truncal STS is confounded by heterogeneous patient cohorts and clinical practices. Multicenter prospective studies are warranted to determine the true incidence of RLNM and whether SLNB could benefit patients with clinically occult RLNM at diagnosis.

Metastatic sarcomatoid carcinoma to bone.

BACKGROUND AND OBJECTIVES: Distinguishing sarcomatoid carcinoma from primary sarcoma is clinically important. We sought to characterize metastatic sarcomatoid bone disease and its management. METHODS: We analyzed the characteristics of all cases of sarcomatoid carcinoma to bone at a single institution from 2001 to 2021, excluding patients with nonosseous metastases. Survival was evaluated using the Kaplan-Meier method. RESULTS: We identified 15 cases of metastatic sarcomatoid carcinoma to bone. In seven cases the primary cancer was unknown at presentation. Renal cell carcinoma was suspected or confirmed in nine cases. Nine patients presented with pathologic fracture and two with concomitant visceral metastases. All patients underwent image-guided core needle or open biopsy. Ten required surgery for discrete osseous metastases; in four cases definitive surgery was delayed (median delay, 19 days) due to inability to rule out sarcoma with frozen section. No patients required reoperation or had construct failure. Thirteen died of disease; median survival was 17.5 months (interquartile range, 6.2-25.1). CONCLUSIONS: Metastatic sarcomatoid carcinoma is a clinically challenging entity. Multidisciplinary input and communication are key to identifying the primary carcinoma, locating osseous metastases, and defining an operative fixation that will survive the remainder of the patient's life.

Surgical management of extremity rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The treatment of extremity rhabdomyosarcoma remains a challenge due to several adverse prognostic factors frequently associated with this tumor site. The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group Soft-Tissue Sarcoma Committee, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. The INSTRuCT surgical committee developed an internationally applicable consensus opinion document for the surgical treatment of extremity rhabdomyosarcoma. This document addresses surgical management, including biopsy, nodal staging, timing of therapy, resection and reexcision, reconstruction, and surgical approach at relapse.

What Proportion of Patients With Musculoskeletal Tumors Demonstrate Thromboelastographic Markers of Hypercoagulability? A Pilot Study.

BACKGROUND: 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. QUESTIONS/PURPOSES: (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? METHODS: 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. RESULTS: 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. CONCLUSION: 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 OF EVIDENCE: Level III, therapeutic study.

Recurrent chondromyxoid fibroma of the distal femur treated with percutaneous cryoablation.

Chondromyxoid fibroma is a rare, benign tumor of the bone with excellent prognosis but a high rate of recurrence. We report a patient presenting with pain and a history of chondromyxoid fibroma of the distal left femur previously treated with multiple prior curettage and bone graft procedures. Magnetic resonance imaging and histopathology indicated a recurrence of tumor. Due to the small size of the tumor recurrence and challenges associated with prior open surgery, the patient underwent cryoablation of the lesion with computed tomography guidance. Follow-up 18 months later indicated a resolution of pain and improvement on magnetic resonance imaging, and no concerns after 20 months. To our knowledge, this is the first reported case of chondromyxoid fibroma treated with cryoablation. This case suggests cryoablation could be considered in the setting of recurrent chondromyxoid fibroma for local tumor control.

Trends of lymph node sampling and metastasis in pediatric and young adult patients with clear cell, epithelioid, and synovial sarcomas.

BACKGROUND: Clear cell sarcoma of soft tissue (CCS), epithelioid sarcoma, and synovial sarcoma are rare tumors historically identified as high risk for lymph node metastasis. This study investigates incident nodal metastasis and associated survival in children and young adults with these subtypes. PROCEDURE: Using the National Cancer Database (2004-2015), we created a retrospective cohort of 1303 patients (aged ≤25 years) who underwent local control therapy for CCS, epithelioid sarcoma, and synovial sarcoma. Kaplan-Meier curves estimated overall survival (OS) by subtype. Stratifying on subtype, Cox regressions assessed OS by lymph node sampling status and nodal metastasis. RESULTS: There were 103 (7.9%) patients with CCS, 221 (17.0%) with epithelioid sarcoma, and 979 (75.1%) with synovial sarcoma. Lymph node sampling was more frequent in patients with CCS (56.3%) and epithelioid sarcoma (52.5%) versus synovial sarcoma (20.5%, p < .001). Synovial sarcoma metastasized to lymph nodes less frequently than CCS or epithelioid sarcoma (2.1% vs. 14.6% and 14.9%, p < .001). Across all subtypes, lymph node metastasis was associated with inferior OS (HR 2.02, CI 1.38-2.95, p < .001). Lymph node sampling was associated with improved OS in CCS (HR 0.35, CI: 0.15-0.78, p = .010), inferior OS in synovial sarcoma (HR 1.60, CI: 1.13-2.25, p = .007), and no statistical association with OS in epithelioid sarcoma. CONCLUSIONS: Lymph node metastasis is rare in children and young adults with synovial sarcoma. Lymph node sampling procedures were not consistently performed for patients with CCS or epithelioid sarcoma, but improved OS supports routine lymph node sampling in children and young adults with CCS.

What Factors Are Associated With Local Metastatic Lesion Progression After Intramedullary Nail Stabilization?

BACKGROUND: Pathologic fracture of the long bones is a common complication of bone metastases. Intramedullary nail stabilization can be used prophylactically (for impending fractures) or therapeutically (for completed fractures) to preserve mobility and quality of life. However, local disease progression may occur after such treatment, and there is concern that surgical instrumentation and the intramedullary nail itself may seed tumor cells along the intramedullary tract, ultimately leading to loss of structural integrity of the construct. Identifying factors associated with local disease progression after intramedullary nail stabilization would help surgeons predict which patients may benefit from alternative surgical strategies. QUESTIONS/PURPOSES: (1) Among patients who underwent intramedullary nail stabilization for impending or completed pathologic fractures of the long bones, what is the risk of local progression, including progression of the existing lesion and development of a new lesion around the nail? (2) Among patients who experience local progression, what proportion undergo reoperation? (3) What patient characteristics and treatment factors are associated with postoperative local progression? (4) What is the difference in survival rates between patients who experienced local progression and those with stable local disease? METHODS: Between January 2013 and December 2019, 177 patients at our institution were treated with an intramedullary nail for an impending or completed pathologic fracture. We excluded patients who did not have a pathologic diagnosis of metastasis before fixation, who were younger than 18 years of age, who presented with a primary soft tissue mass that eroded into bone, and who experienced nonunion from radiation osteitis or an avulsion fracture rather than from metastasis. Overall, 122 patients met the criteria for our study. Three fellowship-trained orthopaedic oncology surgeons involved in the care of these patients treated an impending or pathologic fracture with an intramedullary nail when a long bone lesion either fractured or was deemed to be of at least 35% risk of fracture within 3 months, and in patients with an anticipated duration of overall survival of at least 6 weeks (fractured) or 3 months (impending) to yield palliative benefit during their lifetime. The most common primary malignancy was multiple myeloma (25% [31 of 122]), followed by lung carcinoma (16% [20 of 122]), breast carcinoma (15% [18 of 122]), and renal cell carcinoma (12% [15 of 122]). The most commonly involved bone was the femur (68% [83 of 122]), followed by the humerus (27% [33 of 122]) and the tibia (5% [6 of 122]). A competing risk analysis was used to determine the risk of progression in our patients at 1 month, 3 months, 6 months, and 12 months after surgery. A proportion of patients who ultimately underwent reoperation due to progression was calculated. A univariate analysis was performed to determine whether lesion progression was associated with various factors, including the age and sex of the patient, use of adjuvant therapies (radiation therapy at the site of the lesion, systemic therapy, and antiresorptive therapy), histologic tumor type, location of the lesion, and fracture type (impending or complete). Patient survival was assessed with a Kaplan-Meier curve. A p value < 0.05 was considered significant. RESULTS: The cumulative incidence of local tumor progression (with death as a competing risk) at 1 month, 3 months, 6 months, and 12 months after surgery was 1.9% (95% confidence interval 0.3% to 6.1%), 2.9% (95% CI 0.8% to 7.5%), 3.9% (95% CI 1.3% to 8.9%), and 4.9% (95% CI 1.8% to 10.3%), respectively. Of 122 patients, 6% (7) had disease progression around the intramedullary nail and 0.8% (1) had new lesions at the end of the intramedullary nail. Two percent (3 of 122) of patients ultimately underwent reoperation because of local progression. The only factors associated with progression were a primary tumor of renal cell carcinoma (odds ratio 5.1 [95% CI 0.69 to 29]; p = 0.03) and patient age (difference in mean age 7.7 years [95% CI 1.2 to 14]; p = 0.02). We found no associations between local disease progression and the presence of visceral metastases, other skeletal metastases, radiation therapy, systemic therapy, use of bisphosphonate or receptor activator of nuclear factor kappa-B ligand inhibitor, type of fracture, or the direction of nail insertion. There was no difference in survivorship curves between those with disease progression and those with stable local disease (= 0.36; p = 0.54). CONCLUSION: Our analysis suggests that for this population of patients with metastatic bone disease who have a fracture or impeding fracture and an anticipated survival of at least 6 weeks (completed fracture) or 3 months (impending fracture), the risk of experiencing local progression of tumor growth and reoperations after intramedullary nail stabilization seems to be low. Lesion progression was not associated with the duration of survival, although this conclusion is limited by the small number of patients in the current study and the competing risks of survival and local progression. Based on our data, patients who present with renal cell carcinoma should be cautioned against undergoing intramedullary nailing because of the risk of postoperative lesion progression. LEVEL OF EVIDENCE: Level III, therapeutic study.

Do Disparities in Wait Times to Operative Fixation for Pathologic Fractures of the Long Bones and 30-day Complications Exist Between Black and White Patients? A Study Using the NSQIP Database.

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.

Do contrast-enhanced and advanced MRI sequences improve diagnostic accuracy for indeterminate lipomatous tumors?

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 < 0.001), were useful for differentiating benign tumors from ALTs and DDLs, as were DWI (p = 0.01) and CSI (p = 0.009) metrics. CONCLUSION: 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.

Lymphadenopathy in Fungating Extremity Soft-Tissue Sarcoma: Metastasis or Reactive?

BACKGROUND: Patients with fungating extremity soft-tissue sarcoma (STS) can develop lymphadenopathy, which can represent nodal metastasis or benign reactive adenopathy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review.

BACKGROUND: Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria. RESULTS: Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies. CONCLUSIONS: Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis.

Administration of TGF-ß Inhibitor Mitigates Radiation-induced Fibrosis in a Mouse Model.

BACKGROUND: Radiation-induced fibrosis is a long-term adverse effect of external beam radiation therapy for cancer treatment that can cause pain, loss of function, and decreased quality of life. Transforming growth factor beta (TGF-ß) is believed to be critical to the development of radiation-induced fibrosis, and TGF-ß inhibition decreases the development of fibrosis. However, no treatment exists to prevent radiation-induced fibrosis. Therefore, we aimed to mitigate the development of radiation-induced fibrosis in a mouse model by inhibiting TGF-ß. QUESTION/PURPOSES: Does TGF-ß inhibition decrease the development of muscle fibrosis induced by external beam radiation in a mouse model? METHODS: Twenty-eight 12-week-old male C57BL/6 mice were assigned randomly to three groups: irradiated mice treated with TGF-ßi, irradiated mice treated with placebo, and control mice that received neither irradiation nor treatment. The irradiated mice received one 50-Gy fraction of radiation to the right hindlimb before treatment initiation. Mice treated with TGF-c (n = 10) received daily intraperitoneal injections of a small-molecule inhibitor of TGF-ß (1 mg/kg) in a dimethyl sulfoxide vehicle for 8 weeks (seven survived to histologic analysis). Mice treated with placebo (n = 10) received daily intraperitoneal injections of only a dimethyl sulfoxide vehicle for 8 weeks (10 survived to histologic analysis). Control mice (n = 8) received neither radiation nor TGF-ß treatment. Control mice were euthanized at 3 months because they were not expected to exhibit any changes related to treatment. Mice in the two treatment groups were euthanized 9 months after radiation, and the quadriceps of each thigh was sampled. Masson's trichome stain was used to assess muscle fibrosis. Slides were viewed at 10 × magnification using bright-field microscopy, and in a blinded fashion, five representative images per mouse were used to quantify fibrosis. The mean ± SD fibrosis pixel densities in the TGF-ßi and radiation-only groups were compared using Mann-Whitney U tests. The ratio of fibrosis to muscle was calculated using the mean fibrosis per slide in the TGF-ßi group to standardize measurements. Alpha was set at 0.05. RESULTS: The mean (± SD) percentage of fibrosis per slide was greater in the radiation-only group (1.2% ± 0.42%) than in the TGF-ßi group (0.14% ± 0.09%) (odds ratio 0.12 [95% CI 0.07 to 0.20]; p < 0.001). Among control mice, mean fibrosis was 0.05% ± 0.02% per slide. Mice in the radiation-only group had 9.1 times the density of fibrosis as did mice in the TGF-ßi group. CONCLUSION: Our study provides preliminary evidence that the fibrosis associated with radiation therapy to a quadriceps muscle can be reduced by treatment with a TGF-ß inhibitor in a mouse model. CLINICAL RELEVANCE: If these observations are substantiated by further investigation into the role of TGF-ß inhibition on the development of radiation-induced fibrosis in larger animal models and humans, our results may aid in the development of novel therapies to mitigate this complication of radiation treatment.

Can a Novel Scoring System Improve on the Mirels Score in Predicting the Fracture Risk in Patients with Multiple Myeloma?

BACKGROUND: Stratification of the fracture risk is an important treatment component for patients with multiple myeloma, which is associated with up to an 80% risk of pathologic fracture. The Mirels score, which is commonly used to estimate the fracture risk for patients with osseous lesions, was evaluated in a cohort in which fewer than 15% of lesions were caused by multiple myeloma. The behavior of multiple myeloma lesions often differs from that of lesions caused by metastatic disease, and accurate risk stratification is critical for effective care. To our knowledge, the Mirels score has not been validated specifically for multiple myeloma. QUESTIONS/PURPOSES: Our purpose was: (1) To develop a novel scoring system for the prediction of pathologic fracture in patients with long-bone lesions from multiple myeloma; and (2) to compare the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) area under curve (AUC) between the novel scoring system and the Mirels system. METHODS: Between 2003 and 2017, 763 patients at one center with the diagnosis of multiple myeloma were reviewed, of whom 174 presented with long-bone disease involvement. Of those, 5% (nine of 174) were missing data or radiographs at a minimum of 1 year and had not reached an endpoint (fracture or surgery) before that time and were therefore excluded. Many patients have more than one lesion; consequently, we used the largest lesion in each patient, resulting in 163 lesions in as many patients. Ten percent (16 of 163) of these patients eventually developed a fracture and 4% (six of 163) underwent prophylactic stabilization (excluded from analysis because of outcome uncertainty). During the study period, prophylactic stabilization was performed at the discretion of the orthopaedic oncologist. Fifty-one percent (83 of 163) of patients were female, and the mean (± SD) age was 60 ± 10 years at radiographic lesion identification. All lesions were characterized before determining whether the patient underwent pathologic fracture. We identified variables associated with pathologic fracture on univariate analysis. Variables independently significant on logistic regression analysis were used to generate scoring algorithms at varying weights and scoring cutoffs for comparison via ROC curves. We then selected a novel score based on ROC performance, and compared the sensitivity, specificity, PPV, and NPV of that scoring system to that of Mirels score. ROC AUCs were compared after bootstrapping 100,000 iterations. Alpha was set at 0.05. RESULTS: After controlling for potential confounders, such as age, sex, and duration of myeloma diagnosis, we found the following factors were independently associated with the occurrence of pathologic fracture: larger lesion size (area, cm2) (log odds 0.17; p = 0.03), longer lesion latency (years from diagnosis to lesion identification) (log odds 0.25; p = 0.03), presence of pain (relative risk [RR] 2.9; p = 0.04), and metaphyseal location (RR 3.2, compared with epiphyseal or diaphyseal; p = 0.003). These variables were used to formulate a novel scoring system. Compared with the Mirels system, the novel system was more sensitive (69% [95% CI 61 to 76] versus 38% [95% CI 30 to 46]; p < 0.05) but not different in terms of specificity (87% [95% CI 80 to 91] versus 87% [95% CI 81 to 92]; p > 0.05), PPV (37% [95% CI 29 to 45] versus 25% [95% CI 19 to 33]; p > 0.05), NPV (96% [95% CI 91 to 99] versus 92% [95% CI 87 to 96]; p > 0.05), or AUC (0.85 [95% CI 0.74 to 0.92] versus 0.67 [95% CI 0.51 to 0.81]; p > 0.05). CONCLUSION: The novel scoring system was found to be more sensitive than the Mirels system for predicting pathologic fracture in our retrospective cohort of patients with multiple myeloma-related bone disease. Specificity, PPV, NPV, and ROC AUC were not different with the numbers available. Thus, the novel scoring system may serve as a more effective screening tool to determine which patients with multiple myeloma would benefit from further radiologic or orthopaedic evaluation based on a skeletal survey. LEVEL OF EVIDENCE: Level III, diagnostic study.

Pelvic bone tumor resection: post-operative imaging.

The anatomic extent of a pelvic bone tumor and the need for reconstruction dictate the type of pelvic resection (limb salvage pelvic resection or amputation). If a pelvic bone tumor resection involves two or more critical anatomic structures (the sciatic nerve, femoral neurovascular bundle or the hip joint), then reasonable functional recovery after limb salvage is less likely and amputation should be considered. Both limb salvage and amputation approaches to the pelvis are technically arduous surgeries with significant associated morbidity and complications. As such, imaging plays an important role in the post-operative management of patients who have undergone pelvic bone tumor resection. In this article, we will review optimal imaging techniques as well as the expected post-operative appearance after pelvic bone tumor resection and important complications including infection, tumor recurrence, and complications related to complex soft tissue and osseous reconstruction.

Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

Desmoid tumor mimics local recurrence of extremity sarcoma on MRI.

BACKGROUND AND OBJECTIVES: The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection. METHODS: We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors. RESULTS: Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were ß-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors. CONCLUSIONS: Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management.