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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., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

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., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

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., Competing Interests: Each author certifies that neither he nor she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

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-β) is believed to be critical to the development of radiation-induced fibrosis, and TGF-β 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-β., Question/purposes: Does TGF-β 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-βi, 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-β (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-β 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-βi 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-βi 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-βi 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-βi 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-β inhibitor in a mouse model., Clinical Relevance: If these observations are substantiated by further investigation into the role of TGF-β 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., Competing Interests: Each author certifies that neither he or she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Background: Reported rates of the incidence of lymph node metastasis in soft tissue sarcoma vary considerably. Many are based on single-institution series and small patient populations. Certain sarcoma subtypes, including synovial sarcoma, have been associated with a higher risk of lymph node involvement. Most single centers have insufficient numbers of patients to assess lymph node metastasis accurately, but larger national databases may allow a more accurate estimation., Questions/purposes: We queried a large national database and asked the following questions: (1) What proportion of patients with soft tissue sarcoma have lymph node metastasis and distant metastasis? (2) What histologic subtypes are associated with increased risk of nodal metastasis? (3) What is the impact of lymph node metastases and histologic subtype on survival? (4) Does lymph node excision improve survival of patients with soft tissue sarcoma?, Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program is a national database that covers a geographic cross-section representing approximately 28% of the US population across demographic groups. Using the SEER database, we identified 15,525 adults diagnosed with histologically confirmed soft tissue sarcoma from 2004 to 2013. Proportions of patients with lymph node or distant metastases were calculated using descriptive statistics. Overall survival was computed using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazard regression to calculate the association of lymph node metastasis with overall survival while controlling for patient age, sex, race, tumor size, and tumor location., Results: A total of 820 of 15,525 patients had lymph node metastasis at the time of diagnosis, yielding an overall proportion of 5.3% (95% confidence interval [CI], 4.9%-5.6%). Histologic subtypes that most frequently developed nodal metastasis were rhabdomyosarcoma, clear cell sarcoma, epithelioid sarcoma, and myxoid/round cell liposarcoma. Despite frequent reports regarding its association with lymph node metastasis, the proportion of patients with lymph node metastasis among 885 patients with synovial sarcoma (4.2%) was not different from the proportion with nodal metastasis in the overall soft tissue sarcoma population. For all soft tissue sarcomas, distant metastatic disease was present at diagnosis in 1869 (12%) patients (95% CI, 11.5%-12.6%). After controlling for relevant covariates, lymph node metastasis was associated with poorer overall survival (hazard ratio [HR], 1.34; 95% CI, 1.22-1.48; p < 0.001) as was distant metastasis (HR, 2.87; 95% CI, 2.66-3.09; p < 0.001). When comparing the subgroup of patients with positive lymph nodes, lymphadenectomy in conjunction with local excision/limb salvage was associated with the highest overall 5-year survival (HR, 0.46; 95% CI, 0.31-0.67; p < 0.001)., Conclusions: In clarifying the overall proportion of patients with soft tissue sarcoma with nodal metastases, the current study indicates that lymph node metastases occur at a higher proportion than previous studies have suggested and that synovial sarcoma is not associated with a higher risk of lymphatic spread compared with soft tissue sarcoma overall. Patients with lymph node metastases are associated with poorer survival than those without metastases. Further investigation is needed to clarify the apparent improved overall survival after lymphadenectomy in the setting of nodal metastasis from soft tissue sarcoma., Level of Evidence: Level II, prognostic study.