Sclerostin immunohistochemical staining in surgically treated giant cell tumor of bone.

BACKGROUND: Giant cell tumor of bone (GCTB) is a destructive lesion with a high potential for recurrence. RANK-ligand targeted therapy has provided promising, yet mixed results. Sclerostin (SOST) inhibition results in a net anabolic response and is currently used in the treatment of osteoporosis. The application to GCTB is unknown. OBJECTIVES: We sought to determine if GCTB stained for SOST on immunohistochemistry and correlate its expression with predictor variables. METHODS: All patients at a single institution undergoing surgery for GCTB between 1993 and 2008 with a minimum of 6 months follow-up were included. Primary outcomes included the presence of SOST staining, secondary outcomes included the correlation of patient and tumor-specific predictor variables. RESULTS: SOST antibody staining of any cell type was present in 47 of 48 cases (97.9%). Positivity of the stromal cells was present in 39 of 48 cases (81.3%) and was associated with radiographic aggressiveness (p = 0.023), symptomatic presentation (p = 0.032), prior surgery (p = 0.005), and patient age (p = 0.034). Positivity of giant cells was present in 41 of 48 cases (85.4%) and was not significant with predictive factors. CONCLUSIONS: Sclerostin staining in GCTB is a novel finding and warrants further research to define the role of sclerostin as a prognostic factor and therapeutic target.

Sclerostin Immunohistochemical Staining in Aggressive Maxillofacial Giant Cell Lesions: Initial Results and Potential Therapeutic Target.

INTRODUCTION: Maxillofacial (MF) giant cell lesions (GCLs) are benign, often locally aggressive lesions with potential for recurrence. Systemic treatments have included interferon alpha, calcitonin, bisphosphonates, and denosumab. Sclerostin (SOST) is typically thought to be a negative regulator of bone metabolism and anti-SOST agents have been used to treat osteoporosis; however, its role in central giant cell granuloma is unknown. The purpose of this study was to evaluate the expression of SOST in MF GCLs. MATERIALS AND METHODS: This was a retrospective study of patients with MF GCLs treated at a single institution between 1993 and 2008 with a minimum follow-up of 6 months. Representative tissue was used to create a tissue microarray and SOST immunohistochemical (IHC) staining and grading was performed. The primary outcomes were IHC staining of the stromal cells and giant cells. The secondary outcomes included correlation of IHC staining and patient predictor variables including clinically benign and aggressive lesions. All analyses were completed using univariate statistical tests. RESULTS: A total of 37 subjects were included (29 clinically aggressive and 8 clinically benign). Sclerostin staining was present in 30 of 37 subjects (81%). Of these, 22 (60%) had stromal cell staining and 28 (76%) had giant cell staining. The presence or absence of staining, of either cell type, was not associated with aggressiveness, presence of clinical symptoms, tumor size, previous interferon therapy, previous surgery, or the race or age of the patient. DISCUSSION: Maxillofacial GCLs have an overall high level of SOST staining; however, the role of SOST in treatment and prognosis is unknown and warrants further study.

Development of machine learning model algorithm for prediction of 5-year soft tissue myxoid liposarcoma survival.

BACKGROUND: Predicting survival in myxoid liposarcoma (MLS) patients is very challenging given its propensity to metastasize and the controversial role of adjuvant therapy. The purpose of this study was to develop a machine-learning algorithm for the prediction of survival at five years for patients with MLS and externally validate it using our institutional cohort. METHODS: Two databases, the surveillance, epidemiology, and end results program (SEER) database and an institutional database, were used in this study. Five machine learning models were created based on the SEER database and performance was rated using the TRIPOD criteria. The model that performed best on the SEER data was again tested on our institutional database. RESULTS: The net-elastic penalized logistic regression model was the best according to our performance indicators. This model had an area under the curve (AUC) of 0.85 when compared to the SEER testing data and an AUC of 0.76 when tested against institutional database. An application to use this calculator is available at https://sorg-apps.shinyapps.io/myxoid_liposarcoma/. CONCLUSION: MLS is a soft-tissue sarcoma with adjunct treatment options that are, in part, decided by prognostic survival. We developed the first machine-learning predictive algorithm specifically for MLS using the SEER registry that retained performance during external validation with institutional data.

Adjunct diagnostic strategies in improving diagnostic yields in image-guided biopsies of musculoskeletal neoplasms-A cost-effectiveness analysis.

BACKGROUND: Routine use of adjunct intraprocedural fresh frozen biopsy (FFP) or point-of-care (POC) cytology at the time of image-guided biopsy can improve diagnostic tissue yields for musculoskeletal neoplasms, but these are associated with increased costs. OBJECTIVE: This study aimed to ascertain the most cost-effective adjunctive test for image-guided biopsies of musculoskeletal neoplasms. METHODS: This expected value cost-effectiveness microsimulation compared the payoffs of cost (2020 United States dollars) and effectiveness (quality-adjusted life, in days) on each of the competing strategies. A literature review and institutional data were used to ascertain probabilities, diagnostic yields, utility values, and direct medical costs associated with each strategy. Payer and societal perspectives are presented. One- and two-way sensitivity analyses evaluated model uncertainties. RESULTS: The total cost and effectiveness for each of the strategies were $1248.98, $1414.09, $1980.53, and 80.31, 79.74, 79.69 days for the use of FFP, permanent pathology only, and POC cytology, respectively. The use of FFP dominated the competing strategies. Sensitivity analyses revealed FFP as the most cost-effective across all clinically plausible values. CONCLUSIONS: Adjunct FFP is most cost-effective in improving the diagnostic yield of image-guided biopsies for musculoskeletal neoplasms. These findings are robust to sensitivity analyses using clinically plausible probabilities.

Oncological and Functional Outcomes in Joint-sparing Resections of the Proximal Femur for Malignant Primary Bone Tumors.

BACKGROUND: Joint-sparing resections (JSR) of the proximal femur allow for preservation of the proximal femoral growth plate and native hip joint, but whether this offers fewer complications or better function and longevity of the reconstruction remains unknown. In this study, we compared the functional outcomes of pediatric patients with bone sarcomas undergoing JSR of the proximal femur with intercalary allograft (ICA) reconstruction to those undergoing proximal femoral resections (PFR) with allograft-prosthetic composite (APC) reconstructions. METHODS: We retrospectively reviewed all patients undergoing JSR with ICA reconstruction and PFR with APC reconstructions between 1995 and 2013 at a tertiary pediatric referral center. Primary outcomes included major and minor complications and secondary outcomes included the need for a secondary procedure, presence of local or distant relapse, survival status, and the presence of pain and ambulatory status (limp, assistive device, highest level of function). We assessed differences in outcomes using the Fisher exact and Wilcoxon rank-sum tests. RESULTS: Eight patients underwent a JSR and ICA reconstruction, while 7 patients underwent a PFR with APC reconstruction. Median patient follow-up was 60.4 months (interquartile range: 36.8 to 112.9) Patients undergoing JSR and ICA reconstruction were younger than patients undergoing PFR with APC reconstruction (7.7 vs. 11.7 y, P=0.043); however, we found no other statistically significant differences in patient demographics. There were no statistically significant differences in primary or secondary outcomes between the study groups; however, patients who underwent JSR with ICA had more major complications (62.5% vs. 42.9%, P=0.29) and a lower rate of minor complications (25% vs. 28.6%, P=0.22). CONCLUSION: Treatment of proximal femoral bone sarcomas in pediatric and adolescent patients remains a challenging enterprise. JSR with ICA reconstruction in the proximal femur, when feasible, may provide a similar function and risk of intermediate-term major and minor complications when compared with PFR with APC reconstruction. Further long-term studies are required to determine the impact of the native femoral head retention with respect to revision rates. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Sclerotherapy for Aneurysmal Bone Cysts: Scale for Response.

BACKGROUND: The objective of this study was to develop a response scale for aneurysmal bone cysts (ABCs) treated with sclerotherapy and determine its inter-rater reproducibility. METHODS: Patients treated with sclerotherapy for an ABC between 1993 and 2014 were identified. An attending orthopaedic surgeon and an attending interventional radiologist independently reviewed the radiographic series for each patient and determined response to treatment using a novel grading system. Pain scores were collected from each visit. Inter-rater reliability was assessed using the intraclass correlation coefficient (ICC). General estimating equations analysis was used to evaluate the relationship between radiographic and pain scores and outcome, to develop an algorithm for the study patient population. A receiver operating characteristic curve was constructed to evaluate the diagnostic performance of the radiographic and pain scores in identifying the necessity of further treatment. To quantify the diagnostic utility, the area under the receiver operating characteristic curve was estimated along with a 95% confidence interval (CI). RESULTS: The inter-rater reliability was excellent for magnetic resonance imaging (ICC=0.83; 95% CI=0.74-0.89) and good for computed tomography/x-ray (ICC=0.69; 95% CI=0.51-0.81). The radiographic and pain scores proved to be independent predictors of treatment (P<0.001 and 0.004, respectively). An algorithm to determine the predictive probability for treatment versus observation in the study population was developed and tested based on these assessments. The area under the receiver operating characteristic curve of 0.85 (95% CI=0.79-0.92) indicated the good diagnostic performance of the algorithm. CONCLUSIONS: This novel grading system for radiographic response to sclerotherapy treatment demonstrates excellent to good inter-rater reliability giving providers a platform for discussion among themselves and with patients/parents. When incorporated with an assessment of pain, a predictive algorithm shows how this information could be used to determine the next steps after sclerotherapy treatment. LEVEL OF EVIDENCE: Level IV-case series.

Application of Fluorescence-Guided Surgery to Subsurface Cancers Requiring Wide Local Excision: Literature Review and Novel Developments Toward Indirect Visualization.

The excision of tumors by wide local excision is challenging because the mass must be removed entirely without ever viewing it directly. Positive margin rates in sarcoma resection remain in the range of 20% to 35% and are associated with increased recurrence and decreased survival. Fluorescence-guided surgery (FGS) may improve surgical accuracy and has been utilized in other surgical specialties. ABY-029, an anti-epidermal growth factor receptor Affibody molecule covalently bound to the near-infrared fluorophore IRDye 800CW, is an excellent candidate for future FGS applications in sarcoma resection; however, conventional methods with direct surface tumor visualization are not immediately applicable. A novel technique involving imaging through a margin of normal tissue is needed. We review the past and present applications of FGS and present a novel concept of indirect FGS for visualizing tumor through a margin of normal tissue and aiding in excising the entire lesion as a single, complete mass with tumor-free margins.

Pharmacologic Hemostatic Agents in Total Joint Arthroplasty-A Cost-Effectiveness Analysis.

BACKGROUND: Total knee and hip arthroplasties can be associated with substantial blood loss, affecting morbidity and even mortality. Two pharmacological antifibrinolytics, ε-aminocaproic acid (EACA) and tranexamic acid (TXA) have been used to minimize perioperative blood loss, but both have associated morbidity. Given the added cost of these medications and the risks associated with then, a cost-effectiveness analysis was undertaken to ascertain the best strategy. METHODS: A cost-effectiveness model was constructed using the payoffs of cost (in United States dollars) and effectiveness (quality-adjusted life expectancy, in days). The medical literature was used to ascertain various complications, their probabilities, utility values, and direct medical costs associated with various health states. A time horizon of 10 years and a willingness to pay threshold of $100,000 was used. RESULTS: The total cost and effectiveness (quality-adjusted life expectancy, in days) was $459.77, $951.22, and $1174.87 and 3411.19, 3248.02, and 3342.69 for TXA, no pharmacologic hemostatic agent, and EACA, respectively. Because TXA is less expensive and more effective than the competing alternatives, it was the favored strategy. One-way sensitivity analyses for probability of transfusion and myocardial infarction for all 3 strategies revealed that TXA remains the dominant strategy across all clinically plausible values. CONCLUSION: TXA, when compared with no pharmacologic hemostatic agent and with EACA, is the most cost-effective strategy to minimize intraoperative blood loss in hip and knee total joint arthroplasties. These findings are robust to sensitivity analyses using clinically plausible probabilities.

The Efficacy of Tranexamic Acid in Total Hip Arthroplasty: A Network Meta-analysis.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent commonly used to reduce blood loss in total hip arthroplasty (THA). The purpose of our study was to evaluate the efficacy of TXA in primary THA to support the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons, American Academy of Orthopaedic Surgeons, Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Medicine on the use of TXA in primary total joint arthroplasty. METHODS: A search was performed using Ovid-MEDLINE, Embase, Cochrane Reviews, Scopus, and Web of Science databases to identify all publications before July 2017 on TXA in primary THA. We completed qualitative and quantitative homogeneity testing of all included studies. Direct and indirect comparisons were analyzed using a network meta-analysis followed by consistency testing of the results. RESULTS: Two thousand one hundred thirteen publications underwent critical appraisal with 34 publications identified as representing the best available evidence for inclusion in the analysis. Topical, intravenous, and oral TXA formulations provided reduced blood loss and risk of transfusion compared to placebo, but no formulation was clearly superior. Use of repeat doses, higher doses, or variation in timing of administration did not significantly reduce blood loss or risk of transfusion. CONCLUSIONS: Strong evidence supports the use of TXA to reduce blood loss and risk of transfusion after primary THA. No specific routes of administration, dosage, dosing regimen, or time of administration provides clearly superior blood-sparing properties.

The Efficacy of Tranexamic Acid in Total Knee Arthroplasty: A Network Meta-Analysis.

BACKGROUND: A growing body of published research on tranexamic acid (TXA) suggests that it is effective in reducing blood loss and the risk for transfusion in total knee arthroplasty (TKA). The purpose of this network meta-analysis was to evaluate TXA in primary TKA as the basis for the efficacy recommendations of the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons, American Academy of Orthopaedic Surgeons, Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Medicine on the use of TXA in primary total joint arthroplasty. METHODS: We searched Ovid MEDLINE, Embase, Cochrane Reviews, Scopus, and Web of Science databases for publications before July 2017 on TXA in primary total joint arthroplasty. All included studies underwent qualitative and quantitative homogeneity testing. Direct and indirect comparisons were performed as a network meta-analysis, and results were tested for consistency. RESULTS: After critical appraisal of the available 2113 publications, 67 articles were identified as representing the best available evidence. Topical, intravenous (IV), and oral TXA formulations were all superior to placebo in terms of decreasing blood loss and risk of transfusion, while no formulation was clearly superior. Use of repeat IV and oral TXA dosing and higher doses of IV and topical TXA did not significantly reduce blood loss or risk of transfusion. Preincision administration of IV TXA had inconsistent findings with a reduced risk of transfusion but no effect on volume of blood loss. CONCLUSIONS: Strong evidence supports the efficacy of TXA to decrease blood loss and the risk of transfusion after primary TKA. No TXA formulation, dosage, or number of doses provided clearly improved blood-sparing properties for TKA. Moderate evidence supports preincision administration of IV TXA to improve efficacy.

The Safety of Tranexamic Acid in Total Joint Arthroplasty: A Direct Meta-Analysis.

BACKGROUND: Tranexamic acid (TXA) is effective in reducing blood loss in total joint arthroplasty (TJA), but concerns still remain regarding the drug's safety. The purpose of this direct meta-analysis was to evaluate and establish a basis for the safety recommendations of the combined clinical practice guidelines on the use of TXA in primary TJA. METHODS: A search was completed for studies published before July 2017 on TXA in primary TJA. We performed qualitative and quantitative homogeneity testing and a direct comparison meta-analysis. We used the American Society of Anesthesiologists (ASA) score of 3 or greater as a proxy for patients at higher risk for complications in general and performed a meta-regression analysis to investigate the influence of comorbidity burden on the risk of arterial thromboembolic event and venous thromboembolic event (VTE). RESULTS: Topical, intravenous, and oral TXA were not associated with an increased risk of VTE after TJA. In addition, meta-regression demonstrated that TXA use in patients with an ASA status of 3 or greater was not associated with an increased risk of VTE after total knee arthroplasty. CONCLUSION: Although most studies included in our analysis excluded patients with a history of prior thromboembolic events, our findings support the lack of evidence of harm from TXA administration in patients undergoing TJA. Moderate evidence supports the safety of TXA in patients undergoing total knee arthroplasty with an ASA score of 3 or greater. The benefits of using TXA appear to outweigh the potential risks of thromboembolic events even in patients with a higher comorbidity.

Patient-Reported Outcomes After Revision of Metal-on-Metal Total Bearings in Total Hip Arthroplasty.

BACKGROUND: Failure of metal-on-metal (MOM) total hip arthroplasty (THA) bearings is often accompanied by an aggressive local reaction associated with destruction of bone, muscle, and other soft tissues around the hip. Little is known about whether patient-reported physical and mental function following revision THA in MOM patients is compromised by this soft tissue damage, and whether revision of MOM THA is comparable with revision of hard-on-soft bearings such as metal-on-polyethylene (MOP). METHODS: We identified 75 first-time MOM THA revisions and compared them with 104 first-time MOP revisions. Using prospective patient-reported measures via the Veterans RAND-12, we compared Physical Component Score and Mental Component Score function at preoperative baseline and postoperative follow-up between revision MOM THA and revision MOP THA. RESULTS: Physical Component Score did not vary between the groups preoperatively and at 1 month, 3 months, and 1 year postoperatively. Mental Component Score preoperatively and 1 and 3 months postoperatively were lower in patients in the MOM cohort compared with patients with MOP revisions (baseline: 43.7 vs 51.3, P < .001; 1 month: 44.9 vs 53.3, P < .001; 3 months: 46.0 vs 52.3, P = .016). However, by 1 year, MCS scores were not significantly different between the revision cohorts. CONCLUSION: Postrevision physical function in revised MOM THA patients does not differ significantly from the outcomes of revised MOP THA. Mental function is markedly lower in MOM patients at baseline and early in the postoperative period, but does not differ from MOP patients at 1 year after revision. This information should be useful to surgeons and physicians facing MOM THA revision.

Management of limb length discrepancy after bone sarcoma resection about the knee in the skeletally immature.

Patients with bone sarcomas increasingly choose limb salvage. This can lead to issues with limb length discrepancy (LLD) for the skeletally immature. We synthesize management options into an algorithm and report our results. Patients with bone sarcomas involving any location from the femoral diaphysis to the tibial diaphysis 12 years or younger were reviewed. Our clinical pathway prescribed patients with metadiaphyseal lesions to intercalary allograft reconstruction, epiphyseal lesions and less than 5 cm expected LLD to osteoarticular allograft and patients with more than 5 cm expected LLD to extendable prosthesis. Twenty patients met inclusion criteria: 11 with osteoarticular allografts, 5 with extendable prostheses and 4 with intercalary allografts; median age 11.5 years; median follow-up 8.2 years; and final median LLD 1.6 cm. Five patients had contralateral epiphysiodesis, two patients underwent contralateral femoral shortening and a median of 6 (range 4-8) lengthenings were performed for extendable prostheses. Four patients had residual LLD over 3 cm. There were 13 revisions in 8 patients and 2 amputations. Limb-salvage in paediatric bone sarcoma of the knee can be managed with multiple techniques producing satisfactory results in regards to LLD. Careful pre-operative planning and shared decision making is a requisite given the high rate of secondary procedures for both LLD and reconstructive failures. Level of evidence: Level III Retrospective Comparative Study.

Self-Inflicted Hand Amputation without Replantation in a Patient with Body Integrity Identity Disorder: A Case Report.

CASE: We describe a patient who self-amputated his hand using a log splitter, because of a long-standing belief that the limb "did not belong to him." On admission, he refused replantation and was found to be nonpsychotic. He was diagnosed with body integrity identity disorder (BIID) and declared competent to make his own medical decisions. A revision amputation was performed. CONCLUSION: BIID is a challenging diagnosis that physicians treating traumatic injuries should be aware of. Many ethicists support elective amputation as a definitive treatment, because of potential harm reduction and because BIID does not respond to conservative modalities such as pharmacotherapy.

Acute Tubular Necrosis from Rhabdomyolysis from Leg Compartment Syndrome: A Case Report.

CASE: A 31-year-old male sustained acute compartment syndrome to his left leg after a low-energy fall and required a 4-compartment fasciotomy release. His immediate postoperative course was complicated by acute tubular necrosis (ATN) with creatinine elevated to 4.89 mg/dL from rhabdomyolysis. ATN was managed with aggressive hydration, sodium bicarbonate, and alkaline diuresis, and his creatinine levels improved. CONCLUSIONS: ATN from rhabdomyolysis is a rare complication of compartment syndrome that requires high suspicion and timely treatment to prevent further nephrotoxicity and the resultant increases in mortality. It is imperative for orthopedic surgeons to be aware of this potential complication.

Duration of military service is associated with decision quality in Veterans considering total knee replacement: case series.

PURPOSE: Due to the nature of military service, the patient-physician relationship in Veterans is unlike that seen in civilian life. The structure of the military is hypothesized to result in barriers to open patient-physician communication and patient participation in elective care decision-making. Decision quality is a measure of concordance between a chosen treatment and the aspects of medical care that matter most to an informed patient; high decision quality is synonymous with patient-centered care. While past research has examined how age and other demographic factors affect decision quality in Veterans, duration of military service, rank at discharge, and years since discharge have not been studied. PATIENTS AND METHODS: We enrolled 25 Veterans with knee osteoarthritis at a VA hospital. Enrollees completed a survey with demographic, military service, and decision-making preference questions and the Hip-Knee Decision Quality Instrument (HK-DQI), which measures patients' knowledge about their disease process, concordance of their treatment decision, and the considered elements in their decision-making process. RESULTS: The HK-DQI knowledge score had a significant, positive correlation with duration of military service (R2=0.36, p=0.004). Rank at discharge and years since discharge did not show a significant correlation with decision quality (p=0.500 and p=0.317, respectively). The concordance score did not show a statistically significant correlation with rank, duration of service, and years since discharge (p=0.640, p=0.486 and p=0.795, respectively). Additionally, decision process score was not significantly associated with rank, duration of military service, and years since discharge (p=0.380, p=0.885, and p=0.474, respectively). CONCLUSION: Decision quality in Veterans considering treatment for knee osteoarthritis appears to be correlated positively with duration of military service. These findings may present an opportunity for identification of Veterans at most risk of low decision quality and customization of shared decision-making methods for Veterans by characteristics of military service.

Risk factors for detectable metastatic disease at presentation in Ewing sarcoma - An analysis of the SEER registry.

BACKGROUND: Ewing family of tumors (EFT) represents the second-most common primary bone malignancy in children and adolescents. Approximately 25% of patients have radiographically detectable metastatic disease at presentation and experience poorer five-year survival, yet risk factors for metastatic disease at presentation are poorly characterized. We sought to study patient characteristics associated with metastatic disease upon presentation for patients with EFT. METHODS: We identified EFT cases in the Surveillance, Epidemiology, and End Results Program (SEER) registry from 2004 to 2012. Using univariate analyses and multivariable logistic regression, we explored the relationship between demographic and clinical factors and the presence of detectable metastatic disease at presentation. RESULTS: Among 870 EFT cases, 35% (n = 304) presented with detectable metastatic disease. These patients were commonly older (>24 years: 28% vs 19%, p = 0.002) and had a primary tumor site in the axial skeleton (56% vs 44%, p < 0.001). After adjusting for all covariates, compared to patients <11 years, those >24 years old faced a two-fold increase in the odds of metastatic disease (OR = 1.99, 95% CI: 1.17-3.38). Axial (OR = 2.31, 95% CI: 1.58-3.37) and "other" (OR = 2.35, 95% CI: 1.15-4.81) tumor locations had more than twice the likelihood of presenting with metastatic disease, compared to extremity tumor sites. Increasing tumor size conferred up to a three-fold increase in odds of metastatic disease (pTrend <0.001). CONCLUSIONS: Advanced age, axial tumor location, and increasing tumor size are associated with increased odds of detectable metastatic disease upon presentation with EFT. Although these characteristics are not modifiable, they provide objective factors that may inform patient counseling of metastatic risk.