Search

Metastatic bone disease of the distal extremities, also known as acrometastasis, is very rare. Thus, there is very limited information regarding the clinical manifestations and methods of surgical treatment. The current available literature shows that acrometastases are often encountered in the context of advanced disease and are thus associated with poor patient survival. As metastatic bone disease is generally uncurable, the goal of surgical treatment is to provide the patient with good function with as few complications as possible. In this article, we discuss the clinical manifestation of acrometastases, the methods of surgical intervention, and the expected clinical outcome. Non-surgically managed pathological fractures generally remain ununited; therefore, conservative treatment is reserved for patients with poor general condition or dismal prognosis. The current evidence suggests that in lesions of the lower arm and leg, osteosynthesis (plate and screw fixation or intramedullary nail) is the most common method of reconstruction, whereas local excision or amputation are more commonly used in cases of more distal lesions (such as ankle, foot and hand). Following surgery most patients receive adjuvant radiotherapy, even though its role is poorly documented. Close collaboration between orthopedic surgeons and medical oncologists is necessary to improve patient care and treatment outcome. Further studies are needed in order to provide stronger clinical evidence and improve decision-making, in an effort to optimize the patients’ quality of life and avoid the need for revision surgery.

Synovial sarcomas (SS) are malignant mesenchymal tumors characterized by the SS18-SSX fusion gene, which drives tumorigenesis by altering the composition of the BAF complex. Secondary genomic alterations that determine variations in tumor phenotype or clinical presentation are largely unknown. Herein, we present transcriptome, targeted DNA-sequencing, and proteomics analysis of 91 synovial sarcomas from 55 patients. We identified three SS clusters (SSCs) characterized by distinct histology, tumor microenvironments, genomic complexities, therapeutic effects, and clinical outcomes. Eight BAF complex components are differentially expressed among SSCs, and their role in mesenchymal-epithelial-transition is supported by single cell sequencing. The epithelial cells of biphasic tumors are more susceptible to developing copy number alterations, including amplification of PDCD1 and TMPRSS2. Our findings explain broad concepts in SS biology and imply that the BAF composition at the start of the tumorigenesis (i.e. the cellular linage) may determine the SS subtype, providing a rationale for individualized treatment strategies.

Treatment of high-grade osteosarcoma (OS) relies on a combination of systemic chemotherapy and radical surgical excision of the tumor. Little is known on what happens in case of an irrefutably inadequate (intralesional) margin. We aimed to describe the outcome of patients with high-grade OSs of the trunk and the extremities where planned wide resection resulted in an intralesional margin.A retrospective study from the Scandinavian Sarcoma Group registry and the Royal Orthopaedic Hospital databases including data from 53 patients surgically treated between the years 1990 and 2017.Local recurrence was observed in 13/53 patients. All patients with local recurrence where the neoadjuvant chemotherapy response could be retrieved (n = 9) were shown to be poor responders. None of the patients with good response to chemotherapy relapsed. Postoperative radiotherapy was not associated with improved local control of the disease. Re-excision surgery was performed in only seven patients, and two of them had tumor relapse.Good response to chemotherapy salvages the outcome of surgical excision with a poor margin in patients with high-grade OSs and a watchful waiting strategy may be justified in these cases. Poor responders have a higher recurrence risk and their approach should be individualized.

Background Clear‐cell chondrosarcomas (CCCSs) constitute a very rare subtype of chondrosarcoma. CCCS may radiologically mimic chondroblastoma, and given the difference in surgical approach, it is important to distinguish these two entities preoperatively. Design Using the institutional digital records, we identified histologically verified CCCS between 1996 and 2013, where preoperative fine‐needle aspiration (FNA) cytology was available. Clinical characteristics were categorized and described, and FNAs were reviewed by a panel of senior cytopathologists. In addition, corresponding radiological imaging was reviewed by senior radiologists, and a literature review on CCCS and chondroblastoma was conducted. Results A total of seven CCCS FNAs were identified from six patients. The cytomorphology showed low to intermediate cellular smears of clusters and single round or oval tumor cells. Tumor cells had rounded (sometimes binucleated) nuclei with limited pleomorphism and rich vacuolated cytoplasm. Chondroid background matrix was always found. While CCCS patients had a significantly higher age at diagnosis compared to chondroblastoma, no age cut‐off would distinctly separate the two. Conclusions CCCS has distinguished cytomorphological features on FNA smears. CCCS should be considered as a possible differential diagnosis in adults (>25 years) with a radiological suspicion of chondroblastoma. Since radiology and patient age cannot conclusively distinguish CCCS from chondroblastoma, FNA may prove an important tool for correct preoperative diagnosis of CCCS.

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan–Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.

Background: Sarcomas are rare tumours with heterogeneous clinical behaviour including varying rates of metastasis. Clinical treatment and follow-up rely on crude grading systems with uncertain accuracy for individual patients. Whole genome sequencing (WGS) detects both structural variation and single nucleotide variants and may thus add important diagnostic/prognostic information. Liquid biopsies (LB) may potentially identify hematogenous spread and treatment response rate but further evaluation in sarcomas is needed. Methods: In this study we explore the performance of individualized LB in four patients with different types of sarcomas. Fresh frozen tumour tissue was sequenced using WGS and whole transcriptome sequencing. Three putative driver variants or one fusion gene were selected per case and custom digital droplet PCR (ddPCR) assays were designed, evaluated on tumour DNA and used to assess levels of cell free tumour DNA in plasma taken prior to surgery. Results: In LB, ddPCR identified three variants in one patient with metastatic disease. The remaining three patients had negative LBs and were without disease at follow-up (>18 months after surgery). Conclusions: WGS is a powerful tool to detect all types of genetic changes in sarcoma and can facilitate clinical diagnosis/classification while custom LB may add prognostic information.

Highlights • Prostheses result in lower pain than osteosyntheses in pathological hip fractures. • Surgeons in sarcoma centers generally use prostheses for pathological hip fractures. • Both methods use similar healthcare resources and effectively restore ambulation., Aims How endoprosthetic replacement compares to osteosynthesis in the treatment of pathologic hip fractures as far as functional outcome and use of healthcare resources is concerned remains largely unknown. We aimed to investigate this in a nationwide registry. Methods We analyzed the functional outcome after surgery for a pathological fracture of the hip in terms of post-operative pain and ambulatory capacity. The preferred surgical method depending on the level of the treating unit was also examined. Furthermore, we documented the length of hospital stay and the patterns of discharge and compared them between these two methods. Results Patients operated with an endoprosthesis reported significantly lower pain at follow-up. Both methods (endoprosthetic replacement and osteosynthesis) were equally effective in restoring the ambulatory capacity and demanded a similar length of stay in hospital. Orthopaedic surgeons working in hospitals with dedicated sarcoma teams were more likely to use a prosthesis rather than osteosynthesis, when compared to surgeons working at other university hospitals or emergency hospitals. Conclusion Endoprosthetic replacement results in a better functional outcome in terms of post-operative pain without consuming more healthcare resources. Orthopaedic surgeons working in hospitals with sarcoma centers are more likely to use prostheses as compared to surgeons working at hospitals where dedicated musculoskeletal oncology teams are not available.

Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994–2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at −124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

Simple Summary Ewing sarcoma is a highly aggressive malignancy affecting primarily children and adolescents. It is the second most common bone sarcoma among children, affecting between 1 and 3 persons per million inhabitants. The tumor typically carries a pathognomonic chromosomal translocation resulting in a fusion transcript (EWSR1-FLI1), which plays an orchestral role in tumor development. While the fusion transcript has been known for decades, targeted treatment has been disappointing. However, new molecular techniques such as next-generation sequencing have significantly increased our understanding of this rare disease. Moreover, new closely related tumors with similar morphology but different characteristics have evolved. Treatment today consists of multiagent chemotherapy, radiation treatment, and surgery, all of which are associated with significant short- and long-term side effects. In this review article, we describe the currently existing diagnostic- and treatment-related challenges as well as the most important ongoing or recently conducted studies. Abstract Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years’ technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Simple Summary Immune cells can be powerful regulators of tumor growth and disease progression. Yet, the potential role of professional antigen-presenting cells in soft tissue sarcoma is poorly explored. Both dendritic cells and macrophages may present exogenous antigens through major histocompatibility complex (MHC) class I molecules to CD8+ T cells, a process referred to as cross presentation. With the concept of cellular cross presentation in mind, the present study supports the hypothesis that CD11c+ cells in direct cell-cell contact with CD8+ T cells within the primary tumor are associated with an active anti-tumor immune microenvironment and favorable prognosis. Our work hereby defines a novel biomarker for immune surveillance where presence of spatial cross presentation at tissue level resolution is significantly associated with overall survival. Importantly, this biomarker is independent from established prognostic markers like tumor grade. Biomarkers linked to immune surveillance are expected to gain increasing attention with the advent of immunotherapy in clinical practice. Abstract Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.

Purpose of Review This review presents a selection of regulatory molecules of tumor microenvironmental properties and metastasis. Signaling pathways controlling mesenchymal biology in bone and soft-tissue sarcomas found in children and adolescents are prioritized. Recent Findings The tumor microenvironment of pediatric tumors is still relatively unexplored. Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination. How these processes are involved in a mesenchymal phenotype and metastasis is further discussed in relation to the epithelial to mesenchymal transition (EMT) in epithelial tumors. Cell plasticity is emerging as a concept with impact on tumor behavior. Summary Sarcomas belong to a heterogeneous group of tumors where local recurrence and tumor spread pose major challenges despite intense multimodal treatments. Molecular pathways involved in the metastatic process are currently being characterized, and tumor-regulatory properties of structural components, and infiltrating, non-malignant cell types should be further investigated.

Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole‐transcriptome sequencing (RNA‐seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first‐line treatment. Transcriptome sequencing (RNA‐seq) of 13 ES cases was performed. Among the differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P, Transcriptome profiling may provide prognostic information in the incipient age of genetic‐driven personalized oncology. In this study, Chen et al. identified expression signatures associated with tumor progression and chemotherapy resistance in Ewing sarcomas, including IGF2 expression which was associated with an aggressive clinical course. Transcriptome analysis could potentially become a complementary tool to predict the clinical behavior of rare tumors.

Background The long-term risks and time trends of subsequent primary neoplasms (SPNs) among Ewing (ES) and osteosarcoma (OS) survivors are not fully understood. Methods We performed a nationwide study of all ES and OS patients identified in the Swedish Cancer Registry from 1958 to 2015 with up to 58 years of follow-up. The risk of SPN was compared with that of the general population using standardised incidence ratios (SIRs) and absolute excess risks (AERs). Results One hundred and fifteen SPNs were diagnosed among 1779 patients with ES or OS, yielding an overall SIR of 2.3 (95% confidence interval (CI), 1.9–2.7). The risk remained significantly increased in the latest treatment era (SIR2000-2015 2.0; 95% CI, 1.1–3.5). The highest absolute excess risks (AER) was due to breast cancer (AER 15.2/10,000 person-years; 95% CI, 5.0–29.8) followed by female genital malignancies (AER 9.5/10,000 person-years; 95% CI, 2.4–21.5). The excess breast cancer risk among ES survivors was noted also after 30 years of follow-up with 127 extra breast cancers/10,000 person-years (95% CI, 6.6–419). Conclusions Breast- and female genital malignancies contribute most to the excess risk of SPN among ES and OS survivors. Importantly, excess risks did not decline over calendar time or long-term follow-up.

BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.

Introduction: Bone sarcomas are rare primary mesenchymal tumours affecting children and adults. Since the advent of modern chemotherapeutic and reconstructive techniques, limb salvage has replaced amputation to become the standard of care for bone sarcomas. Surgical principles mandate achieving survival outcomes and maximising limb function. Whilst oncological and functional patient outcomes after limb-salvage surgery are frequently reported in scientific literature, the health related quality of life outcomes are frequently overlooked.Areas covered: Studies examining functional outcomes have generally reported better function after limb-salvage, but this may not necessarily translate into improved quality of life. This article examines functional and quality of life outcomes following amputation, limb-salvage and rotationplasty for bone sarcoma in the lower limbs.Expert commentary: Physical function and everyday competence to perform activities of daily living are predictive of quality of life, n...

AimsSolitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2–STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs.MethodsWe analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions.ResultsActivating −124 C>T (n=12) or −148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%–18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases.ConclusionsActivating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics.

Chondrosarcomas are malignant skeletal tumors with chondroid differentiation. Prognosis is largely dependent on histological grading, which suffer from significant interobserver variability. Telomerase activity and abundant telomerase reverse transcriptase (hTERT) expression has previously been associated with chondrosarcoma grade and metastasis. We therefore analyzed the hTERT promoter in clinicopathologically well-characterized chondrosarcomas (grade 1–3) from 87 patients. Using Sanger sequencing we identified an activating −124 C > T mutation in 23 cases (26%). Promoter mutations were significantly associated with increased histological grade (8% of grade 1, 32% of grade 2 and 46% of grade 3, P = 0.002), suggesting a role in tumor progression. In four chondrosarcomas where the histopathological grade was heterogenous, the hTERT mutation was only identified in the higher-grade areas. Additionally, hTERT promoter mutations were significantly associated with worse metastasis-free survival (P = 0.018), chondrosarcoma-specific survival (P = 0.022) and older patient age (P = 0.003). These data suggest that hTERT promoter mutations are common in high grade conventional chondrosarcomas. Granted that additional studies can confirm these findings; hTERT promoter analysis could potentially serve as an adjuvant prognostic marker in routine chondrosarcoma grading. This study reinforces the rationale of telomerase targeted therapy in a subset of chondrosarcomas.

Limb-preserving surgery using modular megaprostheses for the reconstruction of large skeletal defects is currently the preferred treatment for sarcomas. The authors report the postoperative outcomes after skeletal resection for lower extremity sarcomas and the use of the METS cemented modular implant system (Stanmore Implants, Hertfordshire, United Kingdom) for reconstruction. They retrospectively studied 52 consecutive patients operated on from 2003 to 2012. There were 27 distal femur prostheses, 13 proximal femur, 11 proximal tibia, and 1 total femur implants. Patients were followed for a mean of 4.3 years. Overall patient survival, prosthesis survival, limb salvage rate, and secondary complications were documented. Five years postoperatively, prosthesis survival was 79%. Complications warranting implant revision surgery were documented in 15% of patients, whereas complications warranting surgery of any kind were observed in 27% of the patients. Nonmechanical complications, namely local relapse of the tumor and prosthetic infection, were the most common cause of prosthetic failure, accounting for 88% of major revision surgeries and 100% of amputations. Mechanical complications were rare, observed in only 6% of patients. No patients required secondary revision surgery. The limb salvage rate was 89%. Overall patient survival was 79% at 5 years and 71% at 10 years. The low risk for mechanical complications and the high limb salvage rate support the use of the METS modular megaprostheses for the reconstruction of skeletal defects following lower limb sarcoma surgery. [ Orthopedics. 2015; 38(5):e401–e406.]