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Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published (GA questions). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty-eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Excision of bone tumors and endoprosthetic reconstruction allow patients early weightbearing and a potential functional advantage compared with amputation. These reconstructions do not restore the limb to normal status, however, and patients are subject to complications that may result in revision or loss of the limb. Because better understanding of these complications based on current information might help the patient and surgeon in decision-making, we undertook a systematic review of studies published on this topic., Questions/purposes: (1) What are the primary modes and proportion of failure of tumor endoprostheses in patients undergoing reconstruction after excision of primary extremity bone sarcomas?, Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library for all studies published from April 15, 1998, to April 15, 2018. Three reviewers independently reviewed studies reporting endoprosthetic reconstruction survival and events requiring revision for primary extremity bone tumors treated with endoprosthetic reconstruction for inclusion and performed independent data extraction. We excluded all studies with fewer than five patients, any systematic review/meta-analyses, and any study not reporting on primary extremity bone tumors. All discrepancies were resolved by the study's senior author. Data extracted from included studies were any reoperation event for wound dehiscence, any operative fixation for a pathologic fracture, and any revision of the primary endoprosthesis for implant wear or breakage, deep infection not amenable to prosthesis retention, or for local recurrence. We assessed the overall quality of the evidence with the Methodological Index for Non-Randomized Studies (MINORS) approach with a higher MINORS score representative of a more methodologically rigorous study with a total possible score of 16 points for noncomparative and 24 points for comparative studies. Forty-nine studies met criteria for inclusion from an initial search return of 904 studies, of which no studies were randomized controlled trials. From a total patient population of 2721, there was a mean followup of 93 months (range, 1-516 months) with loss to followup or death occurring in 447 of 2118 (21%) patients with six studies not providing loss to followup data. The mean MINORS score was 14 for prospective studies and 11 for retrospective studies., Results: Overall, there were 1283 reoperations among the 2721 (47%) patients. Reoperation for mechanical endoprosthetic events (soft tissue dehiscence or periarticular soft tissue instability, aseptic loosening, or implant wear/fracture) occurred in 907 of 2721 (33%) patients. Aseptic loosening occurred at a mean of 75 months (range, 1-376 months) in 212 of 315 patients (67%). Deep infection requiring removal of the initial prosthesis occurred in 247 of 2721 (9%) patients with deep infection occurring at a mean of 24 months (range, 1-372 months) in the 190 infections (77%) with time to infection data available. Local recurrence rates requiring revision or amputation occurred in 129 (5%) of all patients. There was an overall primary endoprosthesis survival rate without any surgical reintervention of 63% among reporting studies at a mean of 79 months followup., Conclusions: Failures of endoprosthetic reconstructions after extremity tumor surgery are common, most often resulting from implant wear or fracture, aseptic loosening, and infection. Importantly, the aggregated data are the first to attempt to quantify the time to specific complication types within this patient population. Deep infection not amenable to endoprosthesis retention appears to occur approximately 2 years postoperatively in most patients, with aseptic loosening occurring most commonly at 75 months. Although endoprosthetic reconstruction is one of the most common forms of reconstruction after bone tumor resection, the quality of published evidence regarding this procedure is of low quality with high loss to followup and data quality limiting interstudy analysis. The quality of the evidence is low with high loss to followup and inconsistent reporting of times to reintervention events. Although the most common modes of endoprosthetic failure in this population are well known, creation of quality prospective, collaborative databases would assist in clarifying and informing important elements of the followup process for these patients., Level of Evidence: Level IV, therapeutic study.

Bone tumors account for a small fraction of childhood cancers. Most published reports are from developed countries. The purpose of this study was to review the primary bone tumors in children and adolescents treated at a referral center in Northern Tanzania. We completed a 10-year hospital-based cross-sectional study in which all patients younger than 20 years diagnosed with a primary bone tumor at the Kilimanjaro Christian Medical Center Orthopaedic Department from January 2006 to December 2015 were identified and reviewed. Of the 80 identified patients, 15 (18.8%) were aged 5 to 8 years, and 65 (81%) were aged 9 to 19 years. Forty-seven males (59%) and 33 females (41%) were identified. The most common tumor locations were the femur, tibia, and humerus. Osteosarcoma was the most common malignant diagnosis (49 patients, 61%). No cases of Ewing sarcoma were reported. The most common tribal origins of the patients were Chagga and Maasai. Most primary bone tumors treated at a referral center in Northern Tanzania are malignant, with osteosarcoma representing the vast majority. No cases of Ewing sarcoma were identified in this tertiary referral hospital-based database.

Introduction: Registering study protocols in a trial registry is important for methodologic transparency and reducing selective reporting bias. The objective of this investigation was to determine whether published studies of intimate partner violence (IPV) that had been registered matched the registration record on key study design elements., Methods: We systematically searched three trial registries to identify registered IPV studies and the published literature for the associated publication. Two authors independently determined for each study whether key study elements in the registry matched those in the published paper., Results: We included 66 studies published between 2006 and 2017. Nearly half (29/66, 44%) were registered after study completion. Many (26/66, 39%) had discrepancies regarding the primary outcome, and nearly two-thirds (42/66, 64%) had discrepancies in secondary outcomes. Discrepancies in study design were less frequent (13/66, 20%). However, large changes in sample size (26/66, 39%) and discrepancies in funding source (28/66, 42%) were frequently observed., Conclusions: Trial registries are important tools for research transparency and identifying and preventing outcome switching and selective outcome reporting bias. Published IPV studies often differ from their records in trial registries. Researchers should pay close attention to the accuracy of trial registry records.

Background: The open-access model has changed the landscape of academic publishing over the last 20 years. An unfortunate consequence has been the advent of predatory publishing, which exploits the open-access model for monetary gain by collecting publishing fees from authors under the pretense of being a legitimate publication while providing little-to-no peer review. This study aims to investigate the predatory publishing phenomenon in orthopaedic literature., Methods: We searched Beall's List of Predatory Journals and Publishers and another list of predatory journals for journal titles that are possibly related to orthopaedics. We then searched their web sites for the following information: total number of articles published, journal country of origin, author country of origin, article processing charge (APC), quoted review time, and location of the listed headquarters. We also reported the article quality of a random sample of these journals. We consulted InCites Journal Citation Reports to determine the number of nonpredatory orthopaedic publications that are indexed, and we manually searched a random sample of these legitimate journals for Beall's criteria. Additionally, we searched the Directory of Open Access Journals (DOAJ) and PubMed databases for any possible predatory journal titles., Results: We found 104 suspected predatory publishers, representing 225 possible predatory journals. One journal was indexed in the DOAJ, and 20 were indexed in PubMed. Review time was not identified for 56.2% of the journals, and 36.5% quoted a review time of <1 month. Nearly half of the listed addresses of the publishers were either unsearchable or led to residential or empty lots. Eighty-two legitimate journals were identified. The median APC was $420 for predatory journals and $2,900 for legitimate journals. We found that a random sample of the legitimate journals published studies with higher reporting standards, but a few also contained 1 criterion that is found on Beall's list., Conclusions: This study highlights the scope of orthopaedic predatory publishing. Possibly predatory journals outnumber legitimate orthopaedic journals. Orthopaedic surgeons should be aware of the suspected predatory journals and consult available online tools to identify them because distinguishing them from legitimate journals can be a challenge.

The surgical management of benign and benign aggressive bone tumors typically involves intralesional curettage and reconstruction of the resulting defect with cement or bone graft material. At the authors' institution, an injectable synthetic calcium sulfate-calcium phosphate composite is now the standard graft material for these cases. This study reports the long-term follow-up, specifically the stability of bone regeneration, for the use of the synthetic graft material for oncologic reconstruction. Fourteen patients who underwent intralesional curettage of a primary bone tumor followed by cavitary reconstruction with synthetic graft material who had at least 4-year follow-up were identified from an institutional orthopedic oncology database. Clinical outcome data, focusing on long-term clinical and radiographic features of the reconstruction, were extracted from electronic and paper medical records. Seven females and 7 males were included (mean age at surgery, 28.1 years; range, 13-64 years). Follow-up ranged from 50 to 105 months (mean, 68 months). Most surgical reconstructions were done for the lower limb (n=11), and giant cell tumor of bone was the most common tumor treated. The mean amount of synthetic graft material used was 18.6 cm 3 . Complete radiographic resorption and new bone incorporation was observed within the first year, and bone remodeling was complete in all patients. Bone remodeling remained stable throughout the longer-term follow-up (ie, up to 9 years). The use of an injectable synthetic calcium sulfate-calcium phosphate composite is a viable option in the reconstruction of cavitary bone defects following intralesional curettage of primary benign bone tumors. This reconstruction technique was safe, with no long-term complications, and led to complete radiographic resorption and new bone incorporation with long-lasting stability. [Orthopedics. 2018; 41(6):e868-e875.]., (Copyright 2018, SLACK Incorporated.)

Background: The molecular pathogenesis of many forms of soft tissue sarcomas (STS) have been rigorously characterized in the medical literature, which may be particularly important for the diagnosis and prediction of prognosis in STS., Methods: Electronic databases (2005 to October 2016) were searched. Gastrointestinal stromal tumor and pediatric sarcomas were excluded. The eligible individual study's risk of bias and the quality of aggregate evidence were assessed. Meta-analyses were performed., Results: Of 6674 identified articles, 70 were eligible and analyzed, covering 13 types of STS. Meta-analyses showed that the test of detecting MDM2 amplification by fluorescence in situ hybridization was accurate in differentiating atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma from benign tumors (N = 971; sensitivity = 95%, 95% confidence interval [CI] 89-98; specificity = 100%, CI 89-100) or from other STS (N = 347; sensitivity = 99%, CI 72-100; specificity = 90%, CI 78-95); that the test of detecting SS18-SSX fusion by reverse transcription polymerase chain reaction (PCR) was accurate in differentiating synovial sarcoma from other STS (N = 532; sensitivity = 93%, CI 85-96; specificity = 99%, CI 96-100). The presence of a CTNNB1 S45F mutation detected by PCR was a risk factor for decreased recurrence-free survival in desmoid tumors (N = 418; hazard ratio from 3.50 [CI 1.51-8.14] to 6.20 [CI 2.24-17.15])., Conclusions: Sarcomas are rare cancers whose molecular pathogenesis is becoming increasingly understood. The current evidence demonstrates that molecular analyses are useful in the diagnosis and prediction of prognosis in some STS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Several challenges presently impede the conduct of prospective clinical studies in orthopaedic oncology, including limited financial resources to support their associated costs and inadequate patient volume at most single institutions. This study was conducted to prioritize research questions within the field so that the Musculoskeletal Tumor Society (MSTS), and other relevant professional societies, can direct the limited human and fiscal resources available to address the priorities that the stakeholders involved believe will have the most meaningful impact on orthopaedic oncology patient care., Questions/purposes: The purpose of this study was to use a formal consensus-based approach involving clinician-scientists and other stakeholders to identify the top priority research questions for future international prospective clinical studies in orthopaedic oncology., Methods: A three-step modified Delphi process involving multiple stakeholder groups (including orthopaedic oncologists, research personnel, funding agency representation, and patient representation) was conducted. First, we sent an electronic questionnaire to all participants to solicit clinically relevant research questions (61 participants; 54% of the original 114 individuals invited to participate returned the questionnaires). Then, participants rated the candidate research questions using a 5-point Likert scale for five criteria (60 participants; 53% of the original group participated in this portion of the process). Research questions that met a priori consensus thresholds progressed for consideration to an in-person consensus meeting, which was attended by 44 participants (39% of the original group; 12 countries were represented at this meeting). After the consensus panel's discussion, members individually assigned scores to each question using a 9-point Likert scale. Research questions that met preset criteria advanced to final ranking, and panel members individually ranked their top three priority research questions, resulting in a final overall ranking of research priorities., Results: A total of 73 candidate research questions advanced to the consensus meeting. In the end, the consensus panel identified four research priorities: (1) Does less intensive surveillance of patients with sarcoma affect survival? (2) What are the survival outcomes over time for orthopaedic oncology implants? (3) Does resection versus stabilization improve oncologic and functional outcomes in oligometastatic bone disease? (4) What is the natural history of untreated fibromatosis?, Conclusions: The results of this study will assist in developing a long-term research strategy for the MSTS and, possibly, the orthopaedic oncology field as a whole. Furthermore, the results of this study can assist researchers in guiding their research efforts and in providing a justified rationale to funding agencies when requesting the resources necessary to support future collaborative research studies that address the identified orthopaedic oncology priorities.

Background: The journal impact factor (JIF) is thought to reflect the average number of citations an article will receive and therefore can influence study impact and clinical decision making. However, analysis of citation rates across multiple scientific and research domains has shown that most articles will not reach this expected number of citations. This phenomenon is known as citation skew and it has not previously been examined in the orthopaedic literature. The objective of this study was to determine the extent to which citation skew exists within orthopaedic journals and thus to determine whether the JIF in the orthopaedic literature reflects individual study citation rates., Methods: We used data from the Thomson Reuters (now Clarivate Analytics) Web of Science to determine the 2015 JIF and citation distribution for all orthopaedic journals listed in the database. We calculated the percentage of articles with fewer citations than the JIF for each journal. Finally, we analyzed the citation distribution within groups of orthopaedic subspecialty publications., Results: We identified a total of 74 orthopaedic journals and 29,296 publications for the years 2013 and 2014. Across all orthopaedic journals, 85% of published articles are cited fewer times than the JIF would indicate. The median number of citations of all articles was zero for all journals (interquartile range = 0-0) except for seven journals, for which the median number of citations per article was 1., Conclusion: Citation skew is prevalent across the orthopaedic literature. Most published work is not cited in the first 2 years following publication, and the JIFs are the result of a few highly cited articles. The assessment of an individual orthopaedic study's quality should not be determined by the JIF but rather by direct evaluation of the methodology, relevance, and appropriateness of the study's conclusions., Competing Interests: Dr. Ghert or an immediate family member serves as a board member, owner, officer, or committee member of the Musculoskeletal Tumor Society and the Orthopaedic Research Society, and as a paid consultant for Wright Medical Technology. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Bozzo, Dr. Evaniew, and Dr. Oitment.

Background: The annual number of retracted publications in the scientific literature is rapidly increasing. The objective of this study was to determine the frequency and reason for retraction of cancer publications and to determine how journals in the cancer field handle retracted articles., Methods: We searched three online databases (MEDLINE, Embase, The Cochrane Library) from database inception until 2015 for retracted journal publications related to cancer research. For each article, the reason for retraction was categorized as plagiarism, duplicate publication, fraud, error, authorship issues, or ethical issues. Accessibility of the retracted article was defined as intact, removed, or available but with a watermark over each page. Descriptive data was collected on each retracted article including number of citations, journal name and impact factor, study design, and time between publication and retraction. The publications were screened in duplicated and two reviewers extracted and categorized data., Results: Following database search and article screening, we identified 571 retracted cancer publications. The majority (76.4%) of cancer retractions were issued in the most recent decade, with 16.6 and 6.7% of the retractions in the prior two decades respectively. Retractions were issued by journals with impact factors ranging from 0 (discontinued) to 55.8. The average impact factor was 5.4 (median 3.54, IQR 1.8-5.5). On average, a retracted article was cited 45 times (median 18, IQR 6-51), with a range of 0-742. Reasons for retraction include plagiarism (14.4%), fraud (28.4%), duplicate publication (18.2%), error (24.2%), authorship issues (3.9%), and ethical issues (2.1%). The reason for retraction was not stated in 9.8% of cases. Twenty-nine percent of retracted articles remain available online in their original form., Conclusions: Retractions in cancer research are increasing in frequency at a similar rate to all biomedical research retractions. Cancer retractions are largely due to academic misconduct. Consequences to cancer patients, the public at large, and the research community can be substantial and should be addressed with future research. Despite the implications of this important issue, some cancer journals currently fall short of the current guidelines for clearly stating the reason for retraction and identifying the publication as retracted.

Background: Researchers are experiencing an innovative shift toward online distribution of their work, and metrics related to online scholarly influence are gaining importance. Our objectives were to determine which types of online activity are most prevalent in orthopaedics, to identify associated factors, and to explore a complementary approach to measuring overall scholarly influence using online activity and conventional citations., Methods: We performed a systematic review of randomized controlled trials of surgical or nonsurgical interventions in participants with, or at specific risk for, injuries and diseases of the musculoskeletal system. We collected data on online activity in social media, mainstream media, blogs, forums, and other sources from a commercial provider of alternative metric data for medical journals. We tested associations with use of negative binomial regression., Results: We identified 1,697 trials, published between 2011 and 2014, that had a total of 12,995 conventional citations and 15,068 online mentions. The median number of online mentions of each trial was 2 (interquartile range, 0 to 5). Twitter (82%) and Facebook (13%) mentions were the most prevalent types of online activity. Counts of online mentions correlated with conventional citations (r = 0.11, p < 0.01) but accumulated more rapidly. Higher total counts of online mentions were consistently associated with longer time since publication, higher journal impact factor, higher author h-index values, and less risk of bias (p < 0.01 for each). We found the best model fit for a complementary approach by weighting citations and online mentions equally., Conclusions: Online activity in orthopaedics is dominated by activity on Twitter and Facebook and is associated with increasing time since publication, journal impact factor, and author h-index values, and less risk of bias. Institutions, publishers, funding agencies, and clinicians may consider a complementary approach to measuring scholarly influence that weights online mentions and conventional citations equally.

Background: Level of evidence (LOE) framework is a tool with which to categorize clinical studies based on their likelihood to be influenced by bias. Improvements in LOE have been demonstrated throughout orthopaedics, prompting our evaluation of orthopaedic oncology research LOE to determine if it has changed in kind., Questions/purposes: (1) Has the LOE presented at the Musculoskeletal Tumor Society (MSTS) annual meeting improved over time? (2) Over the past decade, how do the MSTS and Orthopaedic Trauma Association (OTA) annual meetings compare regarding LOE overall and for the subset of therapeutic studies?, Methods: We reviewed abstracts from MSTS and OTA annual meeting podium presentations from 2005 to 2014. Three independent reviewers evaluated a total of 1222 abstracts for study type and LOE; there were 577 abstracts from MSTS and 645 from OTA. Changes in the distributions of study type and LOE over time were evaluated by Pearson chi-square test., Results: There was no change over time in MSTS LOE for all study types (p = 0.13) and therapeutic (p = 0.36) study types during the reviewed decade. In contrast, OTA LOE increased over this time for all study types (p < 0.01). The proportion of Level I therapeutic studies was higher at the OTA than the MSTS (3% [14 of 413] versus 0.5% [two of 387], respectively), whereas the proportion of Level IV studies was lower at the OTA than the MSTS (32% [134 of 413] versus 75% [292 of 387], respectively) during the reviewed decade. The proportion of controlled therapeutic studies (LOE I through III) versus uncontrolled studies (LOE IV) increased over time at OTA (p < 0.021), but not at MSTS (p = 0.10)., Conclusions: Uncontrolled case series continue to dominate the MSTS scientific program, limiting progress in evidence-based clinical care. Techniques used by the OTA to improve LOE may be emulated by the MSTS. These techniques focus on broad participation in multicenter collaborations that are designed in a comprehensive manner and answer a pragmatic clinical question.

There is a demand for providing evidence on the effectiveness of research investments on the promotion of novice researchers' scientific productivity and production of research with new initiatives and innovations. We used a mixed method approach to evaluate the funding effect of the New Investigator Fund (NIF) by comparing scientific productivity between award recipients and non-recipients. We reviewed NIF grant applications submitted from 2004 to 2013. Scientific productivity was assessed by confirming the publication of the NIF-submitted application. Online databases were searched, independently and in duplicate, to locate the publications. Applicants' perceptions and experiences were collected through a short survey and categorized into specified themes. Multivariable logistic regression was performed. Odds ratios (OR) with 95 % confidence intervals (CI) are reported. Of 296 applicants, 163 (55 %) were awarded. Gender, affiliation, and field of expertise did not affect funding decisions. More physicians with graduate education (32.0 %) and applicants with a doctorate degree (21.5 %) were awarded than applicants without postgraduate education (9.8 %). Basic science research (28.8 %), randomized controlled trials (24.5 %), and feasibility/pilot trials (13.3 %) were awarded more than observational designs (p   <  0.001). Adjusting for applicants and application factors, awardees published the NIF application threefold more than non-awardees (OR = 3.4, 95 %, CI = 1.9, 5.9). The survey response rate was 90.5 %, and only 58 % commented on their perceptions, successes, and challenges of the submission process. These findings suggest that research investments as small as seed funding are effective for scientific productivity and professional growth of novice investigators and production of research with new initiatives and innovations. Further efforts are recommended to enhance the support of small grant funding programs., Competing Interests: and adherence to ethical principles Authors acknowledge that they have adhered to the ethical principles and have no commercial associations or any other arrangements that might be a conflict of interest in connection with the submitted manuscript.

Objectives: (1) To provide recommendations regarding the choice of surgery, radiation therapy (RT), or the combination of surgery plus RT in patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy. (2) To determine the appropriate surgical planning imaging (pre-chemotherapy magnetic resonance imaging [MRI] or post-chemotherapy MRI) to identify optimal resection margins in patients with localized Ewing's sarcoma who undergo surgery following neoadjuvant chemotherapy., Methods: MEDLINE, EMBASE, the Cochrane Library (1999 to February 2015), main guideline websites, and relevant annual meeting abstracts (2012 to January 2015) were searched. Internal and external reviews were conducted., Recommendations: 1. Recommendation (1) - In patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy: (a) Surgery alone or RT alone are two reasonable treatment options; the combination of surgery plus RT is not recommended as an initial treatment option. (b) The local treatment for an individual patient should be decided by a multidisciplinary tumour board together with the patient after consideration of the following: (1) patient characteristics (e.g., age, tumour location, tumour size, response to neoadjuvant chemotherapy, and existing comorbidities), (2) the potential benefit weighed against the potential complications from surgery and/or toxicities associated with RT, and (3) patient preferences. 2. Recommendation (2) - In patients with localized Ewing's sarcoma who will undergo surgery: (a) Both pre-chemotherapy and post-chemotherapy MRI scans should be taken into consideration for surgical planning. In certain anatomic locations with good chemotherapy response, the post-chemotherapy MRI may be the appropriate imaging modality to plan surgical resection margins., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Orthopaedic oncology researchers face several obstacles in the design and execution of randomised controlled trials, including finite fiscal resources to support the rising costs of clinical research and insufficient patient volume at individual sites. As a result, high-quality research to guide clinical practice has lagged behind other surgical subspecialties. A focused approach is imperative to design a research programme that is economical, streamlined and addresses clinically relevant endpoints. The primary objective of this study will be to use a consensus-based approach to identify research priorities for international clinical trials in orthopaedic oncology., Methods and Analysis: We will conduct a 3-phase modified Delphi method consisting of 2 sequential rounds of anonymous web-based questionnaires (phases I and II), and an in-person consensus meeting (phase III). Participants will suggest research questions that they believe are of particular importance to the field (phase I), and individually rate each proposed question on 5 criteria (phase II). Research questions that meet predetermined consensus thresholds will be brought forward to the consensus meeting (phase III) for discussion by an expert panel. Following these discussions, the expert panel will be asked to assign scores for each research question, and research questions meeting predetermined criteria will be brought forward for final ranking. The expert panel will then be asked to rank the top 3 research questions, and these 3 research questions will be distributed to the initial group of participants for validation., Ethics and Dissemination: An ethics application is currently under review with the Hamilton Integrated Research Ethics Board in Hamilton, Ontario, Canada. The results of this initiative will be disseminated through peer-reviewed publications and conference presentations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To perform a systematic review to investigate the optimal treatment strategy among the options of surgery alone, radiotherapy (RT) alone, and the combination of RT plus surgery in the management of localized Ewing's sarcoma of bone following neo-adjuvant chemotherapy., Methods: MEDLINE and EMBASE (1999 to February 2015), the Cochrane Library, and relevant conferences were searched., Results: Two systematic reviews and eight full texts met the pre-planned study selection criteria. When RT was compared with surgery, a meta-analysis combining two papers showed that surgery resulted in a higher event-free survival (EFS) than RT in any location (HR = 1.50, 95% CI 1.12-2.00; p = 0.007). However another paper did not find a statistically significant difference in patients with pelvic disease, and no papers identified a significant difference in overall survival. When surgery plus RT was compared with surgery alone, a meta-analysis did not demonstrate a statistically significant difference for EFS between the two groups (HR = 1.21, 95% CI 0.90-1.63). Both surgical morbidities and radiation toxicities were reported., Conclusions: The existing evidence is based on very low aggregate quality as assessed by the GRADE approach. In patients with localized Ewing's sarcoma, either surgery alone (if complete surgical excision with clear margin can be achieved) or RT alone may be a reasonable treatment option. The optimal local treatment for an individual patient should be decided through consideration of patient characteristics, the potential benefit and harm of the treatment options, and patient preference., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)

Purpose: The objective of the study was to characterize the radiographic appearance of graft resorption and new bone incorporation into a postresection defect of the calcium-sulfate calcium-phosphate synthetic bone graft composite following resection of benign bone tumours., Methods: Twenty-five patients who underwent treatment with the CaSO4/CaPO4 synthetic graft following bone tumour resection were retrospectively identified from our oncology database. Postoperative radiographs were assessed for: 1) combined partial graft resorption and ingrowth at the graft site; 2) complete graft resorption with complete incorporation of new bone into the defect. After chronologically grouping radiographs, the volume of graft material used to fill bony defects, radiographic evidence of complications, and patterns of resorption were recorded., Results: Partial resorption of graft material/partial ingrowth of new bone was seen in 21 patients at 2.5 months postoperatively. Complete resorption of graft with complete new bone incorporation at the graft site was seen in 94% of cases (15 of 16) by 10 months after surgery. Mean time to complete incorporation of new bone was 6.7 months. Time to resorption of the graft with new bone ingrowth was found to be related to the volume of graft used with smaller volumes showing earlier resorption. For all cases demonstrating resorption (21 of 21), the pattern observed was peripheral to central. Five patients developed complications, including tumour recurrence, cyst formation, and graft site infection., Conclusion: Our study suggests a characteristic time and volume related radiographic pattern of resorption and new bone ingrowth with the CaSO4/CaPO4 synthetic graft. Findings that deviate from this pattern may represent complication and warrant additional follow-up., (Copyright © 2016 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Giant cell tumor of bone (GCTB) is a relatively rare tumor of bone, characterized by numerous multinucleated cells, severe osteolysis, and local recurrence., Purpose: To explore the role of S-phase kinase-interacting protein 2 (Skp2), cyclin-dependent kinase inhibitor p27, and the transcription factor E2F-1 expression in the development of GCTB, and the relationship of expression of these proteins with tumor recurrence., Methods: Forty-four patients with GCTB were selected and demographic and clinical data were collected. The levels of Skp2, p27, and E2F-1 protein expression were immunohistochemically assessed in surgical specimens., Results: Skp2, p27, and E2F-1 proteins were detected in the nuclei of mononuclear stromal cells. Positive Skp2 expression was observed in 66% (29/44) of GCTB patient samples, and positive p27 expression was found in 39% (17/44) of samples. Within almost all GCTB patients, there was an inverse correlation between Skp2- and p27-positive tumor cells. Positive expression of E2F-1 was present in 28 of 44 (64%) patients. In addition, expression of skp2 and p27, infiltration of soft tissues, and surgical operation were significantly associated with recurrence in patients with GCTB., Conclusion: The immunohistochemical assessment of Skp2, p27 and E2F-1 may be useful in the diagnosis of GCTB and prediction of its prognosis.

Background Context: Randomized controlled trials (RCTs) are the most trustworthy source for evaluating treatment effects, but RCTs of spine surgery interventions often produce discordant results. The Fragility Index is a novel metric to inform about the robustness of statistically significant results., Purpose: The aim was to determine the robustness of statistically significant results from RCTs of spine surgery interventions., Study Design/setting: This was a systematic survey., Patient Sample: The sample included RCTs of spine surgery interventions., Outcome Measures: The Fragility Index is the minimum number of patients in a trial whose status would have to change from a nonevent to an event to change a statistically significant result to a nonsignificant result. Events refer to the occurrence of any dichotomous outcome, such as successful fusion, incident fracture, adjacent segment degeneration, or achievement of a certain functional score. A small Fragility Index indicates that the statistical significance of a result hinges on only a few events, and a large Fragility Index increases one's confidence in the observed treatment effects., Methods: We systematically reviewed a database for evidence-based orthopedics and identified all the RCTs that reported at least one positive outcome (ie, p<.05). Two reviewers independently assessed eligibility and extracted data. We used the Fisher exact test to compute Fragility Index values and multivariable linear regression to evaluate potential associated factors., Results: We identified 40 eligible RCTs with a median sample size of 132 patients (interquartile range [IQR] 79-208) and a median total number of outcome events for the chosen outcome of 31 (IQR 13-63). The median Fragility Index was two (IQR 1-3), which means that adding two events to one of the trial's treatment arms eliminated its statistical significance. The Fragility Index was less than or equal to three events in 75% of the trials, and was less than or equal to the number of patients lost to follow-up in 65% of the trials. Fragility Index values correlated positively with total sample size (r=0.35; p<.05). When adjusted for losses to follow-up and risk of bias, increasing Fragility Index values were associated only with increasingly significant reported p values (p<.01)., Conclusions: Statistically significant results in spine surgery RCTs are frequently fragile. The addition of only a small number of outcome events can completely eliminate significance. Surgeons, researchers, and other evidence users should exercise caution when interpreting the findings from RCTs with low Fragility Index values and applying these results to patient care., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background Context: Meta-analyses are powerful tools that can synthesize existing research, inform clinical practice, and support evidence-based care. These studies have become increasingly popular in the spine surgery literature, but the rigor with which they are being conducted has not yet been evaluated., Purpose: Our primary objectives were to evaluate the methodological quality (credibility) of spine surgery meta-analyses and to propose strategies to improve future research. Our secondary objectives were to evaluate completeness of reporting and identify factors associated with higher credibility and completeness of reporting., Study Design: This study is based on a systematic survey of meta-analyses., Outcome Measures: We evaluated credibility according to the Users' Guide to the Medical Literature and completeness of reporting according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist., Methods: We systematically searched MEDLINE, EMBASE, and The Cochrane Library, and two reviewers independently assessed eligibility, credibility, and completeness of reporting. We used multivariable linear regression to evaluate potential associations. Interrater agreement was quantified using kappa and intraclass correlation (ICC) coefficients., Results: We identified 132 eligible meta-analyses of spine surgery interventions. The mean credibility score was 3 of 7 (standard deviation [SD], 1.4; ICC, 0.86), with agreement for each item ranging from 0.54 (moderate) to 0.83 (almost perfect). Clinical questions were judged as sensible in 125 (95%), searches were exhaustive in 102 (77%), and risk of bias assessments were undertaken in 91 (69%). Seven (5%) meta-analyses addressed possible explanations for heterogeneity using a priori subgroup hypotheses and 24 (18%) presented results that were immediately clinically applicable. Investigators undertook duplicate assessments of eligibility, risk of bias, and data extraction in 46 (35%) and rated overall confidence in the evidence in 24 (18%). Later publication year, increasing Journal Impact Factor, increasing number of databases, inclusion of Randomized Controlled Trials, and inclusion of non-English studies were significantly associated with higher credibility scores (p<.05). The mean score for reporting was 18 of 27 (SD, 4.4; ICC, 0.94)., Conclusions: The credibility of many current spine surgery meta-analyses is limited. Researchers can improve future meta-analyses by performing exhaustive literature searches, addressing possible explanations of heterogeneity, presenting results in a clinically useful manner, reproducibly selecting and assessing primary studies, addressing confidence in the pooled effect estimates, and adhering to guidelines for complete reporting., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine whether vitamin C is effective in preventing complex regional pain syndrome (CRPS) in patients with distal radius fractures., Data Sources: MEDLINE (1946 to present), EMBASE (1974 to present), and The Cochrane Library (no date limit) were systematically searched up to September 6, 2014, using MeSH and EMTREE headings with free text combinations., Study Selection: Randomized trials comparing vitamin C against placebo were included. No exclusions were made during the selection of eligible trials on the basis of patient age, sex, fracture severity, or fracture treatment., Data Extraction: Two reviewers independently screened articles, extracted data, and applied the Cochrane Risk of Bias tool. Evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach., Data Synthesis: Heterogeneity was quantified using the χ test and the I statistic. Outcome data were combined with a random effects model., Results: Across 3 trials (n = 890) of patients with distal radius fractures, vitamin C did not reduce the risk for CRPS (risk ratio = 0.45; 95% confidence interval, 0.18-1.13; I = 70%). This result was confirmed in sensitivity analyses to test the importance of missing data because of losses to follow-up under varying assumptions. Heterogeneity was explained by diagnostic criteria, but not regimen of vitamin C or fracture treatment., Conclusions: The evidence for vitamin C to prevent CRPS in patients with distal radius fractures fails to demonstrate a significant benefit. The overall quality of the evidence is low, and these results should be interpreted in the context of clinical expertise and patient preferences.

Extraskeletal para-articular osteochondromas of the infrapatellar fat pad are unique soft-tissue tumors whose etiology and clinical history remain poorly understood. We report three cases and a systematic review of the literature. Three females, aged 47, 54, and 70 years, presented with pain and a parapatellar knee mass. All three underwent marginal excision with no complications and no recurrence. In the literature, 32 reports describing 42 cases were identified. Mean age at presentation was 51.1 years (range: 12-75). There were 25 females and 20 males. Seven patients (15.6%) had a history of antecedent trauma. Mean duration of presenting symptoms was 63.9 months (range: 2-300). All patients except for one underwent open excision. Mean follow-up was 14.9 months (range: 3-96). There were no reports of recurrence or malignant transformation. Para-articular extraskeletal osteochondromas of the infrapatellar fat pad have a benign clinical history regardless of whether they are managed by arthroscopic or open marginal excision., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Commentary on: Liu S, Liu L. Re: Evaniew N, Yarascavitch B, Madden K, Ghert M, Drew B, Bhandari M, et al. Atlantoaxial instability in acute odontoid fractures is associated with nonunion and mortality. Spine J 2015;15:1160 (in this issue)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background Context: Odontoid fractures are the most common geriatric cervical spine fractures. Nonunion rates have been reported to be up to 40% and mortality up to 35%, and poor functional outcomes are common. Atlantoaxial instability (AAI) is a plausible prognostic factor, but its role has not been previously examined., Purpose: To determine the effect of severe AAI on the outcomes of nonunion and mortality in patients with acute odontoid fractures., Study Design: Retrospective cohort/single institution., Patient Sample: One hundred twenty-four consecutive patients with acute odontoid fractures., Outcome Measures: Rates of nonunion and mortality., Methods: Two independent blinded reviewers measured AAI using postinjury computed tomography scans. Patients were classified as having "severe" or "minimal" AAI on the basis of greater versus less than or equal to 50% mean subluxation across each C1-C2 facet joint. Rates of nonunion and mortality were compared using independent samples t tests and adjusted for age, displacement, and subtype using binary logistic regression., Results: One hundred seven patients had minimal AAI and 17 had severe AAI. Mean follow-up was 4.4 months (standard deviation=4.6). Patients with severe AAI were more likely to experience nonunion (29% vs. 10%, respectively; p=.03) and mortality (35% vs. 14%, respectively; p=.03) regardless of treatment modality. Fracture displacement correlated with AAI (r(2)=0.65). When adjusted for patient age, the odds ratio of nonunion with severe AAI approached significance at 3.3 (95% confidence interval [CI]: 0.9-11.7). Mortality prediction with AAI approached a twofold increased risk (odds ratio=2.1; 95% CI: 0.6-6.8). In patients with Type-II fractures, the odds of mortality with severe AAI approached a threefold higher risk (odds ratio=3.3; 95% CI: 0.9-12.3)., Conclusions: Patients with acute odontoid fractures and severe AAI may be more likely to experience nonunion and mortality, suggesting the possibility that aggressive management could be warranted. Further investigation with a large prospective study including patient-important functional outcomes is justified., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Post-operative spine surgical site infections are associated with substantial morbidity, mortality, and economic burden. Intrawound vancomycin may prevent infections after spine surgery, but recent studies have reported conflicting results. The objectives of this systematic review and meta-analysis were to determine: (1) In patients undergoing spine surgery, does the application of intrawound vancomycin lead to reduced rates of post-operative surgical site infections? (2) Are there differences in the estimates of effect between observational studies and randomized trials? (3) What adverse events are reported in the literature?, Methods: All published comparative studies of intrawound vancomycin in spine surgery were included. Two reviewers independently screened eligible articles and assessed study quality. Observational studies and randomized trials were pooled separately using a random-effects model., Results: Eight observational studies and one randomized controlled trial met the inclusion criteria. Across observational studies, the odds of infection with intrawound vancomycin was 0.19 times the odds of infection without intrawound vancomycin (95 % CI 0.08-0.47, p = 0.0003, I (2) = 52 %). The single randomized controlled trial produced a conflicting result (OR 0.96, 95 % CI 0.34-2.66, p = 0.93). There were no adverse events attributable to intrawound vancomycin. The quality of the evidence was low or very low., Conclusions: There is a lack of high-quality evidence to inform the use of intrawound vancomycin in spine surgery. Surgeons should be cautious before widely adopting this intervention and should be vigilant in monitoring for adverse effects. Further investigation with additional randomized controlled trials is justified.

Background: Evidence Based Medicine (EBM) is increasingly being applied to inform clinical decision-making in orthopaedic surgery. Despite the promotion of EBM in Orthopaedic Surgery, the adoption of results from high quality clinical research seems highly unpredictable and does not appear to be driven strictly by randomized trial data. The objective of this study was to pilot a survey to determine if we could identify surgeon opinions on the characteristics of research studies that are perceived as being most likely to influence clinical decision-making among orthopaedic surgeons in Canada., Methods: A 28-question electronic survey was distributed to active members of the Canadian Orthopaedic Association (COA) over a period of 11 weeks. The questionnaire sought to analyze the influence of both extrinsic and intrinsic characteristics of research studies and their potential to influence practice patterns. Extrinsic factors included the perceived journal quality and investigator profiles, economic impact, peer/patient/industry influence and individual surgeon residency/fellowship training experiences. Intrinsic factors included study design, sample size, and outcomes reported. Descriptive statistics are provided., Results: Of the 109 members of the COA who opened the survey, 95 (87%) completed the survey in its entirety. The overall response rate was 11% (95/841). Surgeons achieved consensus on the influence of three key designs on their practices: 1) randomized controlled trials 94 (99%), 2) meta-analysis 83 (87%), and 3) systematic reviews 81 (85%). Sixty-seven percent of surgeons agreed that studies with sample sizes of 101-500 or more were more likely to influence clinical practice than smaller studies (n = <100). Factors other than design influencing adoption included 1) reputation of the investigators (99%) and 2) perceived quality of the journal (75%)., Conclusion: Although study design and sample size (i.e. minimum of 100 patients) have some influence on clinical decision making, surgeon respondents are equally influenced by investigator reputation and perceived journal quality. At present, continued emphasis on the generation of large, methodologically sound clinical trials remains paramount to translating research findings to clinical practice changes. Specific to this pilot survey, strategies to solicit more widespread responses will be pursued.

Background: Scoping reviews are innovative studies that can map a range of evidence to convey the breadth and depth of a large field. An evidence-based approach to the wide spectrum of surgical interventions for scoliosis is paramount to enhance clinical outcomes. The objectives of this scoping review were to identify critical knowledge gaps and direct future research., Methods: This study was completed according to the methodology of Arksey and O'Malley. Two reviewers performed duplicate systematic screening of eligibility. Studies were classified according to patient age, scoliosis etiology, outcomes reported, study design, and overall research theme., Results: There were 1763 eligible studies published between 1966 and 2013. The literature focused on adolescents (83% of studies) with idiopathic scoliosis (72%). There was a dominance of observational designs (88%), and a paucity of randomized trials (4%) or systematic reviews (1%). Fifty six percent of studies were conducted in North America, followed by 23% in Europe and 18% in Asia. Few high-level studies investigated surgical indications, surgical approaches, surgical techniques, or implant selection. Patient important outcomes including function, health-related quality of life, pain, and rates or re-operation were infrequently reported., Conclusions: Current research priorities are to (1) undertake high-quality knowledge synthesis and knowledge translation activities; (2) conduct a series of planning meetings to engage clinicians, patients, and methodologists; and (3) clarify outcome reporting and strategies for methodological improvement. Higher-quality studies are specifically needed to inform surgical indications, surgical approaches, surgical techniques, and implant selection. Engaging global partners may increase generalizability.

Chondrosarcoma is the most common primary bone malignancy in the adult population with a high rate of pulmonary metastasis. Chondrosarcoma is managed with surgical excision as the tumors do not respond well to conventional chemotherapy or radiation therapy. Thus, there exists a dire need to develop systemic treatment options to target chondrosarcoma cells for metastatic spread. We hypothesized that the expression of miR-145 is low in chondrosarcoma, leading to decreased transcriptional control of SOX9 (the master regulator of chondrogenesis), and downstream activation of the transcription factor ETV5. We have previously shown that ETV5 activates MMP-2 expression in chondrosarcoma, which in turn increases local bone matrix resorption. In this study, we confirm high expression of SOX9 in human chondrosarcoma using real-time PCR, Western blotting, and immunofluorescence. An ETV5 promoter-reporter plasmid was transfected into chondrosarcoma cells to determine if SOX9 directly regulates the expression of ETV5. Co-transfection of the ETV5 promoter-plasmid with SOX9 lentivirus significantly increased the luciferase activity derived from the ETV5 promoter, from which the regulatory relationship between SOX9 and ETV5 is established. MiR-145 was found to be down-regulated in chondrosarcoma cell lines, patient samples, and further confirmed with a public sarcoma database. After stable miR-145 lentiviral transfection, the subsequent mRNA expression levels of SOX9, ETV5, and MMP-2 were significantly decreased in chondrosarcoma cells. The results generated by this study may have important clinical significance in the treatment of patients with chondrosarcoma in that targeted miRNA may have the potential to downregulate the upstream activators of proteases such as MMP-2., (© 2014 Wiley Periodicals, Inc.)

Background: Surgical management of metastatic bone disease (MBD) is typically reserved for lesions with the highest risk of fracture. However, the high risk of perioperative complications associated with surgery may outweigh the benefits of improved pain and/or function. The goal of this study was to (1) assess the quality of current evidence in this domain; (2) confirm that surgical management of metastases to the long bones and pelvis/acetabulum provides pain relief and improved function; and (3) assess perioperative morbidity and mortality rates., Methods: We conducted a systematic review of the literature for clinical studies that reported pain relief and function outcomes, as well as perioperative complications and mortality, in patients with MBD to the long bones and/or pelvis/acetabulum treated surgically. Multiple databases were searched up to January 2012. Pooled weighted proportions are reported., Results: Forty-five studies were included in the final analysis, with 807 patients. All included studies were level IV with 'moderate' overall quality of evidence using the Methodological Index for Non-Randomized Studies scale. Pain relief following surgical management of metastases was 93, 91, and 93 % in the humerus, femur, and pelvis/acetabulum, respectively. Maintained or improved function after surgery was seen in 94, 89, and 94 % in the humerus, femur, and pelvis/acetabulum, respectively. Perioperative complications and mortality were 17 and 4 %, respectively., Conclusions: Despite the inherent limitations of the current evidence, a benefit for the surgical management of bone metastases to the long bones and pelvis/acetabulum is evident; however, there is still substantial risk of perioperative morbidity and mortality that should be considered.

Background: Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment., Methods: Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction)., Results: Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated., Conclusions: Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression., Clinical Relevance: It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative., (Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.)

Due to practical and ethical concerns associated with human experimentation, animal models have been essential in cancer research. However, the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is generally not translated to human trials. Animal models can serve as an important source of in vivo information, but alternative translational approaches have emerged that may eventually replace the link between in vitro studies and clinical applications. This review summarizes the current state of animal model translation to clinical practice, and offers some explanations for the general lack of success in this process. In addition, some alternative strategies to the classic in vivo approach are discussed.

Background: Benign and malignant lower extremity primary bone tumors are among the least common conditions treated by orthopaedic surgeons. The literature supporting their surgical management has historically been in the form of observational studies rather than prospective controlled studies. Observational studies are prone to confounding bias, sampling bias, and recall bias., Questions/purposes: (1) What are the overall levels of evidence of articles published on the surgical management of lower extremity bone tumors? (2) What is the overall quality of reporting of studies in this field based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist? (3) What are the most common pitfalls in reporting that authors might improve on?, Methods: All studies describing the surgical management of lower extremity primary bone tumors from 2002 to 2012 were systematically reviewed. Two authors independently appraised levels of evidence. Quality of reporting was assessed with the STROBE checklist. Pitfalls in reporting were quantified by determining the 10 most underreported elements of research study design in the group of studies analyzed, again using the STROBE checklist as the reference standard. Of 1387 studies identified, 607 met eligibility criteria., Results: There were no Level I studies, two Level II studies, 47 Level III studies, 308 Level IV studies, and 250 Level V studies. The mean percentage of STROBE points reported satisfactorily in each article as graded by the two reviewers was 53% (95% confidence interval, 42%-63%). The most common pitfalls in reporting were failures to justify sample size (2.2% reported), examine sensitivity (2.2%), account for missing data (9.8%), and discuss sources of bias (14%). Followup (66%), precision of outcomes (64%), eligibility criteria (55%), and methodological limitations (53%) were variably reported., Conclusions: Observational studies are the dominant evidence for the surgical management of primary lower extremity bone tumors. Numerous deficiencies in reporting limit their clinical use. Authors may use these results to inform future work and improve reporting in observational studies, and treating surgeons should be aware of these limitations when choosing among the various options with their patients.

Objectives: Increase in periostin (PN) was reported in clear cell renal cell carcinoma (ccRCC). But how PN contributes to ccRCC pathogenesis remains unclear. This research will investigate the underlying mechanism., Methods: The PN protein in 37 adjacent non-tumour kidney (ANK) tissues, their respective ccRCCs, 16 cases of metastasised ccRCC and xenograft tumours was analysed by immunohistochemistry. PN expression in ccRCC cells and NIH3T3 fibroblasts was examined by real time PCR (polymerase chain reaction) and western blot., Results: PN was detected at low levels in the tubular epithelial cells of ANKs. PN was robustly increased in the ccRCC-associated stroma of both organ-confined and metastasised ccRCCs. Furthermore, despite A498 ccRCC cells and their-derived xenograft tumour cells expressing a low level of PN, a strong presence of stromal PN was observed especially in the boundary region between xenograft tumour mass and non-tumour tissue. Collectively, these results suggest that the ccRCC-associated PN was derived from stroma instead of tumours. This notion was supported by the co-existence of PN with α-smooth muscle actin (αSMA), a marker of activated fibroblasts, in both local and metastasised ccRCC. Furthermore, co-culture of NIH3T3 mouse fibroblasts with either human A498 or 786-0 ccRCC cells dramatically enhanced PN transcription only in NIH3T3 cells as well as NIH3T3 cell-mediated accumulation of extracellular PN. In return, extracellular PN significantly enhanced A498 cell attachment. Elevation of PN promotes NIH3T3 cell proliferation and enhanced AKT activation., Conclusions: ccRCC induces fibroblast-mediated accumulation of stromal PN; stromal PN enhances ccRCC cell attachment and fibroblast proliferation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The aim of this study is to determine the efficacy of low-level laser therapy (LLLT) in reducing acute and chronic neck pain as measured by the visual analog scale (VAS). A systematic search of nine electronic databases was conducted to identify original articles. For study selection, two reviewers independently assessed titles, abstracts, and full text for eligibility. Methodological quality was assessed using the Detsky scale. Data were analyzed using random-effects model in the presence of heterogeneity and fixed-effect model in its absence. Heterogeneity was assessed using Cochran's Q statistic and quantifying I (2). Risk ratios (RR) with 95 % confidence intervals (CI) were reported. Eight randomized controlled trials involving 443 patients met the strict inclusion criteria. Inter-rater reliability for study selection was 92.8 % (95 % CIs 80.9-100 %) and for methodological quality assessment was 83.9 % (95 % CIs 19.4-96.8 %). Five trials included patients with cervical myofascial pain syndrome (CMPS), and three trials included different patient populations. A meta-analysis of five CMPS trials revealed a mean improvement of VAS score of 10.54 with LLLT (95 % CI 0.37-20.71; Heterogeneity I (2 )= 65 %, P = 0.02). This systematic review provides inconclusive evidence because of significant between-study heterogeneity and potential risk of bias. The benefit seen in the use of LLLT, although statistically significant, does not constitute the threshold of minimally important clinical difference.

Objective: Objective assessment of resident performance continues to task program directors (PDs) with a formidable challenge. This study evaluated attitudes toward the Orthopaedic In-Training Examination (OITE), compared its value between countries, assessed its value against other metrics of resident performance, and examined program and resident factors predictive of high achievement., Design: Survey., Setting: Orthopedic surgery residency programs across the United States and Canada., Participants: One hundred sixty-six PDs and 945 residents., Results: Eighty-eight PDs and 331 residents completed the surveys (response rates, 54% and 35%, respectively). PDs and residents in the United States assigned greater importance to the OITE than did those in Canada and reported OITE scores from the United States were significantly higher. PDs in the United States reported greater consequences for residents with poor scores than did PDs from Canada, including remediation and reprimand. Observed structured clinical examinations, internal examinations, and in-training evaluation reports were assigned greater importance by PDs and residents in Canada, but low or no importance by those in the United States. In preparation for the OITE, residents strongly favored prior OITE and American Academy of Orthopaedic Surgeons self-assessment questions, the 'AAOS Comprehensive Orthopaedic Review' textbook, the Journal of the American Academy of Orthopaedic Surgeons, and an OITE-based multiple-choice question website. Regression analysis identified resident and program emphasis on OITE studying and higher level of training as positive predictors for higher OITE scores., Conclusions: The OITE is more important to PDs and residents in the United States than it is in Canada, and the reported OITE scores reflect these attitudes. PDs in Canada also employ a greater diversity of evaluative tools, a practice in keeping with recent advances toward competency-based medical education. The findings of this report may help PDs be aware of alternative methods of formative resident evaluation and ultimately improve the training of future independent surgeons., (Copyright © 2013 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Parathyroid-hormone-related protein (PTHrP) has been shown to be an important factor in osteolysis in the setting of metastatic carcinoma to the bone. However, PTHrP may also be central in the setting of primary bone tumors. Giant cell tumor of bone (GCT) is an aggressive osteolytic bone tumor characterized by osteoclast-like giant cells that are recruited by osteoblast-like stromal cells. The stromal cells of GCT are well established as the only neoplastic element of the tumor, and we have previously shown that PTHrP is highly expressed by these cells both in vitro and in vivo. We have also found that the stromal cells exposed to a monoclonal antibody to PTHrP exhibited rapid plate detachment and quickly died in vitro. Therefore, PTHrP may serve in an autocrine manner to increase cell proliferation and promote invasive properties in GCT. The purpose of this study was to use transcriptomic microarrays and functional assays to examine the effects of PTHrP neutralization on cell adhesion, migration and invasion. Microarray and proteomics data identified genes that were differentially expressed in GCT stromal cells under various PTHrP treatment conditions. Treatment of GCT stromal cells with anti-PTHrP antibodies showed a change in the expression of 13 genes from the integrin family relative to the IgG control. Neutralization of PTHrP reduced cell migration and invasion as evidenced by functional assays. Adhesion and anoikis assays demonstrated that although PTHrP neutralization inhibits cell adhesion properties, cell detachment related to PTHrP neutralization did not result in associated cell death, as expected in mesenchymal stromal cells. Based on the data presented herein, we conclude that PTHrP excreted by GCT stromal cells increases bone tumor cell local invasiveness and migration., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Limb salvage surgery (LSS) with endoprosthetic replacement is the most common method of reconstruction following bone tumor resection in the adult population. The risk of a postoperative infection developing is high when compared with conventional arthroplasty and there are no appropriate guidelines for antibiotic prophylaxis., Questions/purposes: We sought to answer the following questions: (1) What is the overall risk of deep infection and the causative organism in lower-extremity long-bone tumor surgery with endoprosthetic reconstruction? (2) What antibiotic regimens are used with endoprosthetic reconstruction? (3) Is there a correlation between infection and either duration of postoperative antibiotics or sample size?, Methods: We conducted a systematic review of the literature for clinical studies that reported infection rates in adults with primary bony malignancies of the lower extremity treated with surgery and endoprosthetic reconstruction. The search included articles published in English between 1980 and July 2011., Results: The systematic literature review yielded 48 studies reporting on a total of 4838 patients. The overall pooled weighted infection rate for lower-extremity LSS with endoprosthetic reconstruction was approximately 10% (95% CI, 8%-11%), with the most common causative organism reported to be Gram-positive bacteria in the majority of cases. The pooled weighted infection rate was 13% after short-term postoperative antibiotics and 8% after long-term postoperative antibiotics. There was no correlation between sample size and infection rate., Conclusions: Infection rates of 10% are high when compared with rates for conventional arthroplasty. Our results suggest that long-term antibiotic prophylaxis decreases the risk of deep infection. However, the data should be interpreted with caution owing to the retrospective nature of the studies.

Introduction: Surgical management of Giant Cell Tumor of Bone of the distal radius (GCTDR) remains controversial due to risk of local recurrence (LR) offset by functional limitations which result from en-bloc resection. This study aims to determine the oncologic and functional outcomes of wide excision (WE) vs intralesional curettage (IC) of GCTDR., Methods: A complete search of the applicable literature was done. Included studies reported on patients from the same cohort who were surgically treated for GCTDR with WE or IC. Two reviewers independently assessed all papers. The primary outcome measure was LR., Results: One-hundred-forty-one patients from six studies were included: 60 treated with WE, and 81 with IC. Five WE patients (8%) suffered LR whereas 25 IC patients (31%) did. The odds of LR were three times less in the WE group vs the IC group. MSTS1993 scores, where available, were on average 'good' with WE and 'excellent' with IC., Conclusions: Within statistical limitations the data support an attempt, where feasible, at wrist joint preservation and superior function with IC. Intralesional curettage is reasonable when the functional benefit outweighs the risk of recurrence as is the case in many cases of GCT of the distal radius.

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer., (Copyright © 2012 Orthopaedic Research Society.)

Benign primary bone tumors are commonly treated with intralesional curettage with or without the use of surgical adjuvants. The reconstructive approach to the resulting contained bone defects is controversial, and clinical practice is varied. Synthetic bone substitutes may provide early mechanical support while minimizing the risks of disease transmission, nonunion, infection, and donor-site morbidity. Limited data exists regarding the use of calcium sulfate-calcium phosphate composite bone substitute for this purpose. The authors retrospectively reviewed the clinical outcomes of 24 patients with benign primary bone tumors who underwent intralesional curettage followed by reconstruction with a calcium sulfate-calcium phosphate composite bone substitute. Mean follow-up was 23 months. The most common diagnosis was giant cell tumor of bone. Six patients had upper-extremity tumors and 18 had lower-extremity tumors. Mean preoperative radiographic tumor volume was 41.0 cm(3). Mean volume of PRO-DENSE (Wright Medical Technology, Arlington, Tennessee) used in each patient was 15.6 cm(3). Mean time to full weight bearing for all patients was 7.3 weeks. Two patients sustained local tumor recurrences. No postoperative fractures occurred, and no complications occurred related to the use of the calcium sulfate-calcium phosphate composite. One case of deep infection occurred secondary to wound breakdown. The use of a calcium sulfate-calcium phosphate composite was associated with rapid biological integration and an early return to activities of daily living, with no composite-related complications. This technique is a viable option in the reconstruction of cavitary bone defects following intralesional curettage of primary benign bone tumors., (Copyright 2013, SLACK Incorporated.)