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Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy. Significance: Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment.

To evaluate the utility and complications of using carbon fiber implants (CFIs) compared with standard titanium alloy (TI) intramedullary implants for stabilization of impending or existing pathologic fractures.Retrospective comparison.Ninety-four patients undergoing intramedullary fixation of 100 impending or existing pathologic fractures between 2014-2019 were identified for inclusion.The primary outcome was postoperative complications. Other outcomes included implant type, pathology, indication, and adjuvant therapy.Fifty-three percent of cases used a CFI, whereas 47% of cases used a TI. There were no differences between groups with regard to anatomic location (P = 0.218), indication for surgery (P = 0.066), histology (P = 0.306), or postoperative adjuvant therapy (P = 0.308). Nineteen percent of cases incurred a postoperative complication in each group (P = 0.530), and no differences were noted with regard to complication type including implant failure (P = 0.442) and wound complications (P = 0.322). There was a cost saving of $400 with TI implants compared with CFI.This is a high-risk population for postoperative complications after stabilization of pathologic fractures. Although there were no statistical differences in complications between CFI and TI, implant choice depends on patient characteristics and surgeon preference.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Protein Expression, Shotgun Proteomics

Quantification and viability of T cell groups

Tumor antigen–specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor-infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor antigen–specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T-cell–intrinsic energy consumption was the process of oxidative protein folding and disulfide bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α). To test this hypothesis, we created TCR transgenic mice with a T-cell–specific PERK gene deletion (OT1+Lckcre+PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T-cell groups displayed superior tumor control compared with T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1+ tumor antigen–specific CD8+ TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1+ CD8+ TILs and bolstered CD8+ TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T-cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.

Supplemental Figures S1-S11

Mixed linear modeling results for tumor curves

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.Significance:Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment.

Introduction The purpose of this study was to evaluate nationwide trends and regional variability in opioid prescriptions after common orthopaedic procedures. Methods A retrospective analysis of privately insured subjects from the MarketScan database between 2015 and 2016 was conducted. Median oral morphine equivalents and interquartile ranges were analyzed by region for the initial post-op prescriptions and 90-day total prescriptions for opioid-naive patients undergoing the following: carpal tunnel release; anterior cruciate ligament reconstruction; arthroscopic meniscectomy; bimalleolar ankle fracture open reduction and internal fixation; distal radius fracture open reduction and internal fixation; arthroscopic rotator cuff repair; single-level anterior cervical discectomy and fusion; and total shoulder, hip, and knee arthroplasties. We hypothesized that notable regional variability exists with postoperative narcotic prescribing habits. Results Seventy three thousand nine hundred twenty-one opioid-naive patients were identified. A notable regional variability was observed across the United States in the prescriptions given for all procedures, except total joint arthroplasty. Furthermore, although patients undergoing soft-tissue-only procedures required the fewest refills, patients undergoing total joint arthroplasty required the most. Discussion Notable regional variability exisits in opioid prescribing patterns for many common orthopaedic procedures. Furthermore, prescriptions were smallest in the region most affected by the opioid epidemic. This information can be used to re-evaluate recommendations, serve as a benchmark for surgeons, and develop institutional and quality improvement guidelines to reduce excess postoperative opioid prescriptions. Level of evidence Level III observational cohort study.

Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a SMARCB1 or SMARCA4 genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES.

Protein synthesis enables cell growth and survival, but the molecular mechanisms through which T cells suppress or maintain protein translation in the stress of solid tumors are unknown. Using mouse models and human tumors we demonstrate that protein translation in T cells is repressed by the solid tumor microenvironment (TME) due to activation of the unfolded protein response (UPR) via phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (p-eIF2α). Given that acute glucose deprivation in T cells exacerbated p-eIF2α, we show that metabolic reprogramming toward glycolytic independence allays the UPR and p-eIF2α, enabling sustained protein translation in T cells in TME stress. UPR mitigation was associated with enhanced degradation of proteins in antitumor T cells, as proteasome inhibition resulted in eIF2α phosphorylation, attenuation of translation, and loss of antitumor efficacy. In contrast, proteasome stimulation relieved translation inhibition, inducing robust T cell tumor control, offering a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.

Surgical specialties are at an increased risk for occupational hazards, including sharps-related injuries. The objective of this study was to report the frequency of sharps injuries and evaluate which characteristics influence the number of injuries and reporting behaviors.A web-based, anonymous survey was available for 10 weeks to 46 US orthopaedic surgery residency programs (1,207 potential residents) participating in an education research collaborative. The survey was divided into the following areas: demographics, training and attitudes concerning occupational hazards, and sharps injuries and reporting. Logistic regression was used to evaluate the association between the above variables on experiencing sharps injuries with significance threshold set at P0.05.In this study, 518 surveys were included yielding a response rate of 42.9% (518/1,207). Nearly 80% of the residents recalled some form of safety training during intern orientation and 62% of the respondents felt that they received adequate occupation safety training specifically related to orthopaedic surgery. Four hundred seventeen residents (80.5%) experienced a sharps injury (mean 2.8). Nearly 20% of the respondents experienced ≥5 sharps injuries. Needle sticks (38.8%) were responsible for the greatest percentage of injuries, followed by Kirschner wires (33.6%), scalpel (22.5%), and bone (17.3%). Only 42% of the residents consistently reported all injuries. Reasons included feelings of no risk (63.1%), too much hassle (58.9%), embarrassment (14.5%), other (8.7%), forgot (5.8%), and unclear what to do (3.3%). Inadequate safety training specific to orthopaedic surgery (odds ratio, 2.32 [95% confidence interval, 1.20 to 4.46]; P = 0.012) and greater training seniority (odds ratio, 2.04 [95% confidence interval, 1.64 to 2.52]; P0.0001) were associated with acquiring five or more sharps injuries.Sharps injuries are a prevalent and concerning reality for orthopaedic surgical trainees. Despite this common occurrence, only 42% of the residents always reported their injuries. Inadequate training specific to orthopaedic surgery and each subsequent year of postgraduate training are associated with increased sharps injuries.Level III, retrospective observational survey.

Resources detailing the scope, details, and duration for teaching and learning surgical model development in research are poorly described. Situated learning and instructional scaffolding are useful skill-building tools. Herein, we discuss educational theory in the context of a training paradigm for surgical researchers, using our experience with a nonunion femoral fracture model as an example. Stages of learning include cognitive, associative, and autonomous stages. In surgical training, the cognitive stage involves the acquisition of basic knowledge, including anatomy, surgical approach, instrumentation, and suturing, which can be taught by using books, videos, skeletons, and cadavers. To these basic skills, the associative stage adds advanced techniques—including anesthesia, asepsis, hemostasis, and the full surgical procedure—through mentored nonsurvival surgical experiences. After a mentor has assured competence, trainees perform supervised and then independent survival surgeries to complete the autonomous stage. Through these stages, instructional scaffolding is applied in the context of a situated learning environment in which trainees learn in a layered approach through their own experiences. Thus, the proposed training paradigm is structured to teach trainees how to think and act as surgeons so they can adapt and grow, rather than only to ensure technical competency in a specific model. Development and mastery of complex surgical models may require as long as 6 mo to achieve optimal outcomes, depending on the preexisting skill of the research surgeons, technical difficulty, and the stage of model evolution.

Background T cells are a secretory immune subset with the capacity to control solid tumors. Protein translation is of paramount importance in CD8 T cells, controlling proliferation, stimulation and lineage fate. Methods Herein, we used both the fluorescent analogue of methionine homopropargylglycine (HPG) incorporation assay and O-propargyl-puromycin (OPP) method which enters the A-site of the ribosome and effectively labels and terminates nascent polypeptide chains to monitor protein synthesis in mouse and human tumors. Moreover, we employed label free quantitative proteomics (LFQ), lipidomics, metabolic analysis, and in vivo animal modeling to elucidate mechanisms of protein translation in antitumor immunity. Results We found that canonical protein synthesis is restricted in endogenous CD8 tumor infiltrating lymphocytes (TILs) by the tumor microenvironment (TME). Proteomic analysis revealed that gluconeogenesis and B-oxidation of fatty acids (FAO) were upregulated in CD8 T cells under tumor stress but these metabolic sources were unable to support translation in the TME. Further, we discovered that glucose metabolism and mammalian target of rapamycin complex 1 (mTORC1) preferentially hinder protein synthesis in CD8 TILs. These data enabled the discovery that proteasomal protein degradation is the optimal source to fuel protein translation in T cells in the stress of solid tumors. We demonstrate that Rapamycin-primed T cells are preferentially powered by proteasomal proteolysis and are able to sustain protein translation in tumors and control tumor growth. Conclusions Our data establish that canonical protein translation governed by mTORC1 and glucose metabolism is subject to inhibition in the TME and promotion of protein catabolism is a new strategy to support antitumor immunity. Ethics Approval All animal experiments were in accordance with the MUSC Institutional Animal Care and Use Committee (IACUC), protocol # IACUC-2018-00422 and # IACUC-2018-00347

Objective The purpose of this study is to evaluate the effect of resident participation on operative time and surgical complications in isolated lower extremity fracture care. Setting Patients who were treated at teaching hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program database. Participants A total of 2,488 patients who underwent surgical fixation of isolated hip fractures, femoral or tibial shaft fractures, and ankle fractures. Design Patients were stratified by surgical procedure and post-graduate year (PGY) of the resident involved. Total operative time and surgical complications were analyzed with respect to resident participation and seniority. Multivariable logistic regression analyses were used to adjust for potential confounders including case complexity, wound class, and patient comorbidity burden. Results As PGY level increased, operative time increased for each procedure. The odds for a deep surgical site infection decreased as resident seniority increased, but the odds for wound dehiscence increased as resident seniority increased. We found no difference in the incidences of superficial infections or return to the OR with respect to PGY level. Academic quarter within the academic year did not correlate with any of the surgical complications. Furthermore, when cases performed with residents were compared to those performed without residents, there was no increased risk of superficial infections, deep infections, or return to the OR. Conclusions This nationally representative dataset demonstrates that operative times for lower extremity orthopedic trauma increased as resident seniority increased. Additionally, senior resident participation was associated with increased wound dehiscence, whereas junior resident participation was associated with an increased risk of deep surgical site infections. However, there was no associated “July effect” for residents at any level of training and there was no increased risk for surgical site infections or return to the OR in cases involving resident participation.

Extensor mechanism injuries are disabling injuries that require prompt evaluation and treatment and complications are often devastating. While smoking has been shown to increase complications following total joint arthroplasty, this relationship has not yet been established in those undergoing extensor mechanism repair. The purpose of this study was to evaluate the risk of smoking on postoperative complications following extensor mechanism repair. The National Surgical Quality Improvement Program (NSQIP) database was used to identify patients who underwent an extensor mechanism repair from 2005 to 2016. Patients were stratified by tobacco use, as either “current” or “nonsmokers.” A multivariate logistic regression was used to control for demographic and comorbid factors while assessing perioperative complications. 5208 patients were identified, and of these, 843 (16.2%) were current smokers. Smokers were younger, male, and with lower BMIs compared to nonsmokers (p = 0.001, p = 0.003, p = 0.002, respectively). They had a higher rate of surgical complications (OR 1.61, CI 1.02–2.52), including deep surgical site infections (OR 3.27, CI 1.03–10.43) and unplanned return to the operating room (OR 2.001, 1.24–3.23). Smokers were more likely to be readmitted within 30 days of surgery (OR 1.78, OR 1.09–2.90). Tobacco use is associated with a 1–2% increase in surgical, but not medical, complications following repair of extensor mechanism injuries. Smokers are at higher risk for deep infections, unplanned return to the OR, and hospital readmission. Identifying these patients preoperatively will allow surgeons to accurately counsel patients on perioperative risks. Counseling in preoperative smoking cessation is valuable for optimizing patient outcomes following extensor mechanism repair. Retrospective comparative study, Level III.

Although bone repair is typically an efficient process, an inadequate healing response can occur, with approximately 5-20% of fractures developing nonunion. Even with improved healing strategies and external fixation devices, overall rate of nonunion has not been significantly reduced, particularly for atrophic nonunion. Atrophic nonunion is characterized by sparse or no callus formation and is difficult to treat clinically, resulting in long-term pain and functional limitation. Reliable preclinical models are needed to study the pathophysiology of atrophic nonunion to create better treatment options. The MouseNail kit (RISystem, Landquart, Switzerland) provides a highly standardized approach in which stabilized segmental bone defects are achieved through interlocked intramedullary nailing. However, reliably performing this surgery is technically challenging, particularly while maintaining strict asepsis. Skilled and aseptic surgical execution is important and necessary because it ensures optimal animal welfare and reproducibility. Therefore, the aim of this paper is to describe:•Novel modifications to the MouseNail kit that allow for: 1) a completely aseptic surgical environment, including description of a hanging limb orthopedic aseptic preparation and 2) a reduction in fracture gap size necessary for induction of atrophic nonunion.•Pre- to post-operative recommendations to facilitate successful performance of murine orthopedic survival surgery., Graphical Abstract Image, graphical abstract

INTRODUCTION The purpose of this study is to investigate the current disparities for major lower extremity amputation in patients with critical limb ischemia (CLI) and infection. METHODS A retrospective analysis of the National Surgical Quality Improvement Program's database for the years 2011 to 2017 was conducted. Multivariate models were used to isolate the effect of race and ethnicity on the likelihood of a below-knee or above-knee amputation (BKA and AKA, respectively) for CLI secondary to type 2 diabetes mellitus, atherosclerosis, peripheral vascular disease, chronic osteomyelitis, and deep soft-tissue infections. RESULTS For all diagnoses, blacks were 93.3%, and Hispanics were 61.9% more likely to undergo a BKA than white patients (P < 0.001). In addition, black patients had a 133.0% higher risk of an AKA than white patients (P < 0.001). Disparities were greatest with blacks undergoing surgery for CLI secondary to atherosclerosis (BKA odds ratio 2.093; AKA: odds ratio 2.625). Black patients also had an elevated risk of amputation secondary to diabetes, peripheral vascular disease, and deep soft-tissue infections (P < 0.001). DISCUSSION This nationally representative, cohort-based study demonstrates that notable racial and ethnic disparities for lower extremity amputations persist, with a higher proportion of black and Hispanic patients undergoing amputation compared with limb salvage procedures for atraumatic CLI and infection. LEVEL OF EVIDENCE Level III prognostic.

BACKGROUND AND OBJECTIVES With recent advances in chemotherapy and surgical techniques, the trend in the treatment of osteosarcoma continues to progress towards limb salvage. However, studies comparing limb salvage with amputation continue to be limited by selection bias and small sample sizes. This study utilized propensity-score matching to minimize potential confounders and selection bias to compare the survival rates in patients with osteosarcoma that were treated with amputation vs limb salvage surgery. METHODS The Surveillance, Epidemiology, and End Results Program was utilized to identify all patients with a diagnosis of extremity osteosarcoma. Patients were matched with demographics, tumor characteristics, and treatment information. These variables were then fitted in a multivariate model and hazard ratios (HR) for overall- and disease-specific mortality was calculated. RESULTS A total of 4107 patients were identified, of which, 1538 were left after propensity-score matching. Older age, Black race, upper extremity location, and higher American joint committee on cancer (AJCC) class were associated with worse overall- and disease-specific mortality rates (P ≤ .0389). Compared with their matched counterparts, patients treated with amputation had higher overall mortality (HR 1.677; P

Background: Osteoarthritis (OA) is a leading cause of morbidity affecting 54 million Americans per year at an annual cost of 304 billion dollars to the US healthcare system. OA is characterized as a disease of joint wear and tear, but mounting evidence suggests a role for aberrant activation of immunity to contribute to disease progression. Methods: We hypothesized that OA patients have differential profiles of immunity between peripheral and synovial compartments as an indication that in situ immunity is affected by OA or vice versa. We used FACS analysis to phenotype T cell and myeloid populations between peripheral and synovial compartments from 16 patients undergoing total joint replacement due to advanced OA. Results: Our finding that Foxp3[Formula: see text] T regulatory (Tregs) increasingly comprise SF immunity of OA patients is novel ([Formula: see text]). Though the periphery harbored greater numbers of lymphocyte and myeloid cells compared to synovial fluid ([Formula: see text]), the synovial fluid revealed elevated percentages of myeloid (Cd11b[Formula: see text]) cells that comprised the CD45[Formula: see text] population ([Formula: see text]). Further, characterization elucidated that CD45/CD11b/CD14[Formula: see text]/CD15- cells upregulated HLADR in the affected synovial fluid ([Formula: see text]) and that these cells increase expression of CD68 ([Formula: see text]). Conclusions: Our data indicate that the affected joint space in OA patients harbors phenotypically distinct T-cell and myeloid populations compared to autologous-matched peripheral immunity. The contribution of aberrant immune populations to development and progression of OA is of interest for novel immunotherapies.

Tumor antigen–specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor-infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor antigen–specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T-cell–intrinsic energy consumption was the process of oxidative protein folding and disulfide bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α). To test this hypothesis, we created TCR transgenic mice with a T-cell–specific PERK gene deletion (OT1+Lckcre+PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T-cell groups displayed superior tumor control compared with T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1+ tumor antigen–specific CD8+ TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1+ CD8+ TILs and bolstered CD8+ TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T-cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.

BACKGROUND Excessive radiation to health-care providers has been linked to risks of cancer and cataracts, but its negative effects can be substantially reduced by lead aprons, thyroid shields, and leaded glasses. Hospitals are required to provide education and proper personal protective equipment, yet discrepancies exist between recommendations and compliance. This article presents the results of a survey of U.S. orthopaedic surgery residents concerning attitudes toward radiation exposure and personal protective equipment behavior. METHODS An invitation to participate in a web-based, anonymous survey was distributed to 46 U.S. allopathic orthopaedic surgery residency programs (1,207 potential resident respondents). The survey was conceptually divided into the following areas: demographic characteristics, training and attitudes concerning occupational hazards, personal protective equipment provision and use, and general safety knowledge. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for the association between these characteristics and compliance with thyroid shield or lead gown wear. RESULTS In this study, 518 surveys were received, with 1 survey excluded because of insufficient response, leaving 517 surveys for analysis (42.8% response rate). Ninety-eight percent of residents believed that personal protective equipment should be provided by the hospital or residency program. However, provision of personal protective equipment was not universal, with 33.8% reporting none and 54.2% reporting provision of a gown and thyroid shield. The prevalence of leaded glasses usage was 21%. Poor lead gown compliance and thyroid shield wear were associated with difficulty finding the corresponding equipment: PR, 2.51 (95% CI, 1.75 to 3.62; p < 0.001) for poor lead gown compliance and PR, 2.14 (95% CI, 1.46 to 3.16; p < 0.0001) for poor thyroid shield wear. Not being provided with personal protective equipment was also significantly associated with low compliance with both lead gowns (PR, 1.47 [95% CI, 1.04 to 2.08]; p = 0.03) and thyroid shields (PR, 1.69 [95% CI, 1.18 to 2.41]; p = 0.004). Respondents from the Southeast, West, or Midwest had lower compliance with lead gown usage. Forgetting was the number 1 reason to not wear a lead apron (42%). CONCLUSIONS Radiation exposure is associated with increased risk of serious health problems. Our findings identified that the availability of lead personal protective equipment leads to increased compliance among residents surveyed. In addition to yearly occupational hazard training specific to orthopaedic surgery, greater efforts by residency programs and hospitals are needed to improve access to lead personal protective equipment and compliance for orthopaedic residents.

Background There are few data on the types of procedures orthopaedic oncologists perform in their first years of practice. Because fellowships are graduating fellows each year and the number of tumor patients is limited, defining the practice patterns of early-career orthopaedic oncologists may help diminish early employment discontent and enhance workforce discussions.

Aneurysmal bone cysts (ABCs) were first described by Jaffe and Lichtenstein in 19421. Eighty percent of these lesions occur during the first two decades of life2; the most common location is the metaphysis of long bones. To the best of our knowledge, only four cases of individuals with multiple ABCs occurring over a period of time (metachronous ABCs) have been described to date3-6 (Table I). The cases all have been similar in presentation, imaging, and pathology to solitary ABCs; the only difference has been regarding the sex of the patient. While solitary ABCs have been shown to be predominant in females (62%)7, the reported cases of metachronous ABCs have all occurred in males. We report the case of an adolescent girl with multiple ABCs presenting separately in the proximal part of the femur and the distal part of the humerus over a five-month period. The patient and her parents were informed that data concerning the case would be submitted for publication, and they provided consent. View this table: TABLE I Reported Cases of Metachronous Aneurysmal Bone Cysts A healthy and active fourteen-year-old girl presented to the sports medicine clinic with unilateral hip pain. She had no history of trauma or an activity-related injury. Radiographs demonstrated a well-defined (5.4 × 2.8 cm) oval lucent geographic lesion in the proximal part of the femur, which initially was thought to be consistent with a unicameral bone cyst. At the short interval follow-up, the pain had worsened, and a new palpable mass was noted. Additional radiographs revealed substantial interval progression of the lesion with extension into the adjacent soft tissues with expansion of the bone (Fig. 1). Fig. 1 Anteroposterior radiograph demonstrates a lucent geographic lesion with a well-defined border (black arrow) in the right hip. However, there is focal extension …

Left ventricular assist devices (LVADs) augment the cardiac function of patients with severe left-sided cardiac disease. These devices are typically used as a bridge to transplantation and have proven effective at improving longevity and overall quality of life1. Improved longevity results in increased numbers of noncardiac surgical procedures for other medical conditions2. Although these procedures carry obvious risk, they have been performed with favorable outcomes1-6. Infection is of utmost concern with noncardiac surgery in a patient with an LVAD. While infection rates have improved with the use of second-generation LVADs, the infection rate remains at 30% to 50%, with 20% to 27% classified as bloodstream infections7. The concerns regarding infection are especially important with arthroplasty procedures because implants are susceptible to biofilms, and complications from infection can be devastating. Also of concern is the nonpulsatile flow that the LVADs deliver, which can have serious implications when a patient is under general anesthesia and placed in the lateral position because preload and systemic vascular resistance are affected. Despite these risks, a literature search revealed two total knee arthroplasties that were performed in patients with LVADs4. Both patients developed postoperative infections related to the LVAD, but neither total knee arthroplasty became infected. In terms of cardiac function, total hip arthroplasty has been shown to be extremely effective at playing a role in improving cardiac function, with postarthroplasty patients showing substantial improvements in exercise duration, maximum workload, peak oxygen consumption, and percentage of predicted maximum oxygen uptake achieved by six months postsurgery8. We present a case of a total hip arthroplasty in a patient with a HeartMate II LVAD (Thoratec Corporation, Pleasanton, California). To the best of our knowledge, there are no previous reports in the literature of a …

Gastrocnemius flaps have been used for decades to reconstruct defects of the proximal tibia and knee. They have proven to be useful in the soft-tissue reconstruction of defects caused by trauma, tumors, and infections about the knee, and the reconstruction of extensor mechanism discontinuity with and without total joint arthroplasty. The flaps have low failure rates and a distinct proximally based blood supply that allows them to be elevated and rotated up to 15 cm above the level of the knee joint. The vascular anatomy is reproducible because rotational flaps do not require microvascular anastomosis. An understanding of the applied surgical anatomy, approaches, and utility of the gastrocnemius flap makes the technique a useful tool for the orthopaedic surgeon when plastic surgery assistance is not readily available.

Background: Osteosarcoma with metastatic disease at the time of presentation necessitates a very different clinical discussion with patients than those who present with isolated disease. Therefore, the purpose of this study was to evaluate the role of local control surgery in patients with metastatic osteosarcoma as well as to further investigate confounding variables such as demographic, socioeconomic, and tumor characteristics on the overall and cancer-specific mortality rates. Methods: The National Cancer Institute’s Surveillance, Epidemiology, and End Results Program was queried for all patients with a diagnosis of metastatic osteosarcoma between the years 2004–2014. Patients who did not undergo any treatment (excisional surgery or chemotherapy) for their disease, were diagnosed at autopsy, or whose histologic subtypes were surface (parosteal and periosteal) or secondary osteosarcomas (Paget’s and radiation-induced) were excluded from further analyses. Multivariate models were used to isolate and evaluate the impact of excisional surgery of the primary tumor on the likelihood of survivorship. Results: A total of 3,277 patients were identified, of which 42.5% underwent excisional surgery of the primary tumor. The 5-year survival rate for all patients with metastatic osteosarcoma was 24.4% whereas it was 34.5% in patients who underwent surgery and 5.8% in those who did not undergo surgery. Patients in the lowest quartile for income and education were more likely to be treated nonoperatively. Older age, axial location, and lower education level portended a much worse overall- and cancer-specific mortality. However, surgical excision of the primary tumor was most strongly associated with prolonged survivorship. Conclusions: Patients with metastatic osteosarcoma whose primary tumor characteristics are amenable to surgery have a better prognosis than patients whose tumor characteristics preclude surgical resection. Level of evidence: III prognostic.

This study investigated complication rates for 68 solid-organ transplant patients who had undergone 94 primary hip or knee joint replacements at a single institution from 1995 to 2008. There was a deep infection rate of 6.8% in the transplant patients compared to a 1.9% deep infection rate for all primary joint replacement patients at the Medical University of South Carolina over the same time period (odds ratio 4.48). All four infections in the transplant group occurred in diabetic patients. The joint revision rate for transplant patients was 13% (deep infection 6.8%, aseptic loosening 5.1%, instability 1.7%). Other complications included superficial infections (5.1%), deep venous thromboses (3.4%), and a nonfatal pulmonary embolus (1.7%). The deep infection rate for joint replacement in solid-organ transplant patients was higher than rates reported by most similar studies, and diabetic patients may be at particular risk.

Background Sentinel lymph node (SLN) biopsy is a staging technique for occult lymph node disease. SLN biopsy has been applied to select patients with sarcoma, although the clinical utility remains uncertain. Methods A PubMed/MEDLINE literature search was performed, and SLN biopsy outcomes were analyzed using a Bayesian meta-analytic approach to obtain point and interval estimates of rates of interest. Results Sixteen studies involving SLN biopsy in patients with sarcoma were identified. Of 114 patients reported, 14 patients had positive SLNs (crude estimate, 12%; meta-analysis estimate, 17%). The meta-analysis false-negative rate was 29% (95% credible interval, 5%–59%). Recurrence and death rates in the SLN-positive group were higher than in the SLN-negative group. Conclusions This investigation highlights the current role of SLN biopsy in select patients with sarcoma for tumor staging. Questions regarding the high false-negative rate and management of micrometastatic lymphatic disease in patients with sarcoma still exist.

Carcinoma of the lung is the most common lethal form of cancer in both men and women worldwide. Orthopedic manifestations of lung cancer frequently include bony metastasis, most commonly the vertebrae (42%), ribs (20%), and pelvis (18%). Acral metastatic disease is defined as metastasis distal to the elbow or the knee. Metastases to the bones of the hand are extremely rare. Only 0.1% of metastatic disease resulting from any type of carcinoma or sarcoma manifests as metastasis in the hand. There are only a few reports in the literature of soft-tissue or muscular metastasis to the hand from a carcinoma. Of these cases, the majority are caused by metastatic lung carcinoma. However, there are no reports in the literature of metastatic disease of squamous cell origin affecting the soft tissues of the hand. We present a case of a man with known metastatic squamous cell carcinoma of the lung who presented with acral soft-tissue metastatic disease. This report highlights a rare clinical scenario that has not been reported in the literature. This report also highlights a rare but important consideration for clinicians who encounter acral soft-tissue lesions in patients with a history of a primary carcinoma.

Objectives To determine the association between race on severe heterotopic ossification (HO) following acetabular fracture surgery. Design Retrospective case control study. Setting Level I university trauma centre. Methods Two hundred and fifty-three patients who were surgically treated for acetabular fractures were retrospectively evaluated. Postoperative radiographs were evaluated for HO by a blinded musculoskeletal radiologist, and classified based on a modified Brooker classification. Results Of the 253 patients that met inclusion and exclusion criteria, 175 (69%) were male and 78 (31%) were female. One hundred and fifty-four (61%) patients were Caucasian, and 99 (39%) were African American (AA). Fifty-five (21%) patients developed severe HO. Of those who developed severe HO, 25 were Caucasian (45%), 30 were African American (55%). Forty-one patients (75%) with severe HO were male, and 14 (25%) were female. No statistical differences (p > 0.05) were found between groups in terms of age, days to surgery, GCS at presentation, surgical approach, perioperative HO prophylaxis, or AO/OTA fracture classification. The patient population was then stratified by race, gender, and race/gender. AA were more likely than Caucasians to develop severe HO (odds ratio [OR], 2.24; confidence interval [CI], 1.22–4.11). When gender was considered independent of race, no statistical differences (p > 0.05) were observed (OR, 1.40; CI, 0.71–2.75). AA males were much more likely to develop severe HO when compared to Caucasian females (OR, 4.4; CI, 1.38–14.06). Conclusion Race is associated with different rates of severe HO formation following acetabular fracture surgery. AA patients are significantly more likely to develop severe HO following acetabular fracture surgery when compared to Caucasian patients.

Chondrosarcoma is a cartilage forming neoplasm, which is the second most common primary malignancy of bone. Clinicians who treat chondrosarcoma patients must determine the grade of the tumor, and must ascertain the likelihood of metastasis. Acral lesions are unlikely to metastasize, regardless of grade, whereas axial, or more proximal lesions are much more likely to metastasize than tumors found in the distal extremities with equivalent histology. Chondrosarcoma is resistant to both chemotherapy and radiation, making wide local excision the only treatment. Local recurrence is frequently seen after intralesional excision, thus wide local excision is sometimes employed despite significant morbidity, even in low-grade lesions. Chondrosarcoma is difficult to treat. The surgeon must balance the risk of significant morbidity with the ability to minimize the chance of local recurrence and maximize the likelihood of long-term survival.

Patients often receive advanced imaging before referral to an orthopaedic oncologist. The few studies that have evaluated the value of these tests have been single-center studies, and there were large discrepancies in the estimated frequencies of unnecessary use of diagnostic tests.(1) Is there regional variation in the use of advanced imaging before referral to an orthopaedic oncologist? (2) Are these prereferral studies helpful to the treating orthopaedic oncologist in making a diagnosis or treatment plan? (3) Are orthopaedic surgeons less likely to order unhelpful studies than other specialties? (4) Are there any tumor or patient characteristics that are associated with the ordering of an unhelpful study?We performed an eight-center prospective analysis of patients referred for evaluation by a fellowship-trained orthopaedic oncologist. We recorded patient factors, referral details, advanced imaging performed, and presumptive diagnosis. The treating orthopaedic oncologist determined whether each study was helpful in the diagnosis or treatment of the patient based on objective and subjective criteria used in prior investigations. We analyzed the data using bivariate methods and logistic regression to determine regional variation and risk factors predictive of unhelpful advanced imaging. Of the 371 participants available for analysis, 301 (81%) were referred with an MRI, CT scan, bone scan, ultrasound, or positron emission tomography scan.There were no regional differences in the use of advanced imaging (range of patients presenting with advanced imaging 66%-88% across centers, p = 0.164). One hundred thirteen patients (30%) had at least one unhelpful study; non-MRI advanced imaging was more likely to be unhelpful than MRIs (88 of 129 [68%] non-MRI imaging versus 46 of 263 [17%] MRIs [p0.001]). Orthopaedic surgeons were no less likely than nonorthopaedic surgeons to order unhelpful studies before referral to an orthopaedic oncologist (56 of 179 [31%] of patients referred by orthopaedic surgeons versus 35 of 119 [29%] referred by primary care providers and 22 of 73 [30%] referred by nonorthopaedic specialists, p = 0.940). After controlling for potential confounding variables, benign bone lesions had an increased odds of referral with an unhelpful study (59 of 145 [41%] of benign bone tumors versus 54 of 226 [24%] of soft tissue tumors and malignant bone tumors; odds ratio, 2.80; 95% confidence interval, 1.68-4.69, p0.001).We found no evidence that the proportion of patients referred with advanced imaging varied dramatically by region. Studies other than MRI were likely to be considered unhelpful and should not be routinely ordered by referring physicians. Diligent education of orthopaedic surgeons and primary care physicians in the judicious use of advanced imaging in benign bone tumors may help mitigate unnecessary imaging.Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Surgical treatment for impending or actual pathologic femoral fractures due to metastatic carcinoma has been shown to improve pain and quality of life. Surgery usually involves manipulation of the intramedullary (IM) portion of the femur to provide adequate stability and to restore function. IM nailing is generally considered the preferred treatment over plate osteosynthesis for most areas of the femur due to load sharing capabilities. Several reports have shown a high incidence of oxygen desaturation, hypotension, fat or air embolism, and mortality in the surgical treatment of femoral metastatic disease. The patient with a metastatic lesion in the femur is at risk for cardiopulmonary complications associated with entering the IM canal. Complications and mortality reported in the literature are varied. Benefits of IM nailing of femoral lesions and associated complications in the literature are discussed. The theoretical benefit of aspiration and irrigation while reaming is also reviewed. Reaming while irrigating under negative pressure provided through suction may potentially minimize cardiopulmonary and oncologic complications.

Chondrosarcoma is a cartilage forming neoplasm, which is the second most common primary malignancy of bone. Clinicians who treat chondrosarcoma patients must determine the grade of the tumor, and must ascertain the likelihood of metastasis. Acral lesions are unlikely to metastasize, regardless of grade, whereas axial, or more proximal lesions are much more likely to metastasize than tumors found in the distal extremities with equivalent histology. Chondrosarcoma is resistant to both chemotherapy and radiation, making wide local excision the only treatment. Local recurrence is frequently seen after intralesional excision, thus wide local excision is sometimes employed despite significant morbidity, even in low-grade lesions. Chondrosarcoma is difficult to treat. The surgeon must balance the risk of significant morbidity with the ability to minimize the chance of local recurrence and maximize the likelihood of long-term survival.

Soft tissue sarcomas are malignant tumors that develop in connective tissue. Treatment with standard chemotherapeutic agents is often minimally effective and approximately half of all patients with soft tissue sarcoma experience disease recurrence and die of metastatic cancer. Therefore, the purpose of this study is to gain a better understanding of the soft tissue sarcoma metastatic environment in order to lead to the development of more effective therapies. Studies have shown that the tumor microenvironment plays a pivotal role in promoting tumor metastasis and one of the most prominent cell types of the tumor microenvironment is the carcinoma associated fibroblast (CAF). Our studies, based upon a murine single hematopoietic stem cell transplantation model have demonstrated that hematopoietic stem cells (HSCs) are a novel source for CAFs and their circulating fibroblast precursors (CFPs). Our research has also shown that murine CFPs are present in the peripheral blood, increase with tumor burden, and contribute to tumor growth. In vitro studies have shown that HSC-derived CFPs enhance tumor cell proliferation, migration, and invasion, processes critical to tumor metastasis in vivo. The role of human CFPs in metastasis of soft tissue sarcoma, however, has yet to be determined. It is our hypothesis that HSC derived CFPs promote sarcoma cell proliferation, migration, and invasion. In order to determine the role of CFPs in sarcoma metastasis, we established a method for culturing fibroblasts from peripheral blood obtained from patients diagnosed with metastatic sarcoma. These cultured cells were then characterized by immunohistochemistry to profile fibroblast and hematopoietic markers. In order to address the functional role of CFPs during sarcoma metastasis, we examined the ability of conditioned media from cultured CFPs from patients with metastatic sarcoma to influence the proliferation, migration, and invasion of HT-1080 cells, a human sarcoma line. Our immunohistochemical findings demonstrate that fibroblasts can be isolated from the circulation of patients with metastatic sarcoma and results from our functional assays indicate that cultured CFPs from patients with metastatic sarcoma promote the proliferation, migration, and invasion of HT-1080 cells. Given that proliferation, migration, and invasion of tumor cells are essential steps in the metastatic cascade, these findings suggest that CFPs promote tumor progression. Ongoing studies involve analysis of CFPs at various time points based upon chemotherapeutic treatment in order to evaluate differences in numbers of CFPs, marker expression, growth factor production, and ability to promote metastasis. Long term, these studies may identify novel biomarkers for disease progression as well as treatment efficacy, potentially leading to the development of more effective therapies for soft tissue sarcomas. Citation Format: Dayvia A. Laws, Andrew S. Kraft, Lee R. Leddy, Amanda C. LaRue. The role of circulating fibroblast precursors in promoting metastatic sarcoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A46. doi:10.1158/1538-7445.CHTME14-A46

Oncogenic osteomalacia is a rare paraneoplastic syndrome of systemic bone demineralization secondary to a tumor-induced dysregulation of phosphorus metabolism. The tumor's low prevalence, small size, and variable location often result in years of muscular weakness and bone pain before diagnosis. With complete treatment, patient's symptoms swiftly dissipate. We report the case of a 63-year-old previously healthy man with a 20-month course of musculoskeletal symptoms before diagnosis and resection of a posterior tibial tumor. Postoperatively, the patient had returned to his previous lifestyle when an insufficiency fracture required prophylactic stabilization.

Background/hypothesis Surgical management of displaced unstable proximal humerus fracture remains a challenge due to poor proximal bone quality and significant deforming forces. We hypothesized that the technique of application and mechanical properties of the proximal humeral locking plate would allow successful treatment of unstable and displaced proximal humeral fractures even in the face of osteoporotic bone. Method We evaluated prospectively the results of open reduction internal fixation of 22 displaced unstable proximal humerus fractures in 22 patients utilizing a proximal humeral locking plate. Results Results according to the ASES scoring system at a minimum of 2 years were excellent in 13, good in 4, fair in 1, and poor in 3. One patient was lost to follow-up. All fractures healed. Anatomic alignment was obtained in 72%. Two patients developed avascular necrosis of the humeral head. There were no cases of hardware failure, infection, or loss of reduction. Three separate reduction maneuvers were employed in this series depending on fracture type. Conclusion The locking plate is an excellent device in the management of displaced unstable proximal humeral fractures and is expanding the indications for ORIF in these fractures.