Targeted inhibition of SCFSKP2 confers anti-tumor activities resulting in a survival benefit in osteosarcoma.

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

SKP2 Knockout in Rb1/p53-Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis.

Osteosarcoma is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in osteosarcoma is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that Skp2 knockout in murine osteosarcoma improved survival and delayed tumorigenesis. Here, we performed RNA sequencing (RNA-seq) on tumors from a transgenic osteosarcoma mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;Skp2-/-), followed by qPCR and immunohistochemistry validation. To investigate the clinical implications of our results, we analyzed a human osteosarcoma patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data. We found large differences in gene expression after SKP2 knockout. Surprisingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors, especially the signature genes for macrophages and to a lesser extent, T cells, B cells, and vascular cells. We also uncovered a set of relevant transcription factors that may mediate these changes. In osteosarcoma patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET osteosarcoma and the TCGA Sarcoma cohorts. Overall, our findings indicate that SKP2 may mediate immune exclusion from the osteosarcoma tumor microenvironment, suggesting that SKP2 modulation in osteosarcoma may induce antitumor immune activation.

Do racial disparities exist in a spine surgery practice that serves a predominately minority population? Outcomes of transforaminal lumbar interbody fusion: A retrospective review.

Background: Racial minority status is associated with inferior peri-operative outcomes following spinal fusion. Findings have largely been reported within institutions serving few minority patients. This study aimed to identify if racial disparities exist for transforaminal lumbar interbody fusion (TLIF) procedures within an urban academic medical center which serves a majority non-White population. Methods: This is a retrospective review of patients who underwent a TLIF procedure at our institution between 06/2016-10/2019. Primary outcome measures included length of stay (LOS), discharge disposition, 30-day return to the emergency department (ED), 30-day readmission rate, and 30-day complication rates. One-hundred-fifty-six patients (female: male, 99: 57) met inclusion criteria. Demographic and clinical data (body mass index (BMI), comorbidities, preoperative lab values) were compared. Results: The mean LOS was 6.2, 5.9, and 6 days in the White, Hispanic, and Black cohorts, respectively (p = 0.92). There were no differences in discharge disposition between groups (p = 0.52). Thirty-day post-operative complication rates did not differ between groups (p > 0.07). Readmission rates did not differ between groups (p > 0.05). ED visits were more prevalent in the Hispanic group with 16 visits as compared to 8 and 4 in the White and Black groups respectively (p = 0.01). Conclusions: We found no racial disparities in terms of LOS, discharge disposition, or 30-day readmission rates. Hispanic patients demonstrated an increased utilization of the ED in the early post-operative period. Efforts to overcome language barriers, communicate instructions clearly, and outline post-operative expectations and plans may prevent the need for post-operative ED visits.

Fluoroscopic Percutaneous Fixation of Periacetabular Metastatic Cancer: The Tripod Technique.

There are an increasing number of patients who present with metastatic bone disease as the survival of patients with cancer improves in recent decades. The pelvis is the second most common site for skeletal metastases. Metastatic lesions in the pelvis can be largely divided into periacetabular lesions (Enneking zone II) and non-periacetabular lesions (zones I, III, and IV). Traditionally, patients with a symptomatic zone II lesion are treated with a cemented total hip arthroplasty (THA) using variations on the traditional Harrington method. These open surgeries are accompanied by many inherent risks. Both a prolonged recovery and wide range of potential complications may delay or interrupt the adjuvant radiation and systemic therapy. It was observed that the articular surface of the hip joint was often intact and that the femoral side was frequently not involved in these patients. A novel minimally invasive technique for hip joint preservation has recently been developed. Three large-bore cannulated screws are placed percutaneously under fluoroscopy in a tripod configuration to reinforce the mechanical axis of the acetabulum. Increased stability improves pain control and permits immediate weight bearing. When the disease progresses, this construct can be easily converted to a cemented THA using the tripod screws as rebar to support an acetabular cup, as part of a staged Harrington procedure. This approach is technically demanding. A detailed guide for the tripod technique should encompass indications, preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, modifications, postoperative care, and subsequent conversion to a cemented THA, if needed.

Percutaneous Screw Stabilization of Non-Periacetabular Pelvic Lesions Caused by Metastatic Cancer and Multiple Myeloma.

BACKGROUND: The pelvis is one of the most common locations for metastatic bone disease. While many of the publications that describe surgical treatments focus on periacetabular lesions (Enneking zone II), there is a lack of investigation into lesions in the non-periacetabular areas (zones I, III, and IV). We recently described a minimally invasive percutaneous screw application for metastatic zone-II lesions with excellent results. In the present study, we aimed to extend this approach to the other pelvic areas. METHODS: Twenty-two consecutive patients with painful non-periacetabular pelvic metastatic cancer were included based on retrospective chart review. There were 16 women and 6 men with an average age of 60 years (range, 36 to 81 years). The most common primary cancers were multiple myeloma (7 cases) and breast (5 cases). The most common locations were the sacrum and the ilium. A pathologic fracture was identified in 15 patients. Most of the lesions were treated with multiple large-diameter screws, except for the isolated zone-III lesions. All of the procedures were completed in a standard operating room without the need for special instruments. Radiation therapy was given to 19 patients; the average dose was 15 Gy. The studied outcomes were pain and functionality as assessed by a visual analog scale (VAS) score and the Eastern Cooperative Oncology Group score (ECOG), respectively. RESULTS: There were no surgical complications and no need for blood transfusion. The average follow-up time was 7 months (range, 0.3 to 34.0 months). Two patients died within 4 weeks of surgery due to COVID-19 infection. There was significant improvement in the postoperative VAS pain score (p < 0.0001) and the ECOG score (p < 0.05) when compared with the preoperative scores. There was no implant failure or revision surgery. Local bone-healing was observed in 12 of 14 patients (86%) who survived for >3 months after surgery. CONCLUSIONS: Percutaneous screw application is safe and effective in the treatment of metastatic non-periacetabular pelvic lesions. Given the simplicity of the technique and the instrumentation and the tolerance for concomitant treatments, this approach is worthy of broader consideration. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCFSKP2 E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27T187A KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27T187A KI mice were crossed on to the DKO background, p27T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCFSKP2 -p27T187A axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer.

A graphic guide to the percutaneous tripod acetabular reconstruction for metastatic cancer.

Symptomatic peri-acetabular metastatic lesions are often treated with open surgery such as modified Harrington procedures. In an effort to avoid surgical complications inherently associated with open surgical approaches, we developed and recently reported a novel Tripod percutaneous screw technique. The tripod technique is minimally invasive and was found to yield excellent outcomes regarding both pain control and functionality. The procedure is performed in a standard operative theater using fluoroscopic guided percutaneous screws. Despite the simplicity of intraoperative set-up and instrumentation, it is technically demanding. Obtaining the correct fluoroscopic views and troubleshooting intraoperative hurdles can be challenging for even an experienced orthopedic surgeon. The technique and bony conduits were previously described in the trauma literature, however, there are key points of difference in the setting of metastatic disease. Here we provide a compilation of a stepwise graphic guide for the tripod model in the setting of metastatic peri-acetabular lesions, as well as the tips and tricks based on our own experience. These encompass preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, postoperative care, and subsequent conversion to a cemented total hip arthroplasty, if needed.

Prognostic and Therapeutic Utility of Variably Expressed Cell Surface Receptors in Osteosarcoma.

BACKGROUND: Six cell surface receptors, human epidermal growth factor receptor-2 (Her-2), platelet-derived growth factor receptor-ß (PDGFR-ß), insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor-3 (VEGFR-3), previously demonstrated variable expression across varying patient-derived and standard osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and/or therapeutic value. METHODS: Patient-derived OS cell lines (n = 52) were labeled with antibodies to Her-2, PDGFR-ß, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The difference in geometric mean fluorescent intensity (geoMFIdiff = geoMFIpositive - geoMFInegative) was calculated for each receptor across all cell lines. Receptor expression was categorized as low (Q1), intermediate (Q2, Q3), or high (Q4). The event-free survival (EFS) and overall survival for the six cell surface receptors were estimated by the Kaplan-Meier method. Differences in hazard for EFS event and overall survival event for patients in each of the three expression levels in each of the six cell surface receptors were assessed using the log-rank test. RESULTS: All 6 receptors were variably expressed in the majority of cell lines. IR and PDGFR-ß expressions were found to be significant predictors for EFS amongst patients with nonmetastatic disease (p=0.02 and 0.01, respectively). The hazard ratio for EFS was significantly higher between high IR and intermediate IR expression (HR = 2.66, p=0.02), as well as between high PDGFR-ß and intermediate PDGFR-ß expression (HR = 5.68, p=0.002). Her-2, c-Met, IGF-1R, and VEGFR-3 were not found to be significant predictors for either EFS or overall survival. CONCLUSION: The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS cell lines tested. Limited prognostic value was offered by IR and PDGFR-ß expression within nonmetastatic patients. The remaining receptors do not provide clear prognostic utility. Nevertheless, their consistent, albeit variable, surface expression across a large panel of patient-derived OS cell lines maintains their potential use as future therapeutic targets.

A Case Report Describing Pre-operative Contouring of an Orthopedic Implant using a 3D-Printed Patient-specific Model.

Introduction: Paget's disease is a metabolic bone disorder characterized by abnormal patterns in bone remodeling, resulting in variable degrees of chronic bone pain, deformation of the long bones and rarely, and pathologic fracture. These issues can pose difficult surgical challenges, particularly in the elderly frail population, where the benefits of orthopedic intervention must be balanced with minimizing inherent surgical risks. Such considerations often include reducing operative time and blood loss, allowing for early mobilization, stabilizing an impending fracture, and providing symptom relief. Case Report: A 77-year-old female with a 10-year history of Paget's disease presented to an outside orthopedic clinic with progressive right leg pain and worsening anterior bowing following minor trauma to the extremity. Ultimately, the patient was offered in situ prophylactic intramedullary (IM) nail fixation, intended to augment her bone's native strength and prevent further microfractures and subsequent deformation. A three-dimensional (3D) printed patient specific model was developed to permit for pre-contouring of an off-the-shelf implant and subsequent sterilization and use at a future point in time. She underwent uneventful IM nailing of her tibia with the pre-contoured implant and proceeded to progress clinically postoperatively. Conclusion: In this report, we present an innovative use of a 3D printed patient-specific tibia model to pre-contour an IM nail. This surgical approach was undertaken to treat an elderly patient with a symptomatic and progressive deformity of the tibia secondary to Paget's disease of bone.

Perioperative Management of Metastatic Paraganglioma-Pheochromocytoma of the Humerus with the Aid of Regional Anesthesia.

A 38-year-old female with a past history of pheochromocytoma and subsequent malignant paraganglioma presented with right arm pain after a fall. Imaging demonstrated a malunited humeral shaft associated with a large cortical destructive lesion and extraosseous extension. Here, we report the use of a multidisciplinary team approach including an endocrinologist, anesthesiologist, and orthopedic surgeon in the perioperative management of a patient with metastatic paraganglioma undergoing a surgical resection of the humerus, internal fixation, reconstruction, and placement of endoprosthesis. The challenges of perioperative anesthetic management and the use of regional anesthesia, especially peripheral nerve block for perioperative pain management, are highlighted.

Late-Onset Bartter Syndrome Type II Due to a Homozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review.

BACKGROUND Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. CASE REPORT Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. CONCLUSIONS To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter's Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation.

Wnt Signaling in Osteosarcoma.

Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator ß-catenin, whereas noncanonical pathways function independent of ß-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.

Characterization of bony anatomic regions in pediatric and adult healthy volunteers using diffuse optical spectroscopic imaging.

SIGNIFICANCE: Diffuse optical spectroscopic imaging (DOSI) measures quantitative functional and molecular information in thick tissue in a noninvasive manner using near-infrared light. DOSI may be useful for diagnosis and prognosis of bone pathologies including osteosarcoma and Ewing's sarcoma, but little is currently known about DOSI-derived parameters in bony anatomic locations where this disease occurs. AIM: Our goal is to quantify the optical characteristics and chromophore content of bony anatomic locations of healthy volunteers and assess differences due to anatomic region, age, sex, ethnicity, race, and body fat. APPROACH: Fifty-five healthy volunteers aged 4 to 72 were enrolled in the study. The optical properties and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids were assessed at the distal humerus, distal femur, and proximal tibia. Body fat was assessed using skinfold calipers. One volunteer underwent a more comprehensive body scan from neck to foot to explore chromophore distributions within an individual. Regression analysis was used to identify the most important sources of variation in the measured data set. RESULTS: Statistical differences between bony locations were found for scattering, water, and lipids, but not for hemoglobin. All chromophores had statistical differences with sex, but there were no significant age-related correlations. Regression analysis revealed that body fat measured with skinfold calipers was the most important predictor of oxy-, deoxy-, total hemoglobin, and lipids. Hemoglobin and lipid levels were highly correlated (ρ ≥ 0.7) over the subject population and within the single-subject body scan. CONCLUSIONS: DOSI can successfully measure bony anatomic sites where osteosarcomas and Ewing's sarcomas commonly occur. Future studies of bone pathology using DOSI should account for the variation caused by anatomic region, sex, race and ethnicity, and body fat as these cause substantial variations in DOSI-derived metrics.

Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

Early Experience Managing a High-volume Academic Orthopaedic Department During the Coronavirus Pandemic in New York City.

Our orthopaedic surgery department at Montefiore Medical Center and Albert Einstein College of Medicine is located within the Bronx, a borough of New York City, and serves a densely populated urban community. Since the beginning of the novel coronavirus outbreak in New York City, the medical center was forced to rapidly adapt to the projected influx of critically ill patients. The aim of this report is to outline how our large academic orthopaedic surgery department adopted changes and alternative practices in response to the most daunting challenge to public health in our region in over a century. We hope that this report provides insight for others facing similar challenges.

Musculoskeletal Tumors.

Pediatric musculoskeletal tumors can arise in both bone and soft tissues. The overwhelming majority of these are benign; however, rarely, malignant neoplasms do occur. These are collectively termed sarcomas, indicating their mesenchymal origin. Sarcoma management requires careful adherence to the well-described tenets of tumor management. This article summarizes the basic principles and recent advances in the management of soft tissue and bone tumors.

Detection and targeting insulin growth factor receptor type 2 (IGF2R) in osteosarcoma PDX in mouse models and in canine osteosarcoma tumors.

Osteosarcoma (OS) represents 3.4% of all childhood cancers with overall survival of 70% not improving in 30 years. The consistent surface overexpression of insulin-like growth factor-2 receptor (IGF2R) has been reported in commercial and patient-derived xenograft (PDX) OS cell lines. We aimed to assess efficacy and safety of treating PDX and commercial OS tumors in mice with radiolabeled antibody to IGF2R and to investigate IGF2R expression on canine OS tumors. IGF2R expression on human commercial lines 143B and SaOS2 and PDX lines OS-17, OS-33 and OS-31 was evaluated by FACS. The biodistribution and microSPECT/CT imaging with 111Indium-2G11 mAb was performed in 143B and OS-17 tumor-bearing SCID mice and followed by radioimmunotherapy (RIT) with 177Lutetium-2G11 and safety evaluation. IGF2R expression in randomly selected canine OS tumors was measured by immunohistochemistry. All OS cell lines expressed IGF2R. Biodistribution and microSPECT/CT revealed selective uptake of 2G11 mAb in 143B and OS-17 xenografts. RIT significantly slowed down the growth of OS-17 and 143B tumors without local and systemic toxicity. Canine OS tumors expressed IGF2R. This study demonstrates the feasibility of targeting IGF2R on OS in PDX and spontaneous canine tumors and sets the stage for further development of RIT of OS using comparative oncology.

LigaSure Use Decreases Intraoperative Blood Loss Volume and Blood Transfusion Volume in Sarcoma Surgery.

INTRODUCTION: The LigaSure system has been successfully used in thoracic and abdominal surgery. However, to date, its use in the resection of sarcomas has not been systematically studied. We aimed to determine whether the use of the LigaSure system reduces blood loss and blood transfusion volumes in sarcoma surgery. METHODS: One hundred forty-two consecutive patients who underwent sarcoma surgeries between July 2010 and October 2016 were included. Conventional electrocautery alone (n = 91) and with LigaSure (n = 51) were compared. Case-matched samples (n = 46) from each group were additionally compared. RESULTS: The use of the LigaSure system resulted in a significant decrease in mean intraoperative blood loss (P = 0.02) and blood transfusion volume (P = 0.04). Likewise, a significant decrease in both mean and median intraoperative blood loss (P = 0.003; P < 0.0001) was seen with LigaSure in the case-matched analysis. In the soft-tissue sarcoma subgroup, a significant decrease was observed in mean hemoglobin reduction (P = 0.03) and mean intraoperative blood loss with LigaSure (P = 0.04). No adverse perioperative complications attributed to the LigaSure system were identified. CONCLUSIONS: The LigaSure vessel sealing and dividing system is a safe and effective hemostatic tool for deep dissection in bone and soft-tissue sarcoma surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

The Role of Intraoperative Navigation in Orthopaedic Surgery.

An orthopaedic surgeon's knowledge of anatomical landmarks is crucial, but other modalities supplement this by providing guidance and feedback to a surgeon. Advances in imaging have enabled three-dimensional visualization of the surgical field and patient anatomy, whereas advances in computer technology have allowed for real-time tracking of instruments and implants. Together, these innovations have given rise to intraoperative navigation systems. The authors review these advances in intraoperative navigation across orthopaedic subspecialties, focusing on the most recent evidence on patient outcomes and complications, the associated learning curve, and the effects on operative time, radiation exposure, and cost. In spine surgery, navigated pedicle screw placement may increase accuracy and safety, especially valuable when treating complex deformities. Improved accuracy of pelvic and peri-articular tumor resection and percutaneous fixation of acetabular and femoral neck fractures has also been achieved using navigation. Early applications in arthroscopy have included surface-based registration for tunnel positioning for anterior cruciate ligament reconstruction and osteochondroplasty for femoro-acetabular impingement. Navigated arthroplasty techniques have addressed knee gap balancing and mechanical axis restoration as well as acetabular cup and glenoid baseplate positioning. Among these orthopaedic subspecialties, significant variation is found in the clinical relevance and dedication to research of navigation techniques.