Identification of a 5-gene signature panel for the prediction of prostate cancer progression.

BACKGROUND: Despite nearly 100% 5-year survival for localised prostate cancer, the survival rate for metastatic prostate cancer significantly declines to 32%. Thus, it is crucial to identify molecular indicators that reflect the progression from localised disease to metastatic prostate cancer. METHODS: To search for molecular indicators associated with prostate cancer metastasis, we performed proteomic analysis of rapid autopsy tissue samples from metastatic prostate cancer (N = 8) and localised prostate cancer (N = 2). Then, we utilised multiple independent, publicly available prostate cancer patient datasets to select candidates that also correlate with worse prostate cancer clinical prognosis. RESULTS: We identified 154 proteins with increased expressions in metastases relative to localised prostate cancer through proteomic analysis. From the subset of these candidates that correlate with prostate cancer recurrence (N = 28) and shorter disease-free survival (N = 37), we identified a 5-gene signature panel with improved performance in predicting worse clinical prognosis relative to individual candidates. CONCLUSIONS: Our study presents a new 5-gene signature panel that is associated with worse clinical prognosis and is elevated in prostate cancer metastasis on both protein and mRNA levels. Our 5-gene signature panel represents a potential modality for the prediction of prostate cancer progression towards the onset of metastasis.

ACAA2 is a novel molecular indicator for cancers with neuroendocrine phenotype.

BACKGROUND: Neuroendocrine phenotype is commonly associated with therapy resistance and poor prognoses in small-cell neuroendocrine cancers (SCNCs), such as neuroendocrine prostate cancer (NEPC) and small-cell lung cancer (SCLC). Expression levels of current neuroendocrine markers exhibit high case-by-case variability, so multiple markers are used in combination to identify SCNCs. Here, we report that ACAA2 is elevated in SCNCs and is a potential molecular indicator for SCNCs. METHODS: ACAA2 expressions in tumour xenografts, tissue microarrays (TMAs), and patient tissues from prostate and lung cancers were analysed via immunohistochemistry. ACAA2 mRNA levels in lung and prostate cancer (PC) patients were assessed in published datasets. RESULTS: ACAA2 protein and mRNA levels were elevated in SCNCs relative to non-SCNCs. Medium/high ACAA2 intensity was observed in 78% of NEPC PDXs samples (N = 27) relative to 33% of adeno-CRPC (N = 86), 2% of localised PC (N = 50), and 0% of benign prostate specimens (N = 101). ACAA2 was also elevated in lung cancer patient tissues with neuroendocrine phenotype. 83% of lung carcinoid tissues (N = 12) and 90% of SCLC tissues (N = 10) exhibited medium/high intensity relative to 40% of lung adenocarcinoma (N = 15). CONCLUSION: ACAA2 expression is elevated in aggressive SCNCs such as NEPC and SCLC, suggesting it is a potential molecular indicator for SCNCs.

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Role of Operating Room Size on Air Quality in Primary Total Hip Arthroplasty.

BACKGROUND: Airborne biologic particles (ABPs) can be measured intraoperatively to evaluate operating room (OR) sterility. Our study examines the role of OR size on air quality and ABP count in primary total hip arthroplasty (THA). METHODS: We analyzed primary THA procedures done within 2 ORs measuring 278 ft2 and 501 ft2 at a single academic institution from April 2019 to June 2020. Temperature, humidity, and ABP count per minute were recorded with a particle counter intraoperatively and cross-referenced with surgical data from the electronic health records using procedure start and end times. Descriptive statistics were used to evaluate differences in variables. P-values were calculated using t-test and chi-squared test. RESULTS: A total of 116 primary THA cases were included: 18 (15.5%) in the "small" OR and 98 (84.5%) in the "large" OR. Between-group comparisons revealed significant differences in temperature (small OR: 20.3 ± 1.23 C versus large OR: 19.1 ± 0.85 C, P < .0001) and relative humidity (small OR: 41.1 ± 7.24 versus large OR: 46.9 ± 7.56, P < .001). Significant percent decreases in ABP rates for particles measuring 2.5 um (-125.0%, P = .0032), 5.0 um (-245.0%, P = .00078), and 10.0 um (-413.9%, P = .0021) were found in the large OR. Average time spent in the OR was significantly longer in the large OR (174 ± 33 minutes) compared to the small OR (151 ± 14 minutes) (P = .00083). CONCLUSION: Temperature and humidity differences and significantly lower ABP counts were found in the large compared to the small OR despite longer average time spent in the large OR, suggesting the filtration system encounters less particle burden in larger rooms. Further research is needed to determine the impact this may have on infection rates.

Larger operating rooms have better air quality than smaller rooms in primary total knee arthroplasty.

INTRODUCTION: Operating room air quality can be affected by several factors including temperature, humidity, and airborne particle burden. Our study examines the role of operating room (OR) size on air quality and airborne particle (ABP) count in primary total knee arthroplasty (TKA). MATERIALS AND METHODS: We analyzed all primary, elective TKAs performed within two ORs measuring 278 sq ft. (small) and 501 sq ft. (large) at a single academic institution in the United States from April 2019 to June 2020. Intraoperative measurements of temperature, humidity, and ABP count were recorded. p values were calculated using t test for continuous variables and chi-square for categorical values. RESULTS: 91 primary TKA cases were included in the study, with 21 (23.1%) in the small OR and 70 (76.9%) in the large OR. Between-groups comparisons revealed significant differences in relative humidity (small OR 38.5% ± 7.24% vs. large OR 44.4% ± 8.01%, p = 0.002). Significant percent decreases in ABP rates for particles measuring 2.5 µm (- 43.9%, p = 0.007) and 5.0 µm (- 69.0%, p = 0.0024) were found in the large OR. Total time spent in the OR was not significantly different between the two groups (small OR 153.09 ± 22.3 vs. large OR 173 ± 44.6, p = 0.05). CONCLUSIONS: Although total time spent in the room did not differ between the large and small OR, there were significant differences in humidity and ABP rates for particles measuring 2.5 µm and 5.0 µm, suggesting the filtration system encounters less particle burden in larger rooms. Larger studies are required to determine the impact this may have on OR sterility and infection rates.

Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

Perioperative Chlorhexidine Gluconate Wash During Joint Arthroplasty Has Equivalent Periprosthetic Joint Infection Rates in Comparison to Betadine Wash.

BACKGROUND: Dilute betadine wash has been used for the prevention of prosthetic joint infection (PJI). Appropriateness for this purpose has recently come into question as the Food and Drug Administration determined that several commercial products did not pass the standards of proper sterility. The goal of this study is to determine if change in our institution's perioperative infection protocol to sterile chlorhexidine gluconate wash affected rates of PJI. METHODS: This is a retrospective study of prospectively collected data for patients who underwent unilateral primary total knee arthroplasty and total hip arthroplasty. Chart review was performed to determine 90-day and 1-year readmissions and the development of PJI as per the diagnostic criteria of the Musculoskeletal Infection Society. RESULTS: A total of 2386 consecutive patients were included in this study. There were no significant demographic differences between the 2 groups. There was no statistically significant difference in the rate of PJI requiring a return trip to the operating room between the 2 cohorts: 4 in chlorhexidine vs 7 in betadine at 3 months (P = .61); and 9 in chlorhexidine and 14 in betadine at 1 year (P = .48, respectively). There was also no difference in the rate of wound complications between the betadine and chlorhexidine use (P = .93). CONCLUSION: When comparing patients who received a betadine wash intraoperatively to those who received a chlorhexidine gluconate wash, there were no statistically significant differences in the rate of postoperative PJIs or return trips to the operating room. Although chlorhexidine gluconate and betadine have equal efficacy in the prevention of PJI, betadine is a far less expensive alternative if their sterility concerns are unwarranted LEVEL OF EVIDENCE: Therapeutic Level III.

GPCR structure and function relationship: identification of a biased apelin receptor mutant.

Biased ligands of G protein-coupled receptors (GPCRs) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling. We discovered that a single residue mutation I109A (I1093.32) in the transmembrane domain 3 (TM3) located in the deep ligand-binding pocket was sufficient to convert a balanced APJ into a G protein signaling biased receptor. APJ I109A mutant receptor retained full capabilities in ligand binding and G protein activation, but was defective in GRK recruitment, ß-arrestin recruitment, and downstream receptor-mediated ERK activation. Based on molecular dynamics simulations, we proposed a molecular mechanism for biased signaling of I109A mutant receptor. We postulate that due to the extra space created by I109A mutation, the phenyl group of the last residue (Phe-13) of apelin rotates down and initiates a cascade of conformational changes in TM3. Phe-13 formed a new cluster of hydrophobic interactions with the sidechains of residues in TM3, including F1103.33 and M1133.36, which stabilizes the mutant receptor in a conformation favoring biased signaling. Interruption of these stabilizing interactions by double mutation F110A/I109A or M113A/I109A largely restored the ß-arrestin-mediated signaling. Taken together, we describe herein the discovery of a biased APJ mutant receptor and provide detailed molecular insights into APJ signaling selectivity, facilitating the discovery of novel therapeutics targeting APJ.

Are Cardiac Complications Associated With Other Adverse Events? A Look at 56,000 Orthopaedic Trauma Patients.

The purpose of this study was to identify those complications for which patients with adverse cardiac events are at risk within the 30-day postoperative period following treatment oforthopaedic trauma cases. This was a retrospective cohort study of orthopaedic trauma patients in the United States between 2006 and 2013. A total of 56,336 patients meeting any one of 89 CPT codes in the American College of Surgeons National Surgical Quality Improvement Program database were used. The main outcome measure was myocardial infarction or cardiac arrest within the 30-day postoperative period. Patients experiencing adverse cardiac events were at a significantly higher risk to have also developed deep surgical site infection, pneumonia, the need for reintubation, pulmonary emboli, a failure to wean off of ventilation, chronic and acute renal failure, urinary tract infection, stroke, deep venous thrombosis, sepsis, and shock. Cardiac complications in orthopaedic trauma patients are relatively uncommon (1.3%); however, cardiac complications are associated with greater risks of other complications, including pneumonia, stroke, and urinary tract infection. (Journal of Surgical Orthopaedic Advances 27(3):198-202, 2018).

Management of Femoral Defects Greater Than 5 cm Following Open Femur Fractures: A 12-Year Retrospective Review.

This study sought to evaluate the outcomes of patients with osseous defects exceeding 5 cm following open femur fractures. Size of the osseous defect, method of internal fixation (plate vs. intramedullary nail), patient demographics, medical comorbidities, and surgical complications were collected. Twenty-seven of the 832 open femur fracture patients had osseous defects exceeding 5 cm. Mean osseous defect size was 8 cm, and each patient had an average of four operations including initial debridement. Average time from injury to bone grafting was 123.7 days. The overall complication rate was 48.1% (n = 13). The most common complications were infection (26.0%, n = 7) and nonunion (41.0%, n = 11). Smoking, diabetes, ASA score, and defect size did not independently increase the risk of a complication. Management of open femur fractures with osseous defects greater than 5 cm is associated with high complication rate, driven primarily by infection and nonunion. (Journal of Surgical Orthopaedic Advances 27(3):203-208, 2018).

Predicting the post-operative length of stay for the orthopaedic trauma patient.

PURPOSE: Length of stay (LOS) is a major driver of cost and quality of care. A bundled payment system makes it essential for orthopaedic surgeons to understand factors that increase a patient's LOS. Yet, minimal data regarding predictors of LOS currently exist. Using the ACS-NSQIP database, this is the first study to identify risk factors for increased LOS for orthopaedic trauma patients and create a personalized LOS calculator. METHODS: All orthopaedic trauma surgery between 2006 and 2013 were identified from the ACS-NSQIP database using CPT codes. Patient demographics, pre-operative comorbidities, anatomic location of injury, and post-operative in-hospital complications were collected. To control for individual patient comorbidities, a negative binomial regression model evaluated hospital LOS after surgery. Betas (ß), were determined for each pre-operative patient characteristic. We selected significant predictors of LOS (p < 0.05) using backwards stepwise elimination. RESULTS: 49,778 orthopaedic trauma patients were included in the analysis. Deep incisional surgical site infections and superficial surgical site infections were associated with the greatest percent change in predicted LOS (ß = 1.2760 and 1.2473, respectively; p < 0.0001 for both). A post-operative LOS risk calculator was developed based on the formula: [Formula: see text]. CONCLUSIONS: Utilizing a large prospective cohort of orthopaedic trauma patients, we created the first personalized LOS calculator based on pre-operative comorbidities, post-operative complications and location of surgery. Future work may assess the use of this calculator and attempt to validate its utility as an accurate model. To improve the quality measures of hospitals, orthopaedists must employ such predictive tools to optimize care and better manage resources.

Open treatment of ankle fracture as inpatient increases risk of complication.

BACKGROUND: Ankle fracture is one of the most common injuries treated by orthopaedic surgeons, and its incidence is only expected to rise with an aging population. It is also associated with often costly complications, yet there is little literature on risk factors, especially modifiable ones, driving these complications. The aim of this study is to reveal whether inpatient treatment after ankle fracture is associated with higher incidence of postoperative complications. As the USA moves towards a bundled payment healthcare system, it is imperative that orthopaedists maximize patient outcome and quality of care while also reducing overall costs. MATERIALS AND METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database to compare complication rates between inpatient and outpatient treatment of ankle fracture. We collected patient demographics, comorbidities, and postoperative complications from both groups, then compared treatments using a multinomial logistic regression model. RESULTS: We identified 7383 patients, with 2630 (36%) in the outpatient and 2630 (36%) in the inpatient group. Of these, 104 (4.0%) inpatients compared with 52 (2.0%) outpatients developed a complication (p < 0.001). CONCLUSIONS: Inpatients developed major complications including deep wound infection and pulmonary embolism, as well as minor complications such as pneumonia and urinary tract infection, at significantly greater rates. As reimbursement models begin to incorporate value-based care, orthopaedic surgeons need to be aware of factors associated with increased incidence of postoperative complications. LEVEL OF EVIDENCE: Level III retrospective comparative study.

Incidence and predictive risk factors of postoperative sepsis in orthopedic trauma patients.

BACKGROUND: Postoperative sepsis is associated with high mortality and the national costs of septicemia exceed those of any other diagnosis. While numerous studies in the basic orthopedic science literature suggest that traumatic injuries facilitate the development of sepsis, it is currently unclear whether orthopedic trauma patients are at increased risk. The purpose of this study was thus to assess the incidence of sepsis and determine the risk factors that significantly predicted septicemia following orthopedic trauma surgery. MATERIALS AND METHODS: 56,336 orthopedic trauma patients treated between 2006 and 2013 were identified in the ACS-NSQIP database. Documentation of postoperative sepsis/septic shock, demographics, surgical variables, and preoperative comorbidities was collected. Chi-squared analyses were used to assess differences in the rates of sepsis between trauma and nontrauma groups. Binary multivariable regressions identified risk factors that significantly predicted the development of postoperative septicemia in orthopedic trauma patients. RESULTS: There was a significant difference in the overall rates of both sepsis and septic shock between orthopedic trauma (1.6%) and nontrauma (0.5%) patients (p < 0.001). For orthopedic trauma patients, ventilator use (OR = 15.1, p = 0.002), history of pain at rest (OR = 2.8, p = 0.036), and prior sepsis (OR = 2.6, p < 0.001) were significantly associated with septicemia. Statistically predictive, modifiable comorbidities included hypertension (OR = 2.1, p = 0.003) and the use of corticosteroids (OR = 2.1, p = 0.016). CONCLUSIONS: There is a significantly greater incidence of postoperative sepsis in the trauma cohort. Clinicians should be aware of these predictive characteristics, may seek to counsel at-risk patients, and should consider addressing modifiable risk factors such as hypertension and corticosteroid use preoperatively. Level of evidence Level III.

Open tibial shaft fracture fixation strategies: intramedullary nailing, external fixation, and plating.

Tibial shaft fractures are one of the most common orthopaedic injuries. Open tibial shaft fractures are relatively common because of the paucity of soft tissue surrounding the bone. Despite the prevalence of these injuries, the optimal fixation strategy is still a topic of debate. The purpose of this article was to review the current literature on open tibial shaft fracture fixation strategies including intramedullary nailing, external fixation, and plating.

Protocol for establishing spontaneous metastasis in mice using a subcutaneous tumor model.

Recapitulating spontaneous metastasis in preclinical models is crucial for understanding mechanisms underlying cancer progression and testing effective therapeutic interventions. We present a protocol for establishing and characterizing the spontaneous metastasis model in mice. We describe steps for generating primary tumors, tumor resection, monitoring metastatic dissemination, and evaluating metastatic burden using histological and imaging techniques. This protocol provides a valuable tool for studying metastasis in vivo and testing therapeutic strategies aimed at preventing or targeting metastatic diseases. For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Arthroscopic Bankart repair versus nonoperative management for first-time anterior shoulder instability: A cost-effectiveness analysis.

Purpose: Arthroscopic Bankart repair (ABR) may be more effective than nonoperative management for patients with anterior shoulder instability following first-time dislocation. The purpose of the study was to determine the most cost-effective treatment strategy by evaluating the incremental cost-effectiveness ratio (ICER) for ABR versus nonoperative treatment. Methods: This cost-effectiveness study utilized a Markov decision chain and Monte Carlo simulation. Probabilities, health utility values, and outcome data regarding ABR and nonoperative management of first-time shoulder instability derived from level I/II evidence. Costs were tabulated from Centers for Medicaid & Medicare Services. Probabilistic sensitivity analysis was performed using >100,000 repetitions of the Monte Carlo simulation. A willingness-to-pay (WTP) threshold was set at $50,000. Results: The expected cost for operative management higher than nonoperative management ($32,765 vs $29,343). However, ABR (5.48 quality-adjusted life years (QALYs)) was the more effective treatment strategy compared to nonoperative management (4.61 QALYs). The ICER for ABR was $3943. Probabilistic sensitivity analysis showed that ABR was the most cost-effective strategy in 100% of simulations. Discussion: ABR is more cost-effective than nonoperative management for first-time anterior shoulder dislocation. The threshold analysis demonstrated that when accounting for WTP, ABR was found to be the more cost-effective strategy.

High expression of Trop2 is associated with aggressive localized prostate cancer and is a candidate urinary biomarker.

Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and pre-operative PSA levels. More importantly, we demonstrate that elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

Clinical course of breast cancer patients with isolated sternal and full-thickness chest wall recurrences treated with and without radical surgery.

BACKGROUND: The role and outcome of radical surgery in contemporary multidisciplinary management of breast cancer patients presenting with isolated sternal or fullthickness chest wall (SCW) recurrence are undefined compared with patients treated without surgery. METHODS: Detailed analyses of all patients with isolated SCW recurrence treated from 1992 to 2011 at a large cancer institution were performed. Univariate and multivariate comparisons of clinicopathologic and treatment characteristics were analyzed. Overall and progression-free survival were compared using the Kaplan­Meier method. RESULTS: Seventy-six patients were identified, 44 treated surgically and 32 nonsurgically. Overall survival at 5 years was not statistically different between patients who underwent surgery and those who did not (30.6 and 49.6 %, respectively; P = 0.52) although patients selected for surgery presented with more advanced and biologically aggressive disease. Surgically treated patients were more likely to have triple-negative breast cancer at recurrence (52 vs. 17 %; P = 0.006). Among surgical patients, 95 % received preoperative systemic therapy. Clinical response with systemic therapy was significantly different, with surgically treated patients more likely to have responsive or stable disease (54 vs. 25 %, P = 0.04). Complications related to radical surgical resection occurred in 25 % of patients. For hormone receptor­positive recurrence, 5-year progression-free survival was significantly higher among surgical patients (46.3 vs. 14.5 %; P = 0.01). CONCLUSIONS: Among patients with isolated SCW recurrence, hormone receptor-positive recurrence is associated with improved survival. Systemic therapy should be the initial treatment, and clinical response can be used to help select patients who may benefit from radical resection.