RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases.

One-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65-70%, patients with LM experience poor survival rates of only 19-30%. Unacceptably, this situation that has remained unchanged for 30 years. Thus, there is an urgent need to elucidate the mechanisms of metastatic spread in OS and to identify targetable molecular pathways that enable more effective treatments for patients with LM. We aimed to identify OS-specific gene alterations using RNA-sequencing of extremity and LM human tissues. Samples of extremity and LM tumors, including 4 matched sets, were obtained from patients with OS. Our data demonstrate aberrant regulation of the androgen receptor (AR) pathway in LM and predicts aldehyde dehydrogenase 1A1 (ALDH1A1) as a downstream target. Identification of AR pathway upregulation in human LM tissue samples may provide a target for novel therapeutics for patients with LM resistant to conventional chemotherapy.

Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy.

BACKGROUND: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (IDH) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining IDH status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. METHODS: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing for IDH1 and IDH2 mutations (n = 47) and RNA sequencing via Nextseq 2000 (n = 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. RESULTS: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on available IDH status, we evaluated 15 IDH WT and 32 IDH mutant tumors as part of this dataset. Out of 15 IDH WT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed in IDH WT tumors compared to IDH mutant tumors. Furthermore, IDH WT and IDH mutant tumors were transcriptomically distinct in the IPA and GSEA, with IDH mutant tumors showing increased activity in methylation pathways and endochondral ossification, while IDH WT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR in IDH WT tumors, but not in IDH mutants. SATB2 was expressed in IDH mutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (p = 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (p = 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (p = 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients with IDH WT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. CONCLUSIONS: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by IDH status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on IDH status, and implies different treatment targets.

Antioxidant 1 copper chaperone gene expression and copper levels in dog osteosarcoma patients.

Twenty-four dogs with OS underwent limb amputation. Serum, OS tumour, and normal bone were harvested at time of surgery. RNA was extracted and gene expression was performed using quantitative polymerase chain reaction (qPCR). Tissue and blood copper concentrations were also determined with spectrophotometry. Compared to bone, tumour samples had significantly higher expressions of antioxidant 1 copper chaperone (ATOX1, p = .0003). OS tumour copper levels were significantly higher than that of serum (p < .010) and bone (p = .038). Similar to our previous observations in mouse and human OS, dog OS demonstrates overexpression of genes that regulate copper metabolism (ATOX1), and subsequent copper levels. Dogs with OS may provide a robust comparative oncology platform for the further study of these factors, as well as potential pharmacologic interventions.

Management of High-Energy Tibial Pilon Fractures.

➤ Pilon fractures in the younger patient population are frequently high-energy, intra-articular injuries and are associated with devastating, long-term impacts on patient-reported outcomes and health-related quality of life, as well as high rates of persistent disability.➤ Judicious management of associated soft-tissue injury, including open fractures, is essential to minimizing complications. Optimizing medical comorbidities and negative social behaviors (e.g., smoking) should be addressed perioperatively.➤ Delayed internal fixation with interval temporizing external fixation represents the preferred technique for managing most high-energy pilon fractures presenting with characteristically substantial soft-tissue trauma. In some cases, surgeons elect to utilize circular fixation for these scenarios.➤ Although there have been treatment advances, the results have been generally poor, with high rates of posttraumatic arthritis, despite expert care.➤ Primary arthrodesis may be indicated in cases with severe articular cartilage injury that, in the opinion of the treating surgeon, is likely unsalvageable at the time of the index management.➤ The addition of intrawound vancomycin powder at the time of definitive fixation represents a low-cost prophylactic measure that appears to be effective in reducing gram-positive deep surgical site infections.

The standardized exploration of the radial nerve during humeral shaft fixation reduces the incidence of iatrogenic palsy.

BACKGROUND: The purpose of this study is to determine if a standardized protocol for radial nerve handling during humeral shaft repair reduces the incidence of iatrogenic nerve palsy post operatively. METHODS: Seventy-three patients were identified who underwent acute or reconstructive humeral shaft repair with radial nerve exploration as part of the primary procedure for either humeral shaft fracture or nonunion. All patients exhibited intact radial nerve function pre-operatively. A retrospective chart review and analysis identified patients who developed a secondary radial nerve palsy post-operatively. In each case, the radial nerve was identified and mobilized for protection, regardless of whether the implant necessitated the extensile exposure. RESULTS: Fractures were classified according to AO/OTA guidelines and included 23 Type 12A, 11 Type 12B, and 3 Type 12C. Eight patients had periprosthetic fractures and 28 fractures could not be classified. All patients in the cohort were fixed with locking plates. Surgery was indicated for 36 patients with humeral nonunions and 37 patients with acute humeral shaft fractures. Of the 73 patients, 2 (2.7%) developed radial nerve palsy following surgery, one from the posterior approach and one from the anterolateral approach. Both patients exhibited complete recovery of radial nerve function by 6-month follow-up. No significant differences (p > 0.05) were found in any demographic or surgical details between those with and without radial nerve injury. CONCLUSIONS: Nerve exploration identification and protection leads to a low incidence of transient radial nerve palsy compared to the rate reported in the current literature (2.7% compared to 6-24%). Thus, radial nerve exploration and mobilization should be considered when approaching the humeral shaft for acute fracture and nonunion repairs. LEVEL OF EVIDENCE: Level III.

Patient obesity is associated with severity of proximal humerus fractures, not outcomes.

PURPOSE: The purpose of this study is to evaluate the effect of obesity on the outcome of operatively treated proximal humerus fractures. METHODS: Between December 2003 and October 2020, 240 patients with proximal humerus fractures requiring surgery were prospectively followed and classified according to the international AO/Orthopedic Trauma Association (AO/OTA) and Neer classifications. Patients' body mass indexes (BMI) were calculated and used to identify two groups, BMI ≥ 30 kg/cm (obese) and < 30 kg/cm (non-obese). Independent t tests were used for statistical analysis of continuous variables and χ2 tests for categorical variables. Regression analysis was performed to determine if BMI was a predictor of fracture pattern severity as determined by the AO/OTA classification. RESULTS: Overall, 223 patients who sustained proximal humerus fractures were analyzed. Patient age at time of injury was 60.5 ± 13.7 years. There were 67 AO/OTA 11A, 79 AO/OTA 11B, and 77 AO/OTA 11C fracture types. Seventy-two patients (32.3%) were obese. No significant differences were seen between groups in regard to demographic variables, Neer classification, or functional and clinical outcomes as determined by DASH scores and shoulder ROM, respectively. Statistical analyses confirmed that obesity is associated with more severe fracture patterns of the proximal humerus as categorized by the AO/OTA classification. An independent t test confirmed that BMI was significantly higher in the complex fracture group based on the AO/OTA classification (p = 0.047). Regression analysis also demonstrated that age (p = 0.005) and CCI (p = 0.021) were predictors of more severe fractures, while BMI approached significance (p = 0.055) based on the AO/OTA classification. CONCLUSION: A significantly higher incidence of complex proximal humerus fracture patterns is observed in patients with higher body mass indexes based on the AO/OTA classification. Age and CCI are also associated with more severe fracture patterns of the proximal humerus as determined by the AO/OTA classification. No differences were seen in outcomes or complication rates between obese patients and non-obese patients. LEVEL OF EVIDENCE: Level III.

Intra-articular Distal Humerus Fractures: Parallel Versus Orthogonal Plating.

Background: Dual-plating osteosynthesis is the standard treatment for Orthopedic Trauma Association (OTA)-type 13-C distal humerus fractures. However, optimal plate position is debated. Purpose: The purpose of this study was to evaluate dual-plate positioning following intra-articular distal humerus fracture repair by comparing outcomes between patients plated in parallel and those plated orthogonally following open-reduction, internal-fixation (ORIF) of intra-articular distal humerus fractures. Methods: All OTA-type 13-C intra-articular distal humerus fractures treated operatively at our institution over a 10-year period were reviewed. Clinical outcomes and complications were compared between those plated in parallel and those plated orthogonally. Data were analyzed using independent-samples t-tests, Mann-Whitney U tests, chi-square tests, and Fisher's exact tests. Results: A total of 69 patients met inclusion criteria. Mean follow-up among this cohort was 19.3 months; 45 (64.8%) patients had orthogonal dual plating, and 24 (35.2%) had parallel plating. Groups did not differ with respect to demographics or duration of follow-up. Clinically, there were no significant differences in time to union, elbow arc of motion at any time point, or patient Mayo Elbow Performance Index (MEPI) scores at final follow-up. Furthermore, there were no differences in complications. Conclusion: Parallel and orthogonal plating following ORIF of distal humerus fractures with modern, contoured locking compression plates had similar outcomes in this study. This study represents the largest comparative series in the literature at the time of its writing. Both techniques may be considered when deciding on dual-plating technique for treating intra-articular distal humerus fractures.

The role of patients' overall expectations of health on outcomes following proximal humerus fracture repair.

INTRODUCTION: The purpose of this study is to evaluate the relationship between patients' own health expectations and treatment outcomes following surgical repair of proximal humerus fractures. HYPOTHESIS: Patients' health expectations will correlate with treatment outcomes following surgical repair of proximal humerus fractures. MATERIAL AND METHODS: Over a 14-year period, 247 patients with a displaced proximal humerus fracture who underwent ORIF with locking compression plates were prospectively followed at one academic institution. Minimum follow-up period was 12 months. Patient-reported functional outcome data for the latest follow up visit (12 months and greater) was obtained from Disabilities of Arm, Shoulder, and Hand (DASH) questionnaires. Survey responses regarding health expectations were recorded at 3-month follow-up and converted to dichotomous variables. Two groups were identified: the high expectations and the low expectations groups. Statistical analysis comparing the two groups and their functional and clinical outcomes was performed using the independent t-test, using p<0.05 for significance. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to further statistically characterize the relationship between health expectations at 3 months and long-term outcomes. RESULTS: One hundred and eighty-five (75.0%) patients available for analysis with a mean follow-up length of 24.8 months. The cohort included 124 (67%) females and 61 (33%) males and the average age at time of injury was 59.5 years. Eighty-six (46.5%) patients had low expectations for their overall health and 99 (53.5%) patients had high expectations for their health. No significant differences were seen between groups in regards to age, gender, follow-up length, Charlson Comorbidity Index (CCI), smoking and tobacco use, fracture pattern (OTA and Neer classifications), early complications (p>0.05), fracture healing, and avascular necrosis. The mean DASH score at the latest follow up for patients with low expectations was 31.42±22.8 whereas the mean for those with high expectations was 16.76±20.2 (p<0.0005). The mean forward flexion of the shoulder for patients with low expectations was 137.8±31.5 degrees as compared to 148.5±26.3 degrees (p<0.05). The positive predictive value of good expectations correlating with good outcomes was 71.7%. DISCUSSION: Patients with high expectations for their health early following injury had better outcomes in the long term. These high expectations also appeared to have an optimal influence on range of shoulder motion. This data suggests attitudinal and psychological factors that affect patient health expectations early on in the course of treatment may also influence patients' functional and clinical outcomes. LEVEL OF EVIDENCE: II; Retrospective Study.

Prognostic factors and survival of patients undergoing surgical intervention for breast cancer bone metastases.

INTRODUCTION: Bone is the most common distant site of breast cancer metastasis. Skeletal lesions can cause significant morbidity due to pain, pathologic fracture, and electrolyte abnormalities. Current treatment for patients with bone metastases (BoM) from breast cancer is highly personalized and often involves a multidisciplinary approach with chemotherapy, hormone therapy, bone-targeted antiresorptive agents, radiation therapy, and surgery. We have retrospectively collected clinical data from a series of patients with bone metastases to evaluate the clinical characteristics, prognostic factors, and survival patterns of patients with breast cancer BoM receiving standard multimodal therapy. METHODS: A consecutive series of 167 patients with breast cancer BoM treated at a single institution between August 2013 and March 2020 were identified. Clinical information was obtained from the medical record and survival analyses were performed to evaluate patient outcomes and identify prognostic factors. RESULTS: Thirty-seven patients (22%) presented with de novo BoM - bone metastases at the time of breast cancer diagnosis - and were 2.6 times more likely to die within the study period than those with asynchronous BoM (HR = 2.62, p = <0.0001). Patients who received bone-targeted medical therapy were 61% less likely to die after BoM diagnosis than those who did not (HR = 0.39, p = 0.001). Operative stabilization of BoM was more frequently employed in patients with lytic (p = 0.02) or mixed (p = 0.02) tumors than it was for those with blastic lesions. Patients treated with surgery had a lower overall bone metastasis survival than those treated without (p < 0.03). DISCUSSION: These findings reflect the current patterns in metastatic breast cancer treatment and associated outcomes. In a series of 167 consecutive patients, we demonstrate the natural history of breast cancer with BoM being treated with modern multimodal therapy. Understanding these treatment patterns and prognostic factors enhances the provider's ability to counsel patients and direct appropriate treatments.

Update on Osteosarcoma.

PURPOSE OF REVIEW: Osteosarcoma (OSA) is the most common primary tumor of bone, mainly affecting children and adolescents. Here we discuss recent advances in surgical and systemic therapies, and highlight potentially new modalities in preclinical evaluation and prognostication. RECENT FINDINGS: The advent of neoadjuvant and adjuvant chemotherapy has markedly improved the disease-free recurrence and overall survival of OSA. However, treatment efficacy has been stagnant since the 1980s. This plateau has prompted preclinical and clinical research into in precision surgery, inhaled chemotherapy to increase pulmonary drug concentration without systemic side effects, and novel immunomodulators intended to block molecular pathways associated with OSA proliferation and metastasis. With the advent of novel surgical techniques and new forms and vectors for chemotherapy, it is hoped that OSA treatment outcomes will exceed their currently sustained plateau in the near future.

The Role of ALDH in the Metastatic Potential of Osteosarcoma Cells and Potential ALDH Targets.

Aldehyde dehydrogenases are a family of enzymes that oxidize aldehydes to carboxylic acids. These enzymes are important in cellular homeostasis during oxidative stress by the elimination of toxic aldehyde by-products from various cellular processes. In osteosarcoma, aldehyde dehydrogenase 1A1has been described as a cancer stem cell marker. Its activity has been found to correlate with metastatic potential and the metastatic phenotype. As such, a more complete understanding of aldehyde dehydrogenase in osteosarcoma will give us a deeper knowledge of its impact on osteosarcoma metastatic potential. Our hope is that this knowledge can be translated into novel antimetastatic therapeutic strategies and thus improve osteosarcoma prognoses.

Final outcomes of radial nerve palsy associated with humeral shaft fracture and nonunion.

BACKGROUND: Little evidence regarding the extent of recovery of radial nerve lesions with associated humerus trauma exists. The aim of this study is to examine the incidence and resolution of types of radial nerve palsy (RNP) in operative and nonoperative humeral shaft fracture populations. MATERIALS AND METHODS: Radial nerve lesions were identified as complete (RNPc), which included motor and sensory loss, and incomplete (RNPi), which included sensory-only lesions. Charts were reviewed for treatment type, radial nerve status, RNP resolution time, and follow-up time. Descriptive statistics were used to document incidence of RNP and time to resolution. Independent-samples t-test was used to determine significant differences between RNP resolution time in operative and nonoperative cohorts. RESULTS: A total of 175 patients (77 operative, 98 nonoperative) with diaphyseal humeral shaft injury between 2007 and 2016 were identified and treated. Seventeen out of 77 (22.1%) patients treated operatively were diagnosed preoperatively with a radial nerve lesion. Two (2.6%) patients developed secondary RNPc postoperatively. Eight out of 98 (8.2%) patients presented with RNP postinjury for nonoperatively treated humeral shaft fracture. All patients who presented with either RNPc, RNPi, or iatrogenic RNP had complete resolution of their RNP. No statistically significant difference was found in recovery time when comparing the operative versus nonoperative RNPc, operative versus nonoperative RNPi, or RNPc versus RNPi patient groups. CONCLUSIONS: All 27 (100%) patients presenting with or developing radial nerve palsy in our study recovered. No patient required further surgery for radial nerve palsy. Radial nerve exploration in conjunction with open reduction and internal fixation (ORIF) appears to facilitate speedier resolution of RNP when directly compared with observation in nonoperative cases, although not statistically significantly so. These findings provide surgeons valuable information they can share with patients who sustain radial nerve injury with associated humerus shaft fracture or nonunion. LEVEL OF EVIDENCE: Level III treatment study.

Surgical Delay Is Not Warranted for Patients With Hip Fractures Receiving Non-Warfarin Anticoagulants.

The purpose of this study was to evaluate whether patients with hip fractures receiving antiplatelet and direct oral anticoagulants treated within 48 hours of admission had worse surgical and clinical outcomes than those whose surgery was delayed more than 48 hours. Consecutive patients 55 years and older with an operatively treated hip fracture were analyzed. Patients receiving the following anticoagulants were included: antiplatelet drugs, factor Xa inhibitors, and direct thrombin inhibitors. Outcomes included surgical blood loss, procedure time, transfusion requirement, length of stay, complication rate, and need for intensive care unit or step-down unit level care. Patients who underwent surgery within 48 hours of presentation were compared with patients whose surgery was delayed more than 48 hours. Of 551 consecutive operative hip fracture patients, 78 (14.2%) were receiving the anticoagulant medications included in this study. Of these 78 patients, 58 had surgery within 48 hours and 20 had surgery after 48 hours. When comparing the early and delayed fixation cohorts, there was no difference in transfusion requirement, length of surgery, or blood loss. Type of anticoagulant made no difference in transfusion requirement, blood loss, or length of surgery. There was also no difference in the mean number of complications or in the need for intensive care unit or step-down unit level care. In this study, patients receiving antiplatelet therapy, factor Xa inhibitors, or direct thrombin inhibitors who underwent surgical fixation of their hip fracture within 48 hours of admission were at no higher risk for transfusion, increased surgical blood loss, longer operative time, or inpatient mortality. [Orthopedics. 2019; 42(3):e331-e335.].

Admitting Service Affects Cost and Length of Stay of Hip Fracture Patients.

INTRODUCTION: The purpose of this study was to analyze the effect of the admitting service on cost of care for hip fracture patients by comparing the cost difference between patients admitted to the medicine service versus those admitted to a surgical service. METHODS: A 2-year cohort of patients 55 years or older who were admitted to a single level 1 trauma center with an operative hip fracture were included. Patient demographics, comorbidities, admitting service, complications, and hospital length of stay were recorded for each patient. Cost of hospitalization, discharge disposition, and 30-day readmissions were collected. Patients who were admitted to the medicine service (medicine cohort) were compared to those admitted to a surgery service (surgery cohort). Multivariate regression models controlling for age, Charlson comorbidity index (CCI), and American Society of Anesthesiology (ASA) scores were used to evaluate hospitalization costs with a P value of <.05 as significant. RESULTS: Two hundred twenty-five hip fracture patients were included; 143 (63.6%) patients were admitted to a surgical service, while 82 (36.4%) were admitted to the medicine service. Patients admitted to medicine service had greater CCI and ASA scores, longer lengths of stay, and more complications than those patients admitted to surgery service. Linear regression model controlling for age, CCI, ASA score, and time to surgery demonstrates that patients admitted to a surgical service will have 2.0-day (95% confidence interval [CI]: 0.561-3.503; P = .007) shorter admissions with a US$4215 reduction in cost (95% CI: US$314-US$8116; P = .034) compared to patients admitted to the medicine service. DISCUSSIONS: In our urban safety net hospital, hip fracture patients admitted to medicine service had longer lengths of stay and higher total hospitalization costs than patients who were admitted to surgery service. CONCLUSIONS: This study highlights that the admitting service should be an area of focus for hospitals when developing programs to provide effective and cost-conscious care to hip fracture patients.

Does Use of Oral Anticoagulants at the Time of Admission Affect Outcomes Following Hip Fracture.

PURPOSE: The purpose of this study was to compare hospital quality outcomes in patients over the age of 60 undergoing fixation of hip fracture based on their anticoagulation status. MATERIALS AND METHODS: Patients aged 60 and older with isolated hip fracture injuries treated operatively at 1 academic medical center between October 2014 and September 2016 were analyzed. Patients on the following medications were included in the anticoagulation cohort: warfarin, clopidogrel, aspirin 325 mg, rivaroxaban, apixaban, dabigatran, and dipyridamole/aspirin. We compared outcome measures including time to surgery, length of stay (LOS), transfusion rate, blood loss, procedure time, complication rate, need for intensive care unit (ICU)/step-down unit (SDU) care, discharge disposition, and cost of admission. Outcomes were controlled for age, Charlson comorbidity index (CCI), and anesthesia type. RESULTS: A total of 479 hip fracture patients met the inclusion criteria, with 367 (76.6%) patients in the nonanticoagulated cohort and 112 (23.4%) patients in the anticoagulated cohort. The mean LOS and time to surgery were longer in the anticoagulated cohort (8.3 vs 7.3 days, P = .033 and 1.9 vs 1.6 days, P = .010); however, after controlling for age, CCI, and anesthesia type, these differences were no longer significant. Surgical outcomes were equivalent with similar procedure times, blood loss, and need for transfusion. The mean number of complications developed and inpatient mortality rate in the 2 cohorts were similar; however, more patients in the anticoagulated cohort required ICU/SDU-level care (odds ratio = 2.364, P = .001, controlled for age, CCI, and anesthesia). There was increased utilization of post-acute care in the anticoagulated cohort, with only 10.7% of patients discharged home compared to 19.9% of the nonanticoagulated group (P = .026). Lastly, there was no difference in cost of care. CONCLUSION: This study highlights that anticoagulation status alone does not independently put patients at increased risk with respect to LOS, surgical outcomes, and cost of hospitalization.