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.

Comparison of Patient-Reported Outcomes With or Without Prophylactic Carpal Tunnel Release After Distal Radius Fracture Stabilization.

Distal radius fractures (DRFs) are frequently complicated by acute carpal tunnel syndrome (CTS), which, if unrecognized, can cause permanent median neuropathy. Some surgeons recommend "prophylactic" carpal tunnel release (CTR) during open reduction and internal fixation (ORIF) of DRF. Patient-reported outcomes (PROs) and safety data regarding prophylactic vs symptomatic CTR strategies during DRF fixation are lacking. We conducted a retrospective review of two management strategies for DRFs at our institution (2017 to 2019). Group 1 consisted of patients operated on by two surgeons performing ORIF and symptomatic CTR only for acute CTS. Group 2 consisted of patients operated on by a third surgeon performing ORIF and prophylactic CTR on all patients irrespective of median nerve symptoms. The PROs included QuickDASH Wrist and PROMIS physical/mental health preoperatively vs at final follow-up. Demographic information, complications, and return to the operating room were recorded. Group 1 (36 patients) and group 2 (76 patients) were demographically similar. The mechanism of injury was more severe in group 1 (P<.05), but preoperative PROs were similar between the two groups. Eight patients (22.2%) in group 1 had symptomatic CTR for acute CTS. Significant improvement occurred within both groups from preoperative to final follow-up for PROMIS physical function and QuickDASH Wrist scores (P<.05). Intergroup PROs were not significantly different at either time point. One patient in group 1 (2.8%) and 2 patients in group 2 (2.6%) returned to the operating room due to median nerve symptoms (P>.05). A prophylactic CTR strategy is not associated with improved PROs compared with a symptomatic strategy during ORIF of DRF. [Orthopedics. 2023;46(6):e362-e368.].

Intraoperative Evaluation of Soft Tissue Sarcoma Surgical Margins with Indocyanine Green Fluorescence Imaging.

Soft tissue sarcomas (STS) are rare malignant tumors often associated with poor outcomes and high local recurrence rates. Current tools for intraoperative and definitive margin assessment include intraoperative frozen section and permanent pathology, respectively. Indocyanine green dye (ICG) is a historically safe fluorophore dye that has demonstrated efficacy for intraoperative margin assessment in the surgical management of both breast and gastrointestinal cancers. The utility of ICG in the surgical management of sarcoma surgery has primarily been studied in pre-clinical mouse models and warrants further investigation as a potential adjunct to achieving negative margins. This study is a prospective, non-randomized clinical study conducted on patients with confirmed or suspected STS. Patients younger than 18 years, with a prior adverse reaction to iodine or fluorescein, or with renal disease were excluded from the study. Intravenous ICG was infused approximately three hours prior to surgery at a dosage of 2.0-2.5 mg/kg, and following tumor resection, the excised tumor and tumor bed were imaged for fluorescence intensity. When scanning the tumor bed, a threshold of 77% calibrated to the region of maximum intensity in the resected tumor was defined as a positive ICG margin, according to published protocols from the breast cancer literature. ICG results were then compared with the surgeon's clinical impression of margin status and permanent pathology results. Out of 26 subjects recruited for the original study, 18 soft tissue sarcomas (STS) were included for analysis. Three subjects were excluded for having bone sarcomas, and five subjects were excluded due to final pathology, which was ultimately inconsistent with sarcoma. The average age of patients was 64.1 years old (range: 28-83), with an average ICG dose of 201.8 mg. In 56% (10/18) of patients, ICG margins were consistent with the permanent pathology margins, with 89% specificity. The use of ICG as an intraoperative adjunct to obtaining negative margins in soft tissue sarcoma surgery is promising. However, studies with larger sample sizes are warranted to further delineate the accuracy, optimal dosage, timing, and types of sarcoma in which this diagnostic tool may be most useful.

Parallel K-Wire Placement Leads to Fusion and Midcarpal Settling in Scaphoid Excision Four-Corner Fusion.

BACKGROUND: Scaphoid excision 4-corner fusion is a motion-sparing procedure in patients with advanced radioscaphoid arthritis. This study introduces an alternate technique for scaphoid excision 4-corner fusion using a parallel Kirschner wire (K-wire) construct across the midcarpal joints that leads to reliable fusion rates, and good patient outcomes. METHODS: This is a single-surgeon, retrospective study of patients who underwent scaphoid excision 4-corner fusion, using a parallel K-wire construct across the midcarpal joints. Once fusion was achieved, K-wires were removed. Radiographic union rate, time to union, capitolunate angle, capitolunate coverage, and amount of midcarpal settling are measured. Patient-reported outcome measures and descriptive statistics are presented. RESULTS: Sixty-five wrists were included in this study with a mean age of 50.1 years. One patient was lost to follow-up. All 64 wrists (100%) fused at an average of 2.6 months. The mean capitolunate angle was 7°, and capitolunate coverage was 99.2%. Fifty-two patients (81%) had adequate radiographs for measurement. Average midcarpal settling was 1.1 mm. Thirty-two patients (51%) were available for long-term follow-up at an average of 5.3 years (0.7-10.2 years), and participated in patient reported outcomes (PRO) surveys. The mean Quick Disabilities of the Arm, Shoulder, and Hand score was 16.6, and numeric pain rating scale score was 1.8. CONCLUSIONS: Parallel K-wire placement across the midcarpal joints with scaphoid leads to a high rate of fusion with good patient outcomes long term. Midcarpal settling that occurs through dynamic compression around the K-wires may have contributed to bony fusion. This technique may provide an alternative approach to achieving reliable fusion across the midcarpal joints.

Postoperative infection and bone sarcoma survival: systematic review of the role of infection in bone sarcoma prognosis.

Background: Osteosarcoma (OS) and chondrosarcoma (CS) are primary bone malignancies whose prognoses have stagnated despite advancements in surgical management, chemotherapy, radiation therapy, and immunotherapy. The role of the immune system in generating anti-cancer physiologic responses is critical to prognosis. Prior studies have explored if immune system activation via infection enhances survival in bone sarcomas without a clear consensus. Methods: This study sought to (I) retrospectively examine the effect of postoperative infection on survival in OS and CS and (II) systematically review the effect of postoperative infection on survival in primary bone malignancies. We performed a retrospective case-control study of 192 patients treated between 1/2000-12/2015 at a single academic sarcoma referral center. Patients with OS or CS undergoing operative resection were included. Eligible patients were grouped by presence of metastasis, and survival was compared between patients with or without postoperative infection. Furthermore, we performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines investigating the effect of infection on primary bone malignancy survival. Risk of bias assessment was performed utilizing the ROBINS-I (Risk of Bias in Non-randomized Studies-of Interventions) assessment tool. All presented studies included author information, study population, and overall or disease-free survival results. Results: One hundred and four patients were included, with 85 without infection (26 metastatic, 59 non-metastatic) and 19 with infection (10 metastatic, 9 non-metastatic). Five-year survival was greatest in patients without metastasis with a postoperative infection (100%), followed by patients without metastasis who were infection-free (80%). Five-year survival was comparatively lower in patients with metastasis who were infection-free (35%) and lowest in patients with metastasis with a postoperative infection (20%). No significant differences were present (P=0.17) on log-rank analysis. Our systematic review collected six studies exploring the impact of infection on primary bone malignancy survival, with two studies reporting significant findings of infection improving survival. Limitations of this review included risk of bias due to confounding, inconsistency comparing outcomes, and differences in patient populations. Conclusions: This retrospective study and systematic review suggests postoperative infection may play a role in modulating immune response to malignancy. Understanding the synergy between anti-pathogen and anti-cancer responses warrants further investigation as an alternative method of targeted cancer treatment.

Current Trends in Use of Epinephrine in Hand Surgery.

BACKGROUND: Epinephrine use during hand surgery has been stigmatized due to a fear of digital necrosis. Clinical experience in the past 2 decades has shown epinephrine in local anesthetic to be safe. We sought to analyze the use of epinephrine among hand surgeons and identify variables associated with it. METHODS: A deidentified 21-question survey was distributed via email to the 914 and 415 members of the American Association for Hand Surgery and the Canadian Society for Surgery of the Hand, respectively. Questions included residency type, years of practice, practice setup/ownership, practice leadership, usage of epinephrine, availability of reversal agents, and reasons for or against usage. RESULTS: Of 188 responders, 170 (90%) used epinephrine in local anesthetic for hand surgery procedures. By nationality, 100% (43) of Canadian surgeons and 89% (108) of US surgeons use epinephrine (P = .01). Among surgeons with practice ownership, 88% (102) used epinephrine compared with 93% (85) of those surgeons that we employed (P = .28). Comparing surgeons with teaching responsibilities versus those without training responsibilities showed that surgeons who did not teach used epinephrine at a higher rate (87% vs 98%, P = .04). In addition, plastic surgery-trained surgeons (111) used epinephrine in 97.2% of cases while orthopedic surgery-trained surgeons (57) used epinephrine in 80.2% of cases (P = .0003). No difference was found when examining the use of epinephrine and surgeon age (P = .28). CONCLUSIONS: Most respondents believe that epinephrine is safe. Training background, location, and practice setup are significant factors in the use of epinephrine, whereas practice ownership and physician age are not major factors.

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.

Rupture Site Location of Surgically Treated Thumb Metacarpophalangeal Ulnar and Radial Collateral Ligaments.

Purpose: Thumb metacarpophalangeal collateral ligament injuries occur in 50 per 100,000 people. The most frequent rupture site locations that are often cited are the thumb ulnar collateral ligament (UCL) occurring distally from the proximal phalanx and the radial collateral ligament (RCL) occurring proximally from the metacarpal head.2,16 In this study, we report the frequency of the rupture site location of both thumb UCL and RCL injuries. Methods: A retrospective analysis of 1,004 consecutive finger collateral ligament surgeries performed at a single academic institution over 17 years was conducted. The inclusion criteria were any patient who underwent either a thumb UCL or RCL surgical repair. Patients were excluded if the rupture etiology was secondary to a laceration or a congenital or chronic deformity. Descriptive statistics were presented. Results: Three hundred forty-seven patients were included in this study, including 288 thumb UCL injuries and 59 thumb RCL injuries. The rupture site location for the thumb UCL was proximal in 5.9% (n = 17) of the cases, distal in 92.7% (n = 267), and midsubstance in 1.4% (n = 4). Fifty-three (18.4%) Stener lesions were noted. The rupture site location for the thumb RCL was proximal in 69.5% (n = 41) of the cases, distal in 25.4% (n = 15), and midsubstance in 5.1% (n = 3). Conclusions: In thumb UCL ruptures, the rupture site occurred most often at the proximal phalanx, whereas RCL injuries occurred most often at the metacarpal head. Overall, there was greater heterogeneity of RCL rupture site location frequency. Careful surgical exposure should be performed when repairing either the UCL or RCL. Further studies will determine if differences in rupture site location portend a difference in prognosis. Type of study/level of evidence: Prognostic III.

Perfusion-CT assessment of blood-brain barrier permeability in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: The goal of this study was to determine which clinical and radiographic variables in patients with subarachnoid hemorrhage (SAH) are associated with in vivo blood-brain barrier permeability (BBBP) assessments obtained using perfusion-CT (PCT) technology. METHODS: SAH patients with confirmed aneurysm etiology and with PCT and angiogram within 24 hours of each other were included, and relationships between clinical and imaging variables were analyzed using random-effects generalized linear models. RESULTS: One thousand one hundred and sixty two vascular territories from 83 patients were evaluated in this study. The mean BBBP increased by severity of vasospasm on DSA, however, in multivariate analysis, only mean transit time (MTT), cerebral blood volume (CBV), and severity of hydrocephalus were significantly associated with BBBP. Increased BBBP was not associated with angiographic vasospasm severity in multivariate analysis. CONCLUSION: Perfusion-CT assessment of BBBP may serve as a unique and useful biomarker in conjunction with angiography, additional perfusion-CT parameters, and clinical assessments, especially in characterizing microvascular dysfunction, or even in targeting treatments. However, future prospective studies will be required to definitively establish its clinical utility in the care of SAH patients.

Automated versus manual post-processing of perfusion-CT data in patients with acute cerebral ischemia: influence on interobserver variability.

INTRODUCTION: The purpose of this study is to compare the variability of PCT results obtained by automatic selection of the arterial input function (AIF), venous output function (VOF) and symmetry axis versus manual selection. METHODS: Imaging data from 30 PCT studies obtained as part of standard clinical stroke care at our institution in patients with suspected acute hemispheric ischemic stroke were retrospectively reviewed. Two observers performed the post-processing of 30 CTP datasets. Each observer processed the data twice, the first time employing manual selection of AIF, VOF and symmetry axis, and a second time using automated selection of these same parameters, with the user being allowed to adjust them whenever deemed appropriate. The volumes of infarct core and of total perfusion defect were recorded. The cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and blood-brain barrier permeability (BBBP) values in standardized regions of interest were recorded. Interobserver variability was quantified using the Bland and Altman's approach. RESULTS: Automated post-processing yielded lower coefficients of variation for the volume of the infarct core and the volume of the total perfusion defect (15.7% and 5.8%, respectively) compared to manual post-processing (31.0% and 12.2%, respectively). Automated post-processing yielded lower coefficients of variation for PCT values (11.3% for CBV, 9.7% for CBF, and 9.5% for MTT) compared to manual post-processing (23.7% for CBV, 32.8% for CBF, and 16.7% for MTT). CONCLUSION: Automated post-processing of PCT data improves interobserver agreement in measurements of CBV, CBF and MTT, as well as volume of infarct core and penumbra.