Androgen receptor activation decreases proliferation in thyroid cancer cells.

The American Cancer Society predicted more than 52 000 new cases of thyroid cancer in 2020, making it the most prevalent endocrine malignancy. Due to the approximately threefold higher incidence of thyroid cancer in women, we hypothesize that androgens and/or androgen receptors play a protective role and that thyroid cancer in men represents an escape from androgen-mediated cell regulation. The analysis of androgen receptor (AR) expression in patient tissue samples identified a 2.7-fold reduction in AR expression (p < 0.005) in papillary thyroid cancer compared with matched, normal tissue. An in vitro cell model was developed by stably transfecting AR into 8505C undifferentiated thyroid cancer cells (resulting in clone 84E7). The addition of DHT to the clone 84E7 resulted in AR translocation into the nucleus and a 70% reduction in proliferation, with a shift in the cell cycle toward G1 arrest. RNASeq analysis revealed significant changes in mRNA levels associated with proliferation, cell cycle, and cell cycle regulation. Furthermore, androgen significantly decreased the levels of the G1-associated cell cycle progression proteins cdc25a CDK6 CDK4 and CDK2 as well as increased the levels of the cell cycle inhibitors, p27 and p21. The data strongly suggest that DHT induces a G1 arrest in androgen-responsive thyroid cancer cells. Together, these data support our hypothesis that AR/androgen may play a protective, antiproliferative role and are consistent with younger men having a lower incidence of thyroid cancer than women.

RHD genotyping of serologic RhD-negative blood donors in a hospital-based blood donor center.

BACKGROUND: Serologic RhD-negative blood donors are tested by a method known to detect weak D antigen expression. Serology does not detect all red blood cells with RhD expression and RHD genotyping has been used to identify variant RHD alleles, which may lead to some RhD expression. The aim of this study was to determine the frequency of RHD variant alleles in serologic RhD-negative blood donors at a hospital-based donor center in Los Angeles. STUDY DESIGN AND METHODS: RHD genotyping of serologic RhD-negative blood donors over a 20-month period was performed using the Immucor RHD BeadChip assay. DNA sequencing was performed when the RHD BeadChip assay failed to assign a genotype. For RHD variants known or suspected to result in RhD expression, recipients of previous blood donations were investigated for alloimmunization. RESULTS: RHD genotyping was performed in 1174 RhD-negative blood donors, and 1122 were genotyped for RHCE variants. Eleven donors (0.94%) harbored mutations predicted to yield RhD expression. The predicted phenotypes were, in decreasing frequency, DEL, partial, and weak D phenotypes. Anti-D was not detected in 16 patients who had received blood from these donors after an average follow up of 182 days. CONCLUSION: Genotyping can be used to identify donors with the potential to sensitize RhD-negative recipients. In this limited study, 0.94% of serologic RhD-negative blood donors were found to have variant RHD alleles that might cause alloimmunization in RhD-negative recipients. To our knowledge, a study of this nature has not been reported in the United States.

Poor Agreement on Classification and Treatment of Subscapularis Tendon Tears.

PURPOSE: To assess the inter- and intraobserver agreement for classification and management of subscapularis tendon pathology based on arthroscopy and magnetic resonance imaging (MRI). METHODS: Twenty-two orthopaedic surgeons from the Multicenter Orthopaedic Outcomes Network (MOON) shoulder group reviewed still arthroscopic and MRI images of the subscapularis tendon from patients with a random assortment of subscapularis morphology. The surgeons were asked to classify the pathology based on 2 systems (Lafosse and Lyons) and choose whether they would repair the tendon and, if so, the method of repair (open or arthroscopic). The survey was administered 3 times to each surgeon. Inter- and intraobserver reliability between testing rounds was determined by kappa analysis. RESULTS: Interobserver reliability on classification of tears was poor based on MRI (k = 0.18 to 0.19) and fair based on arthroscopy (k = 0.26 to 0.29). Interobserver agreement on whether surgical treatment was indicated was fair for both MRI (k = 0.28) and arthroscopy (k = 0.38), while the agreement for type of surgery was poor based on MRI (k = 0.18) and fair based on arthroscopy (k = 0.28). Interobserver agreement did not improve when both MRI and arthroscopy were provided simultaneously (k = 0.24 to 0.30). Intraobserver reliability for classification and treatment was fair to moderate for both MRI (k = 0.32 to 0.50) and arthroscopic imaging (k = 0.39 to 0.56). When considering just those patients with normal tendons, surgeon agreement improved. For all questions, the arthroscopic images had a higher level of agreement among surgeons than the MRI (P < .001). CONCLUSIONS: Although surgeons tended to have higher reliability when presented with arthroscopic images compared with MRI, there was very little agreement on the classification and management of subscapularis tendon tears.

Squamous cell carcinoma in a thyroglossal duct cyst: A case report with review of the literature.

Carcinoma arising within a thyroglossal duct cyst (TGDC) is exceedingly uncommon, occurring in about 1% of TGDC (Chrisoulidou et al., 2013 [1]). Since the first description of TGDC carcinoma in 1911 by Brentano, approximately 200 cases have been reported in the world literature, mostly as single case reports making its true incidence difficult to determine (Hanna, 1996 [2]). There are numerous reports in the literature of papillary and follicular TGDC carcinoma, but only limited reports of squamous cell carcinoma. In order for a lesion to qualify as squamous cell carcinoma of a TGDC, the lesion must arise from the epithelial lining. Recognition and understanding of this entity are important in staging and planning of treatment. Exclusion of primary squamous cell carcinoma arising from an adjacent structure or metastatic central compartment nodal disease is important in the evaluation for diagnosis to be confirmed. A thorough work up should be undertaken to exclude other primary malignancies that may have metastasized. We present a unique case of squamous cell carcinoma, along with supporting pathology and radiology imaging. We then review this rare entity and provide some insight into the diagnosis and management.

Rate Versus Rhythm Control for Atrial Fibrillation.

Atrial fibrillation (AF) is an arrhythmia characterized by disorganized atrial activity with an associated unevenly irregular ventricular response on an electrocardiogram. It is the most common sustained arrhythmia, with a lifetime risk of 25% in patients older than 40 years old. The incidence of AF increases with age and is associated with an increased risk for heart failure, stroke, adverse cardiac events, and dementia. The 2 main aims of AF treatment include anticoagulation for thromboembolism prophylaxis as well as rate vs rhythm control. The focus of this article will be on the treatment strategies in managing AF. Rate control refers to the use of atrioventricular nodal blocking medications, including beta blockers and calcium channel blockers, to maintain a goal heart rate. Rhythm control, on the other hand, refers to a treatment strategy focused on the use of antiarrhythmic drugs (AAD), cardioversion, and ablation to restore and to maintain a patient in sinus rhythm. Currently, the ideal treatment strategy remains greatly debated. Thus, we hope to compare the risks and benefits of rate to rhythm control to highlight how patients with AF are managed here at Kaiser Permanente Northern California.

Patient Satisfaction Following Non-Operative Treatment of Geriatric Hip Fractures: A Case-Control Study.

Introduction: A minority of geriatric hip fracture patients pursue non-operative treatment. Compared with surgical patients, non-operative patients have higher mortality rates. However, patient satisfaction following non-operative vs operative treatment has not been investigated extensively. The purpose of this study was to compare satisfaction among non-operatively vs operatively treated hip fracture patients. Methods: We identified patients aged 60+ years with proximal femur fractures treated over a 10-year period. Excluded were patients with isolated greater/lesser trochanteric fractures. Patients or relatives were asked to complete a 6-question survey about their treatment satisfaction. Results: Survey responses from 56 operative and 28 non-operative patients were recorded. Overall, 91.1% of operative and 82.1% of non-operative patients were satisfied with their treatment course (P = 0.260). However, only 71.4% of non-operative patients were satisfied with treatment option explanations vs 83.9% of operative patients (P = 0.014). While only 64.3% of non-operative respondents were satisfied with the ultimate treatment outcome (vs 85.7% of operative patients, P = 0.025), 89.3% of patients in each cohort would choose the same treatment plan again. Discussion: Our findings highlight the complexity of defining patient satisfaction, particularly in a geriatric hip fracture population. Unlike previous studies, we chose a direct approach to quantifying patient satisfaction by asking participants specifically about satisfaction with treatment outcome and the overall treatment course. Additional survey questions were then included to assess factors considered important in treatment satisfaction, such as health care provider treatment explanations, post-treatment mobility, and palliative care service involvement. Conclusions: We identified significant differences between non-operatively and operatively treated geriatric hip fracture patients regarding satisfaction with the explanation of treatment options, and ultimate treatment outcomes. There was no significant difference in overall satisfaction with the treatment course or likelihood of choosing the same treatment again. Further research investigating patient satisfaction following geriatric hip fracture treatment is warranted.

Mortality Rates After Nonoperative Geriatric Hip Fracture Treatment: A Matched Cohort Analysis.

OBJECTIVE: To compare the mortality rate between geriatric patients with hip fracture treated nonoperatively and a matched cohort treated operatively. DESIGN: Retrospective Observational Matched Cohort Study. SETTING: Academic Level 1 Trauma Center. PATIENTS: Geriatric patients who sustained femoral neck and intertrochanteric/peritrochanteric fractures, excluding isolated greater trochanteric fractures. All patients older than 65 years with hip fractures over a 10-year period were identified. Operative patients were matched at a 2:1 ratio, when possible, to nonoperative patients based on Charlson Comorbidity Index and American Society of Anesthesiologists score. INTERVENTION: Nonoperative treatment or operative treatment (femoral neck fractures: cannulated screw fixation or hemiarthroplasty; intertrochanteric/peritrochanteric fractures: sliding hip screw or cephalomedullary nail fixation; or proximal femoral locking plate). MAIN OUTCOMES: Mortality calculated at 30 and 90 days, and 1-year after injury. Mortality was compared between groups using logistic regression while controlling for age, CVA/TIA, and dementia. RESULTS: Seven hundred seventy-two patients (171 nonoperative and 601 operative) were initially identified. After applying the matching algorithm, 128 nonoperative and 239 operative patients were included in the analysis. There were no significant differences in age, sex, Charlson Comorbidity Index, or American Society of Anesthesiologists score between the cohorts. Nonoperative patients had a significantly higher 1-year mortality rate than operative patients [46.1% vs. 18.0%, Odds Ratio (95% confidence interval): 3.85 (2.34-6.41), P < 0.001]. CONCLUSIONS: Geriatric patients with hip fracture treated nonoperatively had a 1-year mortality rate of 46.1%, more than double the rate among operative patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated ß-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer.

Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a > 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBα and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies.

Prevalence and Treatment of Osteoporosis Prior to Elective Shoulder Arthroplasty.

INTRODUCTION: The rate of preoperative osteoporosis in lower extremity arthroplasty is 33%. The prevalence of osteoporosis in shoulder arthroplasty patients is inadequately studied. The purpose of this study was to (1) determine the prevalence of osteoporosis in patients undergoing elective shoulder arthroplasty, (2) report the percentage of patients having dual-energy x-ray absorptiometry (DEXA) testing before surgery, and (3) determine the percentage of patients who have been prescribed osteoporosis medications within 6 months before or after surgery. METHODS: This retrospective case series included all adults aged 50 years and older who underwent elective shoulder arthroplasty at a single tertiary care center over an 8-year period. National Osteoporosis Foundation (NOF) criteria for screening and treatment were applied. RESULTS: Two hundred fifty-one patients met the inclusion criteria; 171 (68%) met the criteria for DEXA testing, but only 31 (12%) had this testing within 2 years preoperatively. Eighty patients (32%) met the NOF criteria for receipt of pharmacologic osteoporosis treatment, and 17/80 (21%) received a prescription for pharmacotherapy. DISCUSSION: Two-thirds of elective shoulder arthroplasty patients meet the criteria to have bone mineral density measurement done, but less than 20% have this done. One in three elective shoulder arthroplasty patients meet the criteria to receive osteoporosis medications, but only 20% of these patients receive therapy.

Combined VSV oncolytic virus and chemotherapy for squamous cell carcinoma.

OBJECTIVES: Vesicular stomatitis virus (VSV) is a negative-strand ribonucleic acid (RNA) virus that replicates specifically in tumor cells and has oncolytic effects in a variety of malignant tumors. We previously demonstrated recombinant VSV vectors incorporating viral fusion protein (rVSV-F) and interleukin 12 (rVSV-IL12) to have significant antitumor effects against squamous cell carcinoma (SCC) in a murine model. Here we evaluate the potential to combine a potent chemotherapeutic agent for SCC (cisplatin) with rVSV-F and rVSV-IL12 to improve efficacy. STUDY DESIGN: In vitro, three SCC cell lines were tested using rVSV-F and rVSV-IL12 with cisplatin, monitoring viral replication and cell survival. In an orthotopic floor of mouth murine SCC model, intratumoral injections of virus combined with systemic cisplatin were tested for tumor control and animal survival. RESULTS: In vitro, virus and cisplatin combination demonstrated rapid replication and enhanced tumor cell kill. Human keratinocytes were unaffected by virus and cisplatin. In vivo, combined rVSV-F with cisplatin reduced tumor burden and improved survival (P = .2 for both), while rVSV-IL12 monotherapy had better tumor control (P = .06) and survival (P = .024) than combination therapy. CONCLUSIONS: Addition of cisplatin did not affect the ability of either virus to replicate in or kill murine SCC cells in vitro. In vivo, combination therapy enhancedrVSV-F antitumor activity, but diminished rVSV-IL12 antitumor activity. Combination therapy may provide useful treatment for SCC with the development of more efficient viral vectors in combination with different chemotherapy agents or immunostimulatory agents.

The administration of IL-12/GM-CSF and Ig-4-1BB ligand markedly decreases murine floor of mouth squamous cell cancer.

OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell carcinoma (SCC) model. STUDY DESIGN: In vitro and in vivo testing of immune therapy for SCC. METHODS: Multiple SCC lines were infected by using advRSV-interleukin-12 (IL-12) and advCMV-interleukin-12/granulocyte macrophage colony-stimulating factor (IL-12/GM-CSF) and monitored for production of IL-12 and GM-CSF. Intratumoral injections of viral vectors were administered with systemic Ig-4-1BB ligand in an orthotopic murine FOM SCC model and followed for tumor size and survival. RESULTS: In vitro, all cell lines produced substantial levels of IL-12 and GM-CSF. In vivo, tumors treated with advCMV-IL-12/GM-CSF and Ig-4-1BBL showed a striking reduction in tumor volume (vs control P<0.0001) and improved median survival (38 days vs 19 days for control, P<0.0001). CONCLUSION: Combination immune-based therapies effectively improve survival in mice bearing FOM SCC over single-modality therapy.

Intraosseous Bioplasty for a Chondral Cyst in the Lateral Tibial Plateau.

Subchondral lesions are the result of osseous modifications seen in a different array of pathologies such as osteoarthritis, rheumatoid arthritis, calcium pyrophosphate deposition, and osteonecrosis. The physiopathologic changes in all of the aforementioned pathologies are not clear yet. What is clear is that the development of a cystic change in the subchondral bone can cause pain and can lead to modification of the activity of daily life. To provide relief and treatment for such a condition, there are different options with joint replacement as last resort when the cyst develops in communication with the joint; if the cyst is not in communication with the joint, it is possible to perform a bioplasty as we present in this technical report. It is crucial to assess the bone continuity, especially when traumas are reported in the patient history. In our case, the tibial plateau did not have signs of collapse. The technique here presented is a minimally invasive technique that can be reproduced for focal and localized subchondral cysts.

Arthroscopic Bone Marrow Aspirate Concentrate Harvesting From the Intercondylar Notch of the Knee.

Bone marrow aspirate concentrate is commonly harvested to obtain mesenchymal stem cells, progenitor cells, and growth factors. The iliac crest is the most common donor site for bone marrow harvesting and is associated with donor site morbidity of an additional incision and pain from the harvest. Iliac crest harvesting can be cumbersome because it often requires different patient positioning from the surgical procedure and additional sedation or anesthesia for the harvest prior to repositioning. The purpose of this Technical Note and accompanying video is to describe a technique to arthroscopically aspirate bone marrow from the intercondylar femoral notch, reducing the need for iliac crest harvesting.

Graft Retensioning Technique Using an Adjustable-Loop Fixation Device in Arthroscopic Anterior Cruciate Ligament Reconstruction.

Anterior cruciate ligament (ACL) tears are an unfortunate and devastating injury in the athletic patient. Surgical reconstruction of the ACL with a taut graft construct is necessary to restore knee stability and help expedite the patient's return to an active lifestyle. Arthroscopy-assisted ACL reconstruction can be a technically involved procedure, where strong fixation limits graft motion to allow sufficient healing within the tibial and femoral tunnels at the bone-tendon interfaces. Loss of tension in a graft can cause symptomatic anterior or rotatory instability and potential retear of the ACL graft. We describe in this Technical Note and accompanying video a simple and effective technique to implant and retension a tendon graft during ACL reconstruction using a suspensory fixation device. The technical description uses a simple adjustable-loop device to provide strong cortical fixation, along with the unique ability to retension the graft in ACL reconstruction, not otherwise possible with previously described graft fixation techniques.

Arthroscopic Remplissage Using a Double-Pulley System for Hill-Sachs Lesions for Recurrent Shoulder Instability.

Hills-Sachs lesions are bony lesions in the humeral head that occur as a result of an anterior shoulder dislocation. These lesions often happen in conjunction with tears of the labrum, and large, engaging lesions must be addressed in order to avoid recurrent instability. Moderate to large (≥3 mm deep) Hill-Sachs defects can be treated using arthroscopic remplissage to reduce the rotator cuff down into the lesion. We describe in this Technical Note and accompanying video an adaptation of the classic arthroscopic remplissage that uses a knotless double-pulley technique with 2 suture anchors, which increases the footprint of fixation, reduces the technical difficulty of the procedure, and minimizes the number of portals that need to be made.

Anterior Cruciate Ligament Reconstruction With Amnion Biological Augmentation.

Anterior cruciate ligament (ACL) ruptures are common and unfortunate injuries for many athletes. The standard therapy for ACL rupture is ACL reconstruction with either autograft, harvested from hamstring or patellar tendon, or allograft tendon from a tissue donor. Advances in tissue engineering have produced interventions to augment the healing process and may have applications when it comes to ACL reconstruction. In this Technical Note and accompanying video, we describe a simple technique to implant an amnion matrix graft with a tendon graft during ACL reconstruction. This procedure uses the proposed anti-inflammatory, scaffolding, and stem cell-producing effects of the amniotic membrane to biologically augment the healing process of an ACL reconstruction.