30-Day Postoperative Outcomes in Adults with Obstructive Sleep Apnea Undergoing Upper Airway Surgery

Background: Obstructive sleep apnea (OSA) is a chronic disorder of the upper airway. OSA surgery has oftentimes been researched based on the outcomes of single-institutional facilities. We retrospectively analyzed a multi-institutional national database to investigate the outcomes of OSA surgery and identify risk factors for complications. Methods: We reviewed the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (2008–2020) to identify patients who underwent OSA surgery. The postoperative outcomes of interest included 30-day surgical and medical complications, reoperation, readmission, and mortality. Additionally, we assessed risk-associated factors for complications, including comorbidities and preoperative blood values. Results: The study population included 4662 patients. Obesity (n = 2909; 63%) and hypertension (n = 1435; 31%) were the most frequent comorbidities. While two (0.04%) deaths were reported within the 30-day postoperative period, the total complication rate was 6.3% (n = 292). Increased BMI (p = 0.01), male sex (p = 0.03), history of diabetes (p = 0.002), hypertension requiring treatment (p = 0.03), inpatient setting (p < 0.0001), and American Society of Anesthesiology (ASA) physical status classification scores ≥ 4 (p < 0.0001) were identified as risk-associated factors for any postoperative complications. Increased alkaline phosphatase (ALP) was identified as a risk-associated factor for the occurrence of any complications (p = 0.02) and medical complications (p = 0.001). Conclusions: OSA surgery outcomes were analyzed at the national level, with complications shown to depend on AP levels, male gender, extreme BMI, and diabetes mellitus. While OSA surgery has demonstrated an overall positive safety profile, the implementation of these novel risk-associated variables into the perioperative workflow may further enhance patient care

CRITICAL ROLE OF EUKARYOTIC TRANSLATION INITIATION FACTOR 4G IN MEDIATING ISCHEMIA-INDUCED NEURONAL DEATH

Stroke is the third leading cause of death in the United States and the second leading cause of death in the world. Despite the epidemiological significance of this disease, there are few treatment options. The purpose of this dissertation is to expand the understanding of underlying mechanisms mediating neuronal death caused by stroke, or cerebral ischemia. Two major metabolic disturbances occur due to ischemia—persistent protein synthesis inhibition and secondary energy depletion. All ischemia-affected neurons experience protein synthesis inhibition. However, neurons that recover protein synthesis live, while neurons that fail to recover die. This makes protein synthesis a robust predictor of neuronal death. However, the underlying mechanisms of persistent protein synthesis inhibition remain unknown. The hypothesis of this dissertation is that persistent protein synthesis inhibition is caused by activation of the calcium-sensitive protease calpain, which degrades eukaryotic translation initiation factor (eIF) 4G. Inhibition of calpain or overexpression of eIF4G results in increased protein synthesis and increased neuronal viability following the in vitro model of ischemia oxygen glucose deprivation in rat primary cortical neurons. Importantly, the neuroprotective effect of preservation of eIF4G is only partly due to its restoration of protein synthesis. Potential protein synthesis-independent mechanisms eIF4G-mediated protection are discussed. Neurons subjected to ischemia suffer an initial loss of energy in the form of ATP, which returns to baseline within fifteen minutes of restoration of blood flow. However, ischemia-sensitive neurons undergo secondary energy depletion prior to delayed neuronal death. The cause of secondary energy failure is hypothesized to be due to DNA recognition enzyme poly(ADP)-ribose polymerase (PARP)-1 depletion of the energy substrate NAD+. Evidence is presented linking PARP-1 activation to mitochondrial calcium dysregulation with subsequent calpain activation and apoptosis-inducing factor release. The results of these two findings are discussed in depth and future experiments are outlined. The potential of role of eIF4G in mitochondrial biogenesis, inhibition of autophagy and prevention of secondary energy loss is postulated. The research presented in this dissertation provides a novel perspective regarding the mechanisms underlying delayed neuronal death and may eventually lead to the development of clinically applicable neuroprotective strategies

Predicting complications of major head and neck oncological surgery: an evaluation of the ACS NSQIP surgical risk calculator

Abstract Background The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) universal surgical risk calculator is an online tool intended to improve the informed consent process and surgical decision-making. The risk calculator uses a database of information from 585 hospitals to predict a patient’s risk of developing specific postoperative outcomes. Methods Patient records at a major Canadian tertiary care referral center between July 2015 and March 2017 were reviewed for surgical cases including one of six major head and neck oncologic surgeries: total thyroidectomy, total laryngectomy, hemiglossectomy, partial glossectomy, laryngopharyngectomy, and composite resection. Preoperative information for 107 patients was entered into the risk calculator and compared to observed postoperative outcomes. Statistical analysis of the risk calculator was completed for the entire study population, for stratification by procedure, and by utilization of microvascular reconstruction. Accuracy was assessed using the ratio of predicted to observed outcomes, Receiver Operating Characteristics (ROC), Brier score, and the Wilcoxon signed–ranked test. Results The risk calculator accurately predicted the incidences for 11 of 12 outcomes for patients that did not undergo free flap reconstruction (NFF group), but was less accurate for patients that underwent free flap reconstruction (FF group). Length of stay (LOS) analysis showed similar results, with predicted and observed LOS statistically different in the overall population and FF group analyses (p = 0.001 for both), but not for the NFF group analysis (p = 0.764). All outcomes in the NFF group, when analyzed for calibration, met the threshold value (Brier scores < 0.09). Risk predictions for 8 of 12, and 10 of 12 outcomes were adequately calibrated in the FF group and the overall study population, respectively. Analyses by procedure were excellent, with the risk calculator showing adequate calibration for 7 of 8 procedural categories and adequate discrimination for all calculable categories (6 of 6). Conclusion The NSQIP-RC demonstrated efficacy for predicting postoperative complications in head and neck oncology surgeries that do not require microvascular reconstruction. The predictive value of the metric can be improved by inclusion of several factors important for risk stratification in head and neck oncology

Study protocol: randomised controlled trial of conditioned open-label placebo (COLP) for perioperative pain management in patients with head and neck cancer

Introduction Patients with head and neck cancer have a substantial risk of chronic opioid dependence following surgery due to pain and psychosocial consequences from both the disease process and its treatments. Conditioned open-label placebos (COLPs) have been effective for reducing the dose of active medication required for a clinical response across a wide range of medical conditions. We hypothesise that the addition of COLPs to standard multimodal analgesia will be associated with reduced baseline opioid consumption by 5 days after surgery in comparison to standard multimodal analgesia alone in patients with head and neck cancer.Methods and analysis This randomised controlled trial will evaluate the use of COLP for adjunctive pain management in patients with head and neck cancer. Participants will be randomised with 1:1 allocation to either the treatment as usual or COLP group. All participants will receive standard multimodal analgesia, including opioids. The COLP group will additionally receive conditioning (ie, exposure to a clove oil scent) paired with active and placebo opioids for 5 days. Participants will complete surveys on pain, opioid consumption and depression symptoms through 6 months after surgery. Average change in baseline opioid consumption by postoperative day 5 and average pain levels and opioid consumption through 6 months will be compared between groups.Ethics and dissemination There remains a demand for more effective and safer strategies for postoperative pain management in patients with head and neck cancer as chronic opioid dependence has been associated with decreased survival in this patient population. Results from this study may lay the groundwork for further investigation of COLPs as a strategy for adjunctive pain management in patients with head and neck cancer. This clinical trial has been approved by the Johns Hopkins University Institutional Review Board (IRB00276225) and is registered on the National Institutes of Health Clinical Trials Database.Trial registration number NCT04973748

Biologic and behavioral associations of estrogen receptor alpha positivity in head and neck squamous cell carcinoma

ObjectivesTumor HPV status is an established independent prognostic marker for oropharynx cancer (OPC). Recent studies have reported that tumor estrogen receptor alpha (ERα) positivity is also associated with prognosis independent of HPV. Little is known about the biologic and behavioral predictors of ERα positivity in head and neck squamous cell cancer (HNSCC). We therefore explored this in a multicenter prospective cohort study.Materials and methodsParticipants with HNSCC completed a survey and provided a blood sample. Tumor samples were tested for ERα using immunohistochemistry. ERα positivity was defined as ≥1%, standardized by the American Society of Clinical Oncology/College of American Pathologists in breast cancer. Characteristics were compared with χ2 and Fisher's exact test. Odds ratios (OR) were calculated using logistic regression.ResultsOf 318 patients with HNSCC, one third had ERα positive tumors (36.2%, n&nbsp;=&nbsp;115). Odds of ERα expression were significantly increased in those with HPV-positive tumors (OR&nbsp;=&nbsp;27.5, 95% confidence interval[CI] 12.1-62), smaller tumors (≤T2, OR&nbsp;=&nbsp;3.6, 95% CI 1.9-7.1), male sex (OR&nbsp;=&nbsp;2.0, 95% CI 1.1-3.6), overweight/obesity (BMI&nbsp;≥&nbsp;25, OR&nbsp;=&nbsp;1.9, 95% CI 1.1-3.3), and those married/living with a partner (OR&nbsp;=&nbsp;1.7, 95% CI 1.0-3.0). In a multivariate model, HPV-positivity (aOR&nbsp;=&nbsp;27.5, 95% CI 11.4-66) and small tumor size (≤T2, aOR&nbsp;=&nbsp;2.2, 95% CI 1.0-4.8) remained independently associated with ERα status. When restricted to OPC (n&nbsp;=&nbsp;180), tumor HPV status (aOR&nbsp;=&nbsp;17.1, 95% CI 2.1-137) and small tumor size (≤T2, aOR&nbsp;=&nbsp;4.0 95% CI 1.4-11.3) remained independently associated with ERα expression.ConclusionTumor HPV status and small tumor size are independently associated with ERα expression in HNSCC