Intraoperative Image Guidance Improves Outcomes in Complex Orbital Reconstruction by Novice Surgeons.

PURPOSE: This study aims to describe the utility of surgical navigation in improving operative outcomes in complex orbital reconstruction by novice compared with experienced surgical trainees. MATERIALS AND METHODS: A randomized, controlled cadaveric study was conducted at the University of Pittsburgh School of Medicine with otolaryngology and ophthalmology residents and fellows. Participants were divided into novice (postgraduate year 2-4 residents) and experienced (postgraduate year 5 residents and fellows) groups. Ten cadaveric specimens with pre-dissection computed tomography images underwent endoscopic resection of the orbital floor and lamina papyracea bilaterally. Participants performed reconstruction with or without the use of surgical navigation, randomized by laterality and order of the use of navigation. Post-dissection imaging was obtained after reconstruction and compared with pre-dissection imaging. The primary outcome was orbital volume; secondary outcomes included the participant's operative time and National Aeronautics and Space Administration Task Load Index score, a subjective workload assessment measure. Matched-pair t tests and 2-way analysis of variance were used for statistical analysis. RESULTS: Novice participants (n = 6) had improved outcomes with respect to orbital volume when using surgical navigation compared with experienced participants (n = 4). There were no differences in operative times or National Aeronautics and Space Administration Task Load Index scores when using surgical navigation. CONCLUSIONS: In a cadaveric setting, use of surgical navigation by novice surgeons improves post-dissection orbital volume in complex orbital reconstruction. Surgical navigation should be considered as an adjunct to surgical training and simulation curricula.

Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death.

Persistent protein synthesis inhibition (PSI) is a robust predictor of eventual neuronal death following cerebral ischemia. We thus tested the hypothesis that persistent PSI inhibition and neuronal death are causally linked. Neuronal viability strongly correlated with both protein synthesis and levels of eukaryotic (translation) initiation factor 4G1 (eIF4G1). We determined that in vitro ischemia activated calpain, which degraded eIF4G1. Overexpression of the calpain inhibitor calpastatin or eIF4G1 resulted in increased protein synthesis and increased neuronal viability compared with controls. The neuroprotective effect of eIF4G1 overexpression was due to restoration of cap-dependent protein synthesis, as well as protein synthesis-independent mechanisms, as inhibition of protein synthesis with cycloheximide did not completely prevent the protective effect of eIF4G1 overexpression. In contrast, shRNA-mediated silencing of eIF4G1 exacerbated ischemia-induced neuronal injury, suggesting eIF4G1 is necessary for maintenance of neuronal viability. Finally, calpain inhibition following global ischemia in vivo blocked decreases in eIF4G1, facilitated protein synthesis, and increased neuronal viability in ischemia-vulnerable hippocampal CA1 neurons. Collectively, these data demonstrate that calpain-mediated degradation of a translation initiation factor, eIF4G1, is a cause of both persistent PSI and neuronal death.

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia.

Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanism activated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1 expression requires PKA- and p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred, at least in part, via enhanced APE1 expression. Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a unique strategy for neuroprotection against hippocampal injury.

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.

Resection of Condylar Skull Base Tumor via Combined Far Lateral and Infrajugular Approaches with Single-Stage Occipitocervical Fusion.

Epithelioid hemangioma is a rare vascular mesenchymal tumor with a paucity of reports of cranial involvement. In particular, guidance on treatment for lateral skull base lesions is lacking, despite this being a highly technically challenging location. Nuances in the management decisions for this tumor type are discussed. Two major challenges with this location are proximity to critical neurovascular structures and managing secondary craniocervical instability. We present a patient with a lateral skull base epithelioid hemangioma treated with transcondylar resection, single-stage occipitocervical fusion, and adjuvant radiation and chemotherapy. The patient consented to both the procedure and the published report of her case including imaging. Obtaining tissue was necessary for diagnosis. Maximal safe resection, resection of a tumor such that the greatest clinical benefit is achieved with the minimum risk, was favored given the location and vascularity of the lesion. Occipitocervical fusion was recommended given ongoing bony destruction by the tumor and further expected iatrogenic instability upon resection. This was performed as a single stage given expected need for postoperative adjuvant radiation therapy and dynamic neck pain (Video 1). Surgical planning and decision making are detailed, including rationale and potential risks and benefits. We discuss positioning, equipment needs, and the importance of a multidisciplinary surgical team. Park bench positioning was used for part 1, left-sided extended far lateral and infratemporal fossa presigmoid approaches. For part 2, occipitocervical fusion, the patient was transitioned to prone position. The anatomy is highlighted in labeled pictures of the approach and dissection, and surgical video is presented for key surgical steps. Preoperative and postoperative imaging is analyzed. A desirable clinical outcome was obtained.

Surgeon Volume and Laryngectomy Outcomes.

OBJECTIVE: To examine the relationship between surgeon volume and operative morbidity and mortality for laryngectomy. DATA SOURCES: The Nationwide Inpatient Sample was used to identify 45,156 patients who underwent laryngectomy procedures for laryngeal or hypopharyngeal cancer between 2001 and 2011. Hospital and surgeon laryngectomy volume were modeled as categorical variables. METHODS: Relationships between hospital and surgeon volume and mortality, surgical complications, and acute medical complications were examined using multivariable regression. RESULTS: Higher-volume surgeons were more likely to operate at large, teaching, nonprofit hospitals and were more likely to treat patients who were white, had private insurance, hypopharyngeal cancer, low comorbidity, admitted electively, and to perform partial laryngectomy, concurrent neck dissection, and flap reconstruction. Surgeons treating more than 5 cases per year were associated with lower odds of medical and surgical complications, with a greater reduction in the odds of complications with increasing surgical volume. Surgeons in the top volume quintile (>9 cases/year) were associated with a decreased odds of in-hospital mortality (OR = 0.09 [0.01-0.74]), postoperative surgical complications (OR = 0.58 [0.45-0.74]), and acute medical complications (OR = 0.49 [0.37-0.64]). Surgeon volume accounted for 95% of the effect of hospital volume on mortality and 16%-47% of the effect of hospital volume on postoperative morbidity. CONCLUSION: There is a strong volume-outcome relationship for laryngectomy, with reduced mortality and morbidity associated with higher surgeon and higher hospital volumes. Observed associations between hospital volume and operative morbidity and mortality are mediated by surgeon volume, suggesting that surgeon volume is an important component of the favorable outcomes of high-volume hospital care. Laryngoscope, 133:834-840, 2023.

Angiographic Evaluation of Cranial Venous Outflow Patterns in Patients With and Without Idiopathic Intracranial Hypertension.

BACKGROUND: Several collateral venous pathways exist to assist in cranial venous drainage in addition to the internal jugular veins. The important extrajugular networks (EJN) are often readily identified on diagnostic cerebral angiography. However, the angiographic pattern of venous drainage through collateral EJN has not been previously compared among patients with and without idiopathic intracranial hypertension (IIH). OBJECTIVE: To quantify EJN on cerebral angiography among patients both with and without IIH and to determine whether there is a different EJN venous drainage pattern in patients with IIH. METHODS: Retrospective imaging review of 100 cerebral angiograms (50 IIH and 50 non-IIH patients) and medical records from a single academic medical center was performed by 2 independent experienced neuroendovascular surgeons. Points were assigned to EJN flow from 0 to 6 using an increasing scale (with each patient's dominant internal jugular vein standardized to 5 points to serve as the internal reference). Angiography of each patient included 11 separately graded extrajugular networks for internal carotid and vertebral artery injections. RESULTS: Patients in the IIH group had statistically significant greater flow in several of the extrajugular networks. Therefore, they preferentially drained through EJN compared with the non-IIH group. Right transverse-sigmoid system was most often dominant in both groups, yet there was a significantly greater prevalence of codominant sinus pattern on posterior circulation angiograms. CONCLUSION: Patients with IIH have greater utilization of EJN compared with patients without IIH. Whether this is merely an epiphenomenon or possesses actual cause-effect relationships needs to be determined with further studies.

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.

Peri-Operative Pain and Opioid Use in Opioid-Naïve Patients Following Inpatient Head and Neck Surgery.

Pain management is an important consideration for Head and Neck Cancer (HNC) patients as they are at an increased risk of developing chronic opioid use, which can negatively impact both quality of life and survival outcomes. This retrospective cohort study aimed to evaluate pain, opioid use and opioid prescriptions following HNC surgery. Participants included patients undergoing resection of a head and neck tumor from 2019-2020 at a single academic center with a length of admission (LOA) of at least 24 h. Exclusion criteria were a history of chronic pain, substance-use disorder, inability to tolerate multimodal analgesia or a significant post-operative complication. Subjects were compared by primary surgical site: Neck (neck dissection, thyroidectomy or parotidectomy), Mucosal (resection of tumor of upper aerodigestive tract, excluding oropharynx), Oropharyngeal (OP) and Free flap (FF). Average daily pain and total daily opioid consumption (as morphine milligram equivalents, MME) and quantity of opioids prescribed at discharge were compared. A total of 216 patients met criteria. Pain severity and daily opioid consumption were comparable across groups on post-operative day 1, but both metrics were significantly greater in the OP group on the day prior to discharge (DpDC) (5.6 (1.9-8.6), p < 0.05; 49 ± 44 MME/day, p < 0.01). The quantity of opioids prescribed at discharge was associated with opioid consumption on the DpDC only in the Mucosal and FF groups, which had longer LOA (6-7 days) than the Neck and OP groups (1 day, p < 0.001). Overall, 65% of patients required at least one dose of an opioid on the DpDC, yet 76% of patients received a prescription for an opioid medication at discharge. A longer LOA (aOR = 0.82, 95% CI: 0.63-0.98) and higher Charlson Comorbidity Index (aOR = 0.08, 95% CI: 0.01-0.48) were negatively associated with receiving an opioid prescription at the time of discharge despite no opioid use on the DpDC, respectively. HNC patients, particularly those with shorter LOA, may be prescribed opioids in excess of their post-operative needs, highlighting the need the for improved pain management algorithms in this patient population. Future work aims to use prospective surveys to better define post-operative and outpatient pain and opioid requirements following HNC surgery.

Catheter-directed venography for evaluating internal jugular vein pseudo-occlusion.

The incidence and effects of stenosis of the cerebral venous system are poorly understood. When noninvasive computed tomography venography (CTV) of the head and neck suggests complete internal jugular vein (IJV) occlusion, invasive catheter-directed venography can discordantly show venous patency. We compared CTV vs digital subtraction venography (DSV) in the evaluation of patency/occlusion in the suspected IJV and contralateral IJV. We queried the venous intervention database of our U.S. academic tertiary-care hospital to identify patients with complete or near-complete IJV occlusion per CTV from March 1, 2019 to March 1, 2020. We included patients with both noninvasive and invasive imaging of the target segment and the contralateral IJV. Four patients had suspected occlusion of the IJV at the skull base. Invasive catheter-directed venography consisted of DSV to assess direction of flow and vessel caliber, as well as manometry proximal and distal to areas of suspected stenosis. DSV showed patency in all 4 IJVs for which CTV had shown suspected occlusions. CTV findings of the contralateral IJVs were patency (n = 2), moderate stenosis (n = 1), and severe/critical stenosis (n = 1). Contralateral IJV caliber, measured by DSV, was concordant with CTV findings. Median mean-pressure gradients across the apparent occlusion and contralateral segments were 1 (range, 1-4) mmHg and 0 (range, 0-5) mmHg, respectively. Although noninvasive CTV may suggest absence of or attenuated flow within the IJV, this technique may be insufficient to establish complete occlusion. Catheter-directed venography can be used to evaluate patency, vessel caliber, and mean-pressure gradient.

Association of Tumor Site With the Prognosis and Immunogenomic Landscape of Human Papillomavirus-Related Head and Neck and Cervical Cancers.

Importance: Human papillomavirus (HPV)-positive status in patients with oropharyngeal squamous cell carcinoma (OPSCC) is associated with improved survival compared with HPV-negative status. However, it remains controversial whether HPV is associated with improved survival among patients with nonoropharyngeal and cervical squamous cell tumors. Objective: To investigate differences in the immunogenomic landscapes of HPV-associated tumors across anatomical sites (the head and neck and the cervix) and their association with survival. Design, Setting, and Participants: This cohort study used genomic and transcriptomic data from the Cancer Genome Atlas (TCGA) for 79 patients with OPSCC, 435 with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC), and 254 with cervical squamous cell carcinoma and/or endocervical adenocarcinoma (CESC) along with matched clinical data from TCGA. The data were analyzed from November 2020 to March 2021. Main Outcomes and Measures: Positivity for HPV was classified by RNA-sequencing reads aligned with the HPV reference genome. Gene expression profiles, immune cell phenotypes, cytolytic activity scores, and overall survival were compared by HPV tumor status across multiple anatomical sites. Results: The study comprised 768 patients, including 514 (66.9%) with HNSCC (380 male [73.9%]; mean [SD] age, 59.5 [10.8] years) and 254 (33.1%) with CESC (mean [SD] age, 48.7 [14.1] years). Human papillomavirus positivity was associated with a statistically significant improvement in overall survival for patients with OPSCC (adjusted hazard ratio [aHR], 0.06; 95% CI, 0.02-0.17; P < .001) but not for those with non-OP HNSCC (aHR, 0.64; 95% CI, 0.31-1.27; P = .20) or CESC (aHR, 0.50; 95% CI, 0.15-1.67; P = .30). The HPV-positive OPSCCs had increased tumor immune infiltration and immunomodulatory receptor expression compared with HPV-negative OPSCCs. Compared with HPV-positive non-OP HNSCCs, HPV-positive OPSCCs showed greater expression of immune-related metrics including B cells, T cells, CD8+ T cells, T-cell receptor diversity, B-cell receptor diversity, and cytolytic activity scores, independent of tumor variant burden. The immune-related metrics were similar when comparing HPV-positive non-OP HNSCCs and HPV-positive CESCs with their HPV-negative counterparts. The 2-year overall survival rate was significantly higher for patients with HPV-positive OPSCC compared with patients with HPV-negative OPSCC (92.0% [95% CI, 84.8%-99.9%] vs 45.8% [95% CI, 28.3%-74.1%]; HR, 0.10 [95% CI, 0.03-0.30]; P = .009). Conclusions and Relevance: In this cohort study, tumor site was associated with the immune landscape and survival among patients with HPV-related tumors despite presumed similar biologic characteristics. These tumor site-related findings provide insight on possible outcomes of HPV positivity for tumors in oropharyngeal and nonoropharyngeal sites and a rationale for the stratification of HPV-associated tumors by site and the subsequent development of strategies targeting immune exclusion in HPV-positive nonoropharyngeal cancer.

An Immunogenomic Investigation of Oral Cavity Squamous Cell Carcinoma in Patients Aged 45 Years and Younger.

OBJECTIVES/HYPOTHESIS: To investigate differences in the immunogenomic landscape among young patients presenting with oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: Retrospective database review. METHODS: Normalized messenger mRNA expression data were downloaded from The Cancer Genome Atlas (TCGA) database. OCSCC patients were categorized into young and older age groups with a cutoff of 45 years. Human papillomavirus-positive tumors were excluded. Cell fractions, marker expression, and mutational load were compared between age groups using the Wilcoxon rank sum test. Adjustment for multiple comparisons was performed using the Benjamini-Hochberg method, with a false discovery rate of 0.05. RESULTS: Two hundred forty-five OCSCC tumors were included; 21 (8.6%) were young (37.1 ± 7.5 years) and 224 (91.4%) were older (64.5 ± 10.3 years). There was no significant difference between groups in the fraction of B and T lymphocytes, macrophages, monocytes, natural killers, and dendritic cells. Cytolytic activity score was decreased in young patients (8.33 vs. 18.9, P = .023). Additionally, young patients had significantly lower expression of immunomodulatory markers of immune activation, including PD-1 (PDCD1, P = .003), CTLA4 (P = .025), TIGIT (P = .002), GITR (TNFRSF18, P = .005), OX40 (TNFRSF4, P = .009), LAG-3 (P < .001), and TIM-3 (HAVCR2, P = .002). Young patients had a significantly lower number of single nucleotide variant-derived neoantigens (26.2 vs. 60.6, P < .001). CONCLUSIONS: OCSCC patients aged 45 years and younger appear to have an attenuated immune response that may be related to a lower frequency of immunogenic mutations. This may contribute to the pathogenesis of these tumors, and ultimately help inform personalized immune-based therapeutic strategies for young patients with OCSCC. LEVEL OF EVIDENCE: NA Laryngoscope, 131:304-311, 2021.

Melanoma metastatic to the hyoid bone.

Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.

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

OBJECTIVES: Tumor 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 METHODS: Participants 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. RESULTS: Of 318 patients with HNSCC, one third had ERα positive tumors (36.2%, n = 115). Odds of ERα expression were significantly increased in those with HPV-positive tumors (OR = 27.5, 95% confidence interval[CI] 12.1-62), smaller tumors (≤T2, OR = 3.6, 95% CI 1.9-7.1), male sex (OR = 2.0, 95% CI 1.1-3.6), overweight/obesity (BMI ≥ 25, OR = 1.9, 95% CI 1.1-3.3), and those married/living with a partner (OR = 1.7, 95% CI 1.0-3.0). In a multivariate model, HPV-positivity (aOR = 27.5, 95% CI 11.4-66) and small tumor size (≤T2, aOR = 2.2, 95% CI 1.0-4.8) remained independently associated with ERα status. When restricted to OPC (n = 180), tumor HPV status (aOR = 17.1, 95% CI 2.1-137) and small tumor size (≤T2, aOR = 4.0 95% CI 1.4-11.3) remained independently associated with ERα expression. CONCLUSION: Tumor HPV status and small tumor size are independently associated with ERα expression in HNSCC.

Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics.

BACKGROUND AND PURPOSE: Stroke is a major cause of death and disability, and it is imperative to develop therapeutics to mitigate stroke-related injury. Despite many promising prospects, attempts at translating neuroprotective agents that show success in animal models of stroke have resulted in very limited clinical success. SUMMARY OF REVIEW: This review discusses reasons for the lack of translational success based on the therapeutic targets tested and the pathophysiology of stroke. New recanalization therapies and alternative therapeutic strategies are discussed concerning mitochondria-mediated cell death. Mitochondrial death-regulation pathways are divided into 3 categories: Upstream signaling pathways, agents that target mitochondria directly, and downstream death-execution effectors. The apoptosis signal-related kinase/c-Jun-terminal kinase pathway is used as an example to provide rationale as to why inhibiting signaling pathway upstream of mitochondrial dysfunction is a promising therapeutic approach. Finally, the mechanisms of autophagy and mitochondrial biogenesis are discussed in relation to stroke. CONCLUSIONS: Increasing evidence suggests that reperfusion is necessary for improved neurological outcomes after stroke. Development of improved recanalization methods with increased therapeutic windows will aid in improving clinical outcome. Adjunct neuroprotective interventions must also be developed to ensure maximal brain tissue salvage. Targeting prodeath signaling pathways upstream of mitochondrial damage is promising for potential clinically effective treatment. Further understanding of the roles of equilibrium of autophagy and mitochondrial biogenesis in the pathogenesis of stroke could also lead to novel therapeutics.

Association Between Hospital Market Concentration and Costs of Laryngectomy.

IMPORTANCE: High-volume hospital care for laryngectomy has been shown to be associated with reduced morbidity, mortality, and costs; however, most hospitals in the United States do not perform high volumes of laryngectomies. The influence of market competition on charges and costs for such patients has not been defined. OBJECTIVE: To examine the association between regional hospital market concentration, hospital charges, and costs for laryngectomy. DESIGN, SETTING, AND PARTICIPANTS: The Nationwide Inpatient Sample was used to identify 34 193 patients who underwent laryngectomy for a malignant laryngeal or hypopharyngeal neoplasm from January 1, 2003, to December 31, 2011. Hospital laryngectomy volume was modeled as a categorical variable. Hospital market concentration was evaluated using a variable-radius Herfindahl-Hirschman Index from the 2003, 2006, and 2009 Hospital Market Structure Files. Statistical analysis was performed from May 19 to August 15, 2018. MAIN OUTCOMES AND MEASURES: Multivariable generalized linear regression was used to evaluate associations between market concentration and total charges and costs for laryngectomy. RESULTS: Among the 34 193 patients (19.3% female and 80.7% male; mean age, 62.7 years [range, 20.0-96.0 years]), 69.2% of procedures were performed at hospitals in highly concentrated (noncompetitive) markets and 26.2% were performed at hospitals in unconcentrated (highly competitive) markets. Most high-volume hospitals (68.0%) were located in highly concentrated markets, followed by unconcentrated markets (32.0%). Market share and volume were not associated with significant differences in total charges. Unconcentrated markets were associated with 28% higher costs (95% CI, 8%-53%) relative to moderately concentrated and highly concentrated markets. High-volume hospitals were associated with 22% lower costs (95% CI, -36% to -5%). CONCLUSIONS AND RELEVANCE: Competition among hospitals is associated with increased costs of care for laryngectomy. High-volume hospital care is associated with lower costs of care. These data suggest that hospital market consolidation of laryngectomy at centers able to meet minimum volume thresholds may improve health care value.

Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: role of enhanced DNA repair.

BACKGROUND AND PURPOSE: NAD(+) is an essential cofactor for cellular energy production and participates in various signaling pathways that have an impact on cell survival. After cerebral ischemia, oxidative DNA lesions accumulate in neurons because of increased attacks by ROS and diminished DNA repair activity, leading to PARP-1 activation, NAD(+) depletion, and cell death. The objective of this study was to determine the neuroprotective effects of NAD(+) repletion against ischemic injury and the underlying mechanism. METHODS: In vitro ischemic injury was induced in rat primary neuronal cultures by oxygen-glucose deprivation (OGD) for 1 to 2 hours. NAD(+) was replenished by adding NAD(+) directly to the culture medium before or after OGD. Cell viability, oxidative DNA damage, and DNA base-excision repair (BER) activity were measured quantitatively up to 72 hours after OGD with or without NAD(+) repletion. Knockdown of BER enzymes was achieved in cultures using AAV-mediated transfection of shRNA. RESULTS: Direct NAD(+) repletion in neurons either before or after OGD markedly reduced cell death and OGD-induced accumulation of DNA damage (AP sites, single and double strand breaks) in a concentration- and time-dependent manner. NAD(+) repletion restored nDNA repair activity by inhibiting serine-specific phosphorylation of the essential BER enzymes AP endonuclease and DNA polymerase-beta. Knocking down AP endonuclease expression significantly reduced the prosurvival effect of NAD(+) repletion. CONCLUSIONS: Cellular NAD(+) replenishment is a novel and potent approach to reduce ischemic injury in neuronal cultures. Restoration of DNA repair activity via the BER pathway is a key signaling event mediating the neuroprotective effect of NAD(+) replenishment.

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

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.