Copy number alterations identify a smoking-associated expression signature predictive of poor outcome in head and neck squamous cell carcinoma.

Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.

Patterns of Care and Outcomes in Verrucous Carcinoma of the Larynx Treated in the Modern Era.

Background: Verrucous carcinoma of the larynx (VCL) is a rare form of laryngeal squamous cell carcinoma. We analyzed the National Cancer Database (NCDB) to examine national treatment pattern, identify factors associated with primary radiation therapy (RT), and compare outcomes in patients with Tis-T2 N0 VCL treated primary surgery and primary RT. Methods: We accessed the NCDB from 2004 to 2015 for patients with Tis-T2 N0 VCL and recorded the treatment modality employed. Multivariable logistic regression was used to identify predictors for radiation therapy. Cox regression was used to calculate hazard ratios for survival. A propensity score matched Kaplan-Meier analysis compared primary surgical treatment to definitive radiation. Results: We identified 732 patients with laryngeal verrucous carcinoma from the NCDB. The majority were cTis-T2 (87%) N0 (96%). We identified 286 vs. 110 Tis-T2N0 patients treated primary surgery and with definitive radiation, respectively, for the purpose of this study. Predictors of radiation were treatment at a community center, no insurance, and higher T stage. Cox regression identified increased age, higher comorbidity score, and government insurance as predictive of worse survival. Propensity matching revealed a trend toward worse survival with definitive radiation, with a median survival of 98 months compared to 143 months (p = 0.02). When including only T1-2 lesions, that is, invasive disease, the trend toward increased survival with surgery [98 months vs. 135 months (p = 0.08)] persisted. Conclusion: The results of the present study support the use of surgery in the management of Tis-T2 N0 VCL when organ preservation is possible.

Disparate survival of late-stage male oropharyngeal cancer in Appalachia.

The United States Appalachian region harbors a higher cancer burden than the rest of the nation, with disparate incidence of head and neck squamous cell carcinomas (HNSCC), including oral cavity and pharynx (OC/P) cancers. Whether elevated HNSCC incidence generates survival disparities within Appalachia is unknown. To address this, HNSCC survival data for 259,737 tumors from the North American Association for Central Cancer Registries 2007-2013 cohort were evaluated, with age-adjusted relative survival (RS) calculated based on staging, race, sex, and Appalachian residence. Tobacco use, a primary HNSCC risk factor, was evaluated through the Behavioral Risk Factor Surveillance System from Appalachian states. Decreased OC/P RS was found in stage IV Appalachian white males within a subset of states. The survival disparity was confined to human papillomavirus (HPV)-associated oropharyngeal cancers, specifically the oropharynx subsite. This correlated with significantly higher smoking and male smokeless tobacco use in most Appalachian disparity states. Lower survival of Appalachian males with advanced-stage HPV-associated oropharyngeal cancers suggests pervasive tobacco consumption likely generates more aggressive tumors at HPV-associated oropharynx subsites than national averages. Comprehensive tobacco and HPV status should therefore be evaluated prior to considering treatment de-intensification regimens for HPV-associated oropharyngeal cancers in populations with high tobacco consumption.

Middle ear choristoma presenting as cholesteatoma with conductive hearing loss.

A 6-year-old male was seen for evaluation of middle ear polyp with associated hearing loss and otorrhea. CT scan revealed canal polyp with a stalk extending to the middle ear with malformation of the malleus and incus. The patient underwent exploratory tympanotomy which revealed a fistula from the bony-cartilaginous junction connecting to a middle ear mass which had eroded the incus. Intraoperative pathology suggested columnar epithelium without cholesteatoma or muscle. Final pathologic diagnosis reported dense fibrous tissue as well as ectopic salivary gland tissue, consistent with salivary gland choristoma. After removal of the mass, a partial prosthesis was successfully placed. Middle ear salivary gland choristoma is a rare entity. It can be confused clinically with cholesteatoma and is usually diagnosed on pathology. This diagnosis is often associated with other external, middle, and inner ear abnormalities.

Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion.

Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actin-binding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Increased cortactin expression due to gene amplification is observed in head and neck squamous cell carcinoma (HNSCC) and other cancers, corresponding with elevated tumor progression and poor patient outcome. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. Although cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown and potentially present a new avenue for anti-invasive therapeutic targeting. Here we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Collectively these data suggest that CK2α-mediated cortactin phosphorylation at T24 is critical in regulating cortactin binding to Arp2/3 complex and pro-invasive activity, identifying a potential targetable mechanism for impairing HNSCC invasion. IMPLICATIONS: This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/4/987/F1.large.jpg.

Development of Multimodal Analgesia Pathways in Outpatient Thyroid and Parathyroid Surgery and Association With Postoperative Opioid Prescription Patterns.

Importance: Prescription opioid use contributes to drug-related adverse effects and risk for dependence and abuse. Multimodal analgesia (MMA) has been shown to be useful in reducing opioid use following orthopedic, gynecologic, and colorectal surgery, but adoption in head and neck surgery has lagged. Recently, we published findings related to the feasibility of MMA protocols in same-day thyroid, parathyroid, and parotid surgery. However, whether such strategies lead to effective and durable reduction in frequency of opioid prescriptions, and affect physician prescribing practices, remains unclear. Objective: To observe trends in adoption and adherence to institutional MMA protocols following thyroid and parathyroid surgery, and to assess the association of institutional multimodal (nonopioid) analgesia protocols with opioid use and physician prescribing patterns following outpatient thyroid and parathyroid surgery. Design, Setting, and Participants: Cohort study at a head and neck surgery service at a tertiary care hospital of prescription patterns and retrospective review of patient medical records following implementation of an optional institutional MMA protocol in 2015, based on preoperative administration of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and gabapentin, and postoperative use of acetaminophen and ibuprofen for analgesia after thyroid and parathyroid surgery. There were 528 adult patients who underwent thyroid and parathyroid surgery between January 1, 2015, and June 30, 2017. Main Outcomes and Measures: We report on adherence to the MMA protocol over the study period as measure of physician buy-in and adoption of the technique. The frequency of opioid use and physician prescription patterns following thyroid and parathyroid surgery is reported over the study period to study the association of the available MMA pathway with these variables. Results: A total of 528 patients (mean [SD] age, 53.1 [15.7] years; 80.3% female) underwent outpatient thyroid and parathyroid surgery. The frequency of postoperative opioid prescriptions decreased during the study period (16 of 122 [13.1%] in 2015, 22 of 244 [9.0%] in 2016, 3 of 162 [1.9%] in 2017). Adherence to the MMA protocol increased (0 of 122 cases in 2015, 106 of 244 [43.4%] cases in 2016, 142 of 162 [87.7%] cases in 2017), with reduced likelihood of opioid prescription on discharge (2017 vs 2015 odds ratio, 0.13; 95% CI, 0.04-0.44). Only 1 postoperative hematoma was recorded in the study cohort, and 352 (66.7%) patients achieved same-day discharge, whereas 176 (33.3%) maintained outpatient status but received overnight observation prior to discharge. Conclusions and Relevance: Adoption and adherence to the MMA protocol increased substantially over the study period for patients undergoing thyroid and parathyroid surgery and was associated with a simultaneous significant decline in prescription of postoperative opioid analgesics. Use of nonopioid multimodal agents, incorporating NSAIDs, was safe and did not lead to increased incidence of bleeding. Availability of effective nonopioid MMA pathways may favorably influence physician prescribing practices and avoid unnecessary opioid prescriptions.

Emergence of a Novel Staging System for Oropharyngeal Squamous Cell Carcinoma Based on HPV Status.

The staging of oropharyngeal squamous cell carcinoma has undergone key changes in the eighth edition of the American Joint Committee on Cancer Staging Manual, set to take effect January 1, 2018. The most significant change relates to the development of a novel staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas, distinct from that for non-HPV-associated squamous cell carcinomas of the oropharynx. We describe the revised staging parameters and the rationale in support of the changes.