Faculty Bibliography

IMPORTANCE:Recently, the American Joint Committee on Cancer (AJCC) updated its staging system for human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC). The prognostic significance of perineural invasion (PNI) and angiolymphatic invasion (ALI) within this staging system is unknown. OBJECTIVE:To examine the prevalence and prognostic significance of PNI and ALI in HPV-positive OPSCC. DESIGN, SETTING, AND PARTICIPANTS:A retrospective review was performed of all patients with HPV-positive OPSCC treated surgically at the University of Pittsburgh Medical Center from January 1, 1980, through December 31, 2015, with at least 1 year of follow-up or death within 1 year. INTERVENTIONS:Surgical treatment of HPV-positive OPSCC. MAIN OUTCOMES AND MEASURES:The prevalence of PNI and ALI was determined from review of pathologic data, and Kaplan-Meier curves were generated for overall survival and disease-free survival when stratified by the presence of PNI and ALI. Multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS:A total of 201 patients met the inclusion criteria (mean [SD] age, 57.4 [9.0] years; 79.6% [3.0%] male, and 20.4% [3.0%] female). Perineural invasion was identified in 32 of 201 primary specimens (15.9%), whereas ALI was identified in 74 of 201 primary specimens (36.8%). Both were significantly associated with increasing T stage. On multivariate analysis, the presence of at least 1 risk factor was significantly associated with overall and disease-free survival (overall hazard ratio, 2.78; 95% CI, 1.15–6.76; disease-free survival hazard ratio, 3.10; 95% CI, 1.17–8.23). Among patients classified as having stage II disease according to the eighth edition of the AJCC manual, the presence of at least 1 risk factor was associated with worse overall survival (hazard ratio, 11.7; 95% CI, 1.2–111.7). CONCLUSIONS AND RELEVANCE:Both PNI and ALI were commonly found in HPV-positive OPSCC, with increasing prevalence as T stage increased. The presence of at least 1 risk factor was associated with worse overall and disease-free survival. Specifically, among patients classified as having stage II disease according to the eighth edition of the AJCC manual, the presence of ALI or PNI may suggest a poorer prognosis.

ANO1 is a calcium-activated chloride channel that is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and other cancers. While ANO1 expression negatively correlates with survival in several cancers, its epigenetic regulation is poorly understood. We analyzed HNSCC samples from TCGA and a separate dataset of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples to identify differentially methylated regions. E6 and E7 transfected normal oral keratinocytes (NOK) were used to induce hypermethylation of the ANO1 promoter. We found three CpG islands that correlated with ANO1 expression, including two positively correlated with expression. Using two HNSCC datasets with differential expression of ANO1, we showed hypermethylation of positively correlated CpG islands potentiates ANO1 expression. E7 but not E6 transfection of NOK cells led to hypermethylation of a positively correlated CpG island without a change in ANO1 expression. ANO1 promoter methylation was also correlated with patient survival. Our results are the first to show the contribution of positively correlated CpG's for regulating gene expression in HNSCC. Hypermethylation of the ANO1 promoter was strongly correlated with but not sufficient to increase ANO1 expression, suggesting methylation of positively correlated CpG's likely serves as an adjunct to other mechanisms of ANO1 activation.

BACKGROUND:Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC. METHODS:Patients undergoing TORS for OPSCC were enrolled prospectively. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score >2) and was administered on postoperative day (POD) 1, 7, and 30. Patient demographics, weight, pain level, and clinical outcomes were recorded prospectively and focused on time to oral diet, feeding tube placement, and dysphagia-related readmissions. RESULTS:A total of 51 patients were included with pathologic T stages of T1 (n = 24), T2 (n = 20), T3 (n = 3), and Tx (n = 4). Self-reported preoperative dysphagia was unusual (13.7%). The mean EAT-10 score on POD 1 was lower than on POD 7 (21.5 vs 26.6; P = .005) but decreased by POD 30 (26.1 to 12.2; P < .001). Forty-seven (92.1%) patients were discharged on an oral diet, but 57.4% required compensatory strategies or modification of liquid consistency. Ninety-eight percent of patients were taking an oral diet by POD 30. There were no dysphagia-related readmissions. CONCLUSION/CONCLUSIONS:This prospective study shows that most patients who undergo TORS experience dysphagia for at least the first month postoperatively, but nearly all can be started on an oral diet. The dysphagia-associated complication profile is acceptable after TORS with a minority of patients requiring temporary feeding tube placement. Aggressive evaluation and management of postoperative dysphagia in TORS patients may help prevent dysphagia-associated readmissions. Cancer 2017;123:3132-40. © 2017 American Cancer Society.

BACKGROUND:The value of transcervical arterial ligation during transoral robotic surgery (TORS) as a measure to decrease postoperative bleeding incidence or severity is unclear. METHODS:A retrospective single institution study was performed to identify risk factors for hemorrhage after TORS for oropharyngeal squamous cell carcinoma (SCC). RESULTS:Overall, 13.2% of patients (35/265) experience postoperative hemorrhage. T classification, perioperative use of anticoagulants, surgeon experience >50 cases, and tumor subsite were not predictors of postoperative hemorrhage. Of this cohort, 28% underwent prophylactic arterial ligation. The overall incidence of bleeding was not significantly decreased in patients who underwent arterial ligation (12.1% vs 13.6%; p = .84). However, arterial ligation significantly reduced the incidence of major and severe bleeding events (1.3% vs 7.8%; p = .04). Radiation before TORS was a risk factor for major and severe postoperative hemorrhage (p < .02). CONCLUSION:Transcervical arterial ligation during TORS may reduce the severity of postoperative hemorrhagic events. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1510-1515, 2017.

IMPORTANCE:Transoral robotic surgery (TORS) is increasingly employed as a treatment option for squamous cell carcinoma of the oropharynx (OPSCC). Measures of surgical learning curves are needed particularly as clinical trials using this technology continue to evolve. OBJECTIVE:To assess learning curves for the oncologic TORS surgeon and to identify the number of cases needed to identify the learning phase. DESIGN, SETTING, AND PARTICIPANTS:A retrospective review of all patients who underwent TORS for OPSCC at the University of Pittsburgh Medical Center between March 2010 and March 2016. Cases were excluded for involvement of a subsite outside of the oropharynx, for nonmalignant abnormality or nonsquamous histology, unknown primary, no tumor in the main specimen, free flap reconstruction, and for an inability to define margin status. EXPOSURES:Transoral robotic surgery for OPSCC. MAIN OUTCOMES AND MEASURES:Primary learning measures defined by the authors include the initial and final margin status and time to resection of main surgical specimen. A cumulative sum learning curve was developed for each surgeon for each of the study variables. The inflection point of each surgeon's curve was considered to be the point signaling the completion of the learning phase. RESULTS:There were 382 transoral robotic procedures identified. Of 382 cases, 160 met our inclusion criteria: 68 for surgeon A, 37 for surgeon B, and 55 for surgeon C. Of the 160 included patients, 125 were men and 35 were women. The mean (SD) age of participants was 59.4 (9.5) years. Mean (SD) time to resection including robot set-up was 79 (36) minutes. The inflection points for the final margin status learning curves were 27 cases (surgeon A) and 25 cases (surgeon C). There was no inflection point for surgeon B for final margin status. Inflection points for mean time to resection were: 39 cases (surgeon A), 30 cases (surgeon B), and 27 cases (surgeon C). CONCLUSIONS AND RELEVANCE:Using metrics of positive margin rate and time to resection of the main surgical specimen, the learning curve for TORS for OPSCC is surgeon-specific. Inflection points for most learning curves peak between 20 and 30 cases.

TMEM16A, a Ca²⁺ -activated Cl^- channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl^- channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl^- channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.

IMPORTANCE:Management of cervical unknown primary squamous cell carcinoma (CUP) has evolved with the introduction of transoral robotic surgery (TORS). OBJECTIVES:1. To describe the efficacy of TORS lingual and palatine tonsillectomy in identifying the primary site of malignancy. 2. To explore how the extent of surgery affects diagnostic yield. 3. To report margin status of TORS resections. DESIGN, SETTING AND PARTICIPANTS:A retrospective, single-center cohort study utilizing a prospectively collected database of CUP patients in a high-volume tertiary referral center. Patient underwent operative laryngoscopy plus TORS as clinically indicated. MAIN OUTCOMES AND MEASURES:Primary end point was successful identification of the primary. The extent of surgery and margin status were also examined. RESULTS:From 2010-2016, 64 patients with CUP were treated. The primary tumor was found in 51 patients (80%). Fourteen patients (22%) were identified with operative laryngoscopy alone. Fifty patients underwent TORS lingual tonsillectomy ± palatine tonsillectomy with 37 primary tumors identified (74%). The primary was located in the lingual tonsil in 32 patients (86%) and palatine tonsil in 5 patients (10%, p<0.001). Negative margins were achieved in 19 patients (51%). The deep margin was the most commonly positive margin (47%, p=0.049). CONCLUSION AND RELEVANCE:Operative laryngoscopy with TORS is efficacious, localizing the primary in 80% of patients. If a margin was positive, it was most commonly the deep margin. This study provides valuable information that can help standardize surgical technique, further increasing the diagnostic yield and decreasing the negative margin rate of TORS for CUP.

Pediatric robotic surgery is a relatively new technology that has been shown to be safe and feasible for a number of pediatric procedures. Our literature analysis was performed using Pubmed database between January 2005 and December 2015, using key words: "robotic," "robotic surgery," "TORS," "pediatric," "children," "head and neck," and "da Vinci". We selected only publications in English. Eight published reports met the selection criteria. We totally found 41 patients, and the age range was between 2 months and 19 years. The cases are 16 only lingual tonsillectomy, nine base of tongue and lingual tonsillectomy, two malignant disease in the oropharynx (high-grade undifferentiated sarcoma and biphasic synovial sarcoma), one tongue base thyroglossal duct cyst, 11 laryngeal cleft cyst, one posterior glottic stenosis, and one congenital true vocal cord paralysis surgeries. One intraoperative complication was reported. No patient needed postoperative tracheotomy. Hospital duration time had a range of 1-16 days. TORS is new for pediatric patients in head and neck areas, and there were few reports. It is becoming increasingly used in head and neck surgeries and those reports above are encouraging for pediatric robotic airway surgeries in otolaryngology in the future.