Faculty Bibliography

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.

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.

Despite a well-established role for the epidermal growth factor receptor (EGFR) in tumorigenesis, EGFR activities and endocytosis in tumors in vivo have not been studied. We labeled endogenous EGFR with GFP by genome-editing of human oral squamous cell carcinoma cells, which were used to examine EGFR-GFP behavior in mouse tumor xenografts in vivo. Intravital multiphoton imaging, confocal imaging of cryosections and biochemical analysis revealed that localization and trafficking patterns, as well as levels of phosphorylation and ubiquitylation of EGFR in tumors in vivo closely resemble patterns and levels observed in the same cells treated with 20-200 pM EGF in vitro. Consistent with the prediction of low ligand concentrations in tumors, EGFR endocytosis was kinase-dependent and blocked by inhibitors of clathrin-mediated internalization; and EGFR activity was insensitive to Cbl overexpression. Collectively, our data suggest that a small pool of active EGFRs is sufficient to drive tumorigenesis by signaling primarily through the Ras-MAPK pathway.

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.

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: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.