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BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.

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.

Background: Readmissions are major healthcare expenditures, key hospital metrics, and are often preceded by an evaluation in the emergency department (ED). The purpose of this study was to analyze ED visits within 30 days of endoscopic skull base surgery (ESBS), risk factors for readmission once in the ED, and ED‐related evaluation and outcomes. Methods: Retrospective review from January 2017 to December 2022 at a high‐volume center of all ESBS patients who presented to the ED within 30 days of surgery. Results: Of 593 ESBS cases, 104 patients (17.5%) presented to the ED following surgery within 30 days, with a median presentation of 6 days post‐discharge (IQR 5–14); 54 (51.9%) patients were discharged while 50 (48.1%) were readmitted. Readmitted patients were significantly older than discharged patients (median 60 years, IQR 50–68 vs. 48 years, 33–56; p < 0.01). Extent of ESBS was not associated with readmission or discharge from the ED. The most common discharge diagnoses were headache (n = 13, 24.1%) and epistaxis (n = 10, 18.5%); the most common readmitting diagnoses were serum abnormality (n = 15, 30.0%) and altered mental status (n = 5, 10.0%). Readmitted patients underwent significantly more laboratory testing than discharged patients (median 6, IQR 3–9 vs. 4, 1–6; p < 0.01). Conclusions: Approximately half of patients who presented to the ED following ESBS were discharged home but underwent significant workup. Follow‐up within 7 days of discharge, risk‐stratified endocrine care pathways, and efforts to address the social determinants of health may be considered to optimize postoperative ESBS care. [ABSTRACT FROM AUTHOR]

A 39-year-old female presented with persistent unilateral headache and was found to have an encephalocele of the right lateral frontal sinus. Due to the position of the defect, a transorbital neuroendoscopic approach was performed to expose and reduce the encephalocele. A free mucosal graft was harvested from the nasal cavity and used to repair the defect. Postoperative imaging confirmed repair and patient went on to undergo stenting of the right transverse sinus.By Neal R Godse; Tyler Merrill; Raj Sindwani; Troy D. Woodard and Varun R. KshettryReported by Author; Author; Author; Author; Author [Extracted from the article]

Objectives: To identify common reasons for readmission following otolaryngologic surgery at a high‐volume center and identify possible risk factors for readmission. Methods: Retrospective chart review of readmissions identified by hospital‐based electronic medical record reporting mechanism. Results: From January 2019 to September 2020, there were 87 readmissions following 808 index surgeries. The most common reason for readmission was for planned surgery (23%), followed by post‐operative neck infection, bleeding, or pneumonia. Patients with unplanned readmissions had significantly longer index admission duration than patients who were not readmitted (median 7 days vs. median 5 days, resp.; p = 0.0056). Analysis of cases of unplanned readmission for neck infection and bleeding identified the oral cavity/pharynx as the most common site of initial surgery and that a majority of patients had a history of radiation therapy. Conclusion: Neck infection, bleeding, and pneumonia were the most common reasons for unplanned readmission following otolaryngologic surgery, and a large portion of patients required additional procedures during readmission. Unplanned readmissions for bleeding were significantly more costly than readmissions for neck infections. Long‐index hospitalizations, index surgery involving the oral cavity and pharynx, and a history of radiation therapy may be useful clinical features that could stratify the risk of readmission. Level of Evidence: 4, retrospective chart review Laryngoscope, 133:2546–2552, 2023 [ABSTRACT FROM AUTHOR]

Objective  Though microvascular free tissue transfer is well established for open skull base reconstruction, normative data regarding flap design and inset after endoscopic endonasal skull base surgery (ESBS) is lacking. We aim to describe anatomical considerations of endoscopic endonasal inset of free tissue transfer of transclival (TC) and anterior cranial base resection (ACBR) defects. Design and Setting  Radial forearm free tissue transfer (RFFTT) model. Participants  Six cadaveric specimens. Main Outcome Measures  Pedicle orientation, pedicle length, and recipient vessel intraluminal diameter. Results  TC and ACBR defects averaged 17.2 and 11.7 cm 2 , respectively. Anterior and lateral maxillotomies and endoscopic medial maxillectomies were prepared as corridors for flap and pedicle passage. Premasseteric space tunnels were created for pedicle tunneling to recipient facial vessels. For TC defects, the RFFTT pedicle was oriented cranially with the flap placed against the clival defect (mean pedicle length 13.1 ± 0.6 cm). For ACBR defects, the RFFTT pedicle was examined in three orientations with respect to anterior–posterior axis of the RFFTT: anteriorly, posteriorly, and laterally. Lateral orientation offered the shortest average pedicle length required for anastomosis in the neck (11.6 ± 1.29 cm), followed by posterior (13.4 ± 0.7cm) and anterior orientations (14.4 ± 1.1cm) (p  < 0.00001, analysis of variance). Conclusions  In ACBR reconstruction using RFFTT, our data suggests lateral pedicle orientation shortens the length required to safely anastomose facial vessels and protects the frontal sinus outflow anteriorly while limiting pedicle exposure through a maxillary corridor within the nasal cavity. With greater understanding of anatomical factors related to successful preoperative flap planning, free tissue transfer may be added to the ESBS reconstruction ladder. [ABSTRACT FROM AUTHOR]