Faculty Bibliography

Current immunotherapy paradigms aim to reinvigorate CD8⁺ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV⁺), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV⁺ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV⁺ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.

OBJECTIVES/HYPOTHESIS:The incidence of human papillomavirus-positive (HPV+) oropharyngeal cancer is rising, but public knowledge about this diagnosis remains low. This study aimed to investigate the quality and readability of online information about HPV+ oropharyngeal cancer. STUDY DESIGN:Cross-sectional website analysis. METHODS:This study conducted a total of 12 web searches across Google, Yahoo, and Bing to identify websites related to HPV+ oropharyngeal cancer. The QUality Evaluation Scoring Tool (QUEST) was used to measure quality based on seven website criteria. The Flesch Reading Ease Score (FRES) and Flesch-Kincaid Grade Level (FKGL) were used to measure readability, with scores estimating the education level a reader would require to understand a piece of text. Readability improves as FRES increases and FKGL decreases. RESULTS:Twenty-seven unique web pages were evaluated. The mean USA reading grade level as measured by FKGL was 10.42 (standard deviation = 1.54). There was an inverse relationship between quality and readability, with a significant positive correlation between QUEST score and FKGL (r = 0.343, P = .040) and a significant negative correlation between QUEST score and FRES (r = -0.537, P = .002). CONCLUSIONS:With a mean USA reading grade level more than four grades above the American Medical Association's recommendation and results indicating that readability suffers as quality improves, these findings suggest that the currently available online information about HPV+ oropharyngeal cancer is insufficient. Improved patient education practices and resources about this diagnosis are needed. LEVEL OF EVIDENCE:NA Laryngoscope, 131:87-94, 2021.

BACKGROUND:Transcervical arterial ligation has been studied as a useful procedure to prevent bleeding events after transoral robotic surgery (TORS). METHODS:A systematic review of English-language literature on arterial ligation in TORS from 2005 to 2019 was conducted using Cochrane, PubMed, Web of Science (WoS), and ScienceDirect databases. Studies evaluating ligation and rates of postoperative hemorrhage were included. Meta-analysis of included studies was performed to assess impact of ligation on postoperative hemorrhage. RESULTS:Five studies with 2008 patients were included. History of radiation (odds ratio [OR] = 2.26, P = .02) and advanced tumor stage (OR = 1.93, P = .02) were found to predispose patients to postoperative hemorrhage. Arterial ligation was protective against severe hemorrhage in the mixed primary surgical modality cohort (OR = 0.33, P = .03) and in the TORS-only subgroup (OR = 0.21, P = .02), but did not significantly impact overall odds of postoperative hemorrhage. CONCLUSION:Transcervical arterial ligation offers protection against major/severe postoperative hemorrhage in patients undergoing TORS. LEVEL OF EVIDENCE:II.

OBJECTIVE:To analyze the role of transoral robotic base-of-tongue mucosectomy in a cohort of patients with human papilloma virus negative unknown primary carcinoma. STUDY DESIGN:Retrospective database analysis. METHODS:A retrospective database review from 2012 to 2018 was performed at two large tertiary centers to study patients with human papilloma virus (HPV)-negative unknown primary carcinoma who underwent transoral robotic base-of-tongue mucosectomy. P16 testing was used as a surrogate for HPV status. Patients were included that had squamous cell carcinoma metastatic to the lateral neck based on fine needle aspiration or open biopsy. Preoperatively, all patients were classified as having an unknown primary based on normal clinical and flexible endoscopic exam, normal operative endoscopy, nonlocalizing imaging, and tonsillectomy. All patients underwent robotic base-of-tongue mucosectomy. The primary outcome measure was the incidence of pathologic identification of a mucosal primary. RESULTS:Twenty-three patients with p16-negative unknown primary carcinoma were identified and studied. All patients underwent transoral robotic base-of-tongue mucosectomy. Median age was 60 years at the time of diagnosis, and 18 of 23 (78.2%) were male. Pathologic analysis of the base-of-tongue specimens showed a primary tumor in only three of 23 (13.0%) of patients. CONCLUSION:Despite prior evidence suggesting a high rate of primary site identification in HPV-related disease, robotic base-of-tongue mucosectomy may not be indicated for HPV-negative unknown primary carcinoma based on a low likelihood of finding the primary. LEVEL OF EVIDENCE:4 Laryngoscope, 131:78-81, 2021.