Otolaryngology Commons^™

Notch1 Acts As A Tumor Suppressor That Induces Early Differentiation In Head And Neck Cancer, Chenfei Huang, Shhyam Moorthy, Qiuli Li, Kazi M Ahmed, Kalil Saab, Defeng Deng, Jiping Wang, Xiayu Rao, Jiexin Zhang, Yuanxin Xi, Jing Wang, Zhiyi Liu, Noriaki Tanaka, David A Wheeler, Eve Shinbrot, Rami Saade, Curtis R Pickering, Tong-Xin Xie, Adel K El-Naggar, Abdullah A Osman, Kunal Rai, Patrick A Zweidler-Mckay, John V Heymach, Lauren A Byers, Faye M Johnson, Vlad C Sandulache, Jeffrey N Myers, Pedram Yadollahi, Mitchell J Frederick

Faculty, Staff and Students Publications

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early …

Neutrophil-To-Lymphocyte Ratio As A Prognostic Factor Of Survival Outcomes In Head And Neck Squamous Cell Carcinoma Receiving Neoadjuvant Immunotherapy, Pablo Llerena, Praneet C. Kaki, Kathryn Nunes, Eric Mastrolonardo, Kelly Bridgham, Annie Moroco, Hani Samarah, Mouadh Barbirou, David Baek, Chun Wang, Voichita Bar-Ad, David Cognetti, Joseph Curry, Jennifer M. Johnson, Hushan Yang, Larry A. Harshyne, Adam J. Luginbuhl

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is a prognostic marker in cancers treated with immune checkpoint inhibitors (ICI), reflecting the link between inflammation and cancer immune response. This study examines NLR's prognostic value in head and neck squamous cell carcinoma (HNSCC) patients receiving neoadjuvant ICI therapy, focusing on its potential as an independent predictor of overall survival (OS) and disease-free survival (DFS).

METHODS: We conducted a retrospective cohort study including three neoadjuvant trials: durvalumab ± metformin, nivolumab ± tadalafil, or nivolumab ± BMS-986205 from 2017 to 2022. Pre-treatment NLR was calculated using absolute neutrophil and absolute lymphocyte counts obtained before neoadjuvant …

Extracellular Matrix-Mycaf Signatures Correlate With Resistance To Neoadjuvant Apd-L1 Immune Checkpoint Inhibition With Durvalumab + Metformin In Hpv+ Hnscc, Pablo Llerena, Hani Samarah, Kathryn Nunes, Zhao Lin, Kelly Bridgham, Sruti Tekumalla, Amiti Jain, Larry A. Harshyne, Sanket Kumar Shukla, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, John R. Eisenbrey, Scott W Keith, David Cognetti, Voichita Bar-Ad, Adam J. Luginbuhl, Rita S. Axelrod, Rajanikanth Vadigepalli, Hushan Yang, Diana Whitaker-Menezes, Megan Roche, My G. Mahoney, Athanassios Argiris, Charalambos C. Solomides, Jennifer Johnson, Md, Mouadh Barbirou, Amanda Miller, Andrew P. South, Ramkrishna Mitra, Alban J Linnenbach, Ubaldo E. Martinez-Outshoorn, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

PURPOSE: Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICIs, offering promise to improve response rates. We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.

PATIENTS AND METHODS: Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms. We present …

Tumor Microenvironment Governs The Prognostic Landscape Of Immunotherapy For Head And Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis, Priyan Bhattacharya, Alban J Linnenbach, Andrew P. South, Ubaldo E. Martinez-Outshoorn, Joseph M. Curry, Jennifer M. Johnson, Larry A. Harshyne, Mỹ G. Mahoney, Adam J. Luginbuhl, Rajanikanth Vadigepalli

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly …

Artificial Intelligence-Based Virtual Staining Platform For Identifying Tumor-Associated Macrophages From Hematoxylin And Eosin-Stained Images, Arpit Aggarwal, Mayukhmala Jana, Amritpal Singh, Tanmoy Dam, Himanshu Maurya, Tilak Pathak, Sandra Orsulic, Kailin Yang, Deborah Chute, Justin A Bishop, Farhoud Faraji, Wade M Thorstad, Shlomo Koyfman, Scott Steward, Qiuying Shi, Vlad Sandulache, Nabil F Saba, James S Lewis, Germán Corredor, Anant Madabhushi

Faculty, Staff and Students Publications

Background: Virtual staining is an artificial intelligence-based approach that transforms pathology images between stain types, such as hematoxylin and eosin (H&E) to immunohistochemistry (IHC), providing a tissue-preserving and efficient alternative to traditional IHC staining. However, existing methods for translating H&E to virtual IHC often fail to generate images of sufficient quality for accurately delineating cell nuclei and IHC+ regions. To address these limitations, we introduce VISTA, an artificial intelligence-based virtual staining platform designed to translate H&E into virtual IHC.

Methods: We applied VISTA to identify M2-subtype tumor-associated macrophages (M2-TAMs) in H&E images from 968 patients with HPV+ oropharyngeal squamous cell …

Tobacco Smoke Exposure Is A Driver Of Altered Oxidative Stress Response And Immunity In Head And Neck Cancer, Yang Li, Pedram Yadollahi, Fonma N Essien, Vasanta Putluri, Chandra Shekar R Ambati, Karthik Reddy Kami Reddy, Abu Hena Mostafa Kamal, Nagireddy Putluri, Lama M Abdurrahman, Maria E Ruiz Echartea, Keenan J Ernste, Akshar J Trivedi, Jonathan Vazquez-Perez, William H Hudson, William K Decker, Rutulkumar Patel, Abdullah A Osman, Farrah Kheradmand, Stephen Y Lai, Jeffrey N Myers, Heath D Skinner, Cristian Coarfa, Kwangwon Lee, Antrix Jain, Anna Malovannaya, Mitchell J Frederick, Vlad C Sandulache

Faculty, Staff and Student Publications

Background: Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data show cigarette smoke to be a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming of the cellular reductive state.

Methods: Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to …

Potentially Functional Variants Of Chmp4a And Panx1 In The Pyroptosis-Related Pathway Predict Survival Of Patients With Non-Oropharyngeal Head And Neck Squamous Cell Carcinoma, Xiaozhun Tang, Huiling Wang, Hongliang Liu, Guojun Li, Erich M Sturgis, Sanjay Shete, Qingyi Wei

Faculty, Staff and Students Publications

Background: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC).

Methods: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the …

First-In-Human Hyperpolarized Mri For Tumor Metabolism In Hnscc, Stephen Y Lai, Vlad C Sandulache, Dawid Schellingerhout, Clifton D Fuller, Yunyun Chen, Christopher M Walker, James A Bankson

Faculty, Staff and Student Publications

This case report describes the use of hyperpolarized magnetic resonance imaging (MRI) in a patient with head and neck squamous cell carcinoma (HNSCC) to demonstrate its translational viability.

Predictive Capacity Of Immune-Related Adverse Events And Cytokine Profiling In Neoadjuvant Immune Checkpoint Inhibitor Trials For Head And Neck Squamous Cell Carcinoma\, Angela E Alnemri, Sruti Tekumalla, Annie E Moroco, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, Tingting Zhan, David M Cognetti, Joseph M Curry, Athanassios Argiris, Alban Linnenbach, Andrew P South, Larry A Harshyne, Jennifer M Johnson, Adam J Luginbuhl

Faculty, Staff and Student Publications

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status.

METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival …

Predictive Capacity Of Immune-Related Adverse Events And Cytokine Profiling In Neoadjuvant Immune Checkpoint Inhibitor Trials For Head And Neck Squamous Cell Carcinoma, Angela Alnemri, Sruti Tekumalla, Annie Moroco, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, Tingting Zhan, David Cognetti, Joseph Curry, Athanassios Argiris, Alban Linnenbach, Andrew South, Larry Harshyne, Jennifer Johnson, Adam Luginbuhl

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status.

METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival …

P90rsk Pathway Inhibition Synergizes With Cisplatin In Tmem16a Overexpressing Head And Neck Cancer, Abdulkader Yassin-Kassab, Suman Chatterjee, Nayel Khan, Nathaniel Wang, Vlad C Sandulache, Eric H-B Huang, Timothy F Burns, Umamaheswar Duvvuri

Faculty, Staff and Students Publications

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against …

Delays Starting Postoperative Radiotherapy Among Head And Neck Cancer Patients: A Systematic Review And Meta-Analysis, Kelsey A Duckett, Mohamed Faisal Kassir, Shaun A Nguyen, Emily A Brennan, Bhishamjit S Chera, Katherine R Sterba, Chanita Hughes Halbert, Elizabeth G Hill, Jessica Mccay, Sidharth V Puram, Vlad C Sandulache, Russel Kahmke, Salma Ramadan, Brian Nussenbaum, Anthony J Alberg, Evan M Graboyes

Faculty, Staff and Students Publications

OBJECTIVE: Initiating postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery is the first and only Commission on Cancer (CoC) approved quality metric for head and neck squamous cell carcinoma (HNSCC). No study has systematically reviewed nor synthesized the literature to establish national benchmarks for delays in starting PORT.

DATA SOURCES: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed a systematic review of PubMed, Scopus, and CINAHL.

REVIEW METHODS: Studies that described time-to-PORT or PORT delays in patients with HNSCC treated in the United States after 2003 were included. Meta-analysis of proportions and continuous measures …

Influence Of Oral Microbiome On Longitudinal Patterns Of Oral Mucositis Severity In Patients With Squamous Cell Carcinoma Of The Head And Neck, Liangliang Zhang, Erin Marie D San Valentin, Teny M John, Robert R Jenq, Kim-Anh Do, Ehab Y Hanna, Christine B Peterson, Cielito C Reyes-Gibby

Faculty, Staff and Student Publications

Background: This study investigated the influence of oral microbial features on the trajectory of oral mucositis (OM) in patients with squamous cell carcinoma of the head and neck.

Methods: OM severity was assessed and buccal swabs were collected at baseline, at the initiation of cancer treatment, weekly during cancer treatment, at the termination of cancer treatment, and after cancer treatment termination. The oral microbiome was characterized via the 16S ribosomal RNA V4 region with the Illumina platform. Latent class mixed-model analysis was used to group individuals with similar trajectories of OM severity. Locally estimated scatterplot smoothing was used to fit …

Recurrent Oropharyngeal Squamous Cell Carcinomas Maintain Anti-Tumor Immunity And Multinucleation Levels Following Completion Of Radiation, Patricia Castro, Germán Corredor, Can Koyuncu, Luke A Nordstrom, Michelle Tiji, Taylor Leavitt, James S Lewis, Anant Madabhushi, Mitchell J Frederick, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology.

METHODS: We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms.

RESULTS: Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors …

Attempts To Understand Oral Mucositis In Head And Neck Cancer Patients Through Omics Studies: A Narrative Review, Erin Marie D San Valentin, Kim-Anh Do, Sai-Ching J Yeung, Cielito C Reyes-Gibby

Faculty, Staff and Student Publications

Oral mucositis (OM) is a common and clinically impactful side effect of cytotoxic cancer treatment, particularly in patients with head and neck squamous cell carcinoma (HNSCC) who undergo radiotherapy with or without concomitant chemotherapy. The etiology and pathogenic mechanisms of OM are complex, multifaceted and elicit both direct and indirect damage to the mucosa. In this narrative review, we describe studies that use various omics methodologies (genomics, transcriptomics, microbiomics and metabolomics) in attempts to elucidate the biological pathways associated with the development or severity of OM. Integrating different omics into multi-omics approaches carries the potential to discover links among host …

Effect Of Preoperative Programmed Death-1 Or Programmed Death Ligand-1 Immune Check Point Inhibition On Complications After Surgery For Primary Head And Neck Cancer, Ramez Philips, Angela Alnemri, Dev Amin, Jena Patel, Michael C. Topf, Jennifer M. Johnson, Voichita Bar-Ad, Rita Axelrod, Athanassios Argiris, Christopher Fundakowski, Adam J. Luginbuhl, David M. Cognetti, Joseph M. Curry

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: There is sparse literature on the effect of preoperative immunotherapy on complications after surgery for primary head and neck squamous cell carcinoma (HNSCC). The objectives are to compare complication rates in patients receiving surgery with and without neoadjuvant immune checkpoint inhibitors (nICI) for primary HNSCC and to evaluate factors associated with increased odds of surgical complications.

METHODS: A retrospective review of patients who underwent ablation and free flap reconstruction or transoral robotic surgery (TORS) for primary HNSCC between 2017-2021 was conducted. Complications were compared between patients who underwent surgery with or without nICI before and after propensity score matching. …

Outcomes Of Treatment With Neoadjuvant Cemiplimab For Patients With Advanced, Resectable Cutaneous Squamous Cell Carcinoma Of The Head And Neck: Secondary Analysis Of A Phase 2 Clinical Trial, Renata Ferrarotto, Priyadharsini Nagarajan, Jacob M Maronge, Jason M Johnson, David I Rosenthal, Jeffrey N Myers, Neil D Gross

Faculty, Staff and Student Publications

This secondary analysis of a phase 2 clinical trial examines long-term survival for resectable cutaneous squamous cell carcinoma of the head and neck according to pathologic response.

Long-Term Patient-Reported Outcomes In A Population-Based Cohort Following Radiotherapy Vs Surgery For Oropharyngeal Cancer, Michael J Dohopolski, Kevin Diao, Katherine A Hutcheson, Neil S Akhave, Ryan P Goepfert, Weiguo He, Xiudong Jennifer Lei, Susan K Peterson, Yu Shen, Baran D Sumer, Benjamin D Smith, David J Sher

Faculty, Staff and Student Publications

IMPORTANCE: Oncologic outcomes are similar for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with primary surgery or radiotherapy. However, comparative differences in long-term patient-reported outcomes (PROs) between modalities are less well established.

OBJECTIVE: To determine the association between primary surgery or radiotherapy and long-term PROs.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used the Texas Cancer Registry to identify survivors of OPSCC treated definitively with primary radiotherapy or surgery between January 1, 2006, and December 31, 2016. Patients were surveyed in October 2020 and April 2021.

EXPOSURES: Primary radiotherapy and surgery for OPSCC.

MAIN OUTCOMES AND MEASURES: Patients completed …

Development And Validation Of An Automated Image-Based Deep Learning Platform For Sarcopenia Assessment In Head And Neck Cancer, Zezhong Ye, Anurag Saraf, Yashwanth Ravipati, Frank Hoebers, Paul J Catalano, Yining Zha, Anna Zapaishchykova, Jirapat Likitlersuang, Christian Guthier, Roy B Tishler, Jonathan D Schoenfeld, Danielle N Margalit, Robert I Haddad, Raymond H Mak, Mohamed Naser, Kareem A Wahid, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Antti A Mäkitie, Clifton D Fuller, Hugo J W L Aerts, Benjamin H Kann

Faculty, Staff and Student Publications

Importance: Sarcopenia is an established prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC); the quantification of sarcopenia assessed by imaging is typically achieved through the skeletal muscle index (SMI), which can be derived from cervical skeletal muscle segmentation and cross-sectional area. However, manual muscle segmentation is labor intensive, prone to interobserver variability, and impractical for large-scale clinical use.

Objective: To develop and externally validate a fully automated image-based deep learning platform for cervical vertebral muscle segmentation and SMI calculation and evaluate associations with survival and treatment toxicity outcomes.

Design, setting, and participants: For this prognostic study, …

Machine Learning Driven Index Of Tumor Multinucleation Correlates With Survival And Suppressed Anti-Tumor Immunity In Head And Neck Squamous Cell Carcinoma Patients, Can F Koyuncu, Mitchell J Frederick, Lester D R Thompson, Germán Corredor, Sirvan Khalighi, Zelin Zhang, Bolin Song, Cheng Lu, Reetoja Nag, Vidya Sankar Viswanathan, Michael Gilkey, Kailin Yang, Shlomo A Koyfman, Deborah J Chute, Patricia Castro, James S Lewis, Anant Madabhushi, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVES: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation, previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine learning approach.

MATERIALS AND METHODS: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set (D

RESULTS: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25, 1.07-4.71, 0.03), …

Pembrolizumab And Cabozantinib In Recurrent Metastatic Head And Neck Squamous Cell Carcinoma: A Phase 2 Trial, Nabil F Saba, Conor E Steuer, Asari Ekpenyong, Ashley Mccook-Veal, Kelly Magliocca, Mihir Patel, Nicole C Schmitt, William Stokes, James E Bates, Soumon Rudra, Jill Remick, Mark Mcdonald, Marin Abousaud, Aik Choon Tan, Muhammad Zaki Hidayatullah Fadlullah, Ritu Chaudhary, Jameel Muzaffar, Kedar Kirtane, Yuan Liu, Georgia Z Chen, Dong M Shin, Yong Teng, Christine H Chung

Faculty, Staff and Student Publications

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and …

Spatial Pd-L1, Immune-Cell Microenvironment, And Genomic Copy-Number Alteration Patterns And Drivers Of Invasive-Disease Transition In Prospective Oral Precancer Cohort, William N William, Jianjun Zhang, Xin Zhao, Edwin R Parra, Naohiro Uraoka, Heather Y Lin, S Andrew Peng, Adel K El-Naggar, Jaime Rodriguez-Canales, Jaejoon Song, Ann M Gillenwater, Ignacio I Wistuba, Jeffrey N Myers, Kathryn A Gold, Renata Ferrarotto, Patrick Hwu, Teresa Davoli, J Jack Lee, John V Heymach, Vassiliki A Papadimitrakopoulou, Scott M Lippman

Faculty, Staff and Student Publications

BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC).

METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm

RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High …

Ninety-Day Mortality Following Transoral Robotic Surgery Or Radiation At Commission On Cancer-Accredited Facilities, James R Janopaul-Naylor, Manali Rupji, Rachel A Tobillo, Joshua W Lorenz, Jeffrey M Switchenko, Sibo Tian, Azeem S Kaka, David C Qian, Ashley J Schlafstein, Conor E Steuer, Jill S Remick, Soumon Rudra, Mark W Mcdonald, Nabil F Saba, William A Stokes, Mihir R Patel, James E Bates

Faculty, Staff and Student Publications

BACKGROUND: Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown.

METHODS: NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson-Deyo score 0-1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities.

RESULTS: 3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality.

CONCLUSIONS: There is minimal difference between 90-day mortality …

Immunogenetic Determinants Of Susceptibility To Head And Neck Cancer In The Million Veteran Program Cohort, Yanhong Liu, Jennifer R Kramer, Vlad C Sandulache, Robert Yu, Guojun Li, Liang Chen, Zenab I Yusuf, Yunling Shi, Saiju Pyarajan, Spyros Tsavachidis, Li Jiao, Michelle L Mierzwa, Elizabeth Chiao, Yvonne M Mowery, Andrew Shuman, Sanjay Shete, Andrew G Sikora, Donna L White

Faculty, Staff and Student Publications

Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and …

Role Of Sentinel Lymph Node Biopsy For Oral Squamous Cell Carcinoma: Current Evidence And Future Challenges, Sophie S Jang, Morgan E Davis, David R Vera, Stephen Y Lai, Theresa W Guo

Faculty, Staff and Student Publications

Sentinel lymph node biopsy (SLNB) has been used across oncological specialties for prognostication, staging, and identification of occult nodal metastasis. Recent studies demonstrated the potential clinical utility of SLNB in oral cavity squamous cell carcinoma (OCSCC). Elective neck dissection is the current standard of care in early management of OCSCC with depth of invasion greater than 2-4 mm; however, majority of patients ultimately do not have nodal disease on final pathology. SLNB is an alternative procedure widely adopted in early cancer management in many oncological subspecialities. Several considerations such as depth of invasion, nodal mapping, histopathology methods, operator variability, postoperative …

Feasibility Of Clinical Evaluation Of Individuals With Increased Risk For Hpv-Associated Oropharynx Cancer, Nicholas Scott-Wittenborn, Gypsyamber D'Souza, Nafi Aygun, Sakshi R Tewari, Javad Azadi, Peter Vosler, Zhen Gooi, Vikas Mehta, Wojciech Mydlarz, Melonie Nance, Stefan Mlot, Mihir R Patel, Marietta Tan, Brett A Miles, Tanya Troy, Carole Fakhry

Faculty, Staff and Student Publications

BACKGROUND: Human papillomavirus-associated oropharynx squamous cell carcinoma (HPV-OPSCC) has no known pre-malignant lesion. While vaccination offers future primary prevention, there is current interest in secondary prevention. The feasibility of clinical evaluation of individuals at increased risk for HPV-OPSCC is unclear.

METHODS: Individuals with risk factors for HPV-OPSCC were enrolled in a prospective study (MOUTH). Participants positive for biomarkers associated with HPV-OPSCC were eligible for a clinical evaluation which comprised a head and neck examination and imaging with ultrasound and/or magnetic resonance imaging (MRI). This study was designed to evaluate feasibility of clinical evaluation in a screening study.

RESULTS: Three hundred …

Early Detection Of Mandible Osteoradionecrosis Risk In A High Comorbidity Veteran Population, David Chamberlayne Wilde, Sagar Kansara, Logan Banner, Rickey Morlen, David Hernandez, Andrew Tsao Huang, Weiyuan Mai, Clifton David Fuller, Stephen Lai, Vlad Constantin Sandulache

Faculty, Staff and Student Publications

OBJECTIVE: Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively.

STUDY DESIGN: Retrospective analysis of prospective cohort.

SETTING: Tertiary care Veterans Health Administration (VHA) medical center.

METHODS: Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively …

Chemoradiation Therapy Alters The Pd-L1 Score In Locoregional Recurrent Squamous Cell Carcinomas Of The Head And Neck, Brian J Park, Austin K Mattox, Daniel Clayburgh, Mihir Patel, R Bryan Bell, Bevan Yueh, Rom Leidner, Hong Xiao, Marcus Couey, Shiting Li, Tingting Qin, Maureen A Sartor, Belinda Cairns, Tracy Macdonough, Kyle Halliwill, Daniel Deschler, Derrick T Lin, William C Faquin, Peter M Sadow, Sara I Pai

Faculty, Staff and Student Publications

PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did …

Metformin Increases Natural Killer Cell Functions In Head And Neck Squamous Cell Carcinoma Through Cxcl1 Inhibition, Mckenzie Crist, Benyamin Yaniv, Sarah Palackdharry, Maria A. Lehn, Mario Medvedovic, Timothy Stone, Shuchi Gulati, Vidhya Karivedu, Michael Borchers, Bethany Fuhrman, Audrey Crago, Joseph Curry, Ubaldo Martinez-Outschoorn, Vinita Takiar, Trisha M. Wise-Draper

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).

METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell …

Risk And Incidence Of Head And Neck Cancers In Veterans Living With Hiv And Matched Hiv-Negative Veterans, Angela L Mazul, Christine M Hartman, Yvonne M Mowery, Jennifer R Kramer, Donna L White, Kathryn E Royse, Suchismita Raychaudhury, Vlad C Sandulache, Sarah T Ahmed, Jose P Zevallos, Peter A Richardson, Andrew G Sikora, Elizabeth Y Chiao

Faculty, Staff and Students Publications

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study.

METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic …