Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.

International guidelines for intratumoral and intranodal injection of NBTXR3 nanoparticles in head and neck cancers.

BACKGROUND: An international multidisciplinary panel of experts aimed to provide consensus guidelines describing the optimal intratumoral and intranodal injection of NBTXR3 hafnium oxide nanoparticles in head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, and cervical lymph nodes and to review data concerning safety, feasibility, and procedural aspects of administration. METHODS: The Delphi method was used to determine consensus. A 4-member steering committee and a 10-member monitoring committee wrote and revised the guidelines, divided into eight sections. An independent 3-member reading committee reviewed the recommendations. RESULTS: After two rounds of voting, strong consensus was obtained on all recommendations. Intratumoral and intranodal injection was deemed feasible. NBTXR3 volume calculation, choice of patients, preparation and injection procedure, potential side effects, post injection, and post treatment follow-up were described in detail. CONCLUSIONS: Best practices for the injection of NBTXR3 were defined, thus enabling international standardization of intratumoral nanoparticle injection.

Pediatric Robotic Laryngeal Cleft Repair.

OBJECTIVE: Compare surgical and swallow outcomes in robotic versus traditional laryngeal cleft (LC) repairs. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric hospital. METHODS: Pediatric patients who underwent robotic or traditional (open or endoscopic) LC repair between 2010 and 2021 were identified. Patient characteristics, operative times, adverse events, hospital length of stay (LOS), and modified barium swallow study (MBSS) results were compared. RESULTS: Eighteen robotic and thirty traditional LC repairs were identified. Mean surgical (149 vs 111 min, P < .05) and OR times (207 vs 139 min, P < .002) were increased for robotic type I LC repairs, but were similar for type II and III LC. Mean hospital LOS was increased for robotic type I LC repairs (2.6 vs 1.2 days, P < .006), but was decreased for type II (4 vs 12.2 days) and type III (4.3 vs 94.5 days) LC. Postoperative MBSS results were improved for robotic type I LC repairs at 12 months (82% vs 43%, P = .05), and trended toward improvement at 6 months for type II (75% vs 22%), and type III (67% vs 50%) LC repairs, although significance was limited for type II and III LC due to the number of subjects. A robotic approach was used successfully to revise all recurrent LC that failed traditional repairs. CONCLUSION: Robotic type 1 LC repairs demonstrated increased operative times and hospital LOS but improved postoperative swallow outcomes compared to traditional approaches may be particularly useful in cases of recurrent clefts.

Post-surgical readmission risk factors in otolaryngology/head and neck surgery.

BACKGROUND: Otolaryngology patients are a high-readmission-risk group due to the complexity of surgeries, significant alterations to speech and swallowing functions, and high postoperative complications risk. METHODS: A retrospective review was performed on patients who underwent otolaryngologic surgery at a single-academic-institution between March 2019 and February 2020. RESULTS: Among 365 discharges, 21 patients had unplanned readmissions within 30 days. On univariable analysis, acute myocardial infarction, number of total comorbidities, prior chemotherapy/radiation, active smoking, airway surgery, and enteral feeding, and on multivariable analysis, prior chemotherapy/radiation and active smoking were identified as significant readmission risk factors. Readmission risk increased from 2.43% to 7.48% and 41.67% with the addition of each risk factor. CONCLUSION: Nearly 75% of the readmissions were due to potentially preventable reasons. By identifying and proactively intervening on "at risk" patients during the perioperative timeframe, complications and readmission can be reduced, thereby improving the overall quality of care delivered.

The Toxicological Effects of e-Cigarette Use in the Upper Airway: A Scoping Review.

OBJECTIVE: While evidence continues to emerge on the negative health effects of electronic cigarettes (e-cigarettes) on the lungs, little is known regarding their deleterious effects on the upper airway. The purpose of this review is to summarize the toxicological effects of e-cigarettes, and their components, on the upper airway. DATA SOURCES: PubMed, SCOPUS, EMBASE databases. REVIEW METHODS: Systematic searches were performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines from 2003 to 2023. Studies were included if they investigated the toxicological effects of e-cigarette exposure on human or animal upper airway tissue. Two authors independently screened, reviewed, and appraised all included articles. RESULTS: A total of 822 unique articles were identified, of which 53 met inclusion criteria and spanned subsites including the oral cavity (22/53 studies), nasal cavity/nasopharynx (13/53), multiple sites (10/53), larynx (5/53), trachea (2/53), and oropharynx (1/53). The most commonly observed consequences of e-cigarette use on the upper airway included: proinflammatory (15/53 studies), histological (13/53), cytotoxicity (11/53), genotoxicity (11/53), and procarcinogenic (6/53). E-cigarette humectants independently induced toxicity at multiple upper airway subsites, however, effects were generally amplified when flavoring(s) and/or nicotine were added. Across almost all studies, exposure to cigarette smoke exhibited increased toxicity in the upper airway compared with exposure to e-cigarette vapor. CONCLUSION: Current data suggest that while e-cigarettes are generally less harmful than traditional cigarettes, they possess a distinct toxicological profile that is enhanced upon the addition of flavoring(s) and/or nicotine. Future investigations into underexamined subsites, such as the oropharynx and hypopharynx, are needed to comprehensively understand the effects of e-cigarettes on the upper airway.

Implementation and Outcomes of ERAS Protocol for Major Oncologic Head and Neck Surgery.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols have been developed and successfully implemented for many surgical specialties, demonstrating reductions in length of stay, post-operative complications, and resource utilization. Currently, there are few documented applications of ERAS protocols in head and neck surgery. Additional description of head and neck surgery protocol design, implementation, and outcomes will help advance postoperative care. METHODS: An ERAS protocol was designed for patients undergoing glossectomy and primary or salvage laryngectomy with or without free flap reconstruction. Following successful protocol implementation, patient outcomes and perioperative metrics were retrospectively reviewed and compared between patients prior to and following the ERAS protocol. RESULTS: Global comparison of ERAS and control group did not show statistically significant differences in measured perioperative outcomes. There were no statistically significant differences between the ERAS and control groups in age, sex, BMI, surgery type, or cancer stage. The ERAS protocol was associated with reduced variability in hospital length of stay (LOS), demonstrated through tighter interquartile ranges. For patients undergoing salvage laryngectomy, the ERAS protocol was associated with a significant reduction in 30-day readmission rates. Although not statistically significant, the median length of stay in the step-down unit (ISCU) and hospital was lower for specific patient groups. CONCLUSION: The implementation and evaluation of the ERAS protocol demonstrated improvement in select patient outcomes as well as areas for process improvement. This study demonstrates the insights that arise from review of this protocol even for an institution with perceived standardized procedures for major oncologic head and neck surgeries. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:732-740, 2024.

Oncologic Safety of Close Margins in Patients With Low- to Intermediate-Grade Major Salivary Gland Carcinoma.

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. Main Outcomes and Measures: Main outcomes were risk factors for local recurrence. Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Effect of distance of treatment center on survival for HPV-negative head and neck cancer patients.

BACKGROUND: In rural states, travel burden for complex cancer care required for head and neck squamous cell carcinoma (HNSCC) may affect patient survival, but its impact is unknown. METHODS: Patients with HPV-negative HNSCC were retrospectively identified from a statewide, population-based study. Euclidian distance from the home address to the treatment center was calculated for radiation therapy, surgery, and chemotherapy. Multivariable Cox proportional hazards models were used to examine the risk of 5-year mortality with increasing travel quartiles. RESULTS: There were 936 patients with HPV-negative HNSCC with a mean age of 60. Patients traveled a median distance of 10.2, 11.1, and 10.9 miles to receive radiation therapy, surgery, and chemotherapy, respectively. Patients in the fourth distance quartile were more likely to live in a rural location (p < 0.001) and receive treatment at an academic hospital (p < 0.001). Adjusted overall survival (OS) improved proportionally to distance traveled, with improved OS remaining significant for patients who traveled the furthest for care (third and fourth quartile by distance). Relative to patients in the first quartile, patients in the fourth had a reduced risk of mortality with radiation (HR 0.59, 95% CI 0.42-0.83; p = 0.002), surgery (HR 0.47, 95% CI 0.30-0.75; p = 0.001), and chemotherapy (HR 0.56, 95% CI 0.35-0.91; p = 0.020). CONCLUSION: For patients in this population-based cohort, those traveling greater distances for treatment of HPV-negative HNSCC had improved OS. This analysis suggests that the benefits of coordinated, multidisciplinary care may outweigh the barriers of travel burden for these patients.

Development of a Novel Molecular Test for Determining HPV Integration Status in HPV-Positive Oropharynx Cancers.

This diagnostic study describes the development of an assay for human papillomavirus­driven cancers of the oropharynx and the role viral integration could play in the process.

Comprehensive Viral Genotyping Reveals Prognostic Viral Phylogenetic Groups in HPV16-Associated Squamous Cell Carcinoma of the Oropharynx.

Human papillomavirus-positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States and is primarily caused by HPV subtype 16 (HPV16). Favorable treatment outcomes have led to increasing interest in treatment deescalation to reduce treatment-related morbidity. Prognostic biomarkers are needed to identify appropriately low-risk patients for reduced treatment intensity. Targeted DNA sequencing including all HPV16 open reading frames was performed on tumors from 104 patients with HPV16+ OPSCC treated at a single center. Genotypes closely related to the HPV16-A1 reference were associated with increased numbers of somatic copy-number variants in the human genome and poor recurrence-free survival (RFS). Genotypes divergent from HPV16-A1 were associated with favorable RFS. These findings were independent of tobacco smoke exposure. Total RNA sequencing was performed on a second independent cohort of 89 HPV16+ OPSCC cases. HPV16 genotypes divergent from HPV16-A1 were again validated in this independent cohort, to be prognostic of improved RFS in patients with moderate (less than 30 pack-years) or low (no more than 10 pack-years) of tobacco smoke exposure. In summary, we show in two independent cohorts that viral sequence divergence from the HPV16-A1 reference is correlated with improved RFS in patients with moderate or low tobacco smoke exposure. IMPLICATIONS: HPV16 genotype is a potential biomarker that could be easily adopted to guide therapeutic decision-making related to deescalation therapy.

Socioeconomic status, access to care, risk factor patterns, and stage at diagnosis for head and neck cancer among black and white patients.

BACKGROUND: Little is known about how factors combine to influence progression of squamous cell carcinoma of the head and neck (HNSCC). We aimed to evaluate multidimensional influences of factors associated with HNSCC stage by race. METHODS: Using retrospective data, patients with similar socioeconomic status (SES), access to care (travel time/distance), and behavioral risk factors (tobacco/alcohol use and dental care) were grouped by latent class analysis. Relative frequency differences (RFD) were calculated to evaluate latent classes by stage, race, and p16 status. RESULTS: We identified three latent classes. Advanced T-stage was higher for black (RFD = +20.2%; 95% CI: -4.6 to 44.9) than white patients (RFD = +10.7%; 95% CI: 2.1-19.3) in the low-SES/high-access/high-behavioral risk class and higher for both black (RFD = +29.6%; 95% CI: 4.7-54.5) and white patients (RFD = +23.9%; 95% CI: 15.2-32.6) in the low-SES/low-access/high-behavioral risk class. CONCLUSION: Results suggest that SES, access to care, and behavioral risk factors combine to underly the association with advanced T-stage. Additionally, differences by race warrant further investigation.

Evaluation of a 3D-Printed Transoral Robotic Surgery Simulator Utilizing Artificial Tissue.

OBJECTIVES/HYPOTHESIS: Transoral robotic surgery (TORS) poses challenges for operators in training, with limited robot access on a platform requiring distinct surgical skills. Few simulators exist, and current virtual reality training modules exclude head and neck simulations. This study evaluates the construct validity for a novel low-cost TORS simulator. STUDY DESIGN: Single institution prospective observational study. METHODS: Using 3D-printed oral cavity structures and replaceable artificial tissue components, a modular TORS simulator was constructed for short-duration hands-on simulations with the da Vinci SI robot. Sixteen surgeons of differing robotic skill levels, no experience (novice), prior experience, and formal robot training, participated in simulated tonsil and tongue base tumor resections. Video recordings of each participant were graded by a blinded robotically trained surgeon using a 35-point Global Evaluative Assessment of Robotic Surgery (GEARS) criterion adapted for the TORS simulator. RESULTS: Operators reporting formal robotic training or prior robot experience achieved significantly higher mean total GEARS scores compared to novice operators (32 vs. 20.5; P < .001). Overall, mean total GEARS scores correlated with reported experience level; novice operators scored 54% of total points at 19 (4.5), operators with prior experience scored 82.3% of total points at 28.8 (2.6), and robotically trained operators scored 97.1% of total points at 34 (1.7). CONCLUSION: With a GEARS criterion, our simulator successfully differentiated novice from experienced and robotically trained operators of the da Vinci SI robot during simulated tonsillectomy and base of tongue resections. These findings support the construct validity of this prototype simulator and offer a foundation for further testing of predictive validity. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:1588-1593, 2022.

Oncologic outcomes of human papillomavirus-associated oropharynx carcinoma treated with surgery alone: A 12-institution study of 344 patients.

BACKGROUND: The oncologic outcomes of surgery alone for patients with American Joint Committee on Cancer 7th edition (AJCC 7th) pN2a and pN2b human papillomavirus-associated oropharynx squamous cell carcinoma (HPV+OPSCC) are not clear. METHODS: The authors performed a 12-institution retrospective study of 344 consecutive patients with HPV+OPSCC (AJCC 7th pT0-3 N3 M0) treated with surgery alone with 6 months or more of follow-up using univariate and multivariate analyses. RESULTS: The 2-year outcomes for the entire cohort were 91% (182 of 200) disease-free survival (DFS), 100% (200 of 200) disease-specific survival (DSS), and 98% (200 of 204) overall survival (OS). The 18 recurrences within 2 years were 88.9% (16 of 18) local and/or regional recurrences and 11.1% (2 of 18) distant metastases. Recurrences were not significantly associated with smoking, pT stage, or pN stage. The 16 patients with locoregional recurrences within 2 years all underwent successful salvage treatments (median follow-up after salvage: 13.1 months), 43.8% (7 of 16) of whom underwent salvage surgery alone for a 2-year overall salvage radiation need of 4.5% (9 of 200). The 2-year outcomes for the 59 evaluable patients among the 109 AJCC 7th pT0-2 N2a-N2b patients with 1 to 3 pathologic lymph nodes (LNs) were as follows: local recurrence, 3.4% (2 of 59); regional recurrence, 8.4% (5 of 59); distant metastases, 0%; DFS, 88.1% (52 of 59); DSS, 100% (59 of 59); OS, 96.7% (59 of 61); and salvage radiation, 5.1% (3 of 59). CONCLUSIONS: With careful selection, surgery alone for AJCC 7th pT0-T2N0-N2b HPV+OPSCC with zero to 3 pathologic LNs without perineural invasion, extranodal extension, or positive margins results in high DFS, DSS, OS, and salvage treatment success. Because of the short-term follow-up, these data support further investigation of treatment de-escalation in this population.

Genomic heterogeneity and copy number variant burden are associated with poor recurrence-free survival and 11q loss in human papillomavirus-positive squamous cell carcinoma of the oropharynx.

BACKGROUND: Human papillomavirus-positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States. Favorable treatment outcomes have led to increased interest in treatment de-escalation to reduce treatment morbidity as well as the development of prognostic markers to identify appropriately low-risk patients. Intratumoral genomic heterogeneity and copy number alteration burden have been demonstrated to be predictive of poor outcomes in many other cancers; therefore, we sought to determine whether intratumor heterogeneity and genomic instability are associated with poor outcomes in HPV+ OPSCC. METHODS: Tumor heterogeneity estimates were made based on targeted exome sequencing of 45 patients with HPV+ OPSCC tumors. Analysis of an additional cohort of HPV+ OPSCC tumors lacking matched normal sequencing allowed copy number analysis of 99 patient tumors. RESULTS: High intratumorally genomic heterogeneity and high numbers of copy number alterations were strongly associated with worse recurrence-free survival. Tumors with higher heterogeneity and frequent copy number alterations were associated with loss of distal 11q, which encodes key genes related to double-strand break repair, including ATM and MRE11A. CONCLUSIONS: Both intratumor genomic heterogeneity and high-burden copy number alterations are strongly associated with poor recurrence-free survival in patients with HPV+ OPSCC. The drivers of genomic instability and heterogeneity in these tumors remains to be elucidated. However, 11q loss and defective DNA double-strand break repair have been associated with genomic instability in other solid tumors. Copy number alteration burden and intratumoral heterogeneity represent promising avenues for risk stratification of patients with HPV+OPSCC.

CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition.

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy.

Academic Affiliation and Surgical Volume Predict Survival in Head and Neck Cancer Patients Receiving Surgery.

OBJECTIVE: To determine whether the academic affiliation or surgical volume affects the overall survival (OS) of human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) patients receiving surgery. METHODS: A retrospective study of 39 North Carolina Medical Centers was conducted. Treatment centers were classified as academic hospitals, community cancer centers, or community hospitals and were divided into thirds by volume. The primary outcome was 5-year OS. Hazard ratios (HR) were determined using Cox proportional hazard models, adjusting for demographics, tumor site, stage, insurance status, tobacco use, alcohol use, stage, chemotherapy, and radiation therapy. Patients were also stratified by stage (early stage and advanced stage). RESULTS: Patients treated at community cancer centers had significantly better 5-year OS (HR 0.68, 95% confidence interval [CI] = 0.48-0.98), and patients treated at academic hospitals trended toward better 5-year OS (HR 0.72, 95% CI = 0.50-1.04) compared to patients treated at community hospitals. The effect for academic affiliation on survival was more pronounced for patients with advanced stage cancer at diagnosis (HR 0.60, 95% CI = 0.37-0.95). There were no significant survival differences among early stage patients by treatment center type. Top-third (HR = 0.64, 95% CI = 0.42-0.96) centers by surgical volume had significantly better 5-year OS, and middle-third (HR = 0.71, 95% CI = 0.51-1.03) centers by volume trended toward better 5-year OS when compared to the bottom-third centers by volume. CONCLUSION: Patients treated at academic hospitals, community cancer centers, and hospitals in the top third by case volume have favorable survival for HPV-negative HNSCC. The effect for academic hospitals is most pronounced among advanced stage patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E479-E488, 2021.

Novel induction therapy transoral surgery treatment paradigm with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck - Mature clinical and functional outcomes.

OBJECTIVE: Induction chemotherapy in head and neck squamous cell carcinoma (HNSCCA) has principally been studied prior to radiation therapy. We evaluated pre-operative induction therapy followed by surgery followed by risk-adapted adjuvant therapy. This report details the mature 5-year survival statistics, clinical and functional outcomes. METHODS: An IRB-approved single institution prospective phase II clinical trial from October 2012 to November 2016 was conducted for patients with transorally-resectable American Joint Committee on Cancer 7th ed. stage III/IV HNSCCA. Patients were treated once weekly for six weeks with a multi-drug induction regimen of carboplatin, paclitaxel and daily lapatinib followed by transoral surgery and neck dissection. Patients were then stratified based on pathologic response to either observation or adjuvant therapy. Survival statistics and functional patient outcomes were analyzed. Specifically, peri-operative outcomes were analyzed and compared to a matched surgical cohort. RESULTS: 38/40 enrolled patients completed trial therapy. Median hospital stay was 3 days with 9/38 patients receiving a PEG (median 46 days). Median NPO status was 1 day, with a median return to a regular diet in 16 days. Mean patient weight was well preserved from pretreatment to 1 year after surgery (85.1 kg (95% CI 79.6-90.7) vs 83.1 kg (95% CI 77.7-88.6 kg) respectively). Of the 38 patients who completed trial therapy; DSS, PFS and OS were 100%, 97% and 97% respectively with median follow up of 4.9 years (3.33-7.25). CONCLUSION: Transoral surgery was feasible following this novel induction regimen with excellent peri-operative, functional and longterm survival outcomes.

Evaluation of pathologic staging using number of nodes in p16-negative head and neck cancer.

OBJECTIVES: The 8th edition AJCC staging guidelines for head and neck squamous cell carcinoma (HNSCC) recently introduced pathologic staging criteria for nodal disease among p16-positive patients. In this study we evaluate pathologic staging in p16-negative HNSCC. MATERIALS AND METHODS: We compared pathologic staging to the 7th and 8th edition AJCC staging systems using a statewide population-based cohort. All M0 p16-negative surgical patients were included. The outcome was five-year overall survival. RESULTS: Of 304 patients identified, 113 were N0, 157 had 1-4 positive nodes, and 34 had ≥4 nodes. Survival was 71% (95% CI 61-78%) with no nodes, 48% (36%-60%) for 1-4 nodes, and 24% (11 - 39%) for > 4 nodes. When compared to the AJCC systems, the pathologic staging yielded a larger total survival gradient, more montonic survival, better consistency across primary sites, and a slightly lower Bayesian information criterion (1510 vs 1538). After adjusting for disease characteristics, demographics, and tobacco use, hazard ratios for survival were similar using pathologic and AJCC criteria. CONCLUSION: In this cohort, pathological staging was more prognostic than AJCC staging. This is the first study to evaluate pathologic staging in p16-negative cancer; if these findings are verified, a universal nodal staging system could be introduced.

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication.

PURPOSE: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. PATIENTS AND METHODS: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. RESULTS: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%-84%) and 75% (51%-88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. CONCLUSIONS: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

Outcome of radioiodine therapy in thyroid cancer patients with recent contrasted computed tomography.

OBJECTIVE: To document the outcome of radioiodine therapy (RIT) in differentiated thyroid cancer (DTC) patients with recent contrasted computed tomography (CCT). METHODS: Eighteen patients with DTC and recent thyroidectomy who underwent RIT within 90 days after a CCT were included. Disease status following RIT and whether the expected response to RIT was achieved were documented. Disease status was classified into one of three categories based on the patient's thyroglobuline level, radioiodine scan (RIS), and other imaging modalities: no evidence of disease (NED), microscopic residual disease (MRD), or gross residual disease (GRD). Expected response to RIT was based on the overall interpretation of the referring physicians of follow up thyroglobuline values, RIS findings and clinical assessment as reflected in progress notes. Follow-up stimulated thyroglobuline and (or) RIS was performed on average 10.8 months after RIT (median 12 months). The last progress note reviewed was on average 33.3 months after RIT (median 31 months). RESULTS: There were 12 patients with NED, two with MRD and four with GRD. Expected response to RIT was achieved in 17 patients. In one patient, the effectiveness of RIT could not be determined. CONCLUSION: RIT in postthyroidectomy setting can be successfully performed within 90 days after CCT. Further research is needed to confirm our findings.