Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.

Reduced Wide Local Excision Margins are Associated with Increased Risk of Relapse and Death from Merkel Cell Carcinoma.

INTRODUCTION: Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established. METHODS: WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS). RESULTS: Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). At 3 years, the DSS was 57.7%, 82.6%, and 100% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). Multivariable Cox analysis demonstrated that every 1-cm increase in WLE margins was associated with improved RRFS [hazard ratio (HR) = 0.28, 95% confidence interval (CI): 0.11-0.75], DRFS (HR 0.30, CI 0.08-0.99), DFS (HR 0.42, CI 0.21-0.86), and DSS (HR 0.16, CI 0.04-0.61). WLE and pathologic margin size were moderately-to-strongly correlated (r = 0.66). Close or positive pathologic margins (< 3 mm) were associated with reduced DRFS (HR 6.83, CI 1.80-25.9), DFS (HR 2.98, CI 1.31-6.75), and DSS (HR 3.52, CI 1.14-10.9). CONCLUSION: Reduced WLE and pathologic margins were associated with higher risk of relapse and death from MCC. Larger WLE margins are important in populations with lower rates of adjuvant radiation.

Factors associated with skin graft take in fibula and radial forearm free flap donor sites.

LEARNING OBJECTIVES: Identify factors associated with skin graft take in fibula free flaps (FFF) and radial forearm free flaps (RFFF) donor sites. STUDY OBJECTIVES: To determine which factors are associated with decreased skin graft take at the donor site in FFF and RFFF in head and neck patients. DESIGN: Retrospective Chart Review Case Series. SETTING: Multicenter Tertiary Care. METHODS: A multicenter retrospective review was performed at three institutions identifying patients who underwent free tissue transfer, specifically either FFF or RFFF, between 2007 and 2017. Patient demographics, medical history, and social history were examined including age, gender, BMI, smoking status, diabetes and preoperative anticoagulation use. Preoperative, intraoperative data, and postoperative data were also examined including tourniquet use, type of flap, area of skin graft, if the skin graft had a donor site or if it was taken from the flap, wound NPWT use, cast use, use of physical therapy, DVT prophylaxis, limb ischemia, heparin drip, and postoperative aspirin use. Statistical analysis was used to determine which factors were significantly associated with skin graft take. RESULTS: 1415 patients underwent a forearm or fibula flap and 938 patients underwent split-thickness skin graft. Of these, 592 patients had sufficient information and were included in the final analysis. There were 371 males and 220 females. The average age was 55.7. Complete skin graft take was seen in 480 patients (81.1%). On univariate analysis, patients with diabetes (p = .003), type of flap (fibula p < .001), skin graft area (p = .006), tourniquet use (p = .003), DVT prophylaxis (p = .008) and casting (p = .003) were significantly associated with decreased skin graft take rate. In a multivariate analysis, diabetes (OR 2.17 (95%CI 1.16-3.98)), fibula flaps (OR 2.86 (95%CI 1.79-4.76)), an increase in skin graft area (OR 1.01 (95%CI 1.01-1.01)), post-operative aspirin (OR 2.63 (95%CI 1.15-5.88), and casting (OR 2.94 (95%CI 1.22-7.14)) were associated with poor rates of skin graft take. CONCLUSION: Several factors affect skin graft take rate and should be considered when performing a skin graft for a donor site defect.

Tourniquet use and factors associated with hematoma formation in free tissue transfer.

PURPOSE: Our objective was to understand which variables are associated with hematoma formation at both the donor and recipient sites in head and neck free tissue transfer and if hematoma rates are affected by tourniquet use. METHODS: Patients were identified who underwent free tissue transfer at three institutions, specifically either a radial forearm free flap (RFFF) or a fibula free flap (FFF), between 2007 and 2017. Variables including use of tourniquet, anticoagulation, treatment factors, demographics, and post-operative factors were examined to see if they influenced hematoma formation at either the free tissue donor or recipient site. RESULTS: 1410 patients at three institutions were included in the analysis. There were 692 (49.1%) RFFF and 718 (50.9%) FFF. Tourniquets were used in 764 (54.1%) cases. There were 121 (8.5%) hematomas. Heparin drips (p < .001) and DVT prophylaxis (p = .03) were significantly associated with hematoma formation (OR 95% CI 12.23 (4.98-30.07), 3.46 (1.15-10.44) respectively) on multivariable analysis. CONCLUSIONS: Heparin Drips and DVT prophylaxis significantly increased hematoma rates in free flap patients while tourniquets did not affect rates of hematoma.

Management of cervical esophageal and hypopharyngeal perforations.

PURPOSE: Evidence is limited for outcomes of surgical versus conservative management for patients with cervical esophageal or hypopharyngeal perforations. METHODS: Patients with cervical esophageal or hypopharyngeal perforations treated between 1994 and 2014 were identified using an institutional database. Outcomes were compared between patients who underwent operative drainage and those who had conservative management with broad-spectrum antibiotics and withholding oral intake. RESULTS: Twenty-eight patients were identified with hypopharyngeal or cervical esophageal perforations, mostly due to iatrogenic (nasogastric tube placement, endoscopy, endotracheal intubation) injuries (68%). Fourteen were treated initially with conservative management and 14 with initial surgery. Six patients failed conservative treatment and two patients failed surgical treatment. Patients managed conservatively who had eaten between injury and diagnosis (p=0.003), those who had 24 hours or more between the time of injury and diagnosis (p=0.026), and those who showed signs of systemic toxicity (p=0.001) were significantly more likely to fail conservative treatment and require surgery. No variables were significant for treatment failure in the surgical group. Of the 20 patients who ultimately underwent a surgical procedure, two required a second procedure. CONCLUSION: Patients who have eaten between the time of perforation and diagnosis, have 24 hours or more between injury and diagnosis, and those that show signs of systemic toxicity are at higher risk of failing conservative management and surgical drainage should be considered. For patients without these risk factors, a trial of conservative management can be attempted.

Reconstruction of composite oral cavity defects with temporalis flaps after prior treatment.

BACKGROUND: Reconstruction of composite oral cavity defects in the setting of prior surgery and radiotherapy presents a significant challenge. Although free tissue transfer has shown success in such situations, it is not without considerable risk. Regional pedicled flaps may provide a more suitable alternative. In certain patients, however, severe soft tissue fibrosis makes more conventional regional flaps impractical or impossible. In these situations, temporalis flaps (temporalis muscle and temporoparietal fascia flaps) are versatile options for coverage of complex defects. OBJECTIVE: To report our experience using pedicled temporalis flaps for reconstruction of composite oral cavity defects in patients with significant co-morbidities and prior treatment. METHODS: Three patients were identified and their medical records were reviewed. Their clinical courses and functional outcomes are described. We include a discussion of the operative technique and relevant literature. RESULTS: All patients had previously undergone extensive treatment. One patient needed reconstruction after resection of a third head and neck malignancy and two patients presented for treatment of osteoradionecrosis. A temporalis muscle flap was used to reconstruct composite oral cavity defects in two patients and a combined temporalis muscle and temporoparietal fascia flap was used for independent defects in one patient. All flaps survived. Functional status and pain improved or stabilized in all patients. There were no major or minor complications. CONCLUSION: In previously treated fields, where more conventional flaps are impractical, temporalis flaps are a suitable alternative to achieve a stable healing wound and prevent worsening of functional status.

A hybrid epithelial/mesenchymal state in head and neck cancer: A biomarker for survival with differential prognosis by self-reported race.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cause of cancer-related mortality, with racial disparities amplifying the challenges in treatment. Although the relationship between hybrid epithelial/mesenchymal (E/M) states and tumor progression is of interest, no studies have characterized the clinical relevance of hybrid E/M states in head and neck cancer outcomes among self-reported racial cohorts. METHODS: Given the overlap in gene expression between hybrid E/M malignant cells and cancer-associated fibroblasts, we utilized deconvolution of bulk RNA sequencing data from oral cavity and laryngeal squamous cell carcinoma tumors from The Cancer Genome Atlas. We utilized our previously collected single-cell profiles to generate inferred malignant profiles and then scored these for hybrid E/M. We then conducted a survival analysis on overall and disease-free survival among self-reported Black and White Americans. FINDINGS: The hybrid E/M state was differentially associated with head and neck cancer survival by self-reported race and ethnicity, with a stronger association in non-Hispanic Black patients. Black patients with a high hybrid E/M score had a higher risk of death or recurrence (hazard ratio [HR]: 4.18 [95% confidence interval (CI): 2.06, 8.49]) than White patients with a high hybrid E/M score (HR: 1.58 [95% CI: 1.11, 2.26]). CONCLUSION: Our results suggest a complex interplay of social structure, racism, and genetic diversity. We implore researchers to consider the social and biological context contributing to disparities. FUNDING: A.L.M. received support from the National Institute of Minority Health and Health Disparities (K01MD013897 [principal investigator (PI), A.L.M.]). S.V.P. received support from the National Institute of Dental and Craniofacial Research (R01DE032865 [PI, S.V.P.] and R01DE032371 [PI, S.V.P.]).

Trends in ototoxicity monitoring among cisplatin-treated patients with cancer.

PURPOSE: This study aims to characterize patterns in ototoxicity monitoring and identify potential barriers to audiologic follow-up. METHODS: We performed a single-institution retrospective cohort study on adult (≥ 18 years old) cancer patients treated with cisplatin from January 2014 to September 2021. Our primary outcomes were rates of baseline and post-treatment audiograms at the following time points: 3, 6, 12, and greater than 12 months. Time-to-event analyses were performed to describe additional insights to ototoxicity monitoring patterns. RESULTS: Nine hundred fifty-five patients with cancer were included for analysis. The most common primary cancer sites were head and neck (64%), followed by cervical (24%). Three hundred seventy-three patients (39%) underwent baseline audiometric assessment, 38 patients (4%) received audiologic evaluation during chemotherapy, and 346 patients (36%) obtained at least one post-treatment audiogram. Audiologic follow-up was greatest within 3 months of completing chemotherapy (26%), but this tapered dramatically to less than 10% at every other post-treatment time point. Patients with head and neck cancer achieved higher rates of audiologic follow-up at every time point than patients with non-head and neck cancer except for during treatment. CONCLUSIONS: Ototoxicity monitoring is an inconsistent practice, particularly during chemotherapy and for long-term surveillance of hearing loss. Patients with non-head and neck cancer may be at increased risk for loss of audiologic follow-up. IMPLICATIONS FOR CANCER SURVIVORS: Cisplatin ototoxicity is a common occurrence that can be effectively managed with auditory rehabilitation. Therefore, referrals to audiology and counseling on treatment-related ototoxicity are recommended throughout chemotherapy and cancer survivorship.

Race and socioeconomic status interact with HPV to influence survival disparities in oropharyngeal squamous cell carcinoma.

BACKGROUND: HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable prognosis, yet patients of color and low socioeconomic status (SES) continue to experience inferior outcomes. We aim to understand how the emergence of HPV has impacted race and SES survival disparities in OPSCC. METHODS: A retrospective cohort of 18,362 OPSCC cases from 2010 to 2017 was assembled using the SEER (Surveillance, Epidemiology, and End Results) database. Cox proportional regression and Fine and Gray regression models were used to calculate hazard ratios (HRs) adjusting for race, SES, age, subsite, stage, and treatment. RESULTS: Black patients had lower overall survival than patients of other races in HPV-positive and HPV-negative OPSCC (HR 1.31, 95% CI 1.13-1.53 and HR 1.23, 95% CI 1.09-1.39, respectively). Higher SES was associated with improved survival in all patients. Race had a diminished association with survival among high SES patients. Low SES Black patients had considerably worse survival than low SES patients of other races. CONCLUSION: Race and SES interact variably across cohorts. High SES was protective of the negative effects of race, although there remains a disparity in outcomes among Black and non-Black patients, even in high SES populations. The persistence of survival disparities suggests that the HPV epidemic has not improved outcomes equally across all demographic groups.

Audiologic Follow-up in Patients With Head and Neck Cancer Treated With Cisplatin and Radiation.

OBJECTIVES: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center. METHODS: We performed a single-institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post-treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow-up after pre-treatment evaluation. RESULTS: Two hundred ninety-four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post-treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow-up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow-up (aOR = 7.18, 95% CI = 2.75-19.90; aOR = 1.96, 95% CI = 1.02-3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one. CONCLUSIONS: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow-up rates for at least one post-treatment audiogram. However, follow-up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long-term audiologic follow-up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:3161-3168, 2023.

A Multi-institutional Analysis of Late Complications in Scapula, Fibula, and Osteocutaneous Radial Forearm Free Flaps.

OBJECTIVES: (1) Evaluate the association of flap type with late complications in patients undergoing osseous head and neck reconstruction with the fibula free flap (FFF), osteocutaneous radial forearm free flap (OCRFFF), and scapula free flap (SFF). (2) Compare the prevalence of late complications based on minimum duration of follow-up. STUDY DESIGN: Retrospective cohort study. SETTING: Multiple academic medical centers. METHODS: Patients undergoing FFF, OCRFFF, or SFF with ≥6-month follow-up were stratified by type of flap performed. The association of flap type with late complications was analyzed via univariable and multivariable logistic regression, controlling for relevant clinical risk factors. Additionally, the frequency of late complications by minimum duration of follow-up was assessed. RESULTS: A total of 617 patients were analyzed: 312 (50.6%) FFF, 230 (37.3%) OCRFFFF, and 75 (12.2%) SFF. As compared with the SFF, the FFF (adjusted odds ratio [aOR], 3.05; 95% CI, 1.61-5.80) and OCRFFF (aOR, 2.17; 95% CI, 1.12-4.22) were independently associated with greater odds of overall late recipient site wound complications. The SFF was independently associated with the lowest odds of hardware exposure when compared with the FFF (aOR, 2.61; 95% CI, 1.27-5.41) and OCRFFF (aOR, 2.38; 95% CI, 1.11-5.12). The frequency of late complications rose as minimum duration of follow-up increased until plateauing at 36 months. CONCLUSIONS: This multi-institutional study suggests that the long-term complication profile of the SFF and OCRFFF compares favorably to the FFF. The SFF may be associated with the fewest overall late recipient site complications and hardware exposure, while the FFF may be associated with the most of these 3 options.

Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. EXPERIMENTAL DESIGN: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. RESULTS: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. CONCLUSIONS: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Perioperative Outcomes in Patients Who Underwent Fibula, Osteocutaneous Radial Forearm, and Scapula Free Flaps: A Multicenter Study.

Importance: Studies comparing perioperative outcomes of fibula free flaps (FFFs), osteocutaneous radial forearm free flaps (OCRFFFs), and scapula free flaps (SFFs) have been limited by insufficient sample size. Objective: To compare the perioperative outcomes of patients who underwent FFFs, OCRFFFs, and SFFs. Design, Setting, and Participants: This cohort study assessed the outcomes of 1022 patients who underwent FFFs, OCRFFFs, or SFFs for head and neck reconstruction performed at 1 of 6 academic medical centers between January 2005 and December 2019. Data were analyzed from September 17, 2021, to June 9, 2022. Main Outcomes and Measures: Patients were stratified based on the flap performed. Evaluated perioperative outcomes included complications (overall acute wound complications, acute surgical site infection [SSI], fistula, hematoma, and flap failure), 30-day readmissions, operative time, and prolonged hospital length of stay (75th percentile, >13 days). Patients were excluded if data on flap type or clinical demographic characteristics were missing. Associations between flap type and perioperative outcomes were analyzed using logistic regression, after controlling for other clinically relevant variables. Adjusted odds ratios (aORs) with 95% CIs were generated. Results: Perioperative outcomes of 1022 patients (mean [SD] age, 60.7 [14.5] years; 676 [66.1%] men) who underwent major osseous head and neck reconstruction were analyzed; 510 FFFs (49.9%), 376 OCRFFFs (36.8%), and 136 SFFs (13.3%) were performed. Median (IQR) operative time differed among flap types (OCRFFF, 527 [467-591] minutes; FFF, 592 [507-714] minutes; SFF, 691 [610-816] minutes). When controlling for SSI, FFFs (aOR, 2.47; 95% CI, 1.36-4.51) and SFFs (aOR, 2.95; 95% CI, 1.37-6.34) were associated with a higher risk of flap loss than OCRFFFs. Compared with OCRFFFs, FFFs (aOR, 1.77; 95% CI, 1.07-2.91) were associated with a greater risk of fistula after controlling for the number of bone segments and SSI. Both FFFs (aOR, 1.77; 95% CI, 1.27-2.46) and SFFs (aOR, 1.68; 95% CI, 1.05-2.69) were associated with an increased risk of 30-day readmission compared with OCRFFFs after controlling for Charlson-Deyo comorbidity score and acute wound complications. Compared with OCRFFFs, FFFs (aOR, 1.78; 95% CI, 1.25-2.54) and SFFs (aOR, 1.96; 95% CI, 1.22-3.13) were associated with a higher risk of prolonged hospital length of stay after controlling for age and flap loss. Conclusions and Relevance: Findings of this cohort study suggest that perioperative outcomes associated with OCRFFFs compare favorably with those of FFFs and SFFs, with shorter operative times and lower rates of flap loss, 30-day readmissions, and prolonged hospital length of stay. However, patients undergoing SFFs represented a more medically and surgically complex population than those undergoing OCRFFFs or FFFs.

Factors predicting pharyngocutaneous fistula in patients after salvage laryngectomy for laryngeal malignancy - A multicenter collaborative cohort study.

OBJECTIVES: Pharyngocutaneous fistula (PCF) is a major morbidity of salvage total laryngectomy (TL). Understanding the factors predicting PCF is fundamental to managing laryngeal cancer. We aim to assess factors associated with PCF following salvage TL in a multicenter, international retrospective cohort study of academic centers in the US and Canada. RESULTS: In total, 550 patients post-salvage TL were identified (mean [SD; range] age, 64 [10.4; 32-90] years; 465 [85 %] male and 84 [15 %] female) between 2000 and 2014. Rate of PCF was 23 % (n = 127) with median time to PCF of 2.9 weeks. Surgical management of PCF was required in 43 % (n = 54) while 57 % (n = 73) required wound care alone. Rates of PCF differed by primary treatment modality [radiation, 20 % (n = 76); chemoradiation, 27 % (n = 40); not available (n = 6)] and use of vascularized tissue in pharyngeal closure [free/regional flap, 18 % (n = 25); no vascularized tissue/primary closure, 24 % (n = 98); not available (n = 4)]. There was no statistically significant association between PCF and treatment with chemoradiation (HR, 1.32; 95 % CI, 0.91-1.93, p = 0.14) or lack of vascularized tissue reconstruction (HR, 1.41, 95 % CI 0.91-2.18, p = 0.12). Significant association between PCF and advanced stage (T3 or T4), positive margin, close margin (<5mm), lymphovascular invasion and pre-operative tracheostomy were identified on univariable analysis. Positive surgical margin (HR, 1.91; 95 % CI, 1.11 to 3.29) was the only significant association on multivariable analysis. CONCLUSION: We highlight positive surgical margin as the only variable significantly associated with increased risk of PCF following salvage TL on multivariable analysis in a large cohort across several major head and neck oncology centers.

Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival.

BACKGROUND: One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established. MATERIALS AND METHODS: 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01-0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11-0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09-0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06-0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01-0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04-0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02-0.33, p < 0.001), and DSS (HR: 0.21, CI: 0.05-0.89, p = 0.03). CONCLUSION: rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease.

The prognostic significance of race in nasopharyngeal carcinoma by histological subtype.

BACKGROUND: Race has been shown to have variable prognostic importance in nasopharyngeal carcinoma (NPC). However, previous studies are limited by a lack of comprehensive treatment, epidemiologic, and comorbidity data. METHODS: This was a retrospective cohort study utilizing the National Cancer Database from 2004 to 2016. Multivariable Cox proportional hazards regressions were used to calculate adjusted hazard ratios (aHR) for overall survival. RESULTS: A cohort of 9995 patients met inclusion and exclusion criteria. Race, insurance, comorbidity, treatment, stage, age, and histology were independent prognosticators. Among patients with keratinizing NPC, Asians and Hispanics had superior survival (aHR 0.58 [95% confidence interval (CI) 0.48-0.69], aHR 0.76 [95% CI 0.61-0.96]) compared to white patients. Among patients with non-keratinizing differentiated NPC, Asians and black patients had improved survival (aHR 0.71 [95% CI 0.56-0.91], aHR 0.72 [95% CI 0.54-0.95]) compared to white patients. Race was not prognostic in non-keratinizing undifferentiated NPC. CONCLUSION: The prognostic significance of race varies across histological subtypes of NPC.

A Comprehensive Analysis of Complications of Free Flaps for Oromandibular Reconstruction.

OBJECTIVES/HYPOTHESIS: To determine the frequency and management of short- and long-term complications related to oromandibular free flap reconstruction and identify potentially predictive factors of hardware complications. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective database from chart review was formed consisting of 266 oromandibular free flap reconstructions performed at a single institution over a 15-year period. Data were collected on demographics, surgical treatment, complications, and management of complications. Subgroup univariate and multivariate analyses were performed to compare patients with hardware complications and those without. RESULTS: Eighty-one of 266 patients (30.5%) that underwent oromandibular reconstruction had an early complication (<4 weeks after surgery), and the most common complications were cervical wound dehiscence (11.3%) and fistulas (9.40%). Eighty of 266 patients (30.1%) had a long-term complication (>4 weeks after surgery) and the most common complication was plate exposure (26.7%). Univariate and multivariate analyses showed no association between whether there was hardware extrusion and fibula versus scapula, smoking history, virtual surgical planning (VSP), and dental implantation (P > .05). Only early complications (OR, 3.59, 95% CI, 1.83-7.05, P < .01) and patients undergoing oromandibular reconstruction for osteoradionecrosis (OR, 2.26, 95% CI, 1.10-4.64, P = .03) were strongly and independently associated with subsequent hardware extrusion on univariate analysis. CONCLUSIONS: Both short- and long-term complications are common after oromandibular reconstruction. The most important predictive factor for a late complication is an early complication and prior radiation. There was no difference of plate complications among the various free flap types. Dental implantation and use of VSP were not associated with hardware complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1997-2005, 2021.

The role of age in treatment decisions for oral cavity squamous cell carcinoma: Analysis of the National Cancer Database.

BACKGROUND: The number of elderly patients with oral squamous cell carcinoma (OCSCC) is increasing as the elderly population increases. Unfortunately, evidence to guide the management of these patients is lacking. METHODS: Patients with OCSCC identified from the National Cancer Database (NCDB) were stratified into age-based cohorts. Demographics, comorbidities, and treatment patterns were analyzed. Patients were stratified into early stage (Stage I/II) and advanced stage (Stage III/IV) disease. The likelihood of receiving multimodality therapy by age was calculated using multinomial logistic regression for each stratum while controlling for potential confounders. Cox proportional hazard regression was used to calculate 5-year mortality risk while controlling for potential confounders. RESULTS: Surgery alone or palliative options were offered to older patients more frequently. After controlling for confounders, older patients were less likely to receive multimodality therapy for both early stage and advanced stage disease. Patients with advanced disease across all age cohorts had improved 5-year survival with surgery and adjuvant therapy. CONCLUSION: Our analyses suggest that elderly patients have unique demographic and pathologic features. They frequently receive less treatment than similarly staged younger patients, yet they benefit from multimodality therapy when feasible. These data suggest an urgent need to critically appraise the care of elderly OCSCC patients within the broader context of their individual comorbidity burden, functional status, and treatment goals.