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ObjectiveBioselection to assess tumor response after induction chemotherapy has been introduced as an alternative treatment strategy to total laryngectomy for patients with advanced larynx squamous cell carcinoma (LSCC). Tumor-infiltrating lymphocytes (TILs) have proven to serve as prognostic biomarkers in head and neck cancer but have not been evaluated as a way to select patients for treatment paradigms. The aim of this study is to evaluate the role of pretreatment TILs in patients with advanced LSCC undergoing the bioselection paradigm.Study designRetrospective study.SettingTertiary care hospital.MethodsPatients with advanced LSCC treated with bioselection and available tissue were included (N = 76). Patients were stratified into CD8-low and CD8-high cohorts by using the median TIL count. Kaplan-Meier survival analysis and multivariate cox regression were performed with SPSS version 26 (IBM).ResultsAfter controlling for tobacco use, tumor site, and stage, a high CD8 TIL count was an independent predictor of improved 5-year disease-specific survival (hazard ratio, 0.17 [95% CI, 0.03-0.84]; P = .03). CD8 TIL counts did not predict response to induction chemotherapy; however, subgroup analysis of patients treated with chemoradiation therapy revealed that CD8 TIL count was significantly associated with degree of response (P = .012).ConclusionThese findings support prior data published by our group showing that TILs are predictive of disease-specific survival in patients with head and neck cancer. CD8 TIL counts were significantly associated with degree of clinical response after induction chemotherapy. These results suggest that pretreatment assessment of tumor-infiltrating CD8 cells could be useful in selecting patients.

BACKGROUND:Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. METHODS:A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. RESULTS:PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). CONCLUSIONS:PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.

BackgroundRecurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC.MethodsTissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC.ResultsHigh tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC.ConclusionsAn immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

BACKGROUND:We sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene-specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA). METHODS:The tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene-specific alteration frequencies were compared (Chi-Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform. RESULTS:Persistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53. CONCLUSIONS:Our results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.

BACKGROUND:Patients undergoing salvage laryngectomy are predisposed to radiation-induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established. METHODS:A single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed. RESULTS:The fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8-7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6-49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH. CONCLUSION:Postoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression.

Objective: We evaluated vessel counts in the pharyngeal mucosal margins of patients who underwent salvage laryngectomy to establish whether mucosal vascularity might predict fistula risk. Study Design: Retrospective cohort. Setting: Tertiary Medical Center. Methods: Patients who underwent salvage total laryngectomy at our institution between 1999 and 2015 were identified. Pharyngeal mucosal margins from laryngectomy specimens were evaluated histologically for each patient, and vessel counts were performed on 5 ×10 images. The primary outcome measure was fistula within 30 days of surgery and mean vessel counts were assessed as the principle explanatory variable. Results: Seventy patients were included and 40% developed a postoperative fistula. There was a large difference in the mean vessel count in patients who did develop fistula (48.6 vessels/×10 field) compared to those who did not (34.7 vessels/×10 field). A receiver operative characteristic curve found that a cutoff value of 33.9 vessels/×10 field provided a sensitivity of 75% and specificity of 62% to predict the likelihood of fistula occurrence (area under the curve = 0.71, 95% confidence interval [CI]: 0.59‐0.83). In a binary logistic regression, patients with vessel counts greater than 33.9 had a 5‐fold increased risk of developing fistula (95% CI: 1.8‐16.45). Histologically, vessels in the pharyngeal mucosa of patients who developed fistulas were more disorganized. Conclusion: After salvage laryngectomy, patients with higher mean mucosal margin vessel counts are at increased risk of fistula. The mechanism is unknown, but the disorganization of the vasculature may contribute to poor wound healing. Vessel counting may allow for fistula risk stratification and guide postoperative care. [ABSTRACT FROM AUTHOR]

Objective: Traditional hospital accounting fails to provide an accurate cost of complex surgical care. Here we describe the application of time‐driven activity‐based costing (TDABC) to characterize costs of head and neck oncologic procedures involving free tissue transfer. Study Design: Retrospective cohort study. Setting: Single tertiary academic medical center. Methods: An analysis of head and neck oncologic procedures involving microvascular free flap reconstruction from 2018 to 2020 (n = 485) was performed using TDABC methodology to measure cost across operative case and postoperative admission, using quantity of time and cost per unit of each resource to characterize resource utilization. Univariate and generalized linear mixed models were used to examine associations between patient and hospital characteristics and cost of care delivery. Results: The total cost of care delivery was $41,905.77 ± 21,870.27 with operating room (OR) supplies accounting for only 10% of the total cost. Multivariable analyses identified significant cost drivers including operative time, postoperative length of stay, number of return trips to the OR, postoperative complication, number of free flaps performed, and patient transfer from another hospital or via emergency department admission (P <.05). Conclusion: Operative time and postoperative length of stay, but not operative supplies, were primary drivers of cost of care for head and neck oncology cases involving free tissue transfer. TDABC offers granular cost characterization to inform cost optimization through unused capacity identification and postoperative admission efficiencies. [ABSTRACT FROM AUTHOR]

Objective: Gaps in gender‐based equity persist in academic otolaryngology. Here we present a needs‐based assessment of otolaryngology faculty and trainees regarding facilitators and barriers to professional satisfaction and career development in academic medicine. Methods: A qualitative study of otolaryngology faculty, trainees, and administrators who identify as women at an academic tertiary care center was performed from 2020 to 2021 using focus groups and semi‐structured interviews. Five confidential, virtual focus group sessions moderated by a third‐party executive coach were audio‐taped, transcribed, and reviewed for thematic content. Results: Of 48 women invited, 77% participated (18 faculty/administrative leaders, 10 residents/fellows, 4 audiologists). Participants noted direct patient care, support from colleagues who identify as women, and the transition to virtual meetings as facilitators of current professional satisfaction. Five themes emerged as barriers to workplace satisfaction and career development including (1) limited professional schedule flexibility, (2) competing commitments such as childcare exacerbated by pandemic, (3) lack of visible departmental leadership who identify as women, (4) perceived lack of organic sponsorship within subspecialty divisions, and (5) frequent identity‐associated microaggressions from patients and staff outside the department. Strategies identified for improving gender‐based equity included (1) promoting department‐wide awareness of workplace gender‐based differences, (2) implicit bias training within established programming such as grand rounds conferences, and (3) novel faculty programming such as leadership development training and formal junior faculty mentorship. Conclusion: Confidential needs‐based assessment of otolaryngology faculty and trainees identified both persistent gaps and strategies to enhance recruitment, support career development, and grow professional satisfaction of women within academic otolaryngology. Level of Evidence: 3. [ABSTRACT FROM AUTHOR]

Importance: Previous work demonstrated postoperative hypothyroidism adversely affects wound healing in salvage laryngectomy. Currently, no studies have evaluated the association between wound healing and hypothyroidism in patients undergoing salvage oropharyngectomy. Objective: The primary objective was studying hypothyroidism and other factors associated with oropharyngocutaneous fistula development and fistula requiring reoperation within 30 days after salvage oropharyngectomy. Design: Retrospective cohort study. Setting: Tertiary academic center. Participants: All patients who underwent salvage oropharyngectomy for recurrent or second primary oropharyngeal squamous cell carcinoma between 2001 and 2017 after radiation or chemoradiation. Patients with no preoperative thyroid-stimulating hormone (TSH) values were excluded. Exposures: Salvage oropharyngectomy for recurrent or second primary oropharyngeal squamous cell carcinoma. Main Outcomes Measures: The principle explanatory variable was postoperative hypothyroidism, defined as TSH greater than 5.5 mIU/L. Univariate, bivariate, and binary logistical regression multivariate analysis was performed. Results: Fifty-three patients met inclusion criteria, 37.7% of patients developed hypothyroidism, 18.9% developed a fistula, and 9.4% required an operation to manage the fistula. Postoperative fistula rate was 35% among hypothyroid patients, which was significantly greater than among euthyroid patients (9.1%; P =.03). A fistula requiring reoperation occurred in 20% of hypothyroid patients compared with that of euthyroid patients (3%; P =.061). In a multivariate analysis, postoperative hypothyroid patients were at a 9.5-fold increased risk of developing a fistula [95% confidence interval (CI) 1.6-57.0, P =.013]. Additionally, postoperative hypothyroid patients were at 13.6-fold increased risk for development of a fistula requiring reoperation (95% CI 1.2-160.5, P =.038). Conclusions and Relevance: Postoperative hypothyroidism in patients who underwent salvage oropharyngectomy can predict fistula development and fistula requiring operative management. This study supports the treatment of hypothyroidism after surgery to reduce wound complications. [ABSTRACT FROM AUTHOR]