Predictive capacity of immune-related adverse events and cytokine profiling in neoadjuvant immune checkpoint inhibitor trials for head and neck squamous cell carcinoma.

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 were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. RESULTS: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. CONCLUSIONS: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment.

Outcomes of Head and Neck Free Tissue Transfer in Renal Failure Patients.

OBJECTIVE: To assess if there is increased risk of free flap failure in renal failure patients undergoing head and neck reconstruction. We seek to primarily assess free flap outcomes based on stages of chronic kidney disease (CKD) and secondarily determine increased risk for postoperative complications. METHODS: Retrospective chart review was performed at five tertiary care centers. Patients were identified that had undergone microvascular free flap reconstruction of the head and neck with diagnosis of renal failure, classified as Stage 3 CKD or higher. Demographic data was collected. Outcomes in the postoperative period were examined. RESULTS: Seventy-three patients met inclusion criteria. The average patient age was 69 years with a male predominance (n = 48). The majority of patients had CKD Stage 3 (n = 52). Overall flap failure rate was 12.33% (n = 9, CKD stage 3 = 7.69%, CKD stage 4 = 30%, CKD stage 5 = 18%). There was an increased risk of flap failure on multivariate analysis for CKD stage 4/5 patients when compared to CKD 3 patients (p = 0.0095). When compared to matched controls, there was an increased risk of flap failure in CKD patients (p = 0.01) as well as an increased risk of overall complications (p < 0.0001). CONCLUSIONS: Patients with CKD undergoing head and neck reconstruction are at a higher risk of flap failure and overall complications. When comparing CKD stages there may be increased risk of flap failure in later stages of CKD compared to CKD 3. Appropriate patient counseling is recommended pre-operatively in this patient population with consideration for regional flaps in the appropriate patient. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:688-694, 2024.

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.

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. Regression analysis to estimate odds ratios was performed. RESULTS: A total of 463 patients met inclusion criteria. Free flap reconstruction constituted 28.9% of patients and TORS constituted 71.1% of patients. nICI was administered in 83 of 463 (17.9%) patients. There was no statistically significant difference in surgical, medical, or overall complications between patients receiving surgery with or without nICI. In the unmatched cohort, multivariable model identified non-White race, former/current smoking history, free flap surgery, and perineural invasion as factors significantly associated with increased complications. In the matched cohort, multivariable model identified advanced age and free flap surgery as factors significantly associated with increased complications. PLAIN LANGUAGE SUMMARY: It is safe to give immunotherapy before major surgery in patients who have head and neck cancer. Advanced age, non-White race, current/former smoking, free flap surgery, and perineural invasion may be associated with increased the odds of surgical complications.

Impact of Head and Neck Cancer Diagnosis and Treatment on Patient-Partner Intimacy.

OBJECTIVE: To determine the effects of head and neck squamous cell carcinoma diagnosis and treatment on patient- and partner-perceived intimacy and to understand if a diagnosis of HPV-related head and neck squamous cell carcinoma influences patient-partner intimacy. STUDY DESIGN: Prospective observational. SETTING: Single tertiary care center. METHODS: An investigator-developed questionnaire was used to prospectively survey patients and partners in 2 groups based on human papillomavirus (HPV) status: HPV+ and HPV- at diagnosis (visit 1) and after treatment (visit 2). Surveys were scored on a 60-point scale, and results were categorized as follows: loss of intimacy (0-30), stable relationship (31-41), or improvement in intimacy (42-60). Responses of couples who participated together were assessed for concordance. Responses were considered discordant if patient and partner scores equated to different levels of perceived intimacy. Median patient and partner scores were compared via Mann-Whitney U test, and concordance was assessed with a chi-square test. RESULTS: Thirty-four patients and 28 partners completed surveys at visit 1 and 28 patients and 15 partners at visit 2. Median scores among patients and partners were similar at the first time point (HPV+, 45 vs 45, P = .64; HPV-, 42.6 vs 40.8, P = .29) and the second (HPV+, 44.5 vs 44, P = .87; HPV-, 40.2 vs 39.6, P = .90). Concordance rates between HPV+ and HPV- couples were 63% vs 44% (P = .43) for the first time point and 89% vs 50% (P = .24) for the second. CONCLUSION: Patients and partners reported stable or improved intimacy at both time points, and most couples tended to agree on their levels of perceived intimacy. A diagnosis of HPV did not appear to significantly affect intimacy scores.

Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders.

Therapeutic aryl hydrocarbon receptor (AHR) modulating agents gained attention in dermatology as non-steroidal anti-inflammatory drugs that improve skin barrier properties. By exploiting AHR's known ligand promiscuity, we generated novel AHR modulating agents by lead optimization of a selective AHR modulator (SAhRM; SGA360). Twenty-two newly synthesized compounds were screened yielding two novel derivatives, SGA360f and SGA388, in which agonist activity led to enhanced keratinocyte terminal differentiation. SGA388 showed the highest agonist activity with potent normalization of keratinocyte hyperproliferation, restored expression of skin barrier proteins and dampening of chemokine expression by keratinocytes upon Th2-mediated inflammation in vitro. The topical application of SGA360f and SGA388 reduced acute skin inflammation in vivo by reducing cyclooxygenase levels, resulting in less neutrophilic dermal infiltrates. The minimal induction of cytochrome P450 enzyme activity, lack of cellular toxicity and mutagenicity classifies SGA360f and SGA388 as novel potential therapeutic AHR ligands and illustrates the potential of medicinal chemistry to fine-tune AHR signaling for the development of targeted therapies in dermatology and beyond.

CD8+ and FoxP3+ T-Cell Cellular Density and Spatial Distribution After Programmed Death-Ligand 1 Check Point Inhibition.

OBJECTIVES: To analyze CD8+ and FoxP3+ T-cell cellular density (CD) and intercellular distances (ID) in head and neck squamous cell carcinoma (HNSCC) samples from a neoadjuvant trial of durvalumab +/- metformin. METHODS: Paired pre- and post-treatment primary HNSCC tumor samples were stained for CD8+ and FoxP3+. Digital image analysis was used to determine estimated mean CD8+ and FoxP3+ CDs and CD8+-FoxP3+ IDs in the leading tumor edge (LTE) and tumor adjacent stroma (TAS) stratified by treatment arm, human papillomavirus (HPV) status, and pathologic treatment response. A subset of samples was characterized for T-cell related signatures using digital spatial genomic profiling. RESULTS: Post-treatment analysis revealed a significant decrease in FoxP3+ CD and an increase in CD8+ CDs in the TAS between patients receiving durvalumab and metformin versus durvlaumab alone. Both treatment arms demonstrated significant post-treatment increases in ID. Although HPV+ and HPV- had similar immune cell CDs in the tumor microenvironment, HPV+ pre-treatment samples had 1.60 times greater ID compared with HPV- samples, trending toward significance (p = 0.05). At baseline, pathologic responders demonstrated a 1.16-fold greater CD8+ CDs in the LTE (p = 0.045) and 2.28-fold greater ID (p = 0.001) than non-responders. Digital spatial profiling revealed upregulation of FoxP3+ and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in the TAS (p = 0.006, p = 0.026) in samples from pathologic responders. CONCLUSIONS: Analysis of CD8+ and FoxP3+ detected population differences according to HPV status, pathologic response, and treatment. Greater CD8+-FoxP3+ ID was associated with pathologic response. CD8+ and FoxP3+ T-cell distributions may be predictive of response to immune checkpoint inhibition. CLINICALTRIALS: gov (Identifier NCT03618654). LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1875-1884, 2023.

Analysis of cost and outcomes in bony versus soft tissue midface free flap reconstruction.

BACKGROUND: Outcomes and cost of soft tissue versus bony midface free flap reconstruction (MR) with and without virtual surgical planning (VSP) were evaluated. METHODS: Retrospective review of MR including ischemic time (IT), operative duration (OD), length of stay (LOS), and total cost (TC). Eighty-one soft tissue and 76 bony MR (VSP = 23) were reviewed. RESULTS: Bony MR was used for higher complexity defects (p = 0.003) and was associated with higher IT (p < 0.001), OD (p < 0.001), LOS (p = 0.032), and TC (p < 0.001). VSP was associated with a mean 111.2 ± 37.9 minute reduction in OD (p = 0.004) compared to non-VSP bony flaps. VSP was associated with higher itemized cost, but no increase in TC (p = 0.327). CONCLUSIONS: Bony MR was used for higher complexity MR and was associated with increased TC, LOS, OD, and IT. VSP shortened OD with no significant increase in TC.

Cost of Total Intravenous Anesthesia Versus Inhalation Anesthesia in Obstructive Sleep Apnea Surgery.

OBJECTIVES: To compare cost and time spent in surgical and postoperative courses in patients with obstructive sleep apnea (OSA) undergoing surgery with either total intravenous anesthesia (TIVA) or inhalational anesthesia. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective review on patients undergoing surgery for OSA under general anesthesia from January 2019 to October 2020. Cost per service was acquired for the day of surgery. RESULTS: A total of 230 patients were included: 95 received TIVA; 135 received inhalation anesthesia. Total cost was significantly higher in the TIVA nasal surgery group by $286 (P = .035). TIVA produced significantly higher pharmacy and operating room costs across all surgeries and OSA severities. These increased costs were offset by significantly lower supply costs in upper airway stimulator (UAS, -$419.50; P = .007) and uvulopalatopharyngoplasty (UPPP, -$115.16; P = .015) patients receiving TIVA. In the TIVA cohort, there was a trend toward lower recovery room costs after UAS (-$111.09; P = .063) and nasal surgery (-$64.45; P = .096) and anesthesia costs after nasal surgery (-$36.67; P = .054). Total recovery time was reduced by 18 minutes (P = .004) for nasal surgery, 25 minutes (P = .043) for UAS, and 27 minutes (P = .147) for UPPP patients receiving TIVA. CONCLUSION: When used in an outpatient setting for patients with OSA, TIVA adds to pharmacy and operating room costs, but this is usually offset by lower supply, anesthesia, and recovery room costs. We found decreased recovery times in the TIVA cohort. TIVA has proven benefits in patient outcomes and can be cost-effective in OSA surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1487-1494, 2022.

Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma.

PURPOSE: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. RESULTS: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. CONCLUSIONS: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.

Reduced gastroesophageal reflux disease symptom severity following upper airway surgery for comorbid obstructive sleep apnea.

PURPOSE: To evaluate patient-reported quality of life pertaining to gastroesophageal reflux disease symptoms in patients undergoing upper airway surgery for comorbid obstructive sleep apnea. MATERIALS AND METHODS: A prospective survey-based study was conducted on patients with gastroesophageal reflux disease and comorbid obstructive sleep apnea receiving surgery from July 2020-December 2020. Patients completed the Gastroesophageal Reflux Disease-Health Related Quality of Life Questionnaire at two time-points: one week before surgery and at 6 months following surgery. Disease-related symptoms were rated from 0 (no symptoms) to 5 (incapacitating symptoms). Patient survey scores, demographics, medications, and sleep study parameters were collected for analysis. A p-value <0.05 indicated statistical significance. RESULTS: Twenty-two patients completed the baseline preoperative and 6-month postoperative questionnaires. Median baseline vs. 6-month survey scores significantly decreased for symptoms including heartburn in general (3.0 vs. 2.0, p = 0.006), when lying down (2.5 vs. 1.5, p = 0.046), when standing (2.0 vs 1.0, p = 0.003), following meals (2.0 vs. 2.0, p = 0.042), and cumulative survey score (15.5 vs. 11.0, p = 0.029). Heartburn altering diet or sleep, odynophagia, dysphagia, and medication burden did not change following surgery (p > 0.05). More patients were satisfied with their postoperative condition compared to baseline, however this did not reach statistical significance (40.9% vs. 18.2%, p = 0.18). CONCLUSIONS: Our results suggest that upper airway surgery to treat obstructive sleep apnea may have a positive impact on patient-reported symptoms of gastroesophageal reflux disease, and further investigation into the role of surgery in this setting for improvement of both quality of life and true clinical disease severity is merited.