Obesity and Survival After Immune Checkpoint Inhibition for Head and Neck Squamous Cell Carcinoma.

Importance: For patients treated with immune checkpoint inhibitors (ICIs), recent data suggest that obesity has a beneficial effect on survival outcomes in various cancer types. Reports on this association in head and neck cancer are limited. Objectives: To compare overall survival (OS) to 5 years and functional outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with ICIs based on pretreatment body mass index (BMI). Design, Setting, and Participants: This retrospective population-based cohort study used data obtained from the TriNetX Global Collaborative Network database to identify patients with HNSCC who received ICI treatment between January 1, 2012, and December 31, 2023, resulting in a total of 166 patients (83 with BMI of 20.0-24.9 [normal BMI] and 83 with BMI of ≥30.0 [obesity BMI]) after propensity score matching (PSM) for pretreatment medical comorbidities and oncologic staging. Exposure: Normal BMI vs obesity BMI. Main Outcomes and Measures: Overall survival and functional outcomes (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) were measured to 5 years after ICI treatment and compared between patients with obesity BMI and normal BMI. Additional analyses compared OS and functional outcomes in the cohort with normal BMI and cohorts with overweight BMI (25.0-29.9) and underweight BMI (<20.0). Results: Among the 166 patients included in the PSM analysis (112 men [67.1%]; mean [SD] age, 62.9 [15.4] years), obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.54 [95% CI, 0.31-0.96]), 3 years (HR, 0.56 [95% CI, 0.38-0.83]), and 5 years (HR, 0.62 [95% CI, 0.44-0.86]) after ICI treatment, compared with patients with normal BMI. Obesity BMI was also associated with decreased risk of gastrostomy tube dependence at 6 months (odds ratio [OR], 0.41 [95% CI, 0.21-0.80]), 1 year (OR, 0.41 [95% CI, 0.21-0.78]), 3 years (OR, 0.35 [95% CI, 0.18-0.65]), and 5 years (OR, 0.34 [95% CI, 0.18-0.65]). Obesity was also associated with decreased risk for tracheostomy dependence at 1 year (OR, 0.52 [95% CI, 0.28-0.90]), 3 years (OR, 0.45 [95% CI, 0.45-0.90]), and 5 years (OR, 0.45 [95% CI, 0.45-0.90]). There were no differences in rates of dysphagia or immune-related adverse events between cohorts at any points. Conclusions and Relevance: Using population-level data for patients with HNSCC treated with ICIs, these results suggest that having obesity was associated with improved 6-month, 3-year, and 5-year OS compared with having normal BMI. Additionally, obesity was associated with decreased gastrostomy and tracheostomy tube dependence compared with normal BMI. Further investigation is required to understand the mechanism of these findings.

Microvascular reconstruction of midface osteoradionecrosis.

BACKGROUND: Head and neck osteoradionecrosis (ORN) of the midface requiring free flap (FF) reconstruction is uncommon. This multi-institutional study was designed to review outcomes for this rare patient population. METHODS: Retrospective multi-institutional review of FF reconstruction for midface ORN (2005-2022; n = 54). RESULTS: The FF survival rate was 87% (n = 54). Patients were less likely to be tolerating a regular diet at 3 months postoperative if they had a preoperative history of prior head and surgery (80% vs. 95%; p = 0.02), a pathologic fracture (50% vs. 90%; p = 0.04), exposed bone intraorally (43% vs. 94%; p = 0.002), or a fistula (67% vs. 96%; p = 0.03). Mean albumin was higher in patients whose FF survived (3.6 ± 0.5 vs. 2.7 ± 1.4; p = 0.03). Patients with low prealbumin were more likely to undergo a hematoma evacuation (27% vs. 0%; p = 0.02). CONCLUSION: In this series of midface ORN requiring FF reconstruction preoperative nutritional status impacted postoperative complications. Preoperative occurrence of a fistula, pathologic fracture, and intraoral bone exposure correlated with decreased tolerance of a regular diet following reconstruction.

Modified Frailty Index Associates With Transoral Robotic Surgery Complications and Survival: A National Database Study.

OBJECTIVE: The modified frailty index (mFI-5) is a National Surgical Quality Improvement Program-derived 5-factor index that has been proven to reflect frailty and predict morbidity and mortality. We hypothesize that mFI-5 is a valid predictive measure in the transoral robotic surgery (TORS) population. METHODS: Retrospective study utilizing the TriNetX US-collaborative health records network querying for TORS patients. Cohorts were stratified by mFI-5 score which uses five ICD-10 codes: nonindependent functional status, hypertension, obstructive respiratory disease, heart failure, and diabetes mellitus. Cohorts were matched by age using propensity score matching. Outcome measures included survival, infection, pneumonia, tracheostomy dependence, and percutaneous endoscopic gastrostomy dependence. Reported odds ratios were normalized to mFI-5 = 0. RESULTS: A total of 9,081 patients were included in the final analysis. Greater mFI-5 scores predicted decreased survival and increased incidence of postoperative infection and pneumonia. Odds of 5-year mortality were 1.93 (p = 0.0003) for mFI-5 = 2 and 1.90 (p = 0.0002) for mFI-5 = 3. Odds of 2-year mortality were 1.25 (p = 0.0125) for mFI-5 = 1, 1.58 (p = 0.0002) for mFI-5 = 2, and 1.87 (p = 0.003) for mFI-5 = 3. Odds of postoperative infection were 1.51 (p = 0.02) for mFI-5 = 2 and 1.78 (p = 0.05) for mFI-5 = 3. Two-year odds of developing pneumonia were 1.69 (p = 0.0001) for mFI-5 = 2 and 2.84 (p < 0.0001) for mFI-5 = 3. Two-month odds of pneumonia were 1.50 (p = 0.0259) for mFI-5 = 2 and 2.55 (p = 0.0037) for mFI-5 = 3. mFI-5 = 4 or 5 had too few patients to analyze. Using polynomial regression to model age versus incident 5-year post-TORS death (R2 = 0.99), mFI-5 scores better predicted survival than age alone. CONCLUSION: This study demonstrates that mFI-5 predicts mortality, pneumonia, and postoperative infection independently of age. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Safety of Ambulatory Surgery For Obstructive Sleep Apnea: A Retrospective Review.

OBJECTIVE: Assess the safety of ambulatory surgery performed for obstructive sleep apnea. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. METHODS: Demographic data including age, gender, race, body mass index, insurance status, socioeconomic status, and distance traveled for surgery was collected, as well as comorbidities, and apnea-hypopnea index (AHI). Outcome variables included continuous positive airway pressure reinitiation, planned/unplanned postoperative admission, emergency department (ED) presentation, or readmission within 7 and 14 days of surgery. RESULTS: A total of 601 patients were included, who underwent sleep surgery between 2017 and 2022. The median age was 55 years [interquartile range: 19]. A total of 437 patients (73%) were male, 502 (84%) were Caucasian, and the median distance traveled was 20 miles [27]. The median AHI was 27.1 [26]. A total of 286 hypoglossal nerve stimulators, 12 tonsillectomies, 160 expansion sphincteroplasties (ESP), and 201 nasal procedures were performed. There were 9 (1%) planned and 23 (4%) total admissions postoperatively. Sixteen patients (2%) presented to ED within 7 days, and 22 (3%) within 14 days. Nine (1%) were readmitted within 7 days, and 12 (2%) within 14 days. There were significantly more planned admissions, unplanned admissions, ED presentations, and readmissions for ESP. There were no significant differences in demographic or clinical data between patients who underwent single versus multiple surgeries. CONCLUSION: Outpatient sleep surgery is generally safe. Close postoperative monitoring is necessary and overnight observation should be considered in those with very severe sleep apnea and/or significant comorbidities. The distance a patient travels should also be considered for overnight admission.

A novel staging system to consolidate silent sinus syndrome and chronic maxillary atelectasis: A systematic review and case series.

KEY POINTS: Silent sinus syndrome (SSS) and chronic maxillary atelectasis (CMA) represent an overlapping clinical entity, both likely lying on the spectrum of one disease process. There is widespread inconsistency of diagnosis in the literature of reported cases of SSS and CMA. We propose a novel, comprehensive staging system to simplify diagnosis and inform management.

Microvascular reconstruction of medication related osteonecrosis of the head and neck.

BACKGROUND: Medication related osteonecrosis of the jaw (MRONJ) requiring free flap (FF) reconstruction is uncommon with limited reported findings. METHODS: Multicenter, retrospective case series of 49 consecutive adult patients presenting with advanced MRONJ requiring FF reconstruction from 2010 to 2022. Perioperative complications and outcomes were analyzed. RESULTS: Eighty-two percent (n = 40) of cases were of the mandible and 18% (n = 9) were of the maxilla. The mean follow-up was 15 months (±19.6). The majority of FF survived (96%, n = 47). FF reconstructions of the maxilla were more likely to require postoperative debridement (56%, 95% CI [27, 81%] vs. 15%, 95% CI [7, 25%], p = 0.008) or develop intraoral bone exposure (56%, 95% CI [27, 81%] vs. 18%, 95% CI [9, 27%], p = 0.02). Most patients (71%, n = 35) received preoperative antibiotics which was associated with a higher rate of FF survival (100% vs. 86%, 95% CI [60, 96%], p = 0.02) and fewer complications. CONCLUSIONS: Patients undergoing FF reconstruction for MRONJ do well with high rates of FF success. MRONJ of the maxilla have a higher rate of some complications. Preoperative antibiotics correlated with higher FF survival and fewer postoperative complications.

Complications and Functional Outcomes After Esophageal Reconstruction with an Intact Larynx.

BACKGROUND: Esophageal defects can result from primary pathologies such as malignancy or stricture, or secondary ones such as perforation due to trauma or iatrogenic injury. Techniques, management, and outcomes of reconstruction in this setting are poorly understood. Herein, we aim to highlight surgical outcomes in patients undergoing local and free flap reconstruction of esophageal defects in the setting of an intact larynx. METHODS: Retrospective review of patients who underwent esophageal reconstruction with an intact larynx between 2009 and 2022 at our institution was performed. RESULTS: Ten patients met inclusion criteria. Esophageal reconstruction was performed for extruded spinal hardware (n = 8), and esophageal stricture (n = 2). Four patients underwent reconstruction with free tissue transfer, and six with local pedicled flaps. There were no cases of flap failure, esophageal fistula, hematoma, or wound dehiscence. One patient had post-operative bleeding requiring return to the operating room. Three patients had a postoperative wound infection, two of whom required washout. There were no unplanned 30-day readmissions. At three months after operation, all patients who were not tube feed-dependent prior to surgery returned to oral intake. Of the four patients who were tube feed-dependent preoperatively, three were tolerating oral intake at nine months postoperatively. Nine patients (90%) had stable flexible laryngoscopy exams pre- and postoperatively with no voice changes. CONCLUSIONS: Reconstruction of esophageal defects in the setting of an intact larynx can be challenging. In this series, surgical intervention with free tissue transfer and local pedicled flaps was effective in returning patients to oral intake with low long-term morbidity. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1227-1233, 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.

Evaluating ChatGPT Responses on Thyroid Nodules for Patient Education.

Background: ChatGPT, an artificial intelligence (AI) chatbot, is the fastest growing consumer application in history. Given recent trends identifying increasing patient use of Internet sources for self-education, we seek to evaluate the quality of ChatGPT-generated responses for patient education on thyroid nodules. Methods: ChatGPT was queried 4 times with 30 identical questions. Queries differed by initial chatbot prompting: no prompting, patient-friendly prompting, 8th-grade level prompting, and prompting for references. Answers were scored on a hierarchical score: incorrect, partially correct, correct, or correct with references. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. Flesch-Kincaid grade level was calculated for each answer. The relationship between prompt type and grade level was assessed using analysis of variance. References provided within ChatGPT answers were totaled and analyzed for veracity. Results: Across all prompts (n = 120 questions), 83 answers (69.2%) were at least correct. Proportions of responses that were at least partially correct (p = 0.795) and correct (p = 0.402) did not differ by prompt; responses that were correct with references did (p < 0.0001). Responses from 8th-grade level prompting were the lowest mean grade level (13.43 ± 2.86) and were significantly lower than no prompting (14.97 ± 2.01, p = 0.01) and prompting for references (16.43 ± 2.05, p < 0.0001). Prompting for references generated 80/80 (100%) of referenced medical publications within answers. Seventy references (87.5%) were legitimate citations, and 58/80 (72.5%) provided accurately reported information from the referenced publication. Conclusion: ChatGPT overall provides appropriate answers to most questions on thyroid nodules regardless of prompting. Despite targeted prompting strategies, ChatGPT reliably generates responses corresponding to grade levels well-above accepted recommendations for presenting medical information to patients. Significant rates of AI hallucination may preclude clinicians from recommending the current version of ChatGPT as an educational tool for patients at this time.

The Impact of Surgical and Nonsurgical Interventions on Overall Oral, Palpebral Fissure, and Brow Height Symmetry in a Patient with Facial Synkinesis.

Background: The treatment of facial nerve synkinesis remains complex and variable. Objective: To compare oral, palpebral fissure, and brow symmetry among surgical and nonsurgical interventions in patients with facial synkinesis. Methods: Patients with facial nerve synkinesis at a single tertiary care center between 2008 and 2022 were analyzed before and after interventions using Emotrics software. Symmetry was compared among treatment combination groups (chemodenervation and rehabilitation [CR] vs. chemodenervation and surgery [CS] vs. chemodenervation, surgery, and rehabilitation [CSR]) and among surgical intervention groups (selective neurectomy [SN] vs. selective neurectomy with facelift [SnFa] vs. no surgery). Results: Of the 29 patients meeting inclusion criteria, 72.4% were female and the median age was 60.6 years (interquartile range 49.9-67.6). The median follow-up was 32.6 months; patients who received surgery had a greater follow-up time (57.4 months vs. 26.5 months, p = 0.045). The use of a trimodal approach (CSR) was associated with improved symmetry versus CR for smile angle (p = 0.021). Among surgical interventions, the greatest improvement in palpebral fissure symmetry was in patients who received SN versus no surgery (p = 0.039); the greatest improvement in smile angle was in patients who received SnFa versus no surgery (p = 0.008). Conclusion: We recommend a comprehensive approach to the management of facial synkinesis consisting of chemodenervation, rehabilitation, and surgery tailored to each patient's needs.

Association of Smoke and Nicotine Product Consumption With Sensorineural Hearing Loss: A Population-Level Analysis.

OBJECTIVE: To test the hypothesis that use of cigarettes or other products with either cigarette-like smoke profile or high nicotine content by young populations increases the odds of developing sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective cohort study. SETTING: TriNetX US Collaborative Network (2003-2022). PATIENTS: Approximately 3.6 million patients at least 18 years old. INTERVENTION: None. MAIN OUTCOME MEASURES: The primary outcome of interest was diagnosis of SNHL, defined using medical billing codes ( International Classification of Diseases, Tenth Revision , Current Procedural Terminology , etc.). Cohort inclusion criteria included electronic health record entry after 2003, age 18 to 54 or 55+ years at index, and status of cigarette, noncigarette nicotine, or cannabis use. Covariates were controlled via 1:1 propensity score matching for SNHL-related conditions, including diabetes mellitus and ischemic diseases. Odds for developing SNHL were calculated against control subjects aged 18 to 54 years who have no record of nicotine/cannabis use. RESULTS: Odds for developing SNHL are higher for people 18 to 54 years old who use any nicotine product (odds ratio [95% confidence interval], 5.91 [5.71-6.13]), cigarettes only (4.00 [3.69-4.33]), chewing tobacco only (9.04 [7.09-11.63]), or cannabis only (3.99 [3.60-4.44]) compared with control. People 55+ years old who use no products also showed increased odds for SNHL (4.73 [4.63-4.85]). CONCLUSIONS: Both nicotine and smoke exposure seem to be strongly associated with increased odds for developing SNHL, with chewing tobacco having the strongest association.

Differences in Functional and Survival Outcomes Between Patients Receiving Primary Surgery vs Chemoradiation Therapy for Treatment of T1-T2 Oropharyngeal Squamous Cell Carcinoma.

Importance: Due to lack of data from high-powered randomized clinical trials, the differences in functional and survival outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC) undergoing primary transoral robotic surgery (TORS) vs primary radiation therapy and/or chemoradiation therapy (RT/CRT) are unclear. Objectives: To compare 5-year functional (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) and survivorship outcomes in patients with T1-T2 OPSCC receiving primary TORS vs RT/CRT. Design, Setting, and Population: This national multicenter cohort study used data from a global health network (TriNetX) to identify differences in functional and survival outcomes among patients with OPSCC who underwent primary TORS or RT/CRT in 2002 to 2022. After propensity matching, 726 patients with OPSCC met inclusion criteria. In the TORS group, 363 (50%) patients had undergone primary surgery, and in the RT/CRT group, 363 (50%) patients had received primary RT/CRT. Data analyses were performed from December 2022 to January 2023 using the TriNetX platform. Exposure: Primary surgery with TORS or primary treatment with radiation therapy and/or chemoradiation therapy. Main Outcomes and Measures: Propensity score matching was used to balance the 2 groups. Functional outcomes were measured at 6 months, 1 year, 3 years, 5 years, and more than 5 years posttreatment and included dysphagia, gastrostomy tube dependence, and tracheostomy dependence according to standard medical codes. Five-year overall survivorship was compared between patients undergoing primary TORS vs RT/CRT. Results: Propensity score matching allowed a study sample with 2 cohorts comprising statistically similar parameters with 363 (50%) patients in each. Patients in the TORS cohort had a mean (SD) age of 68.5 (9.9) vs 68.8 (9.7) years in RT/CRT cohort; 86% and 88% were White individuals, respectively; 79% of patients were men in both cohorts. Primary TORS was associated with clinically meaningful increased risk of dysphagia at 6 months (OR, 1.37; 95% CI, 1.01-1.84) and 1 year posttreatment (OR, 1.71; 95% CI, 1.22-2.39) compared with primary RT/CRT. Patients receiving surgery were less likely to be gastrostomy tube dependent at 6 months (OR, 0.46; 95% CI, 0.21-1.00) and 5 years posttreatment (risk difference, -0.05; 95% CI, -0.07 to -0.02). Differences in overall rates of tracheostomy dependence (OR, 0.97; 95% CI, 0.51-1.82) between groups were not clinically meaningful. Patients with OPSCC, unmatched for cancer stage or human papillomavirus status, who received RT/CRT had worse 5-year overall survival than those who underwent primary surgery (70.2% vs 58.4%; hazard ratio, 0.56; 95% CI, 0.40-0.79). Conclusions and Relevance: This national multicenter cohort study of patients undergoing primary TORS vs primary RT/CRT for T1-T2 OPSCC found that primary TORS was associated with a clinically meaningful increased risk of short-term dysphagia. Patients treated with primary RT/CRT had an increased risk of short- and long-term gastrostomy tube dependence and worse 5-year overall survival than those who underwent surgery.

Evaluating ChatGPT responses on obstructive sleep apnea for patient education.

STUDY OBJECTIVES: We evaluated the quality of ChatGPT responses to questions on obstructive sleep apnea for patient education and assessed how prompting the chatbot influences correctness, estimated grade level, and references of answers. METHODS: ChatGPT was queried 4 times with 24 identical questions. Queries differed by initial prompting: no prompting, patient-friendly prompting, physician-level prompting, and prompting for statistics/references. Answers were scored on a hierarchical scale: incorrect, partially correct, correct, correct with either statistic or referenced citation ("correct+"), or correct with both a statistic and citation ("perfect"). Flesch-Kincaid grade level and citation publication years were recorded for answers. Proportions of responses at incremental score thresholds were compared by prompt type using chi-squared analysis. The relationship between prompt type and grade level was assessed using analysis of variance. RESULTS: Across all prompts (n = 96 questions), 69 answers (71.9%) were at least correct. Proportions of responses that were at least partially correct (P = .387) or correct (P = .453) did not differ by prompt; responses that were at least correct+ (P < .001) or perfect (P < .001) did. Statistics/references prompting provided 74/77 (96.1%) references. Responses from patient-friendly prompting had a lower mean grade level (12.45 ± 2.32) than no prompting (14.15 ± 1.59), physician-level prompting (14.27 ± 2.09), and statistics/references prompting (15.00 ± 2.26) (P < .0001). CONCLUSIONS: ChatGPT overall provides appropriate answers to most questions on obstructive sleep apnea regardless of prompting. While prompting decreases response grade level, all responses remained above accepted recommendations for presenting medical information to patients. Given ChatGPT's rapid implementation, sleep experts may seek to further scrutinize its medical literacy and utility for patients. CITATION: Campbell DJ, Estephan LE, Mastrolonardo EV, Amin DR, Huntley CT, Boon MS. Evaluating ChatGPT responses on obstructive sleep apnea for patient education. J Clin Sleep Med. 2023;19(12):1989-1995.

Volumetric Analysis of the Sinus and Orbit in Silent Sinus Syndrome After Endoscopic Sinus Surgery.

OBJECTIVE: The term "silent sinus syndrome" (SSS) describes spontaneous enophthalmos secondary to subclinical maxillary sinus atelectasis. Debate remains on whether treatment with endoscopic maxillary antrostomy alone is adequate in reversing atelectasis and globe displacement. This study aims to determine the degree of volume change of the diseased sinus and orbit as well as the change in orbital height in patients treated with endoscopic antrostomy without orbital floor augmentation. STUDY DESIGN: Retrospective review with image analysis. SETTING: Single tertiary care institution. METHODS: Three-dimensional (3D) analysis of computed tomographic imaging data was performed using 3D Slicer. 3D models of the maxillary sinus and orbit of the diseased and normal sides were created, and volume measurements were calculated using the segmentation program. RESULTS: Thirteen patients with SSS who underwent endoscopic sinus surgery (ESS) and had follow-up computed tomographic imaging were analyzed. After endoscopic antrostomy, the mean volume of the diseased maxillary sinus significantly increased by 9.82%, from 6.37 to 7.00 cm3 (p = .0302). There was no significant change in mean orbital volume; however, the mean orbital height decreased by 5.67%, from 38.09 to 35.93 mm from pretreatment to posttreatment samples (p = .0101). All patients had resolution of clinical or radiographic enophthalmos and orbital displacement with ESS alone. CONCLUSION: Endoscopic maxillary antrostomy alone in the treatment of SSS significantly increased maxillary sinus volume and decreased diseased orbital height. These changes were associated with clinical and radiographic improvement in globe displacement. These findings support performing ESS alone, reserving orbital augmentation for patients who do not exhibit adequate clinical improvement.

Metformin Effects on FOXP3+ and CD8+ T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: Alterations of cellular metabolism have been implicated in immune dysfunction in the tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC). Metformin has recently emerged as a candidate of interest for combination with immunotherapy in HNSCC. This study investigated the effect of metformin on immune cell infiltrates of HNSCC. METHODS: Retrospective analysis of T cell infiltrates in primary tumor specimens from patients enrolled in a clinical window of opportunity trial of presurgical metformin. Metformin was titrated to a standard diabetic dose (2000 mg/day) for a minimum of 9 days (mean 13.6 days) prior to surgical resection. Pre and posttreatment surgical specimens from 36 patients (16 HPV+ , 20 HPV- ) were comparatively analyzed. FOXP3+ and CD8+ immune cell infiltrates in the tumor and peritumoral stroma of pre and posttreatment HNSCC specimens were quantified by digital image analysis using Visiopharm software. RESULTS: Metformin treatment was associated with a 41.4% decrease in FOXP3+ T cells in intratumor regions of interest (P = .004) and a 66.5% increase in stromal CD8+ T cells at the leading edge of the tumor (P = .021) when compared to pretreatment biopsies. This was reflected in increased CD8+ /FOXP3+ cell ratios within the tumor (P < .001) and stromal compartments (P < .001). The effects of metformin occurred independently of HPV status. CONCLUSION: Metformin treatment may favorably alter the immune TME in HNSCC independent of HPV status. LEVEL OF EVIDENCE: 1b. This study is most accurately described as a non-randomized controlled trial and therefore may reflect a level of evidence below 1b but above 2a from the provided "levels of evidence" chart. Laryngoscope, 130:E490-E498, 2020.

Metformin Clinical Trial in HPV+ and HPV- Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate.

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC. Methods: Human papilloma virus-(HPV-) tobacco+ mucosal HNSCC samples (n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples (n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients (n = 7) were compared to archival lymph node samples with ECE (n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8). Results: HPV-, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) (p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV-HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) (p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) (p = 0.019). Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV-HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC.