CD8+ CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue.

Recent studies have implicated a role for adenosine-dependent immunosuppression in head and neck tumor microenvironments. We describe expression of CD73, an enzyme critical to the generation of adenosine from extracellular AMP, in T cells and other cell types within human head and neck tumors. Flow cytometric analyses of tumor-infiltrating cells indicate that CD3+ cells are the predominant source of CD73 among immune infiltrating cells and that CD73 expression, especially among CD8+ T cells, is inversely related to indices of T cell infiltration and T cell activation in the microenvironment of head and neck tumors. We provide evidence that CD73 expression on peripheral T cells and levels of soluble CD73 in circulation are correlated with CD73 expression on CD8+ T cells in tumors. Moreover, fluorescent microscopy studies reveal that CD8+ CD73+ cells are observed in close proximity to tumor cells as well as in surrounding tissue. In vitro studies with peripheral blood T cells indicate that anti-CD3-stimulation causes loss of CD73 expression, especially among cells that undergo proliferation and that exogenous AMP can impair T cell proliferation, while sustaining CD73 expression. These data suggest that CD8+ CD73+ T cells may be especially important mediators of immunosuppression in human head and neck cancer.

Surgical Techniques for Head and Neck Reconstruction in the Vessel-Depleted Neck.

The vessel-depleted neck presents a unique and challenging scenario for reconstructive surgery of the head and neck. Prior surgery and radiation often result in significant scarring and damage to the neck vasculature, making identification of suitable recipient vessels for microvascular free tissue transfer exceedingly difficult. Therefore, alternative reconstructive techniques and/or vessel options must be considered to obtain a successful reconstructive outcome for a patient. In this article, we discuss our experience and approach to the management of the vessel-depleted neck, emphasizing the importance of preoperative planning and having multiple backup options prior to surgery. The various preoperative imaging modalities and available options for recipient arteries and veins are presented in detail. Additionally, we discuss modifications of select free flaps to maximize their utility in successful reconstruction. Together with thoughtful preoperative planning, these techniques can help aid the reconstructive surgeon in addressing the complex decisions associated with the vessel-depleted neck.

Post-radiotherapy PET/CT for predicting treatment outcomes in head and neck cancer after postoperative radiotherapy.

PURPOSE: The purpose of this study was to retrospectively review the role of post-treatment (post-tx) FDG-PET/CT scans in patients receiving postoperative intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Eighty-two patients with HNSCC treated with surgery and postoperative IMRT with or without chemotherapy from October 15, 2008 to December 31, 2014 that had post-tx PET/CT within 6 months of completing IMRT were included. PET/CT was considered positive based on multi-disciplinary review integrating clinical information. Survival analysis was performed using the Kaplan-Meier method. Categorical and continuous predictors of positive post-tx PET/CT were evaluated using Fisher's exact test and logistic regression, respectively. Predictors for survival outcomes were evaluated with log-rank testing. A p ≤ 0.05 was considered statistically significant. RESULTS: Median follow-up was 3.88 years. For all patients, 3-year overall survival (OS) and recurrence-free survival (RFS) were 71.8% and 61.3%, respectively. Patients with positive post-tx PET/CT had worse OS compared to those with negative post-tx PET/CT (log rank p < 0.001). For patients with positive post-tx PET/CT, 3-year OS was 11.2% compared to 89.9% for patients with negative post-tx PET/CT. The positive predictive value (PPV) of PET/CT was 100% for local recurrence (LR), regional recurrence (RR) and distant metastasis (DM). The negative predictive values (NPV) for LR, RR and DM were 89.0%, 89.2%, and 85.9%, respectively. Perineural invasion (p = 0.009), p16 status (p = 0.009), non-oropharyngeal primary site (p = 0.002), and the use of chemotherapy (p = 0.01) were independent predictors of positive PET/CT. CONCLUSIONS: Post-tx PET/CT after postoperative radiation is prognostic for survival outcomes. The PPV of post-tx PET for recurrence was excellent, allowing for early detection of recurrent disease. Post-tx PET/CT should be considered after postoperative radiation.

Outcomes of tracheoesophageal puncture in twice-radiated patients.

OBJECTIVE: Previous research has demonstrated the safety of tracheoesophageal puncture voice prosthesis (TEP) placement in radiated patients; however, there is a growing population of twice-radiated patients with limited research on the outcomes of TEP-placement in this cohort. METHODS: After Institutional Review Board approval, a retrospective review of 80 patients that underwent TEP from 2006 to 2017 at a single institution was conducted, of which 16 patients underwent two courses of radiation. Outcome measures include TEP removal, complication and duration of usage. RESULTS: Half of twice-radiated patients had ultimate removal of their voice prosthesis with removal occurring at a median of 24.9 months after placement. Reasons for prosthesis removal included widening tracheoesophageal fistula, local recurrence, and dysphagia/esophageal stenosis. Nearly one-third of these patients required surgical intervention for closure of a widening fistula. In contrast, only 17% of once-radiated patients had their prosthesis removed with removal occurring at a median of 28.1 months. This was statistically fewer than the twice-radiated group (p = 0.02). Reasons for removal included patient preference, persistent leakage, recurrence of disease, enlarging tracheoesophageal fistula, poor voice, and dysphagia. Eleven percent of once-radiated patients required surgical intervention for TEP-related complications (p = 0.057). CONCLUSION: In the twice-radiated patient cohort, there is a higher rate of TEP removal and need for surgical intervention for a voice prosthesis-related complication as compared to a once-radiated cohort.

Post-treatment PET/CT and p16 status for predicting treatment outcomes in locally advanced head and neck cancer after definitive radiation.

PURPOSE: To retrospectively review post-treatment (post-tx) FDG-PET/CT scans in patients with advanced head and neck squamous cell carcinoma (HNSCC) and known p16 status, treated with definitive (chemo)radiation (RT). METHODS: A total of 108 eligible patients had N2A or greater HNSCC treated with chemoRT from August 1, 2008, to February 28, 2015, with post-tx PET/CT within 6 months after RT. Kaplan-Meier curves, log-rank statistics, and Cox proportional hazards regression were used for statistical analysis. RESULTS: Median follow-up was 2.38 years. Sixty-eight (63.0%) patients had p16+ and 40 (37.0%) had p16- status. Two-year overall survival and recurrence-free survival were 93.4% and 77.8%, respectively. The negative predictive value (NPV) of PET/CT for local recurrence (LR) was 100%. The NPV for regional recurrence (RR) was 96.5% for all patients, 100% for p16+ patients, and 88.5% for p16- patients. The positive predictive value (PPV) of PET/CT for recurrence was 77.3% for all patients, 50.0% for p16+, and 78.6% for p16-. The PPV for LR was 72.7% for all patients, 50.0% for p16+ patients, and 72.7% for p16- patients. The PPV for RR was 50.0% for all patients, 33% for p16+, and 66.6% for p16-. Post-tx PET/CT and p16 status were independent predictors of recurrence-free survival (p < 0.01). CONCLUSIONS: Post-tx PET/CT predicts treatment outcomes in both p16 + and p16- patients, and does so independently of p16 status. P16- patients with negative PET have a 10% risk of nodal recurrence, and closer follow-up in these patients is warranted.

The use of the submental island flap in reconstructing palatal and facial defects in a surgical camp in East Africa.

BACKGROUND: The goals of successful reconstructive surgery are to restore function and cosmesis; however, limitation of resources can become an important consideration in low-middle income countries. METHODS: We describe our experience using the submental island flap in two cases during a short-term surgical camp in East Africa. RESULTS: The submental island flap was utilized as an excellent alternative to a free flap to reconstruct a subtotal maxillectomy and a parotidectomy defect in two patients. CONCLUSIONS: We demonstrate the successful use of this flap and describe some necessary modifications to achieve optimal results in a resource limited setting.

Post-operative MRSA infections in head and neck surgery.

PURPOSE: Surgical site infection (SSI) with methicillin-resistant Staphylococcus aureus (MRSA) is a serious post-operative complication, with head and neck cancer patients at greater risk due to the nature of their disease. Infection with MRSA has been shown to be costly and impart worse outcomes on patients who are affected. This study investigates incidence and risks for MRSA SSIs at a tertiary medical institution. MATERIALS AND METHODS: This study reviewed 577 head and neck procedures from 2008 to 2013. Twenty-one variables (i.e. tumor characteristics, patient demographics, operative course, cultures) were analyzed with SPSS to identify trends. A multivariate analysis controlled for confounders (age, BMI, ASA class, length of stay) was completed. RESULTS: We identified 113 SSIs of 577 procedures, 24 (21.23%) of which were MRSA. Of all analyzed variables, hospital exposure within the preceding year was a significant risk factor for MRSA SSI development (OR 2.665, 95% CI: 1.06-6.69, z statistic 2.086, p=0.0369). Immunosuppressed patients were more prone to MRSA infections (OR 14.1250, 95%CI: 3.8133-52.3217, p<0.001), and patients with a history of chemotherapy (OR 3.0268, 95% CI: 1.1750-7.7968, p=0.0218). Furthermore, MRSA SSI resulted in extended post-operative hospital stays (20.8±4.72days, p=0.031). CONCLUSIONS: Patients who have a history of chemotherapy, immunosuppression, or recent hospital exposure prior to their surgery are at higher risk of developing MRSA-specific SSI and may benefit from prophylactic antibiotic therapy with appropriate coverage. Additionally, patients who develop MRSA SSIs are likely to have an extended postoperative inpatient stay.

Use of concurrent chemoradiation in advanced staged (T4) laryngeal cancer.

HYPOTHESIS: Patients with advanced laryngeal cancer sometimes desire organ preservation protocols even if it portends a worse outcome. BACKGROUND: To assess outcomes of patients with T4 laryngeal cancer treated with chemoradiation therapy. METHODS: Case series with chart review at a tertiary university hospital. Twenty-four patients with T4 laryngeal cancer all declined total laryngectomy with adjuvant radiation as the primary treatment modality and alternatively received concurrent chemoradiation therapy. The primary outcome was overall survival. Secondary outcomes were rates of tracheotomy dependence, gastric tube dependence, and need for salvage laryngectomy. RESULTS: All patients had T4 laryngeal disease, 71% had cartilage invasion and 59% had regional metastasis to the neck. Kaplan-Meier analysis determined 2-year and 5-year overall survival to be 64% and 59% respectively. The locoregional recurrence rate was 25%. The distant metastasis rate was 21%. The rate of salvage laryngectomy was 17%, which occurred at a mean of 56.5months after the original diagnosis. The rate of tracheotomy dependence was 33% while gastric tube dependence was 25%. CONCLUSION: Advanced T4 laryngeal cancer, particularly with cartilage invasion, remains a surgical disease best treated with total laryngectomy and adjuvant radiation. This data may help guide patients and practitioners considering concurrent chemoradiation therapy for definitive treatment of advanced laryngeal cancer.

Outcomes of microvascular free tissue transfer in twice-irradiated patients.

BACKGROUND: Patients may require microvascular free tissue transfer (MFTT) following re-irradiation for recurrent cancer or radiation complications. The objective of this study was to describe the indications for and outcomes of free flaps performed in twice-radiated patients. METHODS: A retrospective chart review identified the indications for and outcomes of 36 free flaps performed on 29 twice-irradiated patients. RESULTS: The free flap success rate was 92%. The most common indications requiring MFTT were cancer recurrence and osteoradionecrosis. Sixty-one percent experienced postoperative complications, most commonly wound infection (33%). Twenty-five percent of the procedures required return to the operating room due to postoperative complication. CONCLUSIONS: MFTT can be successfully performed in the twice-irradiated patient population with a success rate comparable to singly-radiated patients. Despite a high success rate, there is also a high rate of surgical site complications, especially infection.

Lateral arm microvascular free tissue reconstruction of a large neck keloid.

Keloid scars pose a surgical challenge in the region of the head and neck. We present a rare case of a large infected and recurrent neck keloid that failed multiple prior reconstructive attempts. Ultimately, the tissue was resected and the surgical bed was repaired with a lateral arm microvascular free flap. This repair emphasizes the need for adequate coverage of the defect while maintaining neck mobility, ease of swallowing, and cosmesis. This is the second report in the literature of free tissue transfer as treatment for a large keloid scar, and the first to show the feasibility of early post operative low dose irradiation of the surgical bed.

Utility of SPECT/CT for periparotid sentinel lymph node mapping in the surgical management of head and neck melanoma.

PURPOSE: Sentinel lymph node (SLN) biopsy is instrumental in staging and treatment of cutaneous melanoma. SPECT/CT, single-photon emission computed tomography (SPECT) integrated with computed tomography (CT), increases the accuracy of SLN mapping to improve surgical planning. SPECT/CT can correct for signal scatter to prevent masking, which is especially common in the head and neck. For periparotid lymph nodes SPECT/CT may improve localization of SLNs compared to lymphoscintigraphy. MATERIALS/METHODS: Hospital charts were reviewed for 14 patients with melanoma and suspected lymphatic drainage to the parotid region who received lymphoscintigraphy followed by SPECT/CT prior to surgical excision and SLN. RESULTS: Overall, SPECT/CT provided data, which changed management in 57% of patients. CONCLUSIONS: Fifty-seven percent of our patients benefited from use of SPECT/CT. The distinction between level II and parotid sentinel lymph nodes was clearly identified through SPECT/CT images. We believe that patients with melanoma draining to the parotid region would benefit from SPECT/CT SLN mapping.

The effect of transfusion on survival in head and neck cancer after free tissue reconstruction.

Objective: To examine if perioperative blood transfusion affects overall survival (OS) and recurrence-free survival (RFS) in head and neck cancer patients who undergo free tissue reconstruction. Design: Retrospective cohort study. Methods: The medical records of free tissue flaps between 2007 and 2010 were reviewed. Differences in demographics and clinical factors based on the level of transfused packed red blood cells (PRBC) were examined using chi-squared tests, Kruskal-Wallis tests, and/or ANOVA tests. Survival time was compared using a Cox proportional hazard model. Results: Data were available for 183 patients. Patients who had PRBC transfusion significantly differed from the non-transfused group by flap type, flap with bone, Charlson Comorbidity Index (CCI), and hemoglobin and hematocrit. When stratified into three groups based on units of PRBC; flap type, flap with bone, CCI, preoperative hemoglobin, and hematocrit were found to differ significantly. The 2-year Kaplan-Meier plot demonstrated improved OS for those who did not receive any PRBC transfusion. The use of more than 3 units of blood decreased 2-year OS significantly when compared to the non-transfused group. Finally, after adjusting for CCI using a Cox proportional hazard model, survival was significantly affected by CCI. Conclusion: After controlling for patient age, oncologic stage, cancer subsite, histology, type of free flap, vascularized bone-containing flap, recurrence type, CCI, and preoperative hemoglobin and hematocrit, patients who received 3 or more units of PRBC in the perioperative period had significantly decreased OS. RFS did not differ between the transfused versus non-transfused groups. Level of Evidence: Level 4.

Fibula Free Flap Reconstruction of Cervical Spine Defects: A Multi-Institutional Study.

INTRODUCTION: Cervical spine defects result in spinal instability, putting the spinal cord and vertebral arteries at risk of damage and possibly devastating neurological injuries. The fibula free flap can span the spinal defects for stability. There is a paucity of literature on this technique. METHOD: Multi-institutional retrospective case series reviewing patients who underwent cervical spine reconstruction with a fibula free flap. Patient demographic information, comorbidities, characteristics of cervical spine defects, and free flap complications were collected. RESULTS: A total of 1187 fibula free flaps across 10 different institutions were reviewed. Thirteen patients (1.09%) underwent cervical spine reconstruction with a fibula free flap. Average age was 52.3 years old with an age range of 12-79 years. There were six males (46.1%) and seven females (53.8%). The most common defect etiology was infection (n = 6, 46.1%). Most commonly involved cervical spine level of the defect was C5 (n = 10) followed by C6 (n = 9) and C4 (n = 8). The majority of reconstructed defects spanned three or more cervical levels, (n = 9, 69.2%). Facial artery was the most common arterial anastomosis (n = 8). Eight patients (61.5%) required a tracheostomy during their postoperative course. None of the patients had symptomatic or radiographic nonunion. CONCLUSION: This case series demonstrates that a vascularized fibula flap is a potential reconstructive option for cervical spine defects, especially in defects greater than three cervical levels, in the setting of infection, and previously radiated patients. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2024.

Beta-defensin index: A functional biomarker for oral cancer detection.

There is an unmet clinical need for a non-invasive and cost-effective test for oral squamous cell carcinoma (OSCC) that informs clinicians when a biopsy is warranted. Human beta-defensin 3 (hBD-3), an epithelial cell-derived anti-microbial peptide, is pro-tumorigenic and overexpressed in early-stage OSCC compared to hBD-2. We validate this expression dichotomy in carcinoma in situ and OSCC lesions using immunofluorescence microscopy and flow cytometry. The proportion of hBD-3/hBD-2 levels in non-invasively collected lesional cells compared to contralateral normal cells, obtained by ELISA, generates the beta-defensin index (BDI). Proof-of-principle and blinded discovery studies demonstrate that BDI discriminates OSCC from benign lesions. A multi-center validation study shows sensitivity and specificity values of 98.2% (95% confidence interval [CI] 90.3-99.9) and 82.6% (95% CI 68.6-92.2), respectively. A proof-of-principle study shows that BDI is adaptable to a point-of-care assay using microfluidics. We propose that BDI may fulfill a major unmet need in low-socioeconomic countries where pathology services are lacking.

Free Flap Donor Sites in Head and Neck Reconstruction.

Microvascular free tissue transfer, also referred to as free flaps surgery, is a reconstructive technique that has become a foundational component of complex head and neck reconstruction. There have been considerable advancements in the field over the last 30 years including the number and variety of free flaps. Each of these free flaps has unique characteristics that must be considered for the defect when selecting a donor site. Here, the authors focus on the most common free flaps used in head and neck reconstruction.

Managing Oromandibular Hardware Failure after Free Flap Surgery.

Hardware failure after oromandibular reconstruction using free tissue transfer can delay additional therapies directed at cancer treatment and prevent patients from returning to normal oral function. Understanding and strict adherence to principles of rigid fixation is critical in preventing complications. Early surgical intervention for hardware exposure as well as utilization of locoregional flaps may prevent the need for more extensive revision surgery.

Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer.

Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.

Association of Neoadjuvant Pembrolizumab for Oral Cavity Squamous Cell Carcinoma With Adverse Events After Surgery in Treatment-Naive Patients.

Importance: Pembrolizumab, a monoclonal antibody targeting programmed cell death 1, is currently approved by the US Food and Drug Administration for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The potential neoadjuvant role of programmed cell death 1 inhibitors in primary surgical management of HNSCC and effects on surgical outcomes are poorly understood. Objective: To evaluate the incidence of postoperative adverse events in treatment-naive patients with advanced oral cavity cancer receiving neoadjuvant pembrolizumab when compared with matched controls, as part of a window-of-opportunity multi-institutional clinical trial assessing neoadjuvant pembrolizumab for locally advanced HNSCC. Design, Setting, and Participants: This retrospective cohort study at a single tertiary academic institution included treatment-naive patients with local regionally advanced oral cavity squamous cell carcinoma (OCSCC) who were undergoing surgical resection. Exposures: Patients with local regionally advanced resectable OCSCC who received neoadjuvant pembrolizumab were retrospectively reviewed for postoperative adverse events. Controls were matched by age, race, smoking status, and overall cancer stage based on historical data at the same institution. Matched-cohort analysis was performed using a McNemar test to assess differences between the groups. Main Outcomes and Measures: Incidence of adverse events following surgical resection of advanced OCSCC within 30 days of surgery and on continued follow-up. Results: A total of 64 patients (32 as part of the prospective clinical trial and 32 as controls; mean [SD] age, 59.6 [10.3] years; 28 [44%] women) were included in the analysis. Postoperative adverse events in the 32 patients receiving pembrolizumab included lymphedema (n = 20 [63%]), trismus (n = 7 [22%]), return to operating room (n = 7 [22%]), wound infection (n = 7 [22%]), fistula (n = 6 [19%]), wound dehiscence (n = 4 [13%]), flap failure (n = 3 [9%]), and hematoma (n = 2 [6%]). The matched control group demonstrated similar complication rates without considerable differences, except for trismus (n = 16 [50%]), which was greater by a difference of 28.1% (95% CI, 5.6%-50.6%) in the control group. Conclusions and Relevance: This cohort study examined surgical complications among patients with local regionally advanced OCSCC treated with neoadjuvant pembrolizumab and found that serious adverse events were similar to those in patients who underwent standard-of-care treatment. This suggests that there is no increased perioperative morbidity in the use of preoperative treatment with immunotherapy. Further prospective studies are needed to validate these findings for oral cavity cancer and other subsites of the head and neck.

Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. PATIENTS AND METHODS: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. RESULTS: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8-88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58-91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)-positive and PD-L1-negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). CONCLUSIONS: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.

Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.