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Introduction: We retrospectively studied young patients with head and neck squamous cell carcinoma (HNSCC) to identify factors associated with disease‐specific survival (DSS). Methods: Patient and tumor characteristics of patients aged ≤45 who received treatments for non‐metastatic HNSCC were collected to identify factors associated with DSS. Proportional hazards regression was applied separately for surgical and non‐surgical patients. Results: 230 patients were included. Surgical and non‐surgical patients had similar DSS. Higher pathologic stages, positive margins, perineural invasion (PNI), extranodal extension and negative HPV status were associated with worse DSS for surgical patients and negative HPV status for non‐surgical patients. In the multivariate analysis, pathologic stages, positive margins, and PNI were associated with worse DSS in surgical patients. Conclusion: Pathologic stages, positive margins, and PNI are independently associated with worse DSS in young surgical HNSCC patients. PNI is a uniquely strong prognostic factor for young patients. [ABSTRACT FROM AUTHOR]

The incidence of human papillomavirus-positive (HPV*) head and neck squamous cell carcinoma (HNSCC) has surpassed that of cervical cancer and is projected to increase rapidly until 2060. The coevolution of HPV with transforming epithelial cells leads to the shutdown of host immune detection. Targeting proximal viral nucleic acid-sensing machinery is an evolutionarily conserved strategy among viruses to enable immune evasion. However, E7 from the dominant HPV subtype 16 in HNSCC shares low homology with HPV18 E7, which was shown to inhibit the STING DNA-sensing pathway. The mechanisms by which HPV16 suppresses STING remain unknown. Recently, we characterized the role of the STING/ type I interferon (IFN-I) pathway in maintaining immunogenicity of HNSCC in mouse models. Here we extended those findings into the clinical domain using tissue microarrays and machine learning-enhanced profiling of STING signatures with immune subsets. We additionally showed that HPV16 E7 uses mechanisms distinct from those used by HPV18 E7 to antagonize the STING pathway. We identified NLRX1 as a critical intermediary partner to facilitate HPV16 E7-potentiated STING turnover. The depletion of NLRX1 resulted in significantly improved IFN-I-dependent T cell infiltration profiles and tumor control. Overall, we discovered a unique HPV16 viral strategy to thwart host innate immune detection that can be further exploited to restore cancer immunogenicity., Introduction The coevolution of oncogenic viruses with transforming epithelial cells encourages pathogens to develop unique mechanisms that enable immune evasion. The type I interferon (IFN-I) system is an ancient and [...]

Background: An international multidisciplinary panel of experts aimed to provide consensus guidelines describing the optimal intratumoral and intranodal injection of NBTXR3 hafnium oxide nanoparticles in head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, and cervical lymph nodes and to review data concerning safety, feasibility, and procedural aspects of administration. Methods: The Delphi method was used to determine consensus. A 4‐member steering committee and a 10‐member monitoring committee wrote and revised the guidelines, divided into eight sections. An independent 3‐member reading committee reviewed the recommendations. Results: After two rounds of voting, strong consensus was obtained on all recommendations. Intratumoral and intranodal injection was deemed feasible. NBTXR3 volume calculation, choice of patients, preparation and injection procedure, potential side effects, post injection, and post treatment follow‐up were described in detail. Conclusions: Best practices for the injection of NBTXR3 were defined, thus enabling international standardization of intratumoral nanoparticle injection. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release. Expression levels of two recently described gene sets were determined in The Cancer Genome Atlas Head and Neck Cancer cohort (n = 522) and validated in the GSE65858 dataset (n = 250) as well as a recently published single-cell RNA sequencing dataset (n = 18). Clustering into HPV(+) and HPV(−) patients was performed in all cohorts for further analysis. Potential associations between gene expression levels, immune cell infiltration, and patient overall survival were analyzed using GEPIA2, TISIDB, TIMER, and the UCSC Xena browser. Compared to normal control tissues, vesiculation-related genes were upregulated in HNSCC cells. Elevated gene expression levels positively correlated (P < 0.01) with increased abundance of CD4(+) T cells, macrophages, neutrophils, and dendritic cells infiltrating tumor tissues but were negatively associated (P < 0.01) with the presence of B cells and CD8(+) T cells in the tumor. Expression levels of immunosuppressive factors NT5E and TGFB1 correlated with the vesiculation-related genes and might explain the alterations of the anti-tumor immune response. Enhanced expression levels of vesiculation-related genes in tumor tissues associates with the immunosuppressive tumor milieu and the reduced infiltration of B cells and CD8(+) T cells into the tumor. The expression of vesiculation-related genes (EVsig) is upregulated in HNSCC and is associated with a specific immune cell landscape. Hereby, the EVsig correlates with a decreased abundance of tumor-infiltrating effector lymphocytes and with the expression of immunosuppressive markers NT5E and TGBF1. [ABSTRACT FROM AUTHOR]

Purpose: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown.Methods and Materials: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms.Results: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol.Conclusions: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593). [ABSTRACT FROM AUTHOR]

Background: We ascertain the role of a low cervical paraspinal skeletal muscle index (CPSMI) as a biomarker for poor treatment tolerance in patients with operable mucosal head and neck squamous cell carcinoma (HNSCC). Methods: A prospective cohort of patients with operable HNSCC requiring microvascular reconstruction was evaluated. Low CPSMI was calculated using preoperative CT neck imaging. Poor treatment tolerance, a composite measure of incomplete therapy or severe morbidity/mortality during treatment, was the primary outcome. Results: One hundred and twenty‐seven patients underwent extirpative surgery with a mean age was 60.5. Poor treatment tolerance occurred in 71 (56%) patients with 21 not completing recommended adjuvant therapy and 66 having severe treatment‐related morbidity. A low CPSMI was independently associated with poor treatment tolerance (OR 2.49, 95%CI 1.10–5.93) and delay to adjuvant therapy (OR 4.48, 95%CI 1.07–27.6) after adjusting for multiple confounders. Conclusion: Low CPSMI was independently associated with poor treatment tolerance in patients with operable HNSCC. [ABSTRACT FROM AUTHOR]

In the randomized, phase 3 CheckMate 141 trial, nivolumab significantly improved overall survival (OS) versus investigator's choice (IC) of chemotherapy at primary analysis among 361 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) post-platinum therapy. Nivolumab versus IC as first-line treatment also improved OS among patients with R/M SCCHN who progressed on platinum therapy for locally advanced disease in the adjuvant or primary setting at 1-year follow-up. In the present long-term follow-up analysis of patients receiving first-line treatment, OS benefit with nivolumab (n = 50) versus IC (n = 26) was maintained (median: 7.7 months versus 3.3 months; hazard ratio: 0.56; 95% confidence interval, 0.34-0.94) at 2 years. No new safety signals were identified. In summary, this long-term 2-year analysis of CheckMate 141 supports the use of nivolumab as a first-line treatment for patients with platinum-refractory R/M SCCHN. [ABSTRACT FROM AUTHOR]

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment. Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors. [ABSTRACT FROM AUTHOR]

Hemorrhage in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) may be attributed to chemotherapy and local tumor irradiation. Evidence of the relationship between hemorrhage in R/M HNSCC and targeted therapies, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, or immune checkpoint inhibitors, is limited. We aimed to identify epidemiological and clinical data related to the occurrence of hemorrhage in R/M HNSCC and to explore its relationship with various therapies. We describe information obtained from literature searches as well as data extracted from a commercial database and a database from the author's institution (Istituto Nazionale dei Tumori of Milan). Evidence suggests that most bleeding events in R/M HNSCC are minor. Clinical trial safety data do not identify a causal association between hemorrhage and anti‐EGFR agents or immune checkpoint inhibitors. In contrast, anti‐VEGF agents are associated with increased, and often severe/fatal, hemorrhagic complications. [ABSTRACT FROM AUTHOR]

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies. Recent studies have highlighted the importance of B cells and tertiary lymphoid structures (TLS) in the modulation of anti-tumor immune responses. Here, the authors characterize how HPV status influences the phenotype of tumor infiltrating B cells in patients with head and neck squamous cell carcinoma and demonstrate that TLS with germinal centres are associated with better survival. [ABSTRACT FROM AUTHOR]

Background: Data objectively evaluating acute post‐transoral robotic surgery (TORS) swallow function are limited. Our goal was to characterize and identify clinical variables that may impact swallow function components 3 weeks post‐TORS. Methods: Retrospective cohort study. Pre/postoperative use of the Modified Barium Swallow Impairment Profile (MBSImP) and Penetration‐Aspiration Scale (PAS) was completed on 125 of 139 TORS patients (2016–2019) with human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scores were retrospectively calculated. Uni/multivariate analysis was performed. Results: Dysfunctional pre‐TORS DIGEST scores were predictive of post‐TORS dysphagia (p = 0.015). Pre‐TORS MBSImP deficits in pharyngeal stripping wave, swallow initiation, and clearing pharyngeal residue correlated with airway invasion post‐TORS based on PAS scores (p = 0.012, 0.027, 0.048, respectively). Multivariate analysis of DIGEST safety scores declined with older age (p = 0.044). Odds ratios (ORs) for objective swallow function components after TORS were better for unknown primary and tonsil primaries compared to base of tongue (BOT) (OR 0.35–0.91). Conclusions: Preoperative impairments in specific MBSImP components, older patients, and BOT primaries may predict more extensive recovery in swallow function after TORS. [ABSTRACT FROM AUTHOR]

Background: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population.Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued.Findings: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure).Interpretation: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT.Funding: Pfizer and Merck KGaA, Darmstadt, Germany. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0–2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles. [ABSTRACT FROM AUTHOR]

Background: The present study evaluated the 2‐year survival of the Asian population in the CheckMate 141 trial. Methods: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed. Results: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2‐year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment‐related adverse events (TRAEs), including skin‐related disorders, showed better OS than the patients without any TRAEs. Conclusions: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum‐refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin‐related disorders, may be favorable prognostic factors for nivolumab efficacy. Clinical trial registration: NCT02105636. [ABSTRACT FROM AUTHOR]

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals -- the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab -- for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S. [ABSTRACT FROM AUTHOR]

Background: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0).Methods: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed.Results: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC.Conclusions: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC. [ABSTRACT FROM AUTHOR]

Background: Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria.Methods: In CheckMate 141, patients with RECIST-defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional ≥10% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab.Results: Of 240 patients randomized to nivolumab, 146 experienced RECIST-defined progression. Sixty-two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7-14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses.Conclusions: Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population. [ABSTRACT FROM AUTHOR]

Background: Mechanisms of resistance to immune‐modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor‐specific monoclonal antibody (mAb) therapy. Methods: HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole‐exome sequencing. Expression of killer‐cell immunoglobulin‐like receptor (KIR) and human leukocyte antigen‐C (HLA‐C) and the effect of KIR blockade were assessed in HNSCC cell lines. Results: Nonresponders to cetuximab had an increased rate of mutations in HLA‐C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab‐activated natural killer (NK) cells induced upregulation of HLA‐C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti‐KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001). Conclusions: Alterations in HLA‐C may provide a mechanism of immune evasion through disruption of NK activation. [ABSTRACT FROM AUTHOR]

Background: Organ preservation protocols have increasingly been applied for the treatment of head and neck cancers, including hypopharyngeal squamous cell carcinoma (HSCC). We sought to evaluate whether patients treated with primary surgery followed by adjuvant therapy had survival benefit over patients treated with initial nonsurgical modalities. Methods: We retrospectively reviewed patients with new diagnosis of HSCC at the University of Pittsburgh (1994‐2014) treated with either primary total laryngectomy with pharyngectomy or organ preservation. Results: One hundred thirty‐seven patients were identified. Surgical cases were more likely to be of advanced T stage. Initial surgery was more likely to be performed in the earlier years of the cohort. After adjusting for this imbalance using a propensity score, primary surgery was associated with improved survival compared with nonoperative therapy (P = 0.02). Conclusions: Due to its survival advantage, primary surgery followed by adjuvant treatment should be considered as a viable treatment of HSCC. [ABSTRACT FROM AUTHOR]

Background: This article is about the eighth edition staging guidelines for upstaged patients with oral cavity squamous cell carcinoma (OCSCC) with >10 mm depth to pT3. This upstages some patients from stage I‐II to stage III, a point at which patients are traditionally considered for postoperative radiation therapy (PORT). The role of PORT in patients upstaged for >10 mm depth is unknown. Methods: We identified patients with surgically resected stage I‐II OCSCC with >10 mm depth who were upstaged to stage III. We used Cox proportional hazard modeling to compare patients who received PORT to those who did not (median follow‐up 38.6 months). Results: We observed that 3.6% of patients with OCSCC were upstaged to stage III for depth >10 mm including 823 eligible patients. On adjusted analyses, PORT was associated with improved overall survival in patients upstaged to stage III (adjusted hazard ratio [aHR] 0.47, 95% confidence interval [CI] 0.30‐0.73). Conclusion: PORT is associated with improved survival for patients with OCSCC upstaged to stage III for >10 mm depth. [ABSTRACT FROM AUTHOR]

Objectives: Sentinel lymph node biopsy (SLNB) has been shown to be an accurate technique for staging the neck in early-stage oral cavity squamous cell carcinoma (OCSCC) and has been incorporated in treatment guidelines as an option instead of elective neck dissection (END). However, utilization of SLNB in the United States remains unclear, and existing prospective studies did not directly compare survival between SLNB and END.Methods: We conducted a retrospective cohort study of patients with stage I to II OCSCC (cT1-2cN0cM0) who underwent staging of the neck in the National Cancer Data Base from 2012 to 2015. We compared the practice patterns and outcomes of patients who underwent SLNB versus END.Results: We identified 8,328 eligible patients with a median follow-up of 35.4 months. SLNB was used for 240 patients, or 2.9% of stage I to II OCSCC. Completion neck dissection was avoided in 63.8% of patients undergoing SLNB. SLNB was associated with reduced perioperative morbidity, with median length of hospital stay of 1.0 days versus 3.0 days after END (P < 0.001). Perioperative 30-day mortality was 0% after SLNB versus 0.7% after END (P = 0.42). Overall 3-year survival was 82.0% after SLNB and 77.5% after END (P = 0.40). After adjustment, overall survival was equivalent between patients who underwent SLNB versus END (adjusted hazard ratio 1.03, confidence interval 0.67-1.59).Conclusions: SLNB for stage I to II OCSCC is associated with reduced length of hospital stay and equivalent overall survival compared with END. Despite these attributes, SLNB remains rarely used in the United States.Level Of Evidence: NA Laryngoscope, 129:162-169, 2019. [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT).Materials and Methods: We identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with surgery alone, adjuvant RT or CRT in the National Cancer Data Base from 2010 to 2013. We compared survival for low-risk patients (≤1 metastatic lymph nodes with no adverse features) and intermediate-risk patients (2-4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion).Results: We examined 1677 patients with median follow-up of 43.9 months. In the intermediate-risk group, 4-year overall survival was 94.0% with surgery alone, 91.5% with adjuvant RT and 92.0% with adjuvant CRT (p = 0.72). There were similar rates of overall survival in the low-risk group. In multivariable models accounting for clinicopathologic differences the dose of adjuvant RT was not associated with mortality. On Cox proportional hazard modeling, adjuvant RT (HR 0.94; CI 0.43-2.08) or CRT (HR 0.96; CI 0.45-2.11) did not significantly improved survival compared with surgery alone in the intermediate-risk group (reference). Similar results were seen in the low-risk group. The composite number of pathologic risk features significantly improved risk stratification.Conclusion: We provide observational evidence that adjuvant RT or CRT does not provide a survival benefit for stage I HPV+ OPSCC with low- or intermediate-risk pathologic features. [ABSTRACT FROM AUTHOR]

Objective: For the first time in 30 years, the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual offers major changes in the staging of oral cavity cancer. We evaluated the predictive ability of the new staging system for oral cavity cancer to validate these changes and hypothesized that the new system would improve prognostic accuracy.Methods: We conducted a retrospective cohort study of patients with oral cavity squamous cell carcinoma in the National Cancer Data Base from 2009 to 2013 and applied the seventh and eighth edition staging AJCC staging systems to all patients. Stage-specific overall survival was calculated using the Kaplan-Meier method and concordance indices to measure the system's prognostic accuracy.Results: We identified 39,361 patients with a median follow-up of 27.1 months (range 0.1-80.4 months). In the seventh edition, there were 43.0%, 15.0%, 10.6%, and 25.7% of patients with pathologic stage I, II, III, and IV disease, respectively. After restaging based on eighth edition pathological guidelines, 10.0% of patients were upstaged (38.1%, 18.1%, 14.2%, and 25.2%, respectively, with stage I, II, III, and IV disease, respectively). The survival concordance index improved from the seventh to eighth edition for pathological staging (concordance index 0.699 and 0.704, respectively) and for clinical staging (concordance index 0.714 and 0.715, respectively).Conclusion: We provide validation of the new AJCC staging system for oral cavity cancer. Eighth edition AJCC staging guidelines upstage a substantial number of patients with greater depth of invasion or extranodal extension. This resulted in slightly improved prognostication.Level Of Evidence: 2c. Laryngoscope, 128:2351-2360, 2018. [ABSTRACT FROM AUTHOR]

Resistance to antitumor immunity can be promoted by the oncogenic pathways operational in human cancers, including the epidermal growth factor receptor (EGFR) pathway. Here we studied if and how EGFR downstream signaling in head and neck squamous cell carcinoma (HNSCC) can affect the attraction of immune cells. HPV-negative and HPV-positive HNSCC cell lines were analyzed in vitro for CCL2, CCL5, CXCL9, CXCL10, IL-6 and IL-1β expression and the attraction of T cells under different conditions, including cetuximab treatment and stimulation with IFNγ and TNFα using qPCR, ELISA and migration experiments. Biochemical analyses with chemical inhibitors and siRNA transfection were used to pinpoint the underlying mechanisms. Stimulation of HNSCC cells with IFNγ and TNFα triggered the production of T-cell attracting chemokines and required c-RAF activation. Blocking of the EGFR with cetuximab during this stimulation increased chemokine production in vitro, and augmented the attraction of T cells. Mechanistically, cetuximab decreased the phosphorylation of MEK1, ERK1/2, AKT, mTOR, JNK, p38 and ERK5. Chemical inhibition of EGFR signaling showed a consistent and pronounced chemokine production with MEK1/2 inhibitor PD98059 and JNK inhibitor SP600125, but not with inhibitors of p38, PI3K or mTOR. Combination treatment with cetuximab and a MEK1/2 or JNK inhibitor induced the highest chemokine expression. In conclusion, overexpression of EGFR results in the activation of multiple downstream signaling pathways that act simultaneously to suppress type 1 cytokine stimulated production of chemokines required to amplify the attraction of T cells. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oligometastasis is a good prognostic indicator when compared to widely metastatic disease in malignancies of other organ systems. We hypothesized that oligometastasis in human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (SCC) would be associated with better overall survival. Methods: This is a retrospective review of all HPV‐positive oropharyngeal SCC treated at one center with at least 1‐year of follow‐up. Patients were stratified into 2 cohorts: oligometastasis (1‐2 metastases, confined to 1 organ system) or polymetastasis (>2 metastases or multiple organ involvement) with cohorts compared for time to distant metastasis and overall survival after metastasis. Results: Thirty‐eight of 506 patients (7.5%) developed metachronous distant metastasis; 12 developed oligometastasis and 26 developed polymetastasis. Median overall survival after oligometastasis was significantly longer than polymetastasis at 45 months (95% confidence interval [CI] 19 months ‐ not reached) and 10 months (95% CI 5‐24 months; P = .00028). Conclusion: Oligometastasis in metastatic HPV‐positive oropharyngeal SCC portends a better prognosis than polymetastasis. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus-infected individuals (HIVIIs) have a higher incidence of head and neck squamous cell carcinoma (HNSCC), and clinical and histopathological differences have been observed in their tumors in comparison with those of HNSCC patients without a human immunodeficiency virus (HIV) infection. The reasons for these differences are not clear, and molecular differences between HIV-related HNSCC and non-HIV-related HNSCC may exist. This study compared the mutational patterns of HIV-related HNSCC and non-HIV-related HNSCC.Methods: The DNA of 20 samples of HIV-related HNSCCs and 32 samples of non-HIV-related HNSCCs was sequenced. DNA libraries covering exons of 18 genes frequently mutated in HNSCC (AJUBA, CASP8, CCND1, CDKN2A, EGFR, FAT1, FBXW7, HLA-A, HRAS, KEAP1, NFE2L2, NOTCH1, NOTCH2, NSD1, PIK3CA, TGFBR2, TP53, and TP63) were prepared and sequenced on an Ion Personal Genome Machine sequencer. DNA sequencing data were analyzed with Ion Reporter software. The human papillomavirus (HPV) status of the tumor samples was assessed with in situ hybridization, the MassARRAY HPV multiplex polymerase chain reaction assay, and p16 immunostaining. Mutation calls were compared among the studied groups.Results: HIV-related HNSCC revealed a distinct pattern of mutations in comparison with non-HIV-related HNSCC. TP53 mutation frequencies were significantly lower in HIV-related HNSCC. Mutations in HIV+ patients tended to be TpC>T nucleotide changes for all mutated genes but especially for TP53.Conclusions: HNSCC in HIVIIs presents a distinct pattern of genetic mutations, particularly in the TP53 gene. HIV-related HNSCC may have a distinct biology, and an effect of the HIV virus on the pathogenesis of these tumors should not be ruled out. Cancer 2018;124:84-94. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC.Methods: Patients undergoing TORS for OPSCC were enrolled prospectively. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score >2) and was administered on postoperative day (POD) 1, 7, and 30. Patient demographics, weight, pain level, and clinical outcomes were recorded prospectively and focused on time to oral diet, feeding tube placement, and dysphagia-related readmissions.Results: A total of 51 patients were included with pathologic T stages of T1 (n = 24), T2 (n = 20), T3 (n = 3), and Tx (n = 4). Self-reported preoperative dysphagia was unusual (13.7%). The mean EAT-10 score on POD 1 was lower than on POD 7 (21.5 vs 26.6; P = .005) but decreased by POD 30 (26.1 to 12.2; P < .001). Forty-seven (92.1%) patients were discharged on an oral diet, but 57.4% required compensatory strategies or modification of liquid consistency. Ninety-eight percent of patients were taking an oral diet by POD 30. There were no dysphagia-related readmissions.Conclusion: This prospective study shows that most patients who undergo TORS experience dysphagia for at least the first month postoperatively, but nearly all can be started on an oral diet. The dysphagia-associated complication profile is acceptable after TORS with a minority of patients requiring temporary feeding tube placement. Aggressive evaluation and management of postoperative dysphagia in TORS patients may help prevent dysphagia-associated readmissions. Cancer 2017;123:3132-40. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs).Methods: CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636.Findings: Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires.Interpretation: In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting.Funding: Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The value of transcervical arterial ligation during transoral robotic surgery (TORS) as a measure to decrease postoperative bleeding incidence or severity is unclear. Methods A retrospective single institution study was performed to identify risk factors for hemorrhage after TORS for oropharyngeal squamous cell carcinoma (SCC). Results Overall, 13.2% of patients (35/265) experience postoperative hemorrhage. T classification, perioperative use of anticoagulants, surgeon experience >50 cases, and tumor subsite were not predictors of postoperative hemorrhage. Of this cohort, 28% underwent prophylactic arterial ligation. The overall incidence of bleeding was not significantly decreased in patients who underwent arterial ligation (12.1% vs 13.6%; p = .84). However, arterial ligation significantly reduced the incidence of major and severe bleeding events (1.3% vs 7.8%; p = .04). Radiation before TORS was a risk factor for major and severe postoperative hemorrhage ( p < .02). Conclusion Transcervical arterial ligation during TORS may reduce the severity of postoperative hemorrhagic events. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1510-1515, 2017 [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to characterize oncologic outcomes in early (T1-T2, N0) and intermediate (T1-T2, N1) oropharyngeal squamous cell carcinoma (SCC) after surgery. Methods Patients with oropharyngeal SCC treated with surgery were identified from 2 academic institutions. Results Of 188 patients, 143 met the inclusion criteria. Eighty-six (60%) had T1 to T2 N0 and 57 (40%) had T1 to T2 N1 disease. Sixty-five patients (45%) underwent a robotic-assisted resection, whereas the remaining had transoral ( n = 60; 42%), mandible-splitting ( n = 11; 8%), or transhyoid approaches ( n = 7; 5%). Human papillomavirus (HPV) status was known for 97 patients (68%), and 54 (55%) were HPV positive. Three-year recurrence-free survival (RFS) was 82% (95% confidence interval [CI] = 0.75-0.89). Since 2008, HPV infection was protective of recurrence (log-rank p = .0334). A single node did not increase the risk of recurrence ( p = .467) or chance of a second primary ( p = .175). Conclusion Complete surgical resection is effective therapy for early and intermediate oropharyngeal SCC. HPV-negative patients were at increased risk for locoregional recurrence or second primary disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1471, 2016 [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. Methods Between January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. Results Advanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) ( p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. Conclusion The TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. © 2016 Wiley Periodicals, Inc. Head Neck 38:1201-1207, 2016 [ABSTRACT FROM AUTHOR]

Background An autologous vaccine of apoptotic tumor cells (ATCs) and dendritic cells (DCs) was administered to patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) to study safety and feasibility. Methods Autologous DCs were generated from monocytes, loaded with ATCs, and delivered intranodally. Delayed-type hypersensitivity (DTH) and immunological endpoints were measured prevaccination and postvaccination. Clinical follow-up was required. Results Tumors obtained from 30 patients yielded 2 × 106 to 2 × 108 tumor cells. Only 19 of 30 (63%) were sterile. Ten of 30 patients (33%) had ≥1 × 107 sterile tumor cells required for vaccine production. Eight of 10 patients had positive recall DTH. Five of 10 patients were leukapheresed to generate DCs. Four of 5 patients were vaccinated. ATC-reactive T cells were detected in 3 of 4 patients. All 4 patients survived >5 years. The trial failed to enroll the projected 12 patients and was terminated. Conclusion This vaccine was safe and immunogenic but feasible only in patients with HNSCC with positive prevaccine DTH and ≥1 × 107 sterile tumor cells. All vaccinated patients were long-term disease-free survivors. © 2015 Wiley Periodicals, Inc. Head Neck 38: E494-E501, 2016 [ABSTRACT FROM AUTHOR]

Background: Squamous cell carcinoma of the head and neck (SCCHN) remains a prevalent and devastating disease. Recently, there has been an increase in SCCHN cases that are associated with high-risk human papillomavirus (HPV) infection. The clinical characteristics of HPV-positive and HPV-negative SCCHN are known to be different but their molecular features are only recently beginning to emerge. MicroRNAs (miRNAs, miRs) are small, non-coding RNAs that are likely to play significant roles in cancer initiation and progression where they may act as oncogenes or tumor suppressors. Previous studies in our laboratory showed that miR-363 is overexpressed in HPV-positive compared to HPV-negative SCCHN cell lines, and the HPV type 16-E6 oncoprotein upregulates miR-363 in SCCHN cell lines. However, the functional role of miR-363 in SCCHN in the context of HPV infection remains to be elucidated.Methods: We analyzed miR-363 levels in SCCHN tumors with known HPV-status from The Cancer Genome Atlas (TCGA) and an independent cohort from our institution. Cell migration studies were conducted following the overexpression of miR-363 in HPV-negative cell lines. Bioinformatic tools and a luciferase reporter assay were utilized to confirm that miR-363 targets the 3'-UTR of myosin 1B (MYO1B). MYO1B mRNA and protein expression levels were evaluated following miR-363 overexpression in HPV-negative SCCHN cell lines. Small interfering RNA (siRNA) knockdown of MYO1B was performed to assess the phenotypic implication of reduced MYO1B expression in SCCHN cell lines.Results: MiR-363 was found to be overexpressed in HPV-16-positive compared to the HPV-negative SCCHN tumors. Luciferase reporter assays performed in HPV-negative JHU028 cells confirmed that miR-363 targets one of its two potential binding sites in the 3'UTR of MYO1B. MYO1B mRNA and protein levels were reduced upon miR-363 overexpression in four HPV-negative SCCHN cell lines. Increased miR-363 expression or siRNA knockdown of MYO1B expression reduced Transwell migration of SCCHN cell lines, indicating that the miR-363-induced migration attenuation of SCCHN cells may act through MYO1B downregulation.Conclusions: These findings demonstrate that the overexpression of miR-363 reduces cellular migration in head and neck cancer and reveal the biological relationship between miR-363, myosin 1b, and HPV-positive SCCHN. [ABSTRACT FROM AUTHOR]

Purpose Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. Methods and Materials From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m 2 on day −7 and then 250 mg/m 2 on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. Results Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. Conclusions SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time. [ABSTRACT FROM AUTHOR]

Background Although existing literature provides surgical recommendations for treating occult disease (cN0) in early-stage oral cavity squamous cell carcinoma (SCC), a focus on late-stage oral cavity SCC is less pervasive. Methods The medical records of 162 patients with late-stage oral cavity SCC pN0 who underwent primary neck dissections were reviewed. Lymph node yield as a prognosticator was examined. Results Despite being staged pN0, patients that had a higher lymph node yield had an improved regional/distant control rates, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Lymph node yield consistently outperformed all other standard variables as being the single best prognostic factor with a tight risk ratio range (RR = 0.95-0.98) even when correcting for the number of lymph nodes examined. Conclusion The results of this study showed that lower regional recurrence rates and improved survival outcomes were seen as lymph node yield increased for advanced T classification oral cavity SCC pN0. This suggests that increasing lymph node yield with an extended cervical lymphadenectomy may result in lower recurrence rates and improved survival outcomes for this advanced stage group. © 2014 Wiley Periodicals, Inc. Head Neck, 36: 1446-1452, 2014 [ABSTRACT FROM AUTHOR]

Objective: Cancer of an unknown primary (CUP) squamous cell carcinoma metastatic to cervical lymph nodes is a challenging problem for the treating physician. Our aim is to determine if identification of the primary tumor is associated with improved oncologic outcomes and/or tumor characteristics including human papilloma virus (HPV) status.Study Design: Retrospective, matched-pairs analysis contrasting 2 cohorts based upon discovery of primary lesion.Setting: Tertiary teaching hospital.Subjects and Methods: Records of 136 patients initially diagnosed as carcinoma of unknown primary were retrospectively reviewed (1980-2010) and divided into 2 cohorts based on discovery of the primary lesion. Primary outcome measures were overall survival and time to recurrence according to Kaplan-Meier analysis. A nested subset of 22 patients in which the primary was discovered were matched to 22 patients remaining undiscovered according to nodal stage and age.Results: Discovered lesions were more likely to exhibit HPV positivity (P < .001). Matched-pairs analyses demonstrated that discovery of the primary was associated with better overall survival (HR = 0.125; 95% confidence interval [CI], 0.019-0.822; P = .030). Discovery of the primary was associated with improved cause-specific survival (HR = 0.142; 95% CI, 0.021-0.93; P = .0418) and disease-free survival (HR = 0.25; 95% CI, 0.069-0.91; P = .03).Conclusion: HPV positivity is associated with discovery of the primary tumor. Discovery of the primary lesion is associated with improved overall survival, cause-specific survival, and disease-free survival in patients initially presenting as CUP in matched-pair and cohort comparison analyses. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy. Interest in developing novel immunotherapies in HNSCC has been reawakened by the success of cetuximab, a therapeutic monoclonal antibody (mAb) against the epidermal growth factor receptor, which likely relies on immune as well as antisignaling mechanisms. This review focuses on novel therapeutic mAbs in current clinical development against established mechanisms of immune evasion in HNSCC, targeting: 1) tumor antigens, with resultant potential to induce antibody-dependent cell-mediated cytotoxicity and T cell activation; 2) immunosuppressive cytokines; 3) costimulatory tumor necrosis factor-family receptors; and 4) coinhibitory immune checkpoint receptors. Clinical trials of immunotherapeutic mAbs as monotherapy, in combination with cytolytic standard therapies exposing tumor antigens or in combination with other immunomodulatory mAbs, are urgently needed in HNSCC. Cancer 2014;120:624-632. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Summary: Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA- targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches. [Copyright &y& Elsevier]

BACKGROUND Extracapsular spread (ECS) in cervical lymph node metastases from head and neck squamous cell carcinoma (SCC) is regarded as an adverse prognostic factor and is often used to select patients who may benefit from adjuvant therapy. The prognostic value of ECS was evaluated for patients with oropharyngeal SCC (OPC; with known p16/human papillomavirus [HPV] status) and for patients with SCC of the oral cavity (OCC). METHODS Disease-specific survival (DSS) was assessed among SCC patients with cervical lymph node metastases (n = 347, including 133 patients with OPC and 214 patients with OCC). All patients were treated surgically between 1983 and 2009. ECS status was determined by pathologists at the time of initial pathologic evaluation and confirmed for this study. HPV status of patients with OPC was determined via immunohistochemistry for p16 and in situ hybridization. RESULTS Among OCC patients, ECS was a significant, independent factor influencing DSS. For OCC patients with ECS, 3-year DSS was 45% (95% confidence interval [CI], 36%-56%); for those without ECS, 3-year DSS was 71% (95% CI, 62%-81%; P = .0018). The effect of ECS was independent of the number of positive lymph nodes as well as other clinical, pathologic, and treatment variables. Of the 133 OPC patients, 76 (57%) were p16-positive and 57 (43%) were p16-negative. ECS status did not correlate with DSS among p16-positive or p16-negative OPC patients. CONCLUSION ECS was not associated with worse DSS in p16-positive or p16-negative OPC patients. Adverse prognostic value of ECS in OCC patients was confirmed. Cancer 2013;119:3302-8. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Although the presence of genetic heterogeneity within the tumors of individual patients is established, it is unclear whether greater heterogeneity predicts a worse outcome. A quantitative measure of genetic heterogeneity based on next-generation sequencing (NGS) data, mutant-allele tumor heterogeneity (MATH), was previously developed and applied to a data set on head and neck squamous cell carcinoma (HNSCC). Whether this measure correlates with clinical outcome was not previously assessed. METHODS The authors examined the association between MATH and clinical, pathologic, and overall survival data for 74 patients with HNSCC for whom exome sequencing was completed. RESULTS High MATH (a MATH value above the median) was found to be significantly associated with shorter overall survival (hazards ratio, 2.5; 95% confidence interval, 1.3-4.8). MATH was similarly found to be associated with adverse outcomes in clinically high-risk patients with an advanced stage of disease, and in those with tumors classified as high risk on the basis of validated biomarkers including those that were negative for human papillomavirus or having disruptive tumor protein p53 mutations. In patients who received chemotherapy, the hazards ratio for high MATH was 4.1 (95% confidence interval, 1.6-10.2). CONCLUSIONS This novel measure of tumor genetic heterogeneity is significantly associated with tumor progression and adverse treatment outcomes, thereby supporting the hypothesis that higher genetic heterogeneity portends a worse clinical outcome in patients with HNSCC. The prognostic value of some known biomarkers may be the result of their association with high genetic heterogeneity. MATH provides a useful measure of that heterogeneity to be prospectively validated as NGS data from homogeneously treated patient cohorts become available Cancer 2013;119:3034-3042. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110a catalytic subunit of phosphoinositide 3- kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. Methods and results PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). Conclusions Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Background Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for patients with recurrent, previously irradiated head and neck cancer; however, data are limited predominantly to squamous cell carcinomas. Herein, we report the efficacy of SBRT in recurrent, nonsquamous cell cancers of the head and neck (NSCHNs). Methods In all, 34 patients with pathologically proven NSCHN were reirradiated with SBRT to a median dose of 40 Gy in 5 fractions (interquartile range, 30-44 Gy). Toxicity and quality of life were followed prospectively. Results Median follow-up was 10 months (absolute range, 0-55 months). The 6-month/1-year local control rate was 77/59%, with a 6-month/1-year overall survival of 76/59%. Local control was significantly improved for tumors <25 mL ( p = .030). Acute/late grade 3 toxicity was 15/6%, with no grade 4-5 toxicity. Conclusions SBRT for previously irradiated, locally recurrent NSCHN provides promising local control, especially for tumors <25 mL, with minimal toxicity. The optimal dose for larger tumors remains to be defined. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Tumor cells were first shown to exhibit a distinct metabolic phenotype over 80 years ago. Since then, it has become clear that multiple oncogenic events contribute to the development of a metabolic phenotype that supports rapid proliferation. Because this phenotype represents an essential component of tumorigenesis and disease progression, it also represents a potential source of biomarkers associated with aggressive disease. In addition, the addiction of tumor cells to specific nutrients and the up-regulation of key metabolic enzymes provide unique opportunities for pharmacologic manipulation. Despite the use of multimodality treatment, survival rates for patients with advanced head and neck squamous cell carcinoma (HNSCC) remain low, partially attributed to the development of drug resistance. In this review, we evaluate the role of altered HNSCC metabolism as both a source of novel biomarkers and a means to bypass resistance mechanisms to conventional forms of therapy. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Background. Human papillomavirus (HPV)-positive cases of squamous cell carcinoma of the head and neck (SCCHN) have a much better disease outcome compared to SCCHN cases lacking HPV. Differences in microRNA (miRNA) expression may affect their clinical outcomes. Methods. The miRNA expression was studied using microarrays and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in HPV-16-positive and HPV-negative SCCHN cell lines. The role of HPV-16 E6 and E7 oncogenes in altering miRNA expression was investigated using human foreskin keratinocytes (HFKs). Results. The miRNAs miR-363, miR-33, and miR-497 were upregulated, whereas miR-155, miR 181a, miR-181b, miR-29a, miR-218, miR-222, miR-221, and miR-142-5p were downregulated in HPV-positive cells compared to both HPV-negative SCCHN and normal oral keratinocytes. HPV-16 E6 oncogene altered miRNA expression in HFKs and in an HPV-16–positive cell line with E6 knockdown using siRNA. Conclusion. miRNAs differentially expressed in the presence of HPV-16 may provide biomarkers for SCCHN and identify cellular pathways targeted by this virus. [ABSTRACT FROM AUTHOR]

The microenvironment of aerodigestive cancers contains tumor-promoting inflammatory signals often involved in innate immunity. The epithelial malignancy, squamous cell carcinoma of the head and neck (SCCHN), is characterized by secretion of inflammatory mediators that can promote tumorigenesis and lymph node metastasis. Human β-defensin (hBD) 3 is one such antimicrobial mediator of innate immunity produced by squamous epithelial cells in response to tissue damage and inflammation. Here, we hypothesized that the observed overexpression of hBD3 in SCCHN may have a tumor-promoting effect or contribute to nodal metastasis, which has previously been linked to chemokine receptor (CCR) 7 overexpression. Indeed, treatment of non-metastatic SCCHN cells with hBD3 induced surface CCR7 expression and migration toward its ligand, CCL19. The hBD3-induced CCR7 upregulation in SCCHN cells was significantly reduced by inhibition of nuclear factor (NF)-κB, an inflammatory transcription factor known to influence CCR7 expression. Moreover, hBD3 stimulation provided anti-apoptotic signals to SCCHN cells, as evidenced by tumor resistance to cisplatin-induced cell death, which was regulated by phosphoinositide-3-kinase/Akt activation. Interestingly, the observed hBD3-mediated effects were not dependent on G-protein coupled receptors or toll-like receptors, as has been previously published, but hBD3 was internalized through endocytosis, allowing intracellular signal transduction. Our findings suggest that hBD3 represents a novel NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their survival and metastasis. [ABSTRACT FROM AUTHOR]

The TP53 tumor suppressor gene contains a well-studied polymorphism that encodes either proline (P) or arginine (R) at codon 72, and over half of the world’s population is homozygous for R at this codon. The wild-type sequence (wt) p53 peptide, p5365–73, has been identified as a CD8+ T cell-defined tumor antigen for use in broadly applicable cancer vaccines. However, depending on the TP53 codon 72 polymorphism of the recipient, the induced responses to the peptides incorporating R (p5372R) or P (p5372P) can be “self” or “non-self.” Thus, we sought to determine which wt p5365–73 peptide should be used in wt p53-based cancer vaccines. Despite similar predicted HLA-A2-binding affinities, the p5372P peptide was more efficient than the p5372R peptide in HLA-A2 stabilization assays. In vitro stimulation (IVS) of CD8+ T cells obtained from healthy HLA-A2+ donors with these two peptides led to the generation of CD8+ T cell effectors in one-third of the samples tested, at a frequency similar to the responsiveness to other wt p53 peptides. Interestingly, regardless of their p53 codon 72 genotype, CD8+ T cells stimulated with either p5372P or p5372R peptide were cross-reactive against T2 cells pulsed with either peptide, as well as HLA-A2+ head and neck cancer (HNC) cell lines presenting p5372P and/or p5372R peptides for T cell recognition. Therefore, the cross-reactivity of CD8+ T cells for the polymorphic wt p5365–73 peptides, irrespective of their p53 codon 72 polymorphism, suggests that employing either peptide in wt p53-based vaccines can result in efficient targeting of this epitope. [ABSTRACT FROM AUTHOR]

Background Cumulative evidence implicates the epidermal growth factor receptor (EGFR) as an important therapeutic target in head and neck squamous cell carcinoma (HNSCC). The basis for the lack of correlation between EGFR expression in the HNSCC tumor and clinical responses to EGFR inhibitors is incompletely understood. Although a variety of mechanisms likely contribute to the effectiveness of EGFR blockade, this review focuses on the biologic implications of known EGFR variations and the role of the immune system in mediating clinical responses to EGFR inhibitors. Methods A Medline review of articles published in the last 10 years (1999-present) on EGFR in HNSCC was performed in combination with preliminary data from our laboratories. Results Studies published to date suggest no association between the expression of EGFR on HNSCC tumors and clinical responses to EGFR inhibitors. Several mechanisms have been proposed to mediate clinical response to EGFR inhibitors in HNSCC. Cumulative results from our laboratories support the role of several mechanisms, including cellular immune activation and mutated EGFR variants, in contributing to the discrepancy between level of EGFR expression and clinical response to EGFR inhibitors. Conclusion The efficacy of EGFR targeted therapies may be mediated, at least in part, by the immune system and the presence of the truncated EGFR variant, EGFRvIII, among other factors. Criteria to identify the subset of patients likely to be responsive to EGFR targeted therapies are needed. © 2010 Wiley Periodicals, Inc. Head Neck, 2010 [ABSTRACT FROM AUTHOR]

Objective: To study the retropharyngeal lymph node status (RPLN) by pretreatment PET-CT imaging in patients with squamous cell carcinomas of the oropharynx (OPSCC). Study Design: Retrospective. Methods: 101 patients with a biopsy proven OPSCC were identified. 53 patients meeting inclusion criteria were further analyzed. Results: The frequency of RPLN was 20.8% (11/53). Advanced T stage cancer (OR = 5.6250, 95% CI: 1.06 - 29.80, p = 0.0410) and advanced clinical N stage cancer (i.e. N2+) had higher odds (OR = 3.9773, 95% CI: 0.9628 - 16.4291) of being RPLN positive as compared to N0-1 patients. Conclusions: Pre-treatment PET-CT can be used as a staging tool to aid in treatment planning of OPSCC, as rates of RPLN and nodal metastasis are consistent with those reported in the literature. Advanced T and N stage are associated with a greater odds ratio of being RPLN positive by PET-CT imaging. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiated patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to 44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Evaluation Criteria in Solid Tumors and [18F]-fluorodeoxyglucose standardized uptake value change on positron emission tomography–computed tomography (PET-CT). Results: No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Four objective responses were observed, for a response rate of 17% (95% confidence interval 2%–33%). The maximum duration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was 4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affected by treatment. Fluorodeoxyglucose PET was a more sensitive early-measure response to treatment than CT volume changes. Conclusion: Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants further evaluation in combination with conventional and targeted therapies. [Copyright &y& Elsevier]