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Background: Preclinical evidence suggests a link between the renin‐angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC). Methods: Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results‐Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer‐specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI). Results: No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09–1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00–1.50, p = 0.050). Conclusions: ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN. [ABSTRACT FROM AUTHOR]

Radiation therapy remains at the center of head and neck cancer treatment. With improvements in treatment delivery, radiation therapy has become an affective ablative modality for head and neck cancers. Immune checkpoint inhibitors are now also playing a more active role both in the locally advanced and metastatic setting. With improved systemic options, local noninvasive modalities including radiation therapy are playing a critical role in overcoming resistance in head and neck cancer. The aim of this review is to describe the role of radiation therapy in modulating the tumor microenvironment and how radiation dose, fractionation and treatment field can impact the immune system and potentially effect outcomes when combined with immunotherapy. The review will encompass several common scenarios where radiation is used to improve outcomes and overcome potential resistance that may develop with immunotherapy in head and neck squamous cell carcinoma (HNSCC), including upfront locally advanced disease receiving definitive radiation and recurrent disease undergoing re-irradiation. Lastly, we will review the potential toxicities of combined therapy and future directions of their role in the management of HNSCC. [ABSTRACT FROM AUTHOR]

Background: Persistent controversy exists with regard to how and when patients with head and neck cancer should undergo imaging after definitive therapy. The current study was conducted to evaluate whether the type of imaging modality used in posttreatment imaging impacts cancer‐specific survival for patients with advanced head and neck squamous cell carcinoma. Methods: A retrospective study of National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program–Medicare‐linked data in patients with an advanced stage of the 3 most common head and neck malignancies (oral cavity, oropharynx, and larynx) was conducted. Hazard ratios and 95% CIs for cancer‐specific survival were estimated for patients diagnosed with any of these cancers between 2006 and 2015. Results: Significant improvement with regard to cancer‐specific survival was observed among patients with American Joint Committee on Cancer stage III and stage IVA laryngeal cancer who underwent positron emission tomography (PET) and/or computed tomography (CT) imaging during the first 6 months after receipt of definitive treatment (hazard ratio, 0.517; 95% CI, 0.33‐0.811) compared with those who underwent CT. There was a trend toward an improvement in cancer‐specific survival among patients with oral cavity or oropharyngeal malignancies who underwent PET/CT imaging, but it did not reach statistical significance. Conclusions: Compared with CT imaging, posttreatment imaging with PET was associated with improved survival in patients with advanced laryngeal carcinoma. Persistent controversy exists regarding how and when patients with head and neck cancer should undergo imaging after receiving definitive therapy. The current study evaluates whether the type of imaging modality used in posttreatment imaging impacts cancer‐specific survival for patients with advanced head and neck squamous cell carcinoma and finds that, compared with computed tomography imaging, posttreatment imaging using positron emission tomography is associated with improved survival in patients with advanced laryngeal carcinoma. [ABSTRACT FROM AUTHOR]

Objective: Management of tracheal squamous cell carcinoma (TSCC) has been complicated by the lack of prognostic data and staging. We describe the epidemiology of TSCC and current treatment approaches.Methods: Five hundred thirty-two adult patients with primary TSCC from 2004 to 2012 in the National Cancer Database were identified. Demographic, clinical factors, and 5-year overall survival were analyzed. Staging was classified as localized, regional extension, and distant spread. Treatment modality was defined as "no treatment (NT)," "limited surgery (LS)," "curative surgery (CS)," "LS with any adjuvant therapy (AT) (LS+AT)," "CS with AT (CS+AT)," "radiation therapy (RT)," or "chemoradiation (CRT)."Results: Overall survival was 25%. Majority of cases were males, white, and occurred in sixth/seventh decades. Twenty-six percent of cases received CRT, 20% underwent LS+AT or CS+AT, 20% underwent LS or CS only, and 17% underwent RT alone. On multivariate analysis, CS (HR 0.42, 95% CI: 0.26-0.69), CS+AT (HR 0.44, 95% CI: 0.36-0.77), CRT (HR 0.48, 95% CI: 0.35-0.67), and RT (HR, 0.66 95% CI: 0.46-0.94) were associated with decreased likelihood of death compared to NT. Elderly patients and those with poor performance status had worse outcomes even on multivariate analysis.Conclusions: TSCC is increasingly treated with surgery and systemic therapy in addition to RT, with improved survival outcomes. CS, CS+AT, CRT, or RT provided improved survival advantage in patients with variable levels of improvement based on the extent of the disease. Prospective trials would help differentiate survival advantages between treatment modalities. Patients' goals of care, comorbidities, and age should be considered when deciding appropriate treatment recommendations.Level Of Evidence: NA Laryngoscope, 130:405-412, 2020. [ABSTRACT FROM AUTHOR]

Background: Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.Methods: We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided.Results: Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation.Conclusion: We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation. [ABSTRACT FROM AUTHOR]

Aim To present our experience comparing cisplatin- and cetuximab-based radiotherapy for locally-advanced head and neck squamous cell carcinoma. Background The comparative effectiveness of cisplatin-based chemoradiotherapy (CRT) versus cetuximab-based bioradiotherapy (BRT) for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) continues to be explored. Materials and methods Outcomes of LAHNSCC patients treated with CRT (125) or BRT (34) at two institutions were compared retrospectively, with attention to overall survival (OS), cancer-specific survival (CSS), locoregional control (LRC), and distant control (DC). Univariate analysis (UVA) using Cox regression was performed to explore the association of intervention with survival and disease control, and multivariate (MVA) Cox regression was then performed to assess the association of intervention with survival. Results There were significant baseline differences between the CRT and BRT groups with respect to age, race, performance status, N-classification, tobacco history, and human papillomavirus status. UVA demonstrated inferiority of BRT versus CRT with respect to both OS (hazard ratio [HR] 2.19, 95% confidence interval [95%CI] 1.03–4.63, p = 0.04) and CSS (HR 3.33, 95%CI 1.42–7.78, p < 0.01), but non-significantly different outcomes in LRC (HR 0.99, 95%CI 0.37–2.61, p = 0.98) and DC (HR 2.01, 95%CI 0.78–5.37, p = 0.14). On MVA, there was no significant OS difference between interventions (HR 1.19, 95%CI 0.42–3.35, p = 0.74); there were too few events for the other outcomes to draw meaningful conclusions with MVA. Conclusions In our retrospective analysis, patients undergoing CRT experienced improved OS and CSS over those receiving BRT; however, disease control did not significantly differ. These findings may inform management of LAHNSCC patients. [ABSTRACT FROM AUTHOR]

Background: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality.Methods: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching.Results: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR, 0.696 [P = .002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P = .001]) or chemotherapy alone (HR, 1.834 [P<.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P = .045]).Conclusions: Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival. Cancer 2017;123:3040-49. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Previous groups have shown contralateral submandibular gland sparing to improve xerostomia with safe outcomes, but primarily in early-stage disease. In this study, we present a large cohort of patients with locally advanced head and neck cancer that underwent contralateral submandibular gland-sparing radiotherapy, to demonstrate feasibility and safety specifically in patients with locally advanced disease. Methods We retrospectively analyzed patients who were treated prospectively with contralateral submandibular gland sparing. Only patients who underwent bilateral neck radiotherapy with contralateral submandibular gland doses <39 Gy were included. Results We identified 71 patients. Approximately 80% of patients had ≥N2b disease. The contralateral submandibular gland mean dose was 33 Gy and, at a median follow-up of 27.3 months, no patients experienced treatment failure in the contralateral level IB lymph nodes. Conclusion Xerostomia remains a significant morbidity despite parotid sparing and can be minimized further by contralateral submandibular gland sparing. These data provide important preliminary evidence that contralateral submandibular gland sparing is feasible and may be safe even in locally advanced cancers. © 2015 Wiley Periodicals, Inc. Head Neck 38: 506-511, 2016 [ABSTRACT FROM AUTHOR]

Objective: Stereotactic body radiotherapy (SBRT) is increasingly used to treat a variety of tumors, including head and neck squamous cell carcinoma (HNSCC) in the recurrent setting. While there are published data for re-irradiation using SBRT for HNSCC, there are limited data supporting its use as upfront treatment for locally advanced disease. Study Design/Methods: Here, we describe three patients who received SBRT as the primary treatment for their HNSCC along with a reviewof the current literature and discussion of future pathways. Results: The three cases discussed tolerated treatment well with manageable acute toxicities and had either a clinical or radiographic complete response to therapy. Conclusion: Head and neck squamous cell carcinoma presents a unique challenge in the elderly, where medical comorbidities make it difficult to tolerate conventional radiation, often given with a systemic sensitizer. For these individuals, providing a shortened course using SBRT may offer an effective alternative. [ABSTRACT FROM AUTHOR]

Background: Inverted papilloma (IP) of the nasal cavity is a benign tumor that represents 0.5-4% of all nasal tumors and have been known to rarely undergo malignant transformation to squamous carcinoma and even more rarely adenocarcinoma. Synchronous association with low-grade esthesioneuroblastoma (ENB) has been reported in only one case report where a small-sized lesion was treated with surgery alone. Here we report the first case of invasion of IP by high-grade ENB with nodal metastasis that was treated with combined modality therapy. Case Presentation: A case of a 64-year-old African American gentleman presented to the otolaryngology with a 3-month history of recurrent epistaxis. Imaging revealed a large right nasal cavity mass extending into the right sphenoid sinus but without intracranial exten-sion. Surgical pathology revealed high-grade ENB invading IP. An orbitofrontal craniotomy approach was used to achieve complete resection of the mass but with positive margins. Post-operative positron emission tomography/computed tomography showed nodal metastasis. The patient was then treated with adjuvant chemoradiation and remains with-out evidence of disease at 42 months post-treatment.We discuss the disease presentation, histopathologic features, and disease management with literature support. Conclusion: In this very rare disease presentation where two extremely rare malignancies collide,we showthat aggressive management with trimodality therapy of surgery, adjuvant radiation with stereotactic radiosurgical boost, and adjuvant chemotherapy gives excellent results. Given the natural history of the disease, however, long follow-up is needed to declare complete freedom from the disease. [ABSTRACT FROM AUTHOR]

Immunotherapy clinical trials targeting the programmed-death ligand axis (PD-1/PD-L1) show that most head and neck squamous cell carcinoma (HNSCC) patients are resistant to PD-1/PD-L1 inhibition. We investigated whether local radiation to the tumor can transform the immune landscape and render poorly immunogenic HNSCC tumors sensitive to PD-L1 inhibition. We used the first novel orthotopic model of HNSCC with genetically distinct murine cell lines. Tumors were resistant to PD-L1 checkpoint blockade, harbored minimal PD-L1 expression and tumor infiltrating lymphocytes at baseline, and were resistant to radiotherapy. The combination of radiation and PD-L1 inhibition significantly enhanced tumor control and improved survival. This was mediated in part through upregulation of PD-L1 on tumor cells and increased T-cell infiltration after RT, resulting in a highly inflamed tumor. Depletion of both CD4 and CD8 T-cells completely abrogated the effect of anti PD-L1 with radiation on tumor growth. Our findings provide evidence that radiation to the tumor can induce sensitivity to PD-L1 checkpoint blockade in orthotopic models of HNSCC. These findings have direct relevance to high risk HNSCC patients with poorly immunogenic tumors and who may benefit from combined radiation and checkpoint blockade. [ABSTRACT FROM AUTHOR]

Objectives: Recent preclinical research has renewed interest in the interplay between glucose dysregulation and cancer. Metformin holds promise as an adjunctive antineoplastic agent in head and neck cancer (HNC). We aimed to explore the impact of metformin in HNC patients from a population-based dataset.Patients& Methods: Patients diagnosed with HNC from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset and categorized into three groups: non-diabetics (nD), diabetics not taking metformin (DnM), and diabetics taking metformin (D + M). Overall survival (OS) and cancer-specific survival (CSS) were compared between groups using Kaplan-Meier and Cox regression controlling for sociodemographic, clinical, and treatment covariates. The incidence of toxicities associated with HNC therapy was compared among groups using χ2 analysis.Results: Among 1646 patients, there were 1144 nD, 378 DnM, and 124 D + M. 2-year OS rates was 65.6% for nD, 57.7% for DnM, and 73.4% for D + M by Kaplan-Meier (p < 0.01), and corresponding rates of 2-year CSS were 73.7%, 66.1%, and 88.8% (p < 0.01), respectively. On Cox multivariable analysis, OS among the three groups did not significantly differ; however, CSS was significantly worse among both nD versus DnM as compared to D + M. Toxicity rates were not significantly increased among D + M.Conclusion: HNC patients with diabetes taking metformin experience improved CSS. Prospective investigation of the addition of metformin to standard-of-care HNC therapy is warranted. [ABSTRACT FROM AUTHOR]

Objectives: Studies have shown the utility of lipid-lowering agents in improving outcomes in various cancers. We aim to explore how statins affect overall survival and cancer specific survival in head and neck cancer patients using population-based datasets.Patients and Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset, we separated HNC patients into three groups: those with no hyperlipidemia (nH), those with hyperlipidemia and not taking a statin (HnS), and those with hyperlipidemia and taking a statin (H + S). Overall survival (OS) and cancer specific survival (CSS) were compared between the three groups based on disease subsite (oral cavity, oropharynx, and other) using Kaplan-Meier and multivariate Cox regression analysis (MVA), controlling for demographic, socioeconomic, staging, treatment, and comorbidity covariates. Using Pearson chi-square analysis, we also compared the incidence of cancer-related toxicity events.Results: There were 495 nH, 567 HnS, and 530 H + S patients. H + S patients had superior OS and CSS (73.0, 81.2%) relative to nH (58.6, 69.1%) and HnS groups (61.7, 69.2%) (p < 0.01). On MVA, H + S patients showed improved OS (p < 0.01) and CSS (p = 0.04) compared to nH (HR = 1.64, 1.56) and HnS (HR = 1.40, 1.37). MVA stratified by subsite yielded similar results for oral cavity and oropharyngeal disease. Toxicity-related events did not differ significantly between the groups.Conclusion: HNC patients with hyperlipidemia and taking a statin demonstrated improved outcomes compared to nH and HnS patients, further supporting statins' role as a potential adjuvant anti-neoplastic agent in HNC. Further prospective studies to investigate the impact of statins on HNC outcomes are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Extracapsular extension (ECE) in regional lymph nodes and positive surgical margins (PSM) are considered high-risk adverse pathologic features in patients with oropharyngeal squamous cell carcinoma (OPSCC) that each constitute an indication for postoperative adjuvant chemoradiation. We identify pre-operative clinical factors that can predict post-operative ECE and/or PSM and create a nomogram to help clinical decision making.Methods: Adult patients with non-metastatic OPSCC with initial surgical treatment and confirmed HPV status diagnosed between 2010 and 2014 were selected from the National Cancer Database. Clinical staging was modified to American Joint Committee on Cancer 8th edition parameters. Logistic regression was used for multivariate analysis to identify predictors of pathologic ECE and/or PSM.Results: 5065 patients were included. 47.5% of the 3336 HPV-positive (HPV+) patients had ECE/PSM. 40.4% of the 1729 HPV-negative (HPV-) patients with had ECE/PSM. A model was built that included age, clinical ECE, tumor grade, and clinical T and N staging for HPV+ patients. Increasing N-classification was highly predictive of pathologic ECE and/or PSM (N1 OR = 3.6, N2 OR = 7.0, N3 OR = 11.2, p < 0.01). Clinical ECE (OR = 4.1, p < 0.01), tumor grade (ORs 2.2-4.4 with p < 0.05), and increasing clinical T-classification (ORs 1.2-1.8, p < 0.05) were also associated with ECE and/or PSM. A similar model was built for HPV- with similar predictive capability. Two internally validated nomograms were designed that demonstrated good discrimination (HPV+ AUC = 0.66, 95% CI: 0.64-0.68, and HPV- AUC = 0.70, 95% CI: 0.67-0.72) and good calibration (goodness-of-fit statistic of HPV+ 6.32, p = 0.61 and HPV- 11.66, p = 0.17).Conclusions: These are the first nomograms designed to help predict ECE or PSM for both HPV+ and HPV- OPSCC. The nomograms can facilitate shared decision-making between clinicians and patients as they consider upfront treatment selection for OPSCC. [ABSTRACT FROM AUTHOR]