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Objectives: The aim of surgery for head and neck squamous cell carcinoma (HNSCC) is to achieve clear resection margins, whilst preserving function and cosmesis. Fluorescent markers have demonstrated potential in the intraoperative visualisation and delineation of tumours, such as glioma, with consequent improvements in resection. The purpose of this scoping review was to identify and compare the fluorescent markers that have been used to detect and delineate HNSCC to date., Methods: A literature search was performed using the Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, ClinicalTrials.gov and ICTRP databases. Primary human studies published through September 2023 demonstrating the use of fluorescent markers to visualise HNSCC were selected and reviewed independently by two authors., Results: The search strategy identified 5776 records. Two hundred and forty-four full texts were reviewed, and sixty-five eligible reports were included. The most used fluorescent markers in the included studies were indocyanine green (ICG) (n = 14), toluidine blue (n = 11), antibodies labelled with IRDye800CW (n = 10) and 5-aminolevulinic acid (5-ALA) (n = 8). Toluidine blue and ICG both have limited specificity, although novel targeted options derived from ICG may be more effective. 5-ALA has been demonstrated as a topical marker and, recently, via enteral administration but it is associated with photosensitivity reactions. The fluorescently labelled antibodies cetuximab-IRDye800CW and panitumumab-IRDye800CW are promising options being investigated by ongoing trials., Conclusion: Multiple safe fluorescent markers have emerged which may aid the surgical resection of HNSCC. Further research in larger cohorts is required to identify which marker should be considered gold standard., (© 2024 The Author(s). Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Purpose: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC., Experimental Design: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort., Results: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73., Conclusions: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption., (©2023 The Authors; Published by the American Association for Cancer Research.)

Radiotherapy (RT) continues to play a key role in the management of head and neck cancer (HNC). Xerostomia remains a principal detriment to the quality of life (QoL) for 80 % of surviving patients receiving head and neck radiation. Radiation-induced injury to the salivary glands is dose-dependent, and thus efforts have been focused on decreasing radiation to the salivary glands. Decreased saliva production reduces both short-term and long-term quality of life in head and neck survivors by impacting on taste and contributing to dysphagia. Several radioprotective agents to the salivary gland have been investigated. Although not widely practiced, surgical transfer of the submandibular gland prior to RT is the mainstay of surgical options in preventing xerostomia. This review focuses on the strategies to improve xerostomia following radiation therapy in head and neck cancers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Head and neck cancer patients can face debilitating treatment related side-effects, resulting in requirement for support and negatively impacting on care outcomes. This study aimed to develop a digital recovery support package and assess its acceptability with head and neck cancer patients to support their information needs and assist with their self-management. It provided additional support through development of a WebXR platform 'recovery' package, which allowed patients to live a 'virtual reality' experience, entering and moving inside a 'virtual room', accessing targeted resources and specific learning materials related to their cancer., Method: A qualitative intervention development study consisting of three phases. This study followed the COREQ checklist for qualitative research. Phase 1- Focus groups with seven head and neck cancer patients and six healthcare professionals. Phase 2- Development of 'recovery' package based on the focus group data which informed the content and design of the WebXR recovery platform. Phase 3- Technology acceptance study. Once developed, the platform's acceptability of the experience lived inside the virtual room was assessed via qualitative interviews with six different patient participants., Results: Most participants felt comfortable using the virtual reality platform, finding it a realistic and useful support for identifying resources and signposting to relevant materials. Participants agreed the WebXR platform was a feasible tool for the head and neck cancer setting and helped reduce anxiety., Conclusions: Head and neck cancer patients welcome specific targeted, information and advice to support their ability to self-manage their rehabilitation and thus focus their nursing care. The platform was implemented during the Covid-19 pandemic, demonstrating its versatility and accessibility in providing complementary support to head and neck cancer patients, to empower them to adjust to their 'new' normal as part of their ongoing cancer journeys., Competing Interests: Declaration of competing interest I can confirm that none of the authors have or had a conflict of interest with regard to this study submitted to you for consideration., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Purpose: Use of 18-FDG PET-CT is increasing in patients with head and neck cancer, enabling the identification of metastases or synchronous malignancies, but also 'incidental' disease. We aimed to establish the rate of 'incidental' findings resulting from 18-FDG PET-specific imaging, that would not have been otherwise identified on other imaging, in patients with head and neck cancer undergoing staging or surveillance of disease., Methods: 18-FDG PET-CT was performed for investigation or surveillance. Case notes were reviewed retrospectively. Unexpected findings identifiable on CT imaging alone, or by FDG-PET were recorded. For those only identifiable with FDG-PET, findings were divided into either 'incidental' or 'intentional', and benign or malignant., Results: 93 patients underwent 18- FDG PET-CT. 86.0% had new pathology identified. 3.2% had a new malignancy identified. 37.6% had new findings on FDG-PET that would not have been identified on CT alone: 5.4% had 'intentional findings' (metastasis), and 32.3% had 'incidental findings' (synchronous malignancy or benign). 1.1% had a new malignancy on FDG-PET alone., Conclusions: Intentional and incidental findings are likely on 18-FDG PET-CT. Whilst important for patient management, there is an associated emotional and financial cost, which needs acknowledgement and further investigation.

Objectives: The diagnosis of cancer of unknown primary (CUP) in head and neck occurs when the treating clinicians have utilised all available diagnostic tests and failed to identify the origin of the disease. There is no agreed consensus on which diagnostic investigations to use, or the order in which to use them in, although broad recommendations exist. Small tumours arising in the tongue base can be below the limits of resolution of conventional diagnostic techniques. Given the difficulty in targeting the tongue base, current practice involves blind random biopsies, which leads to a variable detection rate. Robotically assisted surgical removal of the tongue base, tongue base mucosectomy (TBM) has been shown to improve diagnostic yield. This study reports the diagnostic hit rate for tongue base primaries using this technique., Design: Retrospective case review., Setting: UK Head and Neck Centres., Participants: Patients presenting as an unknown primary, investigated with clinical examination, PET-CT and palatine tonsillectomy., Main Outcome Measures: The detection of a primary site of head and neck cancer in the otherwise unknown primary tumour., Results: The primary tumour site was identified in the tongue base in 53% (n=17) of patients. In 15 patients the tumour was in the ipsliateral tongue base (88%) while in two cases (12%) the tumour was located in contra lateral tongue base., Conclusions: Trans-oral robotic assisted TBM raises the possibility of identifying over 50% of tumours that would otherwise be classified as CUP. Identifying these in the contralateral tongue base has implications for treatment planning and outcome., (© 2017 John Wiley & Sons Ltd.)

Background: Mucosal melanoma of the upper aerodigestive tract (MM-UADT) occurs in a complex anatomic region. It represents a small number of tumors of the head and neck and a small number of melanoma cases., Methods: Search strategies initially identified 600, 11 of which were included in this study., Results: All studies involved surgery and radiotherapy. None were randomized, and all were assessed as having a high risk of selection and performance bias. No studies reported quality of life, treatment-related mortality, or morbidity. The results indicate that the addition of radiotherapy to surgery reduces the rate of locoregional recurrence (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42-0.87). There was no statistically significant difference in overall survival (HR, 1.16; 95% CI, 0.98-1.37)., Conclusion: Surgical resection with postoperative radiotherapy remains the optimal treatment strategy for locoregional control. More robust studies and the use of molecular targeted therapies need to be undertaken to improve overall survival. © 2016 Wiley Periodicals, Inc. Head Neck 39: 819-825, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: This study investigated long-term survival outcomes in surgically treated oropharyngeal cancer patients with known human papilloma virus status., Methods: A case note review was performed of all patients undergoing primary surgery for oropharyngeal cancer in a single centre over a 10-year period. Human papilloma virus status was determined via dual modality testing. Associations between clinicopathological variables and survival were identified using a log-rank test., Results: Of the 107 cases in the study, 40 per cent (n = 41) were human papilloma virus positive. The positive and negative predictive values of p16 immunohistochemistry for human papilloma virus status were 57 per cent and 100 per cent, respectively. At a mean follow up of 59.5 months, 5-year overall and disease-specific survival estimates were 78 per cent and 69 per cent, respectively. Human papilloma virus status (p = 0.014), smoking status (p = 0.021) and tumour stage (p = 0.03) were significant prognostic indicators., Conclusion: The long-term survival rates in surgically treated oropharyngeal cancer patients were comparable to other studies. Variables including human papilloma virus status and tumour stage were associated with survival in patients treated with primary surgery; however, nodal stage and presence of extracapsular spread were non-prognostic.

Introduction: It is common practice to irrigate the operative site following tumor resection during major head and neck surgery. A variety of irrigation solutions are used, but there are few data on their relative efficacies in this context., Methods: The effect of different irrigation solutions on cell survival was assessed by clonogenic survival assay in 5 head and neck squamous cell carcinoma cell lines at different time points., Results: Saline had no effect on cell survival in any of the cell lines tested. Hydrogen peroxide, povidone-iodine, and a hydrogen peroxide/povidone-iodine mix caused complete cell death in all cell lines. Irrigation with distilled water caused a significant reduction in cell survival in 3 cell lines. Duration of exposure showed no effect on cell survival., Conclusion: These data suggest a significant difference in the cytocidal effect of commonly used irrigation solutions on head and neck cancer cells in an in vitro model., (© The Author(s) 2014.)

Background: Hypoxia is an important mechanism of treatment resistance in head and neck squamous cell carcinoma (HNSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The authors have investigated the role of 3 microRNAs, including the hypoxia-induced hsa-miR-210, as potential markers of hypoxia or prognosis., Methods: Three hypoxia-related microRNAs, hsa-miR-210, hsa-miR-21, and hsa-miR-10b, were measured in 46 samples from patients with HNSCC. Expression levels were correlated with clinicopathological variables and other markers of hypoxia: a published 99-gene hypoxia metagene, individual hypoxia-related genes such as TWIST1, and immunohistochemical expression of hypoxia-inducible factor 1 and its target gene carbonic anhydrase 9. We then performed survival analyses to investigate the prognostic significance of these microRNAs., Results: Only the level of hsa-miR-210 was significantly correlated with other markers of hypoxia, including the 99-gene hypoxia metagene (rho = 0.67, P < .001). We found no association between hsa-miR-210, hsa-miR-21, or hsa-miR-10b and clinicopathological variables such as tumor size, differentiation, and stage. However, high levels of hsa-miR-210 were associated with locoregional disease recurrence (P = .001) and short overall survival (P = .008). hsa-miR-21 and hsa-miR-10b had no prognostic significance., Conclusions: Expression of hsa-miR-210 in head and neck cancer correlates with other approaches for assessing hypoxia and is associated with prognosis. This warrants further study as a classification marker of patients for therapies involving modulation of hypoxia., ((c) 2010 American Cancer Society.)

Background: Techniques for detecting circulating tumor cells in the peripheral blood of patients with head and neck cancers may identify individuals likely to benefit from early systemic treatment., Methods: Reconstruction experiments were used to optimise immunomagnetic enrichment and RT-PCR detection of circulating tumor cells using four markers (ELF3, CK19, EGFR and EphB4). This method was then tested in a pilot study using samples from 16 patients with advanced head and neck carcinomas., Results: Seven patients were positive for circulating tumour cells both prior to and after surgery, 4 patients were positive prior to but not after surgery, 3 patients were positive after but not prior to surgery and 2 patients were negative. Two patients tested positive for circulating cells but there was no other evidence of tumor spread. Given this patient cohort had mostly advanced disease, as expected the detection of circulating tumour cells was not associated with significant differences in overall or disease free survival., Conclusion: For the first time, we show that almost all patients with advanced head and neck cancers have circulating cells at the time of surgery. The clinical application of techniques for detection of spreading disease, such as the immunomagnetic enrichment RT-PCR analysis used in this study, should be explored further.

Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16-48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (P=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.

Introduction: Treatment of advanced neck disease (N2c/N3) in head and neck squamous cell carcinoma is contentious. The aim of this study was to review the survival outcome following surgical excision of neck disease and the complications of this surgery., Patients and Methods: A retrospective review of the case notes of 39 patients treated at the Oxford Radcliffe Infirmary Head and Neck Unit with squamous cell carcinoma and advanced neck metastases confirmed as either pN2c or pN3 on histological examination was performed. Patients were treated with surgery and, in some cases, with adjunctive postoperative radiotherapy at the centre between August 1996 and November 2004. The study sought to establish the demographics, UICC staging/pathology, method of treatment, complications, recurrence and survival. Kaplan-Meier curves were used for statistical analysis of survival. Comparisons were then made between the cohort and historical control groups., Results: All patients were UICC stage IV disease. The 2- and 5-year overall survival in patients with resectable disease was 63% and 52%, respectively., Discussion: Patients with advanced neck disease have traditionally been thought to have terrible prognosis and, therefore, treatment is controversial. In treating advanced head and neck cancer, there has been a recent trend away from surgery towards chemotherapy and/or radiotherapy., Conclusions: Comparing this study group to historical controls that include chemotherapy and/or radiotherapy, the outcomes appear favourable. The use of a combination of radiotherapy and surgery is advocated; it is suggested that advanced neck disease can have an acceptable prognosis and morbidity and that local disease control may be achieved.

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.

Background: Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1alpha and HIF-2alpha, which have different effects in genetic knock-out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF-alpha expression in tumors., Methods: The expression of HIF-1alpha, HIF-2alpha, carbonic anhydrase-9 (CA-9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome., Results: High HIF-1alpha was expressed in 45 of 140 tumors (30%), HIF-2alpha was expressed in 21 of 139 tumors (14%), and CA-9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF-1alpha expression and HIF-2alpha expression (P =.0001). HIF-1alpha alone was associated with a worse disease-specific survival (DSS) (P =.05) and disease-free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF-1alpha and high HIF-2alpha. High HIF-1alpha/high HIF-2alpha expression was an independent prognostic factors in DSS (P = .04) and DFS (P =.005) in multivariate analyses. There was no correlation noted between Hb and HIF-1alpha, HIF-2alpha, or CA-9., Conclusions: HIF-1alpha alone was correlated with DSS and DFS. The additive effect of HIF-2alpha on poor prognosis suggested that different pathways may be regulated by HIF-2alph. Anemia that was not related to HIF-alpha expression suggests that tumor intrinsic factors regulate HIF-alpha therefore, anemia may be a surrogate marker for other factors that affect outcome.

Purpose: The use of erythropoietin in head and neck squamous cell carcinoma (HNSCC) has been associated with poor survival. This study examines the protein and mRNA expression of erythropoietin and erythropoietin receptor in HNSCC and their relation to hypoxia, hemoglobin (Hb), and clinical outcome., Experimental Design: The immunohistochemical expression of erythropoietin and erythropoietin receptor was assessed in 151 cases of HNSCC. Expression was compared with the hypoxia-dependent proteins hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase-9 (CA-9) and correlated with clinical outcome. The mRNA expression of erythropoietin and erythropoietin receptor was measured in paired samples of HNSCC., Results: Erythropoietin and erythropoietin receptor were expressed in 95% and 99% of tumors, respectively. Using a weighed expression score, there was a positive correlation between erythropoietin and erythropoietin receptor expression (r = 0.18, P = 0.03). HIF-1alpha (r = 0.38, P < 0.01) and CA-9 (r = 0.26, P = 0.002) correlated with erythropoietin expression, but there was no correlation with erythropoietin receptor. No correlation was found between Hb and erythropoietin (r = 0.07, P = 0.36) or erythropoietin receptor (r = -0.02, P = 0.8), and no survival difference between high and low erythropoietin or erythropoietin receptor expression (P = 0.59 and P = 0.98, respectively). The mRNA expression of erythropoietin (P = 0.03) but not erythropoietin receptor (P = 0.62) was significantly increased in 11 paired samples of HNSCC., Conclusion: In vivo, the HIF pathway regulates erythropoietin at the mRNA level but not erythropoietin receptor expression in HNSCC. Anemia does not seem to influence the hypoxic microenvironment of tumors sufficiently to alter the expression of erythropoietin. The effects of exogenous erythropoietin may be acting via receptors expressed on tumor cells in vivo, or on vascular cells, which also express the pathway.