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Background: We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC)., Methods: A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients., Results: HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases., Conclusion: HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objectives: Ultrasound-guided wire (USGW) localisation for small non-palpable tumours before a revision head and neck surgery is an attractive pre-operative option to facilitate tumour identification and decrease potential complications. We describe five cases of pre-operative USGW localisation of non-palpable head and neck lesions to facilitate surgical localisation and resection., Methods: All patients undergoing pre-operative USGW localisation for non-palpable tumours of the head and neck region at London Health and Sciences Center, London, Ontario, Canada, were included. All the USGW localisations were performed by the same interventional radiologist, and the surgeries were performed by fellowship trained head and neck surgeons., Results: Five patients were included. All patients were undergoing revision surgery for recurrent or persistent disease. All successfully underwent a pre-operative USGW localisation of the non-palpable lesion before revision surgery. All lesions were localised intra-operatively with no peri-operative complications., Conclusions: USGW localisation is a safe and effective pre-operative technique for the identification of small non-palpable head and neck tumours., (Copyright © 2023 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Purpose: Head and neck cancer (HNCa) presents numerous challenges secondary to treatment. While there is substantial clinical awareness to the range of challenges demonstrated in this population, information on the impact of post-treatment fatigue is limited. This study investigated the degree of perceived fatigue in those treated for HNCa., Methods: The study was a cross-sectional, self-report, survey design. Adult participants (n = 47) completed a series of three questionnaires; two validated fatigue measures - the Fatigue Screening Inventory (FSI) and the Multidimensional Fatigue Inventory (MFI-20) and a general health-related quality of life measure the European Organisation of Research on the Treatment of Cancer - Quality of Life Questionnaire (EORTC-QLQC30) and the head and neck site specific module (QLQ - H&N 35) were administered., Results: Of the 47 participants, more than half (55%) were identified as having clinically significant self-reported levels of fatigue. Correlational analysis revealed an inverse relationship between fatigue and overall health-related quality of life (HRQOL) implying that as fatigue increases, one's perceived HRQOL decreases., Conclusions: These data suggest that efforts to proactively screen for and index fatigue and seek anticipatory interventions may benefit both short- and long-term HRQOL outcomes in those diagnosed with HNCa., Level of Evidence: IV., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV + OPSCC patients., Methods: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes., Findings: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10 -5 ) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation., Interpretation: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV + OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned., Funding: CIHR, European Union, and the NIH., Competing Interests: Declaration of interests PYFZ, JWB, PCB, JSM and ACN have a US patent pending for the UWO3 score. All other authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Primary radiation therapy with or without chemotherapy (RT/CRT) is the most common treatment for oropharyngeal squamous cell carcinomas (OPSCC), but there has been an increase in transoral surgery (TOS) for T1-2 tumors. Because only a subset of T1-2 tumors are TOS-favorable, nonrandomized comparisons between RT/CRT and TOS could be confounded by indication. We aimed to compare outcomes of potential TOS-candidates versus non-TOS candidates, among patients who underwent RT/CRT for early T-stage OPSCC., Methods and Materials: For patients treated with RT/CRT for early-stage human papilloma virus positive OPSCC between 2014 and 2018, pretreatment imaging was reviewed by 3 head and neck surgeons, blinded to outcomes, to assess primary-site appropriateness for TOS, and extracapsular extension (ECE) was scored by a head and neck neuroradiologist. We compared outcomes based on surgical favorability pertaining to (1) the primary site tumor alone and (2) the primary site and an absence of ECE. Kaplan-Meier estimates for overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared using the log-rank test, with Cox regression used for multivariable modeling., Results: One hundred and forty-three patients were evaluated, of which 121 were male (84.6%), the median age was 59.4 years, and all of them were p16 positive (100%). The primary site was TOS-favorable in 115 of 143 (80.4%). Patients with TOS-favorable primary site experienced superior 5-year OS (89.8% vs 71.2%, P = .017), DSS (90.4% vs 63.4%, P = .022), and RFS (83% vs 49.4%, P = .04) compared with TOS-unfavorable patients. Similarly, patients with a TOS-favorable primary site and no ECE on imaging 101 of 143 (70.6%), had improved OS, DSS, and RFS (P < .05) compared with TOS-unfavorable patients., Conclusions: In this first study to assess surgical favorability as a prognostic factor among patients with T1/2 p16+ OPSCC, patients with TOS-favorable early-stage OPSCC have better outcomes than TOS-unfavorable patients. This provides valuable prognostic information for patients, and also suggests the risk of confounding by indication in nonrandomized comparisons of treatment modalities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown., Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC., Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up., Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings)., Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects., Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively)., Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes., Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Background: Neck carcinoma of unknown primary (CUP) is a frequent scenario. Transoral robotic mucosectomies (TORM) of pharynx have increased rate of primary identification, but come with cost of treatment delay., Methods: We reviewed patients who underwent CUP protocol from 2014 to 2020. Patients with cervical nodes carcinoma and failure to localize a primary source were classified as CUP. We determined primary identification rate and postoperative complications., Results: We included 65 patients underwent TORM. Surgical approach consisted of lingual and/or palatine tonsillectomies. The primary detection rate was 49.2%. Average weight reduction was 2.5 ± 4.3 kg. The average number of days from consultation to definitive treatment was 52.2 ± 18.3., Conclusion: A systematic approach to patients with CUP showed a promising primary identification rate compared to panendoscopy alone. TORM carries a small risk of complications. The benefits of primary identification must be weighed with the morbidity and delay to definitive treatment., (© 2022 Wiley Periodicals LLC.)

Background: Numerous studies of head and neck squamous cell carcinoma (HNSCC) have demonstrated disparate outcomes by race and ethnicity. Beyond known associations with socioeconomic variables, whether these are also associated with differences in tumor molecular composition has thus far been poorly explored., Methods: We downloaded clinical and multiplatform molecular data from The Cancer Genome Atlas and other published studies. These were compared between non-Hispanic Black (n = 43) and White (n = 354) patients with non-HPV-related tumors, using multivariable models. Publicly available validation cohorts were used., Results: Black patients had poorer progression-free survival than White patients. Tumors of Black patients had greater copy number aberrations, and increased SFRP1 methylation and miRNA-mediated PRG4 silencing associated with poor survival. PI3K/AkT/mTOR pathway proteins were differentially expressed., Conclusions: There are molecular differences between tumors of Black and White patients that may partially account for differences in survival. These may inform targeted treatment decisions to achieve equitable outcomes., (© 2022 Wiley Periodicals LLC.)

Purpose: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking., Methods: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial., Results: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time ( P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years ( P = .015). Dry mouth scores were higher in RT patients over time ( P = .041)., Conclusion: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355)., Competing Interests: Anthony C. NicholsResearch Funding: Novartis Canada Pharmaceuticals Inc (Inst) Eric BertheletResearch Funding: Eisai Eric WinquistConsulting or Advisory Role: Merck, Bayer, Eisai, Amgen, Roche, IpsenResearch Funding: Roche/Genentech (Inst), Merck (Inst), Pfizer (Inst), Eisai (Inst), Ayala Pharmaceuticals (Inst) David A. PalmaThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: London Health Sciences Centre (LHSC)Patents, Royalties, Other Intellectual Property: US patent: a method for analyzing a three-dimensional computed tomography image, US patent application no. 61/896349 (not licensed, no commercial or financial impact)No other potential conflicts of interest were reported.

Purpose: Individuals with head and neck cancer (HNCa) face myriad biopsychosocial challenges. Even after treatment completion, these challenges may cause continued disablement and diminished quality of life (QoL). Resilience may serve to minimize the disabling impact of HNCa and, in turn, maximize QoL. The purpose of this study was to formally assess resilience in HNCa survivors and explore its relationship with QoL., Methods: A cross-sectional descriptive study was conducted. Forty HNCa survivors completed three validated, self-report questionnaires pertaining to the collection of resilience and QoL data. Descriptive and correlational analyses were performed., Results: Resilience was identified in HNCa survivors and a positive correlation was found between resilience and QoL., Conclusions: Data suggest that resilience may buffer the influence of HNCa on QoL. Thus, screening for reduced levels of resilience may proactively facilitate identification of those who are most vulnerable to the psychosocial impact of HNCa. Interventions that foster resilience may ameliorate the challenges of HNCa and maximize QoL.

Objectives/hypothesis: Free flap transfer offers a versatile option for reconstruction in head and neck surgery, with success rates over 95%. There remains a substantial re-exploration rate of roughly 5% to 15%, with early recognition of compromise essential to flap survival. Monitoring techniques are highly desirable, with the gold standard being clinical monitoring. The Cook-Swartz Doppler (CSD) probe utilizes Doppler technology to inform clinicians about real-time flow. We aim to describe our adoption of this technology in 100 consecutive free flaps., Study Design: Prospective case series., Methods: Prospective data were collected from July 2014 to June 2015 on 100 consecutive free flaps performed at a head and neck unit in London, Ontario. All patients had a CSD inserted for arterial and venous monitoring., Results: A total of 100 free flaps were performed on 99 patients. Sensitivity was 87.1% and specificity was 85.7%. Positive predictive value was 98.8% and negative predictive value was 33.3%. False-negative and false-positive rate were 1.0% and 12.0%, respectively. The exploration rate was 12%, with no flap loss and two partial debridements. The CSD was helpful in management in 9% of cases and was clinically unhelpful in 11% of cases, with 10 of 11 abnormal signals ignored. There were three unique CSD complications; one retained wire, one pedicle laceration during extraction, and one clot around the probe interrupting signal., Conclusions: The CSD is a helpful adjunct to clinical monitoring but has unique complications, which were not previously described. Pros and cons must be considered for new centers adopting this technology., Level of Evidence: 4 Laryngoscope, 131:E1854-E1859, 2021., (© 2021 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Importance: Although the survival impact of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is well known, there has been conflicting and scarce evidence on the role of HPV in non-OPSCC., Objective: To undertake a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of all published studies on the association between HPV status and survival outcomes in patients with non-OPSCC, analyzing each site separately., Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to December 16, 2019, for English-language articles., Study Selection: Analysis comprised randomized clinical trials or observational studies that each included at least 10 patients with non-OPSCC in which the presence of HPV was analyzed, survival outcomes were reported, and a clinical follow-up of 1 year or more was performed. Studies excluded were those in which data on OPSCC and non-OPSCC were not distinguished between both cohorts and studies on patients with distant metastatic tumors at diagnosis. Final analysis included outcomes that were analyzed in at least 3 studies., Data Extraction and Synthesis: Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model., Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points were disease-specific survival (DSS) and disease-free survival (DFS)., Results: Of the 3947 articles screened, a total of 22 observational and 2 randomized clinical trials were included in the analysis, representing 24 854 patients. In oral cavity locations, OS was not significantly associated with HPV positivity (hazard ratio [HR], 1.16; 95% CI, 0.83-1.61; I2 = 71%); however, HPV-positive tumors showed worse DFS (HR, 1.81; 95% CI, 1.12-2.91; I2 = 47%). Laryngeal and hypopharyngeal HPV-positive tumors were associated with improved OS (HR, 0.71; 95% CI, 0.54-0.92; I2 = 38% and HR, 0.60; 95% CI, 0.47-0.76; I2 = 0%), respectively, whereas, in nasopharyngeal locations HPV was not associated with OS (HR, 0.82; 95% CI, 0.49-1.38; I2 = 46%) or DSS (HR, 0.55; 95% CI, 0.22-1.42; I2 = 65%)., Conclusions and Relevance: In this meta-analysis of 24 studies, HPV was associated with improved OS in laryngeal and hypopharyngeal locations but not in the oral cavity and the nasopharynx. This information may be useful for future clinical studies of laryngeal and hypopharyngeal tumors and whether HPV status should be incorporated in prognostication of patients with these cancers.

Background: Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs)., Methods: Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance., Results: Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib., Conclusions: We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

Objectives: Survival in head and neck squamous cell carcinoma (HNSCC) has been associated with patient sex, typically with males experiencing poorer outcomes. It is unclear if this disparity is based in divergent tumor biology. We analyzed the TCGA HNSCC cohort to uncover disparities in the somatic single nucleotide variation (SNV), copy number alteration (CNA) and mRNA abundance profiles between males and females. Critically, we stratified our results by tumor HPV status to control for this significant confounder., Methods: SNV, CNA and mRNA abundance differences between males and females were compared separately for the HPV-positive (n = 67) and negative (n = 431) TCGA HNSCC cohorts. Overall survival outcomes were compared in males and females in both HPV-positive and HPV-negative subsets of patients., Results: Females were found to have poorer overall survival than males (p = 0.048), largely due to higher rates of HPV-positive disease among men. SNV analysis revealed that in HPV-positive disease, there were no differences by sex after accounting for the false discovery rate (FDR). In HPV-negative tumors, BRWD3 mutations occurred more frequently in the tumors of female patients compared to males after adjusting for the FDR (p = 0.02). Further, HPV-negative BRWD3 mutant tumors were found to have significantly worse 5-year overall survival compared to wildtype on multivariate analysis (p = 0.02). There were 88 heterozygous deletions and 14 amplifications that were differentially altered between male and female HPV-negative tumors and associated with expression changes. Pathway analysis of these genes revealed that tumors from males were enriched in five pathways including chemokine and phosphophatidylinositol signaling., Conclusions: Reanalysis of the TCGA HNSCC dataset stratified by sex revealed that males in this cohort had a significant survival advantage, due to a higher proportion of HPV-positive disease. Mutations in BRWD3 were more frequent in HPV-negative tumors of females and were associated with poorer overall survival. BRWD3 may represent a novel biomarker of patient outcomes, but will require additional validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC., Materials and Methods: SYK protein abundance in patient tumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models., Results: Moderate to high protein expression of SYK was observed in 24% of patient tumors and high SYK expression was exclusively observed in HPV-positive samples (p < 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models., Conclusions: HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Considerable evidence now indicates that individuals living in underprivileged neighbourhoods have higher rates of mortality and morbidity independent of individual-level characteristics. This study explored the impact of geographical marginalization on smoking cessation in a population of individuals with a diagnosis of head and neck cancer. The aims of this study were twofold: (1) assess the prevalence of smoking cessation in those with a previous diagnosis of head and neck cancer, (2) analyze the determinants of smoking alongside area-based measures of socioeconomic status., Methods: This was a cross-sectional study. We administered a self-reported nicotine dependence package to participants between the ages of 20-90 with a previous mucosal head and neck cancer diagnosis and with a history of tobacco use. Using the Canadian Marginalization (CAN-Marg) Index tool based on 2006 Canada Census data we compared the degree of marginalization to the smoking status. For those individuals who were currently smoking, nicotine dependence and readiness to quit were assessed. A summative score of marginalization was compared to smoking status of individuals., Results: The results from this study indicate that the summative level of marginalization developed from the combined factors of residential instability, material deprivation, ethnic concentration and dependency may be important factors in smoking cessation., Conclusions: This analysis of determinants of smoking alongside area-based measures of socioeconomic status may implicate the need for targeted population-based smoking cessation interventions.

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signaling axis, particularly in the PIK3CA gene. PI3K-targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K-targeted drugs for patients, in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28-cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K-targeted drugs. Further, we reveal PI3Kα inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients., (© 2018 UICC.)

Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Importance: There is a need to summarize the available evidence and provide quantitative data of the most important prognostic factors for patients with metastatic cutaneous squamous cell carcinoma of the head and neck region with regional lymph node metastasis (McSCCHN)., Objective: To undertake a PRISMA-compliant systematic review and meta-analysis of all published studies on the risk factors for overall survival (OS), locoregional control (LRC), locoregional recurrence (LRR), and disease-specific survival (DSS) for patients with McSCCHN., Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to August 2018 for English-language articles., Study Selection: Inclusion criteria were randomized clinical trials or observational studies reporting on at least 10 patients with McSCCHN; studies analyzing 1 defined risk factor; reporting OS, LRC, LRR, or DSS; and clinical follow-up of 1 year of more. For the final analysis we included risk factors that were analyzed for the same outcome in at least 3 studies. Of the 2923 articles screened, 21 articles met the inclusion criteria., Data Extraction and Synthesis: PRISMA guidelines were used for abstracting the data. Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model. All analysis took place between January and October 2018., Main Outcomes and Measures: The primary end point was OS. Secondary end points included LRC, LRR, and DSS., Results: A total of 20 observational studies and 1 randomized clinical trial were identified, representing 3534 patients (some reviewed articles reported no demographic characteristics), and were included in the analysis. Significant risk factors associated with OS were immunosuppression (hazard ratio [HR] of death, 2.66; 95% CI, 2.26-3.13), extracapsular spread (HR, 1.90; 95% CI, 1.12-3.23), adjuvant radiotherapy (HR, 0.45; 95% CI, 0.27-0.78), lymph node ratio (HR, 1.91; 95% CI, 1.09-3.35), and advanced age (HR, 1.03; 95% CI, 1.00-1.07). Immunosuppression (HR, 3.82; 95% CI, 2.47-5.92) and adjuvant radiotherapy (HR, 0.52; 95% CI, 0.33-0.84) were also significant risk factors for DSS., Conclusions and Relevance: Immunosuppressed patients and those with extracapsular extension have poor prognosis. Adjuvant radiotherapy is associated with an improvement in OS. These risk factors will assist with better risk stratification and may also help to inform future clinical trials.

Objectives: The PI3K/AKT/mTOR pathway is frequently altered in head and neck squamous cell cancer (HNSCC), making this pathway a logical therapeutic target. However, PI3K targeting is not universally effective. Biomarkers of response are needed to stratify patients likely to derive benefit and exclude those unlikely to respond., Materials and Methods: We examined the sensitivity of cell lines with constitutively-active (G12V mutant) HRAS and wild-type HRAS to PI3K inhibition using flow cytometry and cell viability assays. We then overexpressed and silenced HRAS and measured sensitivity to the PI3K inhibitor BYL719. Immunoblotting was used to determine activation of the PI3K pathway. MEK and mTOR inhibitors were then tested in HRAS mutant cells to determine their efficacy., Results: HRAS mutant cell lines were non-responsive to PI3K inhibition. Overexpression of HRAS led to reduced susceptibility to PI3K inhibition, while knockdown improved sensitivity. Immunoblotting revealed suppressed AKT phosphorylation upon PI3K inhibition in both wild-type and HRAS mutant cell lines, however mutant lines maintained phosphorylation of S6, downstream of mTOR. Targeting mTOR effectively reduced viability of HRAS mutant cells and we subsequently examined the ERK-TSC2-mTOR cascade as a mediator of resistance to PI3K inhibition., Conclusions: HRAS mutant cells are resistant to PI3K inhibition and our findings suggest the involvement of a signalling intersection of the MAPK and PI3K pathways at the level of ERK-TSC2, leading to persistent mTOR activity. mTOR inhibition alone or in combination with MAPK pathway inhibition may be a promising therapeutic strategy for this subset of HNSCC tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

PIK3CA is the only frequently-mutated, directly druggable oncogene in head and neck squamous cell carcinoma (HNSCC). However, it is unclear if a molecularly-driven intervention trial can be launched successfully, particularly within a single-institution setting secondary to the infrastructure necessary for mutation detection, mutation prevalence, and patient willingness to participate. This study aimed to evaluate 1) local frequency of PIK3CA activating mutations in HNSCC, 2) timeliness of our mutation-profiling clinical pathway, and 3) patients' willingness to enroll in a novel neoadjuvant drug trial. Tissue biopsies of 25 consecutive cases of HNSCC were tested for activating PIK3CA mutations at three mutational hotspots by real-time polymerase chain reaction. Mutations prevalence and number of working days accrued in determining PIK3CA mutational status were calculated. In addition, 30 HNSCC patients were surveyed prospectively regarding their willingness to participate in a hypothetical drug trial. Survey data were summarized descriptively. 4 of 25 (16 %) tumors harbored a PIK3CA activating mutation, including one at codon E542K, two at codon E545K/D, and one at codon H1047R. On average, this result was obtained in approximately 15 working days (range, 9-24 working days). The majority of patients surveyed (70 %) indicated their willingness to participate in a targeted PIK3CA trial. This study provides evidence that within a single institution, PIK3CA activating mutations can be detected with expected frequency, with sufficient timeliness and sufficient patient interest to mount a targeted intervention trial that may lead to improved tumor response in selected HNSCC patients.

Objectives/hypothesis: Medical students graduate with the knowledge and skills to be undifferentiated general physicians. Otolaryngology-head and neck surgery (OtoHNS) is an essential component of primary healthcare, but is disproportionately under-represented in undergraduate medical education (UME). Advances and innovations in educational technology may represent an exciting and creative solution to this important problem. Failure to meet this educational need will result in substantial downstream effects in primary healthcare delivery. The objectives of this study were to 1) demonstrate current deficits in OtoHNS teaching at the UME level; 2) develop, validate, and critically appraise educational innovations that may enrich OtoHNS teaching in medical school curricula; and 3) propose a process for standardization of learning objectives for OtoHNS in UME as it relates to development and deployment of such educational tools., Study Design: A white paper, prepared as a Triological Society thesis, which consolidates a prospective 10-year investigation of the problem of and potential solutions for under-representation of OtoHNS in UME. Cited datasets include multicenter surveys, cohort studies, and prospective, randomized controlled trials., Methods: A series of published and unpublished data were synthesized that addresses the following: 1) the current state of OtoHNS teaching at the UME level with respect to content, volume, structure, and methods; and 2) educational innovations including e-learning and simulation with emphasis on validity and learning effectiveness. Educational innovations specific to postgraduate (residency) training were excluded., Results: Data support the observation that there is uniformly disproportionate under-representation of OtoHNS within UME curricula. Medical school graduates, especially those pursuing primary care specialties, report poor overall comfort levels in managing OtoHNS problems. A series of novel teaching methods were developed and validated using e-learning and simulation. Selected technologies may have a role in medical student teaching. It has been shown that e-learning has limited value in teaching complex spatial anatomy to novice learners, but good value in teaching basic clinical knowledge and selected technical skills. The role of simulation as it pertains to the novice learner is evolving. Important factors to consider during development of these tools include: 1) knowledge base and learning style of the learner, 2) complexity and nature of the learning objectives, 3) understanding the features and limitations of different technological genres, and 4) a team approach to module development. There remains a role for traditional teaching paradigms such as lectures, labs, and standardized patients; however, the choice of instructional genre should be fundamentally tailored to the nature of the learning outcomes., Conclusions: Enriching OtoHNS teaching in medical school is essential optimize primary care delivered to patients. Although e-learning and simulation are broadly accepted and desirable by today's medical students, these technologies should be woven into the fabric of UME pedagogical principles judiciously, and only after empiric assessment. Foundational to the development and implementation of these technologies is the framework of standardized competency-based learning objectives, common to all graduating medical students., Level of Evidence: NA, (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: To evaluate the feasibility and efficacy of transtympanic L-N-Acetylcysteine (L-NAC) administration in patients receiving cisplatin chemotherapy for head and neck cancer., Study Design: Prospective randomized nonblinded open-label clinical trial., Methods: Transtympanic 2% L-NAC was administered to one randomly selected ear with the other ear as control in each patient. Primary outcome parameter was the difference in the loss of pure tone averages (PTA) at 2, 4, and 8 kHz between the L-NAC and control ear at 1 to 2 months following chemotherapy., Results: Eleven patients completed the study, with two patients demonstrating significantly better hearing in the L-NAC treated ear (18.2%). However, for the overall group, the difference in hearing preservation did not reach significance. Two percent L-NAC administration was well tolerated in this patient population. There were no adverse effects associated with L-NAC., Conclusion: Although the study did not demonstrate a significant benefit overall, transtympanic L-NAC was associated with significantly better hearing in two patients. Better delivery methods may improve the efficacy of this treatment. L-NAC remains a promising drug in preventing cisplatin-induced ototoxicity., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To assess the oncological and functional outcomes of T1b squamous cell carcinoma (SCC) of the glottic larynx treated with laser in comparison with radiation., Design: A Canadian multicenter cohort study., Setting: Three tertiary referral centers for head and neck cancer- Dalhousie University in Halifax, Nova Scotia, Western University in London, Ontario and the University of Manitoba, Winnipeg., Methods: Patients with T1b glottic SCC who underwent transoral laser resection or radiation as the primary modality of treatment., Outcome Measures: Oncological outcomes were evaluated using local control, laryngeal preservation, disease free survival and disease specific survival. Voice outcomes were assessed using the Voice Handicap Index-10 (VHI-10)., Results: 63 patients met study criteria. 21 were treated with laser and 42 with radiation. Oncologic outcomes at 2 years for laser and radiation demonstrated local control of 95% and 85.9%; laryngeal preservation of 100% and 85.9%; disease free survival of 88.7% and 85.9% and overall survival of 94.1% and 94.8% respectively. VHI-10 data was available for 23/63 patients. During the last follow up visit VHI-10 ranged from 0 to 11 (median 6) in the laser group and 0 to 34 (median 7) in the radiation group., Conclusion: T1b SCC of the glottis can be effectively treated with transoral laser microsurgery with oncological outcomes that are at least equivalent to radiation. For patients with VHI scores, voice quality was similar between the two groups. To our knowledge this is the first study directly comparing the oncologic and voice outcomes with laser and radiation for the treatment of glottic cancer involving the anterior commissure.

Due to significant differences in healthcare structure between the United States and Canada, there are unique barriers to adopting new medical technology in Canada. In this article, we describe our experience developing a transoral robotic surgery (TORS) program at Western University. Specifically, we outline the steps that were necessary to obtain institutional and multidisciplinary team approval, financial support, as well as surgeon and allied healthcare personnel training. This experience can potentially be used as a roadmap for other Canadian institutions pursuing a TORS program.

Background: An epidemic of human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC) has been reported worldwide largely due to oral infection with HPV type-16, which is responsible for approximately 90% of HPV-positive cases. The purpose of this study was to determine the rate of HPV-positive oropharyngeal cancer in Southwestern Ontario, Canada., Methods: A retrospective search identified ninety-five patients diagnosed with OPSCC. Pre-treatment biopsy specimens were tested for p16 expression using immunohistochemistry and for HPV-16, HPV-18 and other high-risk subtypes, including 31,33,35,39,45,51,52,56,58,59,67,68, by real-time qPCR., Results: Fifty-nine tumours (62%) were positive for p16 expression and fifty (53%) were positive for known high-risk HPV types. Of the latter, 45 tumors (90%) were identified as HPV-16 positive, and five tumors (10%) were positive for other high-risk HPV types (HPV-18 (2), HPV-67 (2), HPV-33 (1)). HPV status by qPCR and p16 expression were extremely tightly correlated (p < 0.001, Fishers exact test). Patients with HPV-positive tumors had improved 3-year overall (OS) and disease-free survival (DFS) compared to patients with HPV-negative tumors (90% vs 65%, p = 0.001; and 85% vs 49%, p = 0.005; respectively). HPV-16 related OPSCC presented with cervical metastases more frequently than other high-risk HPV types (p = 0.005) and poorer disease-free survival was observed, although this was not statistically significant., Conclusion: HPV-16 infection is responsible for a significant proportion of OPSCC in Southwestern Ontario. Other high-risk subtypes are responsible for a smaller subset of OPSCC that present less frequently with cervical metastases and may have a different prognosis.

Background: Early detection of circulating tumor cells (CTCs) offers the possibility of improved outcome for patients with head and neck squamous cell cancer (HNSCC)., Methods: Patients with advanced-stage HNSCC (stage III/IV) were tested for CTCs using the CellSearch system (a registered trade name), which has been approved by the U.S. Food and Drug Administration (FDA) for monitoring CTCs in other cancers., Results: CTCs were detected in 6 of 15 patients with advanced-stage HNSCC (range, 1-2 cells/7.5 mL of blood). CTCs were significantly associated with patients with lung nodules >1 cm (p = .04). There was also a suggestion of improved survival in the CTC-negative versus the CTC-positive patients (p = .11)., Conclusions: CTCs can be successfully isolated in patients with advanced-stage HNSCC using the CellSearch system. CTC detection may be important for prognosis, evaluating treatment outcome, and for determining efficacy of adjuvant treatments., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Radiotherapy is commonly used to treat neoplasms of the head and neck, and fibrosis is a known side effect. The Cutometer is a device that quantifies properties of the skin. The goal of the study was to validate the Cutometer in normal neck tissues and then quantify fibrosis in radiated necks., Methods: We performed a prospective study of 251 patients. The elasticity and stiffness parameters were recorded. Control patients were compared to determine the correlation between their left and right sides. Next, the treatment groups were compared using a nonparametric test (Kruskal-Wallis)., Results: We found a significant correlation between the left and right sides of the control patients' necks, supporting the view that the Cutometer provides reproducible measurements in the normal neck. Furthermore, the Cutometer demonstrated reduced elasticity in necks treated with radiation, surgery-radiation, and chemoradiation. No significant difference in stiffness was seen., Conclusion: The Cutometer may serve as a valuable and valid tool for the measurement of neck skin elasticity. Radiated patients have a quantifiable decrease in their skin elasticity.

Purpose: Both short- and long-term outcomes for individuals with head and neck cancer (HNCa) may be influenced by multiple factors. Identification of distress in those with HNCa may provide a critical dimension that influences quality of life (QoL). Consequently, this investigation assessed distress and QoL in those with HNCa., Methods: This study utilized a cross-sectional, self-report survey design. Participants included 49 adults diagnosed with HNCa. Upon assessment, post-diagnosis time ranged between 3-12 months. All participants completed a validated distress screening measure, the Brief Symptom Inventory 18 (BSI-18), and the EORTC general QoL assessment tool (EORTC-QLQ-C30) and HNCa module (EORTC-QLQ-H&N35)., Results: Approximately 22% of participants demonstrated clinically significant distress. Additionally, distress was significantly related to QoL status and specific symptoms., Conclusions: Screening for distress in those with HNCa may permit early identification of problems that influence QoL outcomes. The ability to identify distress early may also facilitate timely intervention to reduce distress and optimize QoL.

Objective: To conduct high-throughput mutational analysis in 6 commonly used head and neck cancer cell lines. Comprehensive mutation analysis of primary head and neck squamous cell carcinoma (HNSCC) tumors has recently been reported, and mutations in the NOTCH receptors, TP53 and CDKN2A, were key findings. Established cell lines are valuable tools to study cancer in vitro. Similar high-throughput mutational analysis of head and neck cancer cell lines is necessary to confirm their mutational profile., Design: DNA was extracted from American Type Culture Collection (ATCC) cell lines Cal27, Detroit562, FaDu, SCC4, SCC15, and SCC25. Cell line identity was confirmed by short tandem repeat (STR) analysis, and human papillomavirus (HPV) infection status was assessed by real-time polymerase chain reaction. A total of 535 cancer-associated genes were sequenced through a limited exome capture on the Illumina HiSeq system., Setting: London Regional Cancer Program., Results: The identity of the 6 cell lines was confirmed by STR analysis, and all lines tested negative for HPV infection. We achieved an average of 129-fold coverage with paired-end 100 base-pair reads. Sequencing revealed an average of 38 damaging mutations in each cell line (range, 30-45). The TP53 mutations, predicted to confer loss of function, were noted in all cell lines, and damaging CDKN2A mutations were found in all lines except SCC15., Conclusions: High-throughput sequencing of head and neck cancer cell lines revealed similar mutations to those observed in primary tumors. Thus, these lines reflect the tumor biology of HNSCC and can serve as valuable models to study HNSCC in vitro.

Background: The ability to palpate neck masses and lymph nodes and appreciate qualities such as size, location, and consistency is critical for patient care and an important clinical skill for all physicians. Medical students currently learn neck palpation by practicing on healthy, standardized patients; however, studies of similar procedures have shown that educational models with simulated pathology help improve technique and confidence., Objective: Our goal was to create a tissue-mimicking neck model with palpable masses., Methods: Iterative design and development of a high-fidelity neck model using polyvinyl alcohol-cryogel (PVA-C), a nontoxic and biocompatible polymer that exhibits favourable tissue-mimicking elastic properties. Model geometries were digitally reconstructed from high-resolution cadaveric magnetic resonance imaging sections to create physical moulds through stereolithography. PVA-C was formulated to mimic the characteristics of human tissue., Results: A life-like neck model was built and consists of these components: muscle, larynx, spine, soft tissue, pathologic nodes, and skin., Discussion: A final neck model prototype has been completed and will be evaluated by otolaryngology consultants and residents for face and construct validity and assessed in a randomized, controlled trial to evaluate how it impacts students' ability to detect neck masses.

Purpose of Review: This article reviews the buccinator flap, its relevant surgical anatomy, surgical technique, and applications in head and neck reconstruction., Recent Findings: Reconstruction of defects after extirpation of head and neck neoplasms can be challenging and complex. Various reconstructive techniques, including skin grafts, regional flaps, and free tissue transfer, can be employed in restoration of form and function after ablative surgery. Although a wide array of reconstructive options is available, the technique employed will largely depend on the surgeon preference and experience. Commonly used pedicled flaps and free tissue transfer techniques can share several disadvantages, including prolonged operative time, poor cosmesis, donor site morbidity, functional limitations, and excessive tissue bulk for intraoral reconstruction. The ideal reconstructive method would adhere to the plastic surgery principle of replacement of 'like with like'. The ease of dissection and useful application makes the buccinator flap an excellent additional reconstructive option for the head and neck surgeon., Summary: The buccinator myomucosal flap is a versatile and dependable flap for head and neck reconstruction. Its minimal donor site morbidity, pliability, ease of elevation, and flexible usage while offering optimal functional and cosmetic results make it a viable option for select defects.

Background: The aim of this preliminary study was to determine the prevalence of trismus in head and neck cancer patients treated with radiotherapy with or without concomitant chemotherapy and surgery., Methods and Materials: Patients with malignant lesions in the head and neck treated with curative intent were comprehensively evaluated for trismus using subjective and objective measures., Results: A large proportion of the 70 patients recruited demonstrated moderate to severe subjective trismus (45.7%). Similarly, the vast majority of patients showed slight to severe trismus (91.4%) according to objective secondary outcome measures. Of these patients, 21 (65.6%) were also treated with concurrent chemoradiotherapy. When the radiation field involved the pterygoid muscles, 30 (93.8%) patients reported subjective trismus. Similarly, bilateral pterygoid muscle inclusion resulted in 28 (87.5%) patients with trismus., Conclusions: Trismus is a significantly prevalent consequence of treatment for head and neck cancer. Predictive factors include treatment with concurrent chemoradiotherapy and bilateral inclusion of the structures of mastication in the high-dose radiotherapy volume.

Objective: To study the treatment outcomes of N3 neck disease following primary chemoradiotherapy., Design: Retrospective cohort., Setting: Tertiary care centre., Methods: A review was conducted of 25 consecutive patients with N3 neck disease treated with primary platinum-based chemoradiotherapy. A neck dissection (ND) was offered in the event of clinical and/or radiologic evidence of residual disease on follow-up., Main Outcome Measures: Recurrence-free, disease-specific, and overall survival and patterns of failure., Results: A regional complete response (CR) was noted in 48% of the patients. ND was performed in 36% of the cases. The median duration between the end of radiation and ND was 71 days. The recurrence-free survival rates at 1 and 2 years were 73% and 64%, respectively. The 2-, 3-, and 5-year overall survival rates were 66.7%, 52%, and 31.2%, respectively. Disease-specific survival rates were 69.6%, 63.3%, and 50.6%, respectively. Nine patients developed distant recurrence, with one having concurrent local and regional recurrence as well. Patients in the CR group remained free of regional recurrence. Among the initial partial responders, 54% eventually developed distant metastasis compared to 17% in the CR group., Conclusion: Patients with N3 disease may be managed with chemoradiotherapy, with ND reserved for salvage. Distant metastasis accounts for most recurrences and for the reduction in survival.

Objective: To review the experience with scapular free tissue transfer at the University of Western Ontario and to describe the various applications of both the fasciocutaneous and osteocutaneous versions., Design: Retrospective review., Setting: Tertiary care centre., Methods: A retrospective review was conducted of patients who underwent a scapular free flap reconstruction between 1997 and 2007. Osteocutaneous and fasciocutaneous flaps were included. Demographic data including gender and age were collected. Defect analysis and complications were also reviewed., Main Outcome Measures: Defect analysis, flap-related complications, and non-flap-related complications., Results: Sixty procedures, including 31 osteocutaneous and 29 fasciocutaneous flaps, were performed. Most fasciocutaneous flaps were used for large lateral skull base and facial defects (70%). The skin paddle dimensions ranged from 4 × 3 to 15 × 10 cm. All osteocutaneous flaps were used for mandibular reconstruction. The length of the bony defect ranged between 4 and 12 cm. Eleven patients required osteotomies. In most cases, the facial or external carotid arteries and internal jugular or facial veins were selected as recipient vessels. A vein graft was required in four cases. The total flap failure rate was 5%. Seven patients who had osteocutaneous flaps suffered medical complications, including one mortality., Conclusions: Scapular free flaps are reliable options. Fasciocutaneous applications are suitable for defects requiring facial contouring or complex skull base defects. Osteocutaneous flaps are acceptable options for patients with comorbidities requiring bony reconstructions. The flap complication rates were acceptable even in medically higher-risk patients.

Background: Mucositis is one of the most debilitating side effects of head and neck cancer therapy and is currently believed to arise from an inflammatory cascade leading to cellular damage. However, no effective treatment has been identified despite extensive attempts with anti-inflammatory medications., Objective: To compare real-time microvascular inflammatory changes with oral mucositis levels in patients undergoing radiotherapy or chemoradiotherapy for head and neck tumours., Design: Prospective, longitudinal, cohort, observational study., Setting: Regional cancer program., Methods: Twenty patients with head and neck tumours were assessed on a weekly basis throughout the course of radiotherapy. Levels of mucositis were graded objectively using the Oral Mucositis Assessment Scale and subjectively using a patient symptom questionnaire. Video imaging of the sublingual microcirculation was obtained using orthogonal polarized spectral imaging to quantify inflammatory markers such as microcirculatory velocity, white blood cell margination, and extravasation., Results: Despite very high levels of objective and subjective mucositis, inflammatory changes were not present in the microcirculation., Conclusions: Typical microvascular inflammatory changes are not demonstrated in radiation-induced mucositis. These findings contradict the currently proposed mechanism of mucosal damage and may therefore have important implications in the development of novel therapeutic interventions.

Background: A quasi-experimental retrospective study was undertaken to evaluate a new concept of free tissue volume restoration combined with bridging reconstruction plate (compartment approach) to reduce plate-related complication rates., Methods: We evaluated 40 patients with large lateral mandible defects and associated complex soft tissue defects reconstructed with a revascularized soft tissue flap and titanium hollow screw reconstruction plates. A case-control comparison was performed based on reconstruction type: restoration of soft tissue defect (conventional approach-group 1) versus over-reconstruction of soft tissue defect (compartment approach-group 2)., Results: Plate exposure rate was 6 of 16 (38%) in group 1 versus 2 of 24 (8%) in group 2, and the difference was statistically significant (p = .04). The mean time to exposure was 10 months. Plate fracture rate was 6 of 23 (26.1%) in dentulous patients versus 1 of 17 (5.9%) in edentulous patients. Gastrostomy tube dependence was 6 of 16 (38%) in group 1 versus 6 of 24 (25%) in group 2., Conclusion: The "compartment approach" reduces plate exposure rate and gastrostomy tube dependence. Revascularized osseocutaneous reconstruction is still required in dentulous patients.

Objective: To comprehensively evaluate long-term quantitative and qualitative donor-site morbidity following radial forearm free tissue harvest., Design: A single-centre retrospective cohort study with internal controls was undertaken., Methods: Quantitative measurements of range of motion (ROM) of the forearm, wrist, and digits were performed. Grip and pinch strength and hand dexterity were also evaluated. Qualitative assessment was performed using the Michigan Hand Outcomes Questionnaire (MHQ), a validated quality of life instrument., Main Outcome Measures: Quantitative primary outcome measures were (1) wrist flexion and extension, (2 forearm pronation and supination, and (3) hand dexterity. The qualitative primary outcome measure was overall MHQ score., Results: The operated side demonstrated decreased hand dexterity (p = .008), with no change in wrist and forearm ROM. An increase in ROM of the little finger was found (p = .002). The MHQ demonstrated a perceived decrease in function (p = .031), an increase in pain (p = .045), and no difference in appearance (p = .486)., Conclusions: The radial forearm free flap results in measurable quantitative changes in hand function and limited changes in patient perception. Donor-site appearance does not seem to be an important factor.

Quality of life (QOL) considerations are uniquely important in head and neck oncology outcomes research due to the multidimensional impact of these tumors and their treatment. Patient variables, tumor variables and treatment variables must be considered comprehensively in order to maximize the validity of QOL outcome measures. There are a multitude of QOL instruments, which can be classified into: (1) general measures of health-related QOL, (2) general QOL instruments for patients with cancer, (3) disease-specific instruments for patients with head and neck cancer, (4) treatment-specific instruments and (5) symptom-specific instruments. This article will highlight commonly used validated QOL instruments in head and neck oncology.