Search

Background: Insurance status has been shown to impact survival outcomes. We sought to determine whether insurance affects the choice of treatment modality among patients with advanced (T4) oral cavity squamous cell carcinoma., Methods: This is a retrospective, population-based cohort study using the Survival, Epidemiology, and End Results Program database. The population included all adult (age ≥ 18) patients with advanced (T4a or T4b) oral cavity squamous cell carcinoma diagnosed from 2007 to 2016. The main outcome was the odds of receiving definitive treatment, defined as primary surgical resection. Insurance status was categorized into uninsured, any Medicaid, and insured groups. Univariable, multivariable, and subgroup analyses were performed., Results: The study population consisted of 2628 patients, of whom 1915 (72.9%) were insured, 561 (21.3%) had Medicaid, and 152 (5.8%) were uninsured. The multivariable model showed that patients who were 80 years or older, unmarried, received treatment in the pre-Affordable Care Act (ACA) period, and who were on Medicaid or uninsured were significantly less likely to receive definitive treatment. Insured patients were significantly more likely to receive definitive treatment compared to those on Medicaid or uninsured (OR = 0.59, 95% CI 0.46-0.77, p < 0.0001 [Medicaid vs. Insured]; and OR = 0.48, 95% CI 0.31-0.73 p = 0.001 [Uninsured vs. Insured]), however these differences did not persist when considering only those patients treated following the 2014 expansion of the ACA., Conclusions: Insurance status is significantly associated with treatment modality among adults with advanced stage (T4a) oral cavity squamous cell carcinoma. These findings support the premise of expanding insurance coverage in the US., (© 2023. The Author(s).)

Importance: High local recurrence rates with aggressive disease remain the main concern in oral cancer survival. Use of a translational device using fluorescence visualization (FV) approved by the US Food and Drug Administration and Health Canada, has shown a marked reduction in the 3-year local recurrence rate of high-grade oral lesions in a single-center observational study., Objective: To determine whether FV- guided surgery can improve local control rates in the treatment of in situ or T1 to T2 category oral squamous cell carcinoma (OSCC)., Design, Setting, and Participants: A multicenter randomized clinical trial was conducted in a surgical setting. A total of 457 patients were enrolled between January 18, 2010, and April 30, 2015. Data analysis of the intention-to-treat population was performed from April 3, 2019, to March 20, 2020. Patients with histologically confirmed high-grade dysplasia/carcinoma in situ or T1 to T2 category OSCC were randomized to receive traditional peroral surgery or FV-guided surgery., Intervention: Fluorescence visualization during surgery., Main Outcomes and Measures: The primary outcome was local recurrence of OSCC. Secondary outcomes were failure of the first-pass margin, defined as a histologically confirmed positive margin for severe dysplasia or greater histologic change of the main specimen (ie, not the margins taken from the resection bed), regional or distant metastasis, and death due to disease., Results: Of the 457 patients enrolled in the study, 443 patients (264 [59.6%] men; mean [SD] age, 61.5 [13.3] years) completed the randomized treatment: 227 FV-guided and 216 non-FV guided surgery. The median follow-up was 52 (range, 0.29-90.8) months. In total, 45 patients (10.2%) experienced local recurrence. The 3-year local recurrence rate was 9.4% in the FV-guided group and 7.2% in the non-FV group (difference, 2.2%; 95% CI, -3.2% to 7.4%). Other similarities between the FV vs non-FV groups included failure of first-pass margin (68/227 [30.0%]) vs 65/216 [30.1%]), regional failure (39/227 [17.2%] vs 37/216 [17.1%]), disease-specific survival (23/227 [10.1%] vs 19/26 [8.8%]), and overall survival (41/227 [18.1%] vs 38/216 [17.6%]) were also similar between groups. No adverse events were judged to be related to the intervention., Conclusions and Relevance: In this randomized clinical trial, FV-guided surgery did not improve local control rates in the treatment of patients with in situ or T1 to T2 category oral cancer. Under a controlled environment, FV-guided surgery did not have an evident effect in reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence., Trial Registration: ClinicalTrial.gov Identifier: NCT01039298.

Background: Human Papillomavirus (HPV) infection is well established in oropharyngeal squamous cell carcinoma (OPSCC) and cervical cancer (CC). However, the association between both HPV related cancers remains unclear. The purpose of this study was to investigate the association between HPV related cancers of the oropharynx and cervix., Methods: A provincial cancer registry was used to retrospectively identify all patients diagnosed with OPSCC from 1997-2015. The standardized incidence ratio (SIR) of CC history in women with p16+/-OPSCC was measured., Results: From 372 women with OPSCC included, the SIR of CC was significantly higher across all ages compared to the general population in Alberta, Canada (p < 0.0001)., Conclusions: Women with HPV/p16+ OPSCC have a significantly higher risk of CC compared to the general population., (Copyright © 2019. Published by Elsevier B.V.)

Background: There is a paucity of studies reporting long-term survival outcomes for HPV/p16 positive oropharyngeal squamous cell carcinoma (OPSCC). This study aims to compare long-term outcomes of advanced stage p16 positive and negative OPSCCs, treated by surgical and non-surgical modalities., Methods: OPSCC patients from 1998 to 2012 were identified through a prospectively collected cancer registry. P16 immunohistochemistry was used as a surrogate marker for HPV-OPSCC. Overall survival (OS) and aspiration free survival (AFS) comparisons were made between patients treated with chemoradiation (CRT) versus primary surgery and radiation/chemoradiation (S+RT/CRT) at 5, 10 and 15 years post-treatment., Results: A total of 319 patients were included. P16 positive patients and non-smokers had significantly higher long-term (5, 10 and 15-year) OS. Smokers and p16 negative patients treated with S+RT/CRT had improved long-term OS compared to patients who received CRT. Smokers and p16 negative patients had lower long-term AFS. Multivariate analysis showed improved OS was associated with p16 positivity (HR 0.42, 0.28-0.61) and surgery (HR 0.47, 0.32-0.69), whereas lower OS was associated with ECOG ≥ 2 (HR 2.46, 1.61-3.77), smoking (HR 2.37, 1.41-3.99) and higher stage (HR 1.68, 1.05-2.68)., Conclusions: In smokers and p16-negative OPSCC patients, primary surgery may be associated with improved long-term survival and dysphagia-related outcomes., (Copyright © 2018. Published by Elsevier B.V.)

Background: This study aims to investigate EGFR as a prognostic biomarker in oropharyngeal squamous cell carcinoma (OPSCC)., Methods: OPSCC patients from retrospective (1998-2009) and prospective cohorts (2014-2017) were included. Retrospectively collected tumors were used to construct tissue microarrays (TMAs), which were stained with EGFR, p16, DAPI and Pan-cytokeratin, and digitally quantified. EGFR, CDKN2A and HPV E6/7 levels from prospectively collected OPSCC was measured by droplet digital PCR (ddPCR). Biomarkers were compared to patient covariates, factors and survival outcomes., Results: A total of 249 patients were included retrospectively and 64 patients were enrolled prospectively. p16 status (p < 0.001), smoking above 10 pack years (p = 0.04), smoking above 20 pack years (p < 0.001), total EGFR tumor levels (p = 0.016), and high EGFR within high or low Ki67 tumor nuclear staining (p = 0.03) were found to be significant predictors of 5-year disease specific survival (DSS). A Cox proportional hazard model of DSS showed smoking status and eGFR expression to be dependent of each other on predicting 5-year DSS. ddPCR analysis showed a significant association between smoking status and EGFR levels., Conclusions: Total EGFR tumor levels are predictive of 5-year DSS. EGFR levels correlate with. smoking and could be an objective marker for this disease etiology.

Background: The role of molecular biomarkers in oropharyngeal squamous cell carcinoma (OPSCC) has recently been increasingly recognized. There is conflicting evidence in the literature with regards to the prognostic value of p53 and Bcl-xL., Objective: The purpose of this study was to investigate the association between p53 and Bcl-xL expression profiles and survival outcomes in OPSCC., Methods: Patients diagnosed with OPSCC and treated with curative intent between 1998 and 2009 were included in the study. Patient demographics, disease, treatment, and oncologic outcomes were collected prospectively. A tissue microarray (TMA) from patients' biopsies or surgical specimens was retrospectively constructed. The expression levels of p53, Bcl-xL, and p16 were digitally quantified and correlated to patient survival outcomes., Results: One hundred and sixty-six patients were included (mean age 56.7 years; standard deviation (SD) ± 10.0; 78% male). High expression of Bcl-xL (p= 0.04) was significantly associated with nodal disease at presentation, and decreased overall survival (OS) (p= 0.04). Combined expression of low Bcl-xL and low p53 conferred a survival advantage in non-smokers (p= 0.04). Multivariate analysis supported smoking and p16 status as independent prognosticators for OS., Conclusions: This study suggests that biomarker profiling using Bcl-xL and p53 levels may be of prognostic value in select patients with OPSCC.

Background: Xerostomia is a debilitating side effect of radiotherapy for head and neck cancer. Combining surgical submandibular-gland transfer (SMGT) with intensity-modulated radiotherapy (IMRT) may provide greater protection of salivary function., Methods: This was a single-institution, prospective phase II feasibility trial. Patients with head and neck cancer or unknown primary with neck node metastases received primary surgery with SMGT and postoperative radiotherapy with tomotherapy (60 Gy in 30 fractions). Toxicity and quality of life (QOL) were assessed before surgery, before RT, and after RT., Results: Forty patients received SMGT and IMRT. Only 1 patient experienced grade 3 salivary gland toxicity. At 12 months post-RT, the rate of absent or only mild xerostomia was 89%, and salivary flow rates were approximately 75% of pre-RT levels., Conclusions: The combination of IMRT with SMGT is feasible and with improved dose constraints may maximally spare the parotid and submandibular glands, leading to decreased xerostomia and improved patient QOL., (© 2018 Wiley Periodicals, Inc.)

Importance: No guidelines at present describe when fludeoxyglucose F 18-labeled positron emission tomography and computed tomography (FDG PET-CT) should be used in the initial posttreatment period for evaluation of oropharyngeal squamous cell carcinoma treatment outcome and recurrence., Objective: To compare accuracies of the initial posttreatment PET-CT between primary treatment groups and to define indicators of false-positive findings., Design, Setting, and Participants: This retrospective cohort study identified adults with a new diagnosis of oropharyngeal squamous cell carcinoma who received treatment with curative intent from October 1, 2006, through November 30, 2016, using the Alberta Cancer Registry (n = 380). Patients who underwent PET-CT within 1 year of treatment completion were included (n = 190). Of these, 103 patients (54.2%) had PET-CT findings positive for residual or recurrent disease, and 61 (32.1%) had false-positive findings. Among the 61 patients, 42 (68.9%) had received chemoradiotherapy (CRT) and 19 (31.1%) had primary surgery. Forty-two patients had true-positive findings, indicating a prevalence rate of disease of 22.1%. Data were analyzed from July through October 2017., Exposures: One of 2 primary treatment modalities (surgery with or without adjuvant therapy vs CRT). All patients had posttreatment FDG PET-CT., Main Outcomes and Measures: Primary outcome measures included the diagnostic odds ratio, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET-CT for detecting residual and/or recurrent disease. A multivariate analysis determined indicators of false-positive findings. Discriminative ability was assessed using receiver operating characteristic curve analysis of maximum standardized uptake value (SUVmax) metabolic data., Results: Of the 190 participants, 77.9% were men, with a mean (SD) age at diagnosis of 58.5 (8.5) years. The diagnostic odds ratio was 19.3 (95% CI, 5.7-65.1); pooled sensitivity, 93.3% (95% CI, 80.7%-98.3%); and pooled specificity, 57.9% (95% CI, 49.4%-66.0%). The PPV of detecting disease was 54.7% (95% CI, 38.8%-69.8%) for primary surgery and 31.1% (95% CI, 20.2%-44.4%) for CRT. The NPV was 100% (95% CI, 94.7%-100%) for primary surgery and 96.6% (95% CI, 89.5%-99.1%) for CRT. Multivariate analysis identified treatment type, p16 disease, and smoking status as indicative of false-positive findings. In the receiver operating characteristic curve analysis for primary tumors, the optimal cutoff SUVmax for indicating true- vs false-positive results was 5.1 for surgically treated patients (area under the curve, 0.729; 95% CI, 0.570-0.888) and 5.3 for patients treated with CRT (area under the curve, 0.844; 95% CI, 0.700-0.989)., Conclusions and Relevance: The results indicate a higher specificity for FDG PET-CT for initial posttreatment surveillance imaging among patients treated with primary surgery compared with nonsurgical management. Both sets of patients with posttreatment FDG PET-CT findings with an SUVmax greater than 5.0 should undergo close evaluation for possible residual or recurrent disease.

Background: To determine the impact of Human Papillomavirus (HPV) status on speech, swallowing, and quality of life (QOL) outcomes after surgical treatment of oropharyngeal cancer (OPSCC)., Methods: A retrospective review of a prospectively collected database of all patients with OPSCC diagnosed and treated from 1998 to 2009. Speech, swallowing, and quality of life data were gathered at 3 different evaluation points. HPV status was determined using p16 positivity as a surrogate marker. Univariate and multivariate statistical analyses were performed to identify whether p16 status is a significant predictor of functional outcome and QOL., Results: One hundred twelve patients with OPSCC and known p16 status were treated with primary surgery between 1998 and 2009, with mean age of 56 years. Out of those patients 63 (56%) were p16 positive. Speech intelligibility remained high at 1-year post operation (95.4%). Only 11.5% of the patients required a feeding tube at 1 year after surgery to maintain their daily caloric requirements and the risk of aspiration after surgery was not significant (p = 0.097). There was no statistically or clinically significant difference in speech, swallowing ability, swallowing safety and QOL outcomes between p16-positive and negative OPSCC., Conclusions: Surgically treated OPSCC patients demonstrate excellent swallowing function and can achieve excellent speech perception. P16 status may not be predictive of functional outcomes or QOL in surgically treated OPSCC.

Background: Management of the clinically node-negative neck (cN0) in patients with early stage oral cavity squamous cell carcinoma (OCSCC) is challenging. Accurate imaging alternatives to elective neck dissections would help reduce surgical morbidity. While pooled studies suggest that imaging modalities have similar accuracy in predicting occult nodal disease, no study has examined the utility of PET-CT in this specific population of low-volume, clinically T1 and T2 OCSCC patients., Methods: A retrospective review of patients in the Alberta Cancer Registry who were diagnosed with cT1 or T2N0M0 OCSCC who underwent elective unilateral or bilateral neck dissections was performed. Pre-operative PET-CT and CT necks were reviewed for number of radiographically suspicious lymph nodes. Surgical pathology reports were reviewed to obtain the total number of nodes sampled and number of malignant nodes., Results: Between 2009 and 2013, 148 patients were diagnosed with cT1 or T2N0M0 OCSCC. Of these, 96 patients underwent elective neck dissections. All patients underwent preoperative CT of the neck with 32 patients having undergone additional preoperative PET-CT. Based on finally surgical pathology, the overall rate of occult metastasis was 13.5% (13/96). The overall sensitivity and specificity of PET-CT in this cohort was 21.4% and 98.4%, respectively with a negative predictive value of 99.1%. Although sensitivity improved in patients with tumors ≥2 cm and depth ≥4 mm, specificity remained unchanged., Conclusion: In patients with cT1 and T2N0 OCSCC, PET-CT has high negative predictive value. These patients can be considered for treatment with single modality surgical resection and elective neck dissection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes., Methods: We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines., Results: Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays., Conclusions: Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation.

Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by oncogenic human papillomavirus (HPV) is rising worldwide. HPV-OPSCC is commonly diagnosed by RT-qPCR of HPV E6 and E7 oncoproteins or by p16 immunohistochemistry (IHC). Droplet digital PCR (ddPCR) has been recently reported as an ultra-sensitive and highly precise method of nucleic acid quantification for biomarker analysis. To validate the use of a minimally invasive assay for detection of oncogenic HPV based on oropharyngeal swabs using ddPCR. Secondary objectives were to compare the accuracy of ddPCR swabs to fresh tissue p16 IHC and RT-qPCR, and to compare the cost of ddPCR with p16 IHC., Methods: We prospectively included patients with p16 + oral cavity/oropharyngeal cancer (OC/OPSCC), and two control groups: p16 - OC/OPSCC patients, and healthy controls undergoing tonsillectomy. All underwent an oropharyngeal swab with ddPCR for quantitative detection of E6 and E7 mRNA. Surgical specimens had p16 IHC performed. Agreement between ddPCR and p16 IHC was determined for patients with p16 positive and negative OC/OPSCC as well as for healthy control patients. The sensitivity and specificity of ddPCR of oropharyngeal swabs were calculated against p16 IHC for OPSCC., Results: 122 patients were included: 36 patients with p16 + OPSCC, 16 patients with p16 - OPSCC, 4 patients with p16 + OCSCC, 41 patients with p16 - OCSCC, and 25 healthy controls. The sensitivity and specificity of ddPCR of oropharyngeal swabs against p16 IHC were 92 and 98% respectively, using 20-50 times less RNA than that required for conventional RT-qPCR. Overall agreement between ddPCR of tissue swabs and p16 of tumor tissue was high at ĸ = 0.826 [0.662-0.989]., Conclusion: Oropharyngeal swabs analyzed by ddPCR is a quantitative, rapid, and effective method for minimally invasive oncogenic HPV detection. This assay represents the most sensitive and accurate mode of HPV detection in OPSCC without a tissue biopsy in the available literature.

Objectives/hypothesis: The treatment for most advanced head and neck cancers (stage III and IV) usually includes radiation, and the most common side effect of this treatment modality is a permanent decrease in salivary production. Xerostomia is a devastating complication that significantly affects patients' quality of life by interfering with functions of taste, mastication, deglutition, and speech production. Treatment of xerostomia is varied, but one of the strategies developed by our group was to preserve one submandibular gland by surgically transferring it to the submental space and shielding it from the full dose of radiation. This procedure is proven to reduce the rate of radiation-induced xerostomia, but its main disadvantage is that it is contraindicated in oral cavity cancer. This study describes and evaluates a modification of the submandibular gland transfer (SGT) procedure, where the submandibular gland contralateral to the disease process is relocated to the parotid region. This modification has the potential of expanding the benefits of submandibular gland transfer procedures to patients with oral cavity cancers., Study Design: Prospective feasibility study., Methods: This study involved nine patients with a new diagnosis of advanced head and neck cancer undergoing major head and neck cancer resection with postoperative adjuvant radiation therapy. The new modified salivary gland transfer procedure was performed on all nine patients, and the glands total dose received with radiation therapy was assessed., Results: All the modified SGT procedures were successful with no post-operative complications. The radiation oncology team has been able to successfully localize the transferred submandibular glands and shield them from the radiation beam postoperatively., Conclusions: We have successfully demonstrated that surgical transfer of a submandibular salivary gland to the parotid region is feasible, surgically viable, oncologically sound, and does not interfere with radiation therapy., Level of Evidence: 4 Laryngoscope, 126:2492-2496, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC., Methods: The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays., Results: EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53., Conclusion: Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC.

Objective: To determine the variables that are predictive of failed decannulation (FD), delayed decannulation (DD), and days to decannulation in patients who underwent head and neck cancer resection with free tissue transfer reconstruction for head and neck squamous cell carcinoma., Design: Case series with chart review., Setting: Tertiary care otolaryngology-head and neck surgery referral center., Subject and Methods: Patients (N = 108) were included who underwent head and neck cancer resection with free tissue transfer reconstruction and tracheostomy between 2011 and June 2014. Patients with laryngectomy, previous tracheostomy, and other airway pathology necessitating tracheotomy were excluded. Preoperative patient variables and cancer site/staging variables were analyzed, as well as extent of structures resected and type of reconstruction. Univariate and multivariate binary logistic and Cox regression analyses were used to determine predictors of FD and DD. Cox regression analysis was used to determine predictors of days to decannulation., Results: Of the 108 included patients, 16 had FD, and 26 had DD. Univariate analysis demonstrated that advanced stage (r = 0.233, P = .021), total glossectomy (r = 0.924, P < .001), anterolateral thigh flap reconstruction (r = 0.906, P < .001), smoking at time of surgery (r = 0.319, P = .002), and pack years (r = 0.322, P = .001) were associated with FD. Cox regression analysis showed that total glossectomy, exp(B) = 15.837 (95% confidence interval [95% CI]: 1.949-128.679); anterolateral thigh flap reconstruction, exp(B) = 8.439 (95% CI: 2.435-29.620); and smoking status, exp(B) = 2.970 (95% CI: 1.617-5.456) were independent predictors of days to decannulation and FD., Conclusions: Patients with total glossectomy defects and those who continue to smoke are at increased risk for FD and DD. Aggressive smoking cessation programs may decrease the risk of FD and DD. Patients should be counseled about their risk profiles., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Background: Despite the promise of metabolic tumor volume (MTV) as a risk-stratifying marker, the retrospective design of the initial study limits its generalizability. Therefore, this study sought to validate MTV as a prognostic factor for oral cavity squamous cell carcinoma (OCSCC) treated with primary surgery within an independent data set., Methods: The validation data set consisted of 42 patients diagnosed with OCSCC between 2008 and 2012. The original cohort consisted of 80 patients. MTV and SUVmax were calculated for the primary tumor and nodal metastasis separately, as well as combined. Before statistical analysis, MTV and SUVmax values were divided into intertertile thirds to allow for intergroup survival analysis. Validation analysis was conducted on the validation data set alone. Data from both cohorts were then combined (n=122) to increase statistical power., Results: An increase in combined MTV of 17.5cm(3) was associated with statistically significant increase in risk of disease recurrence (HR=19.2, p<0.001) and death (HR=9.2, p<0.05). Combined SUVmax failed to predict overall (HR=1.0, p>0.05) and disease-free survival (HR=1.0, p>0.05). Increase in the MTV of the primary tumor was associated with an increase in the risk of disease recurrence (HR=21.7, p=0.0001) and risk of death (HR=7.0, p=0.0001), while increase in the MTV of the locoregional neck metastasis was not (p>0.05). An MTV cutoff value of greater than 10.2cm(3) was found to significantly affect survival., Conclusion: Due to the reproducibility of MTV findings, this study validates MTV as an independent prognostic factor for OCSCC treated with primary surgery., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The incidence of oropharyngeal squamous cell carcinoma caused by oncogenic HPV (HPV-OPSCC) is rising worldwide. HPV-OPSCC is commonly diagnosed by RT-qPCR of HPV-16 E6 and E7 oncoproteins or by cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 (p16) immunohistochemistry (IHC). Droplet digital PCR (ddPCR) has been recently reported as ultra-sensitive and highly precise method of nucleic acid quantification for biomarker analysis. We aimed to validate this method for the detection of HPV-16 E6 and E7 in HPV-OPSCC., Methods: Participants were recruited from January 2015-November 2015 at initial presentation to the University of Alberta Head and Neck Oncology Clinic. RNA was extracted, purified and quantified from prospectively collected participant tissues, and ddPCR was performed with fluorescent probes detecting HPV-16 E6 and E7. Results from ddPCR were compared with p16 IHC performed by clinical pathology as standard of care., Results: Head and neck tissues were prospectively obtained from 68 participants including 29 patients with OPSCC, 29 patients with non-OPSCC and 10 patients without carcinoma. 79.2% of patients with OPSCC were p16 positive. The sensitivity and specificity of ddPCR HPV E6/E7 compared with p16 IHC in OPSCC was 91.3 and 100%, respectively. The amount of target RNA used was ≤1 ng, 20-50 times lower than reported by other for RT-qPCR HPV E6/E7., Conclusions: The ddPCR of HPV E6/E7 is a novel and highly specific method of detecting HPV-16 in OPSCC. Cancer 2016;122:1544-51. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: The purpose of this study was to compare survival outcomes of patients with advanced stage oropharyngeal squamous cell carcinoma (SCC) according to surgical and nonsurgical treatments, when stratified by smoking and p16 status., Methods: We conducted a prospective longitudinal population-based study of 279 patients diagnosed with advanced oropharyngeal SCC. Patients were stratified by smoking and p16 status., Results: There was no significant disease-specific survival (DSS) difference in combined modality treatment groups in nonsmokers that had p16-positive cancers, however, in smokers with p16-positive cancers, the DSS surgery + postoperative chemoradiotherapy (S+CRT) was significantly higher than chemoradiotherapy (CRT) alone. Patients who had p16-negative cancers had the highest DSS when treated with surgery + adjuvant therapy (S+RT)/CRT. Multivariate Cox regression analysis showed that increasing Eastern Cooperative Oncology Group (ECOG) score, smoking, p16 status, higher stage, and treatment with surgery protocols were significant determinants of survival., Conclusion: Primary surgical approaches offer the best survival outcomes in smokers with p16-positive cancers and in patients with p16-negative cancers. © 2015 Wiley Periodicals, Inc. Head Neck 38: E-E, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: The purpose of this study was to investigate the possible epidemiological association between oropharyngeal carcinoma and anogenital tumors., Methods: Population-based demographic and pathologic data on all male patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) and anogenital cancer between 1980 and 2011 in the province of Alberta was collected. The risk of association between anogenital cancers and OPSCCs was estimated., Results: Between 1980 and 2011, a total of 2105 male patients were diagnosed with OPSCC and 914 with anogenital cancers. Only 5 patients were diagnosed with both., Conclusion: In our male population, there was no significant association between anogenital and OPSCCs. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2100-E2102, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been rising in recent years. Given the clinical impact of HPV/p16 positivity in OPSCC, identifying surrogate markers of this disease early in the diagnostic work-up of these patients could improve patient care., Methods: Demographic, pathologic, staging and PET-CT data from patients diagnosed with OPSCC from 2009-2014 were obtained from a prospectively collected provincial cancer registry. Tumor HPV/p16 status was correlated to the maximum standard uptake value (SUVmax) of the primary tumor and cervical nodes. Comparisons of means and multinomial regression models were used to determine associations between p16 status and SUVmax. A diagnostic odds ratio was calculated using a cut off value for predicting HPV/p16 positivity based on nodal SUVmax., Results: PET-CT and HPV/p16 data was obtained for 65 patients treated surgically for OPSCC. Significantly higher nodal SUVmax was associated with HPV/p16 positive nodes (SUVmax 10.8 vs 7.9). No significant differences were seen between HPV/p16 positive vs negative primary tumor SUVmax (10.3 vs 13.7). In combination with other clinical parameters, higher nodal SUVmax was highly correlated with HPV/p16 positivity., Conclusion: Elevated nodal SUVmax is a significant predictor of HPV/p16 positive disease.

Background: Hypothyroidism following radiation therapy (RT) for treatment of Head and Neck Cancer (HNC) is a common occurrence. Rates of hypothyroidism following RT for Early Stage Laryngeal Squamous Cell Carcinoma (ES-LSCC) are among the highest. Although routine screening for hypothyroidism is recommended; its optimal schedule has not yet been established. We aim to determine the prevalence and optimal timing of testing for hypothyroidism in ES-LSCC treated with RT., Method: We conducted a population-based cohort study. Data was extracted from a prospective provincial head and neck cancer database. Demographic, survival data, and pre- and post-treatment thyroid stimulating hormone (TSH) levels were obtained for patients diagnosed with ES-LSCC from 2008-2012. Inclusion criteria consisted of patients diagnosed clinically with ES-LSCC (T1 or 2, N0, M0) treated with curative intent. Patients were excluded if there was a history of hypothyroidism before the treatment or any previous history of head and neck cancers., Results: Ninety-five patients were included in this study. Mean age was 66.1 years (range: 44.0-88.0 years) and 82.3% of patients were male. Glottis was the most common subsite at 77.9% and the average follow-up was 40 months (Range: 12-56 months). Five-year overall survival generated using the Kaplan-Meier method was 79%. Incidence of hypothyroidism after RT was found to be 46.9%. The greatest frequency of developing hypothyroidism was at 12 months., Conclusions: We found a high prevalence of hypothyroidism for ES-LSCC treated with RT, with the highest rate at 12 months. Consequently, we recommend possible routine screening for hypothyroidism using TSH level starting at 12 months. To our knowledge, this is the first study to suggest the optimal timing for the detection of hypothyroidism.

This study examines functional outcome (speech and swallowing), survival, and disease control in patients receiving an intensified treatment regimen with primary aggressive surgery, and postoperative radiotherapy or postoperative concomitant chemoradiotherapy, for previously untreated, resectable, stage III and IV squamous cell carcinoma (SCC) of the tongue base. Sixty-six consecutive patients treated from June 1997 to June 2006 were followed prospectively through the Multidisciplinary Head and Neck Surgery Reconstruction Clinic. Speech and swallowing data were gathered at four evaluation times during the first year. Speech assessment was conducted by PERCI, Nasometer, and C-AIDS and swallowing assessment by Modified barium swallow, Diet survey and G-tube. Also, the overall survival, disease-specific survival and loco regional control were measured. The average age of the patients was 56.8, 85 % male and 15 % female. All patients had primary surgical resection and 83 % received postoperative radiotherapy and 17 % chemoradiation therapy. Overall survival at 3 years was 80.3 % and 5 years 52.2 %. Disease-specific survival at 3 years was 86.7 % and 5 years was 77.5 %. Local control was 94 %. Distal metastasis and second primary were found to be 7.5 % each. Primary surgical treatment of advanced BOT cancer offers excellent functional outcome, local control and disease-specific survival.

Objective: To evaluate the cost-effectiveness of transoral robotic surgery (TORS) compared to intensity-modulated radiotherapy (IMRT) for early stage (T1-2, N0, M0) oropharyngeal squamous cell carcinoma (OPSCC)., Patients and Methods: A Markov decision tree model with a 5-year time horizon was developed. Comparative groups were: i) TORS with concurrent ipsilateral neck dissection +/- adjunctive IMRT, and ii) primary IMRT. Primary outcome was cost/quality adjusted life year (QALY). Perspective was the United States third party payer. Costs and effects were discounted at a rate of 3.5%. A threshold and probabilistic sensitivity analysis were performed., Results: TORS strategy cost $30,992 and provided 4.81 QALYs/patient. The IMRT strategy cost $26,033 and provided a total of 4.78 QALYs/patient. The incremental cost effectiveness ratio for TORS vs. IMRT in the reference case was $165,300/QALY. The probability that TORS is cost-effective compared to IMRT at a maximum willingness-to-pay threshold of $50,000/QALY is 42%., Conclusion: An IMRT strategy for management of early stage OPSCC is more likely to be cost-effective compared to TORS. To improve the value of TORS for early stage OPSCC, consolidating TORS procedures to create high-volume centers of excellence may be a potential strategy to increase incremental effectiveness and reduce incremental costs. J. Surg. Oncol. 2015 111:155-163. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: To assess the survival outcomes of oral cavity squamous cell carcinoma (OCSCC) by differing geographical location., Methods: Demographic, pathologic, treatment, and survival data was obtained from OCSCC patients from 1998-2010 in Alberta, Canada. 554 patients were included from 660 OCSCC patients. Overall, disease-specific, and disease-free survivals were estimated with Kaplan-Meier and Cox regression analyses. Patients were grouped by geographic locations., Results: Patients from urban locations had improved overall, disease-specific, and disease-free survival compared to rural locations (p<0.05). Two and five year estimates of overall survival were significantly higher in the urban cohort at 84% and 78%, versus rural with 48% and 44%, respectively (p<0.05). Disease-specific and disease-free survival rates were also superior in the urban group (p<0.05). Diagnosis to treatment time for all 3 geographical groups was not found to be statistically significant (p>0.05)., Conclusion: This study shows that patients with OCSCC living in urban settings have improved survival compared to rural groups., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Importance: Keratinization is a histologic feature on hematoxylin-eosin staining associated with adverse outcomes in head and neck cancer, particularly oral cavity squamous cell carcinoma. However, the prognostic value of keratinization has not been demonstrated in oropharyngeal squamous cell carcinoma (OPSCC) in a large cohort of patients., Objective: To quantify the prognostic value of keratinization in a large cohort of patients with OPSCC with subgroup analysis based on p16 status, basaloid differentiation, and smoking status., Design, Setting, and Participants: Retrospective cross-sectional study using a prospectively collected database that identified 208 patients with OPSCC diagnosed and treated at a single tertiary cancer center from 2002 to 2009. Tissue microarrays (TMAs) were generated from 208 patient specimens stained with hematoxylin-eosin and immunohistochemical markers. Digital images from stained TMAs were scored for the presence of keratinization and/or basaloid differentiation and for p16 status., Interventions: Patients were treated with curative intent with surgery, radiation, and/or chemotherapy., Main Outcomes and Measures: The primary outcome measure was 5-year disease-specific survival (DSS) in OPSCC according to keratinization. Univariate and multivariate survival analyses were performed to estimate survival according to histopathologic profile and smoking status., Results: In the 208 samples, 96 were keratinizing and 112 were nonkeratinizing. Patients with keratinizing tumors were more likely to have advanced-stage disease and be p16 negative. Keratinization was independently associated with adverse outcomes. The 5-year DSS was significantly higher for nonkeratinizing tumors (63.3%) compared with keratinizing tumors (44.8%; P = .007). In subgroup analysis, nonkeratinization was associated with improved DSS in those with nonbasaloid and p16-negative tumors and in patients who were smokers. When stratifying patients based on keratinization, p16-status, and smoking status, patients with p16-negative keratinizing tumors who were smokers had the lowest 5-year DSS (26.7%)., Conclusions and Relevance: Patients with nonkeratinized OPSCC have improved survival compared with those with keratinizing tumors. Information on keratinization is most useful prognostically in those who have p16-negative and nonbasaloid tumors and in patients who are smokers. Survival can be stratified using keratinization, p16 status, and smoking status.

Background: The management of patients with advanced stages of head and neck cancer requires a multidisciplinary and multimodality treatment approach which includes a combination of surgery, radiation, and chemotherapy. These toxic treatment protocols have significantly improved survival outcomes in a distinct population of human papillomavirus (HPV) associated oropharyngeal cancer. HPV negative head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat because there is only a modest improvement in survival with the present treatment regimens, requiring innovative and new treatment approaches. Oncolytic viruses used as low toxicity adjunct cancer therapies are novel, potentially effective treatments for HNSCC. One such oncolytic virus is Respiratory Orphan Enteric virus or reovirus. Susceptibility of HNSCC cells towards reovirus infection and reovirus-induced cell death has been previously demonstrated but has not been compared in HPV positive and negative HNSCC cell lines., Objectives: To compare the infectivity and oncolytic activity of reovirus in HPV positive and negative HNSCC cell lines., Methods: Seven HNSCC cell lines were infected with serial dilutions of reovirus. Two cell lines (UM-SCC-47 and UM-SCC-104) were positive for type 16 HPV. Infectivity was measured using a cell-based ELISA assay 18 h after infection. Oncolytic activity was determined using an alamar blue viability assay 96 h after infection. Non-linear regression models were used to calculate the amounts of virus required to infect and to cause cell death in 50% of a given cell line (EC50). EC50 values were compared., Results: HPV negative cells were more susceptible to viral infection and oncolysis compared to HPV positive cell lines. EC50 for infectivity at 18 h ranged from multiplicity of infection (MOI) values (PFU/cell) of 18.6 (SCC-9) to 3133 (UM-SCC 104). EC50 for cell death at 96 h ranged from a MOI (PFU/cell) of 1.02×10(2) (UM-SCC-14A) to 3.19×10(8) (UM-SCC-47). There was a 3×10(6) fold difference between the least susceptible cell line (UM-SCC-47) and the most susceptible line (UM-SCC 14A) EC50 for cell death at 96 h., Conclusions: HPV negative HNSCC cell lines appear to demonstrate greater reovirus infectivity and virus-mediated oncolysis compared to HPV positive HNSCC. Reovirus shows promise as a novel therapy in HNSCC, and may be of particular benefit in HPV negative patients.

Background: Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck cancer, affecting approximately 2000 Canadians yearly. Analysis of Canadian Cancer Registry data has shown that the incidence of oral cavity cancer is decreasing and survival outcomes are improving. There are significant health disparities in First Nations (FN) people in Canada. The incidence of cancer in FN groups is significantly lower when compared to the general population, but the cancer-related morbidity and mortality is significantly higher. There is no Canadian literature currently for OCSCC, or any other head and neck cancer, that compares survival outcomes of FN to the overall population. Therefore, the objective of this study is to determine whether there is a difference in epidemiology and survival outcomes between FN and non-FN patients with OCSCC., Methods: This is a retrospective study of a population-based, prospectively-collected database from Alberta Cancer Registry (ACR). Patients with OCSCC, diagnosed and treated in Alberta between 1998 and 2009 were included. ACR data collected included patient gender, age at diagnosis, tobacco and alcohol use, FN status, TNM staging, performance status, date of death, cause of death, and follow-up. FN status was identified through the Alberta Health and Wellness registry and through postal code correlation for those who live on reserves., Results: A total of 583 patients with OCSCC were included in this study. Of these, 19 were identified as being FN, leaving 564 non-FN patients. When comparing the FN and non-FN groups, there is no significant difference in baseline demographics. Estimated yearly incidences for OCSCC in the Alberta population (all ages) and FN patients are 1.74/100,000 and 1.32/100,000 respectively (p = 0.23). Significant differences are seen in overall survival (OS) (5-year OS 58.1% for non-FN and 33.7% for FN) and for disease-specific survival (DSS) (5-year DSS 67.8% for non-FN and 44.5% for FN). Multivariate analysis confirmed FN patients have a significant increase risk of death in OS and DSS, with hazard ratios of 4.20 (p = 0.01) and 4.57 (p = 0.02), respectively., Conclusions: The overall survival and disease specific survival are significantly lower in FN patients compared to non-FN patients with OCSCC.

Background: Metabolic tumour volume (MTV) obtained from pre-treatment 18 F-fluorodeoxydeglucose positron emission tomography with computed tomography (PET-CT) has been validated as an independent predictive factor of outcomes in head and neck cancer patients (HNC) treated with primary chemoradiotherapy (CRT). However its role in patients treated with primary surgery has not yet been studied., Objective: To evaluate the prognostic value of MTV in patients treated with primary surgery for oral cavity squamous cell carcinoma (OCSCC)., Method: Demographic and survival data was obtained from patients diagnosed with OCSCC from 2008-2012 in Alberta, Canada. All patients included in the study had PET-CT scan before curative surgical resection. MTV and maximum standardized uptake value (SUVmax) value was delineated from pre-treatment PET-CT scans using Segami Oasis software (Columbus, OH). MTV and SUVmax were divided into intertertile thirds before statistical analysis to allow for in-group comparison of survival., Results: A total of 80 patients were analyzed using SPSS ver. 20.0 (SPSS Inc, Chicago, IL). Five-year overall, and disease-free survival using Kaplan-Meier curves were 70% and 73% respectively. When the combined SUVmax (tumour primary and locoregional metastasis) was evaluated, it failed to predict overall (HR = 1.0, p = 0.99) or disease-free survival (HR = 1.0, p = 0.227)., Conclusions: This study shows that MTV is an independent adverse prognostic factor for death and disease recurrence in OCSCC treated with primary surgery.

Background: Human papillomavirus (HPV) is recognized as the key risk factor for a distinct subset of oropharyngeal squamous cell carcinoma. P16 is a reliable, sensitive surrogate marker for HPV and confers a positive prognostic advantage. Basaloid differentiation on hematoxylin and eosin (H&E) staining is anecdotally noted by some pathologists to be associated with p16 positivity. This association, however, has not been adequately quantified in the literature, nor has the prognostic implications of basaloid differentiation been described., Objectives: 1) To correlate the H&E staining feature of basaloid differentiation with p16 positivity in oropharyngeal cancer. 2) To investigate the prognostic utility of basaloid differentiation in oropharyngeal cancer survival., Methods: Retrospective cross-sectional study of all patients diagnosed with and treated for oropharyngeal cancer at a single tertiary cancer center from 2002 to 2009. Tissue microarrays (TMAs) were generated from 208 oropharyngeal tumor specimens stained with H&E and immunohistochemical markers. These oropharyngeal TMAs were utilized in several previous publications. Samples were scored for basaloid differentiation by a pathologist blinded to the p16 result. A multivariate survival analysis with Cox-regression and Kaplan-Meier survival analysis was performed., Results: In the 208 samples, basaloid differentiation correlated with p16 positivity (Spearman's rho 0.435). Basaloid differentiation and p16 positivity were both independent predictors of improved survival. The 5 year disease specific survival (DSS) was 73% for p16 positive tumors and 35% for p16 negative tumors (p < 0.001). Similarly, the 5 year DSS of basaloid differentiated tumors was 74% compared to 41% for non-basaloid tumors (p = 0.001). Patients with p16 positive and basaloid differentiated tumors had the best survival outcomes with a 5 year DSS of 80%., Conclusions: Basaloid differentiation is a feature on H&E which correlates with p16 positivity and is a simple, inexpensive, independent, positive prognostic indicator of comparable magnitude to p16 status. Due to the added prognostic value of basaloid differentiation, this feature should be routinely reported by qualified pathologists.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing due to fundamental changes in oncogenesis related to effects of the human papilomavirus (HPV). Virally-mediated tumours behave and respond to treatment differently than their classic, carcinogenically-mediated counterparts despite similar stage and grade of disease. This difference in behaviour has lead to investigation of etiologies of OPSCC at the molecular level., Objective: This study was designed to identify biomarker profiles predictive of locoregional and distant metastases and recurrence in OPSCC., Methods: Cross-sectional study of a prospectively-collected oropharyngeal tumour database was undertaken. All patients with OPSCC presenting to the University of Alberta Hospital from 2002-2009 were included in the study. Data collection from the Alberta Cancer Registry, including demographics, nodal status, distant metastases, treatment, recurrence, and survival, was undertaken. Tissue micro-arrays (TMAs) were constructed for each tumour specimen using triplicate cores (0.6mm) of formalin-fixed, paraffin-embedded (FFPE) pre-treatment tumour tissue. TMAs were processed using immunohistochemistry for p16, EGFR, Ki67, p53, and Bcl-XL. Positivity for each biomarker was determined using quantified AQUAnalysis ® scores on histoplots. Multivariate statistics were utilized to assess the relationship between each biomarker and locoregional and distant metastases, as well as recurrence-free survival (RFS)., Results: High expression of p16 (p=0.000) and Bcl-XL (p=0.039) independently demonstrated a significant association with nodal disease at presentation. Kaplan-Meier analysis demonstrated improved RFS in patients with high p16 and decreased RFS in patients with high p53 expression. Cox regression analysis supported p16 as an independent prognosticator for improved RFS. p53 demonstrated an association with recurrence, but when compared to p16 status, nodal status, and staging, was not an independent predictor of recurrence., Conclusions: Biomarker profiling using p16, Bcl-xL, and p53 may be useful in prognostication and treatment planning in patients with OPSCC.

Background: Bilateral neck treatment in oropharyngeal squamous cell carcinoma (OPSCC) is controversial. This study determined the rate of bilateral neck metastases in OPSCC and formulated a neck treatment algorithrm for OPSCC., Methods: In all, 212 consecutive patients with OPSCC underwent ipsilateral level I-V and contralateral I-III or I-V neck dissections. Pathology results were used to identify factors predicting bilateral neck metastases., Results: A total of 171 patients (81%) had ipsilateral and 41 patients (24%) bilateral neck metastases. Multivariate logistic regression found cT4 and ≥cN2a significantly associated with contralateral neck metastases (p < .05). However, tumor site was not predictive (p > .05). High-risk pathology features predicted contralateral neck disease (p < .05). cN0 and cN1 necks were unlikely to harbor disease in level V (<5%). Both 2- and 5-year contralateral neck recurrence rates were 1% and 2%., Conclusions: Bilateral neck disease in OPSCC is more common than once thought. Patients with OPSCC with cT4 or cN2a+ would benefit from bilateral neck treatment. Posttreatment high-risk features should guide treatment escalation., (Copyright © 2013 Wiley Periodicals, Inc.)

Introductions: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCCs) is rising in developed nations. Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer., Objective: The purpose of this study was to evaluate the rate of second primary tumors and the diagnostic yield of field cancerization work up in the upper aerodigestive tract in patients with HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma., Design: Retrospective review., Setting: Tertiary cancer care centers in Alberta., Methods: Retrospective review of 406 patients diagnosed with OPSCC in Alberta between 2005 and 2009. HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16., Primary Outcome: incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC., Secondary Outcomes: diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients., Results: The overall rate of SPTs was 7.4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02)., Conclusions: Patients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways.

Background: The oral cavity is the most common site for head and neck squamous cell carcinoma. Treatment of advanced stage oral cavity squamous cell carcinoma (OCSCC) has classically involved surgical resection with postoperative adjuvant radiotherapy (S-RT).Despite this aggressive dual modality therapy, the disease outcomes have remained poor. The treatment options expanded in 2004 when two international trials showed the addition of postoperative chemotherapy to radiation improved outcomes. These trials were, however not oral cavity site specific., Objective: To assess survival outcomes of advanced OCSCC treated by differing modalities. The primary goal was to determine if the addition of postoperative chemotherapy (S-CRT) improves survival compared to other treatment regimens., Methods: Demographic, pathologic, treatment, and survival data was obtained from patients diagnosed with OCSCC from 1998-2010 in Alberta, Canada. 222 patients were included in the final analysis from 895 OCSCC patients. Actuarial overall, disease-specific, disease-free, and metastasis-free survivals were estimated with Kaplan-Meier and Cox regression analyses. Patients were grouped by treatment., Results: Patients receiving S-CRT had improved overall, disease-specific, disease-free, and metastasis-free survival compared to S-RT, CRT or RT(p < 0.05). Two and five year estimated overall survival was significantly higher in the S-CRT group at 77 and 58% (p < 0.05), versus S-RT with 55 and 40% rates(p < 0.05). Results were similar for disease-specific, disease-free, and metastasis free survival with S-CRT being favoured. Patients with extracapsular spread (ECS) treated with S-CRT versus S-RT had 55% survival advantage at 5 years (p < 0.05)., Conclusion: This study shows that adding adjuvant chemotherapy to S-RT improves survival outcomes in advanced OCSCC, especially in patients with ECS.

Objectives: To evaluate any disparity in clinical versus pathological TNM staging in oral cavity squamous cell carcinoma (OCSCC) patients and any impact of this on survival., Design: Demographic, survival, staging, and pathologic data on all patients undergoing surgical treatment for OCSCC in Alberta between 1998 and 2006 was collected. Clinical and pathological TNM staging data were compared. Patients were stratified as pathologically downstaged, upstaged or unchanged., Setting: Tertiary care centers in Alberta, Canada., Main Outcome Measures: Survival differences between groups were analyzed using Kaplan-Meier and Cox regression models., Results: Patients with clinically early stage tumors were pathologically upstaged in 21.9% of cases and unchanged in 78.1% of cases. Patients with clinically advanced stage tumors were pathologically downstaged in 7.9% of cases and unchanged in 92.1% of cases. Univariate and multivariate estimates of disease-specific survival showed no statistically significant differences in survival when patients were either upstaged or downstaged., Conclusions: Some disparity exists in clinical versus pathological staging in OCSCC, however, this does not have any significant impact on disease specific survival.

Background: Epigenetic modifications are defined as heritable changes in gene expression that are not encoded in deoxyribonucleic acid (DNA). Despite the importance of epigenetics in tumorigenesis, there is a paucity of information regarding the epigenetic profiles of oropharyngeal squamous cell carcinoma (OPSCC)., Objective: The objective of this study was to identify epigenetic signatures associated with human papillomavirus (HPV)-positive and -negative OPSCC., Methods: We collected demographic, pathologic, and survival data from 44 patients with advanced-stage OPSCC treated with surgery and chemoradiation at the University of Alberta between January 2006 and December 2008. Tumour specimen from these patients were retreived and sectioned for immunohistochemical analysis. Double immunofluorescence staining was performed with p16 (HPV surrogate) and a panel of epigenetic markers, namely, histone methyl-lysines 4, 9, and 27 and H4 methyl-lysine 20. Correlation between p16 and epigenetic markers was measured using Metamorph and Image J software., Results: Forty-one percent of patients were p16 positive. No statistically significant differences were found between p16-positive and -negative patients in terms of age at diagnosis, tumour subsite, or smoking history. We found significant differences in histone methylation between p16-positive and -negative tumours. OPSCC tumours positive for p16 had global elevations of histone H4 monomethylated lysine 20 (H4K20me1) and H3 trimethylated lysine 27 (H3K27me3) with depletions of H4 trimethylated lysine 20 (H4K20me3). In contrast, p16-negative tumours had depleted levels of H4K20me1 and H3K27me3 with high levels of H4K20me3., Conclusions: HPV-positive and -negative OPSCCs have distinct epigenetic profiles representing broad gene expression differences between these tumours.

Background: Positron emission tomography/computed tomography (PET/CT) is a newer imaging modality that combines whole-body PET using [(18)F]fluorodeoxyglucose (FDG) and contrasted high-resolution CT. This has the advantage of combining the functional imaging of FDG-PET with the anatomic detail afforded by CT., Objective: To assess the cost-benefit of whole-body PET/CT as a diagnostic tool in head and neck cancer., Methods: A retrospective cohort (American Joint Committee on Cancer III-IVB squamous cell carcinoma in 2003) was reviewed for costs of diagnostic tests, distant metastases, and treatment type. This was compared to a hypothetical cohort of patients using PET/CT as a sole diagnostic tool using the current literature on test characteristics in the detection of distant metastases. The main outcome measure was the cost of the diagnostic workup, and the secondary outcome measure was the cost of the treatment., Results: The cost of the traditional workup was $450 per patient, whereas the cost of PET/CT workup was $722 per patient. The sensitivity of the traditional workup for lung metastases at 12 months was 14.3%. The average cost of curative surgery was $81,290, radiotherapy was $8,224, and chemotherapy was $1,158. In the cohort of 76 patients reviewed, improved PET/CT sensitivity would theoretically detect three more cases of metastatic disease and reduce the total cohort cost of treatment by $198,526 by relegating these patients to palliation., Conclusions: PET/CT is a more expensive test when used alone in the diagnostic workup of head and neck cancer but results in an overall cost savings by reducing the number of futile radical treatments. There is a cost benefit to the use of PET/CT as the diagnostic and staging test for head and neck cancer patients.

Objective: Human papillomavirus (HPV) is a well-established etiologic factor in oropharyngeal squamous cell carcinoma (OPSCC). The objective of this study was to evaluate the association between OPSCC and HPV-related cancerous lesions of the cervix., Methods: Demographic, survival, and pathologic data on all female patients diagnosed with OPSCC in Alberta between 1998 and 2008 were collected. A review of pathology reports in these patients was undertaken to identify HPV-related cancerous lesions of the cervix. Standardized incidence ratios (SIRs) of cervical cancer in oropharyngeal cancer patients were calculated using control data obtained from provincial cancer surveillance. Overall and disease-specific survival of patients with OPSCC only versus patients with OPSCC and cervical cancer was calculated using Kaplan-Meier and Cox regression models., Results: Our results show a significantly elevated overall incidence of cervical cancer in women with OPSCC in comparison to the control population (SIR 29.4, 95% CI 12.05-74.98). Patients with OPSCC and cervical cancer also had a significantly improved disease-specific survival in comparison to patients with no history of cervical cancer., Conclusions: Women with OPSCC have a significantly elevated risk of developing HPV-related genital cancers, which suggests frequent HPV coinfection of oropharyngeal and genital tissues in this patient population. Women with OPSCC with cervical cancer also have an improved disease-specific survival, as previously shown with HPV-associated OPSCC.

Background: reconstruction of a total nasal defect presents a significant challenge to the reconstructive surgeon. The form, function, and aesthetic appeal of all the nasal subunits must be addressed. Classic teaching emphasizes the importance of restoring the internal lining of the nose, the rigid scaffolding, and the outer skin and soft tissue layer., Methods: a restrospective review was undertaken in eight patients who had undergone total nasal reconstruction in two Canadian tertiary care centres. All eight patients had their nasal defect reconstructed with a radial forearm free flap for internal lining, titanium mesh for structural support, and a paramedian forehead flap for skin and soft tissue cover. Nasal function, graft survival, patient satisfaction, and complications were recorded., Results: seven of eight patients were satisfied with the cosmetic outcome of their nasal reconstruction. Two patients reported poor nasal breathing owing to nasal stenosis. Two cases of minor titanium extrusion required operative intervention for repair. There were no cases of loss of the radial forearm free flap or paramedian forehead flap in this series., Conclusions: reconstruction with a radial forearm free flap, titanium mesh, and a paramedian forehead flap is a reliable, cosmetically appealing, and functional method for total nasal reconstruction. Minor surgical revisions should be anticipated to achieve the best cosmetic outcome. This is the first reported series using these three entities together to reconstruct total and subtotal rhinectomy defects.

Background: Head and neck oncologists are often confronted with the difficult challenge of balancing cancer cure with the preservation of function when deciding the patient's best treatment protocol. This task is especially difficult in cancer of the base of tongue. The purpose of this manuscript is to describe the beavertail modification of the radial forearm-free flap in base of tongue reconstruction., Methods: Thirty-one consecutive patients treated for base of tongue cancer with primary surgery were followed prospectively. The technique of the beavertail modification is described. Swallowing and speech function were assessed preoperatively and postoperatively., Results: All the flaps survived. Thirty (97%) patients started consuming oral diet within 1 year, and all had normal speech intelligibility., Conclusions: The beavertail modification of the radial forearm arm flap seems to provide the reconstructive elements that allow patients with large base of tongue extirpations to develop functional swallowing and speech production postoperatively.

Objective: To determine if the implantable Cook-Swartz Doppler Flow Monitoring System (Cook Vascular Inc, Vandergrift, Pennsylvania) improves surgical salvage rates for compromised free flaps., Design: Retrospective medical record review spanning 2002 to 2006 for a large head and neck oncology program., Setting: A tertiary care hospital., Patients: A consecutive series of 351 patients (244 men and 107 women; mean age, 58.63 years) who underwent free flap reconstruction of head and neck defects that were monitored using the implantable Doppler probe were included., Results: The most common indication for surgery was squamous cell carcinoma (81.0%), followed by functional reconstruction (4.3%). The most common free flap used was radial forearm (68.0%), followed by the fibular free flap (19.0%). With operative exploration used as the gold standard, the Cook-Swartz Doppler Flow Monitoring System had a sensitivity of 65.8% and specificity of 98.2% for the detection of flap compromise. For the detection of vascular compromise of the monitored vessel (excluding flap compromise cases whereby flow in the monitored vessel was not compromised on operative exploration, ie, venous obstruction, hematoma formation, and necrotizing fasciitis), the sensitivity increased to 100%., Conclusions: This is the largest reported series, to our knowledge, of implantable Cook-Swartz Doppler use, and our experience would suggest that this is a reliable technique for postoperative monitoring in head and neck reconstruction. Our use of the implantable Doppler probe allowed us to recognize vascular compromise early, resulting in an overall flap success rate of 98.1%, with a 92.0% salvage rate of flaps that experienced vascular compromise of the monitored vessel.

Hypothesis: We hypothesized that the use of reovirus as an intraoperative adjunct would improve local control of positive margins in a human squamous cell carcinoma nude mouse model., Purpose: This study was designed to (1) develop a nude mouse human squamous cell carcinoma positive margin model and (2) assess the effect of adjunct intraoperative treatment with reovirus irrigation and injection on local control of resections with positive margins., Materials and Methods: We developed a positive margin nude mouse model using the University of Michigan SCC-22B cell line. Established tumours in 39 mice were resected, leaving behind a 1 mm positive margin. The mice were then divided into five treatment groups: (1) no treatment was provided, (2) ultraviolet (UV)-inactivated reovirus was irrigated into the wound bed, (3) UV-inactivated reovirus was injected into the positive margin intratumorally and peritumorally, (4) reovirus was injected into the positive margin intratumorally and peritumorally, and (5) reovirus was irrigated into the wound bed. The mice were followed for 28 weeks and sacrificed., Results: The results of the irrigations showed that tumours recurred in all (100%) of the control groups (no treatment and UV-inactivated virus). The mice irrigated with active reovirus solution had recurrence in 3 of the 14 sites (21%). These findings were statistically significant, with p > .001. The results of the injection showed that tumours recurred in all (100%) of the control groups (no treatment and UV-inactivated virus). The mice injected with reovirus solution had recurrence in 6 of the 16 sites (38%). These findings were statistically significant, with p > .007., Conclusions: Reovirus adjunctive treatment is a novel, safe, and effective method of improving local control in the positive margin human squamous cell carcinoma mouse model.

Purpose: To assess the susceptibility of human squamous cell carcinoma to reovirus infection in vitro and in vivo using a murine model of cancer-contaminated wounds., Methods: The University of Michigan squamous carcinoma 22B cell line was cultured and inoculated with reovirus in vitro. The effect of the reovirus was assessed with microscopy and a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. We used the previously established cancer-contaminated wound SCID mouse model to test saline and reovirus irrigation in vivo. Fifty-five mice were used; 15 were controls, 20 had immediate irrigation, and 20 had delayed irrigation. Surgical sites were assessed for palpable tumour biweekly., Results: The microscopy and MTT assay both showed evidence of reovirus-mediated squamous cancer cell lysis. The control mice grew palpable tumours in 80% of the wounds. Immediate irrigation with saline delayed the onset of palpable tumour and demonstrated a persistent reduction in the rate of development of palpable tumours (p = .004 compared with controls). This effect disappeared when the saline irrigation was delayed, resulting in a tumour development rate that was not significantly different from that of the control. Wounds that were irrigated with reovirus, both immediately and delayed, did not produce palpable tumour (p < .0005 when compared with controls)., Conclusions: (1) The University of Michigan squamous cell carcinoma 22B cell line is susceptible to reovirus in vitro. (2) Immediate irrigation with saline resulted in a significant delay in clinically evident tumour growth and a reduction in the rate of tumour development in the SCID mouse model. (3) The reovirus irrigation resulted in a significant reduction of tumour development in both the immediate and delayed groups in the SCID mouse model. (4) The efficacy of the reovirus irrigation in the delayed group suggests that the major mechanism of action is through a selective and specific targeting of implanted cancer cells.

Objective: This study examines prospectively the functional outcomes of a cohort of patients who had undergone hemiglossectomy and reconstruction with a bilobed radial forearm free flap (RFFF) for oral tongue squamous cell carcinoma., Methods: Speech and swallowing data were compiled for patients treated for oral tongue cancer with hemiglossectomy and and reconstruction with a bilobed RFFF. The three evaluation periods were preoperative, postoperatively, and postradiation therapy., Results: Eleven patients were included in the study. A significant difference between preoperative and postoperative single-word intelligibility scores was observed. There was no significant difference across any of the evaluation times for sentence intelligibility. Swallowing analysis revealed fewer instances of laryngeal penetration with liquids postoperatively. No significant differences were found in laryngeal penetration with either the pudding or cookie consistencies across any of the evaluation times. There was no incidence of aspiration at any of the evaluation times. There were no significant differences in the number of problems with the oral or oral preparatory phases across any of the evaluation times. The neurotization status of the RFFF had no significant effect on any of the observed speech or swallowing parameters., Conclusions: The bilobed RFFF provides functional speech and excellent swallowing outcomes in the reconstruction of hemiglossectomy defects.

Background and Purpose: Xerostomia is a significant morbidity of radiation treatment in the management of head and neck cancers. We hypothesized that the surgical transfer of one submandibular salivary gland to the submental space, where it can be shielded from radiation treatment (XRT), would prevent xerostomia., Materials and Methods: We conducted a prospective Phase II clinical trial and the patients were followed clinically with salivary flow studies and the University of Washington Quality of Life questionnaire., Results: We report the results on 76 evaluable patients. The salivary gland transfer was done in 60 patients. Nine patients (of 60) did not have postoperative XRT and in eight patients (of 60) the transferred gland was not shielded from XRT due to proximity of disease. The median follow up is 14 months. Of the 43 patients with the salivary gland transfer and post-operative XRT with protection of the transferred gland, 81% have none or minimal xerostomia, and 19% developed moderate to severe xerostomia. Three patients (6.9%) developed local recurrence, five patients (11.6%) developed distant metastases and five patients (11.6%) have died. There were no complications attributed to the surgical procedure., Conclusion: Surgical transfer of a submandibular salivary gland to the submental space preserves its function and prevents the development of radiation induced xerostomia.

Introduction: Historically, squamous cells exfoliated from head and neck carcinoma resection have been implicated in locoregional recurrence, but there have been few studies demonstrating the presence of these cells. This study was designed to evaluate the presence of exfoliated malignant cells in surgical irrigation fluid collected during head and neck cancer resection., Methods: Thirty patients undergoing surgery for biopsy-proven squamous cell carcinoma had their surgical sites irrigated with 1,000 cc of normal saline. Surgical gloves and instruments were also washed. These samples were prepared and stained using standard squamous cell cytologic stains. All cases were reviewed by one cytopathologist., Results: Eighteen patients (60%) had positive or suspicious cytology detected in at least one of the surgical samples. In patients with T0 and T1 tumours, all surgical samples were negative. Positive or suspicious cytology was detected in the primary site and glove and instrument irrigation in 40% of patients with T2 tumours, 42% of patients with T3 tumours, and 50% of patients with T4 tumours. This was statistically significant (p < .05). Positive or suspicious cytology was detected in the neck and glove and instrument irrigation in 29% of patients with an N0 neck, 31% of patients with an N1 neck, 39% of patients with an N2 neck, and 100% of patients with an N3 neck. Five of seven patients (71%) with previous radiation therapy had positive or suspicious cytology in at least one of the surgical samples., Conclusions: Higher tumour and nodal staging and a previous history of radiation therapy are associated with an increased incidence of positive or suspicious cytology in surgical irrigation fluid. These findings have implications for surgical protocols.

Objective: Radiation-induced xerostomia is a significant morbidity of radiation therapy in the management of patients with head and neck cancers. We have recently reported a method of transfer of one submandibular gland to the submental space in a small pilot series of eligible surgical patients. The submental space was shielded during postoperative radiation therapy. The transferred gland continued to function after the completion of radiation therapy and none of the patients developed xerostomia. The purpose of this article is to present the technique of submandibular gland transfer in detail and to evaluate the postoperative survival and function of the transferred submandibular glands., Design: Prospective clinical trial., Methods: The submandibular gland was transferred on eligible patients as part of their surgical intervention. The patients were followed clinically, with salivary flow and radioisotope studies., Results: We performed the surgical transfer of the submandibular salivary gland in 24 of 25 patients placed on the protocol. All the glands survived transfer and functioned well postoperatively as demonstrated on the salivary flow and the radioisotope studies. The surgical transfer was relatively simple and added 45 minutes to the surgical procedure. There were no complications attributed to the submandibular gland transfer., Conclusions: We have successfully demonstrated that the submandibular gland can be surgically transferred to the submental space with its function preserved. The gland seems to continue functioning even after radiation therapy with the appropriate shielding. This surgical transfer procedure has the potential to change the way we currently manage patients with head and neck cancer.

Forty-four patients were reviewed to determine the incidence of atelectasis following pectoralis major myocutaneous flap reconstruction of head and neck defects. Patients underwent tumor resection with subsequent pectoralis major myocutaneous flap reconstruction (flap group, n = 24) or another major head and neck procedure (control group, n = 20). Chest roentgenograms taken on the first postoperative day were scored for atelectasis by preestablished criteria. Sixty-five percent of control and 70% of flap patients demonstrated postoperative atelectasis roentgenographically. The flap patients with skin paddles larger than 40 cm2 had a 60% incidence of major atelectasis compared with 5% in control patients. The skin island area was strongly correlated with the atelectasis score in the flap group. These results suggest that atelectasis is common following pectoralis major myocutaneous flap reconstruction of head and neck defects. As well, decreased chest wall compliance after primary closure of large donor defects may contribute to the atelectasis observed.