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Dentists are well-positioned to discuss oral health issues related to Human Papillomavirus (HPV) and recommend the HPV vaccine to their patients, mainly because the HPV virus causes oropharyngeal cancers.. We assessed Los Angeles (LA) County dentists opinions on discussing HPV-related oral health issues and recommending the HPV vaccine to their patients. We tested if opinions differed between dentists whose primary patient population was only adults versus children and adults. We mailed a 19-item survey to 2000 randomly sampled LA County dentists for this cross-sectional study. The primary outcome variable was a summary opinion score of 7 opinion statements. We ran descriptive, bivariate comparisons and adjusted linear regression models. Overall, 261 dentists completed the survey. A majority (58.5%) worried they would lose patients if they recommended the vaccine; 49% thought dentists were not appropriate to educate, counsel, or advise on HPV-related issues; 42% were concerned about the safety of the vaccine; and 40% did not feel comfortable recommending the vaccine. The mean summary opinion score was 21.4 ± 5.4 for the total sample. Regression analysis showed no differences in opinions between dentists whose primary patient population was only adults versus children and adults (Coefficient = 0.146, p = 0.83). Overall, the responding dentists were not very favorable about discussing oral health-related HPV issues and recommending the HPV vaccine to their patients. Additionally, the overall opinions were similar between dentists whose primary patient population was only adults versus children and adults.

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPVOPSCC) is increasing in incidence. Compared to oropharyngeal cancers related to smoking and alcohol consumption, patients with HPVOPSCC are younger, have lower rates of comorbid illness and have a markedly improved chance of long-term survival. Despite global efforts evaluating different strategies to lower treatment intensity while maintaining survival, there have been no significant changes to the standard of care for patients with radiotherapy alone (RT) or in combination with chemotherapy (CRT) in more than two decades. It is anticipated that a large number of patients with HPVOPSCC will enter survivorship in the coming two decades, and this commands a renewed evaluation of the health-related quality of life (HRQL) profiles and unmet needs of this expanding cohort. In this thesis, I evaluated profiles of HRQL outcomes before, during and after treatment while also quantifying the burden of emotional distress and the importance and course of sexual health in HPVOPSCC patients. Survivorship commences from the time a patient is diagnosed with cancer, and this thesis includes studies that capture the early experiences of patients, including their HRQL, unmet needs and priorities before they commenced treatment. The papers from this thesis were sourced from several different studies, including both primary and secondary analyses of a cross-sectional study evaluating sexual health, emotional distress and HRQL at the Peter MacCallum Cancer Centre, the primary analysis of a prospective longitudinal multi-site study evaluating sexual health in HPVOPSCC patients which was designed specifically for this thesis, and two secondary analyses of a randomised clinical trial conducted across Australia and New Zealand. The latter provided the experiences of a clinical trial population of patients with favourable risk disease, while the two other studies revealed the experiences of a real-world cohort. Each of

OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland malignancy. Herein, we present the largest single-institution review of SDC to date. METHODS: This is a retrospective cohort study of all histologically confirmed cases of SDC seen at our institution from January 1, 2002, to August 1, 2022. Patient demographics, treatment, histological characteristics, tumor staging, and outcomes were extracted from the electronic medical record. Kaplan-Meier and Cox regression survival analyses were performed. RESULTS: This study included 119 patients with a mean age of 66.2 years. Most primary tumors arose from the parotid gland (72.3%), and 23.5% were noted to be carcinoma ex-pleomorphic adenoma. 57.1% of patients presented with regional lymph node metastasis, whereas 23.5% presented with distant disease. Kaplan-Meier analysis demonstrated a 62.4% 5-year overall survival (OS) and a 69.0% 5-year disease-specific survival (DSS). Univariate analyses indicated that presence of regional lymph node disease (p<.001), distant metastasis (p<.001), perineural invasion (p = .027), and lymphovascular invasion (p = .018) were predictive of decreased OS and DSS. Trastuzumab administration was not associated with survival in HER-2-positive patients receiving chemotherapy. Multivariate analyses demonstrated that presence of nodal disease (HR 30.337, 95% CI 2.782-330.851, p = .005) and carcinoma ex pleomorphic adenoma (HR 5.54, 95% CI 1.024-29.933, p = .047) were associated with decreased OS. CONCLUSION: Our patients had more favorable survival rates compared to prior studies, which may be due to lower incidence of nodal disease. Factors associated with worse survival included nodal and distant metastases, perineural invasion, lymphovascular invasion, and tumor size. LEVEL OF EVIDENCE: Level 3.

Head and neck cancer (HNC) is a prevalent and aggressive form of cancer with high mortality rates and significant implications for nutritional status. Accurate assessment of malnutrition in patients with HNC is crucial for optimizing treatment outcomes and improving survival rates. This study aimed to evaluate the use of ultrasound techniques for predicting nutritional status, malnutrition, and cancer outcomes in patients with HNC. A total of 494 patients with HNC were included in this cross-sectional observational study. Various tools and body composition measurements, including muscle mass and adipose tissue ultrasound evaluations, were implemented. Using regression models, we mainly found that high levels of RF-CSA (rectus femoris cross-sectional area) were associated with a decreased risk of malnutrition (as defined with GLIM criteria (OR = 0.81, 95% CI: 0.68–0.98); as defined with PG-SGA (OR = 0.78, 95% CI: 0.62–0.98)) and sarcopenia (OR = 0.64, 95% CI: 0.49–0.82) after being adjusted for age, sex, and BMI. To predict the importance of muscle mass ultrasound variables on the risk of mortality, a nomogram, a random forest, and decision tree models were conducted. RF-CSA was the most important variable under the random forest model. The obtained C-index for the nomogram was 0.704, and the Brier score was 16.8. With an RF-CSA < 2.7 (AUC of 0.653 (0.59–0.77)) as a split, the decision tree model classified up to 68% of patients as possessing a high probability of survival. According to the cut-off value of 2.7 cm2, patients with a low RF-CSA value lower than 2.7 cm2 had worse survival rates (p < 0.001). The findings of this study highlight the importance of implementing ultrasound tools, for accurate diagnoses and monitoring of malnutrition in patients with HNC. Adipose tissue ultrasound measurements were only weakly associated with malnutrition and not with sarcopenia, indicating that muscle mass is a more important indicator of overall health and nutritional statu

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer., This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Purpose Evaluate the occupational variation in incidence of oropharyngeal cancer (OPC). Methods We calculated standardized incidence ratios (SIRs) of OPC in occupational categories in the Nordic countries relative to the entire national populations. The data covered 6155 OPC cases. Results Among men high risk of OPC was observed, among else, in waiters (SIR 6.28, 95% CI 4.68–8.26), beverage workers (SIR 3.00, 95% CI 1.72–4.88), and artistic workers (SIR 2.97, 95% CI 2.31–3.76). Among women high risk of OPC was observed in waiters (SIR 2.02, 95% CI 1.41–2.81) and packers (SIR 1.73, 95% CI 1.07–2.64). The lowest SIRs were observed in female gardeners (SIR 0.27, 95% CI 0.12–0.51) and male farmers (SIR 0.30, 95% CI 0.25–0.35). Conclusion The 20-fold variation in incidence of OPC between occupations needs further investigation in studies with detailed information on occupational and non-occupational risk factor, Purpose: Evaluate the occupational variation in incidence of oropharyngeal cancer (OPC). Methods: We calculated standardized incidence ratios (SIRs) of OPC in occupational categories in the Nordic countries relative to the entire national populations. The data covered 6155 OPC cases. Results: Among men high risk of OPC was observed, among else, in waiters (SIR 6.28, 95% CI 4.68–8.26), beverage workers (SIR 3.00, 95% CI 1.72–4.88), and artistic workers (SIR 2.97, 95% CI 2.31–3.76). Among women high risk of OPC was observed in waiters (SIR 2.02, 95% CI 1.41–2.81) and packers (SIR 1.73, 95% CI 1.07–2.64). The lowest SIRs were observed in female gardeners (SIR 0.27, 95% CI 0.12–0.51) and male farmers (SIR 0.30, 95% CI 0.25–0.35). Conclusion: The 20-fold variation in incidence of OPC between occupations needs further investigation in studies with detailed information on occupational and non-occupational risk factors.

To better identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) and a poor prognosis after treatment, we compared the gene expression in tumours from patients with a poor or a favourable prognosis in a case-control setting. The results were thereafter validated in two separate cohorts on the RNA and protein levels. High RNA or protein expression of FGF11 was correlated with a poor patient survival in all three cohorts. Taken together, the data imply that FGF11 may play a major role in the prognosis of patients and that FGF11 could serve as a prognostic marker in HPV-positive oropharyngeal cancer.Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000-2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as

Global trends in human papillomavirus (HPV)-associated head and neck cancers (HNC), specifically in the oropharynx subsite, have been dynamically changing, leading to new staging and treatment paradigms. Epidemiologic studies have noted regional variations in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). While HPV vaccination remains the main preventative approach, vaccination policy in relation to gender neutrality is heterogeneous and particularly sparse in low- and middle-income countries, where the burden of global cancer cases and HPV-associated HNC are not well-characterized in certain regions. This review summarizes the existing literature on regional variations of HPV-associated OPSCC and gender-neutral vaccine policies. Based on available data, the incidence of HPV-associated OPSCC is highest in North America, Europe, and Oceania. As of 2022, 122 of 195 (63%) World Health Organization (WHO) member states had incorporated HPV vaccinations nationally; of these, 41 of 122 (34%) member states have introduced gender-neutral vaccine coverage. Future research is needed to describe continued evolving trends in HPV-associated OPSCC, understand underlying risk factors leading to regional variation in disease, and implement gender-neutral policy more broadly.

Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs. Keywords: oropharyngeal cancer; head and neck cancer; squamous cell carcinoma; human papillomavirus; head and neck ultrasound; transoral ultrasound; intraoral ultrasound; transcervical ultrasound; neck ultrasound; oropharyngeal squamous cell carcinoma, Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs.

Objective(s): To investigate dysphagia and quality of life (QoL) outcomes 3 years after treatment of oropharyngeal cancer with either primary trans oral robotic surgery (TORS) or radiotherapy (RT). Methods: A prospective cohort study conducted at the Copenhagen University Hospital. Endpoints were objective swallowing function, examined using fiberoptic endoscopic evaluation of swallowing (FEES) and video fluoroscopy (VF). QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30), Head & Neck Module (EORTC QLQ-HN35), and MD Anderson Dysphagia Inventory (MDADI). A comparison was made between 1-, and 3-year results. Results: Forty-four patients were included prior to treatment, 31 treated with TORS and 13 with RT. One-year results for this cohort have previously been published (https://doi.org/10.1080/00016489.2020.1836395). Significant improvement on FEES in retention at the piriform sinus was noted in both groups. Patients treated with TORS had improved safety scores as well as dynamic imaging grade of swallowing toxicity (DIGEST) and efficiency scores, whereas patients treated with RT only had improvements in the latter two. Improvement in QoL scores was only noted for patients treated with TORS in composite MDADI scores. Conclusion: We found significant improvements in objective swallowing function from one to 3 years after treatment, particularly in patients treated with TORS. However, these improvements were not reflected as clinically meaningful improvements in QoL. Level of Evidence: Level 3, cohort follow-up study Laryngoscope, 2022.

Purpose of Review: The burden of HPV co-infection in people living with HIV is high leading to increase incidence of HPV-related malignancies. Antiretroviral therapy and HPV vaccination appears to have made a significant impact on the prevention and treatment of HPV-related cancers. Recent Findings: Cervical and anal cancer data on survival and risk factors in people living with HIV showed a better prognosis with antiretroviral treatment and immune reconstitution. HPV vaccination has been demonstrated effective and safe in HIV infection but showed no impact on progression of precancerous lesions. Head and neck and other genital cancer are more frequent in HIV population, but no standardized screening is available and only few studies addressed vaccine efficacy. Summary: Cervical and anal cancer incidence and prognosis in people living with HIV depends on access to screening, treatment, and vaccination. Only few data are available on other HPV-related cancers in HIV infection.

Second primary cancer (SPC) is the second most common cause of death among patients diagnosed with head and neck cancer. This study examined the risk of SPC following oropharyngeal squamous cell carcinoma (OPSCC) and the impact of human papillomavirus (HPV) on survival following SPC. The study was a population-based, retrospective study including all patients diagnosed with OPSCC in eastern Denmark from 2000–2020 who received curative intended treatment. The incidence rate ratio (IRR), age-adjusted incidence rates (AAIR), and hazard ratios (HR) were calculated. A total of 2584 patients with primary OPSCC were included (median follow-up time: 3.1 years), with 317 patients (12.3%) diagnosed with SPC. The risk of SPC was approximately five times the occurrence of cancer in the general population (IRR: 4.96). The median time to SPC after a primary OPSCC was 2.0 years (interquartile range (IQR) = 0.6–4.2 years). HPV-positive (HPV+) patients had a significantly longer median time to SPC, and a significant better survival compared to HPV-negative (HPV-) patients. SPC was most frequently found in lungs, head, and neck (LHN) for HPV- OPSCC patients and lungs followed by gender-specific (prostate, ovaries, or endometrium) for HPV+ OPSCC. There was a significant difference between the two groups when distributed between “within” or “outside” LHN. Patients with SPC outside LHN had a significant better overall survival. This knowledge should be considered during post-treatment surveillance and might guide targeted imaging.

Several viruses are known to be associated with the development of certain cancers, including human papillomavirus (HPV), an established causative agent for a range of anogenital and head and neck cancers. However, much of the available data has analysed causality based on the presence of the virus, or its genetic material, in the sampled tumours. While this approach is a great tool as a starting point to identify possible links, it does not consider the early stages of tumorigenesis, nor the possibility of loss of the viral genetic material during the development of the tumour. Although some cancers were found to be addicted to the continued expression of viral oncogenes, this might not be the case for all virally initiated cancers. Here, we hypothesize that the absence of viral genes from the tumour does not necessarily exclude the viral aetiology. The hit-and-run theory suggests that the viruses have a triggering role in the cancer formation, and the viral genome can be entirely lost after the host cell accumulates numerous mutations. If this mechanism occurs, it will imply that many cancers not associated with viruses might, in fact, have arisen firstly as virus-positive cancers that have lost viral DNA. In this study, we tested this theory in an HPV-driven oropharyngeal cancer (OPC) tumour model. HPV OPCs are oncogenic addicted to the presence of the HPV oncogene, E7, where the genetic removal of this oncogene regresses tumours in vivo. Remarkably, E7 deleted tumours recurred overtime and develop new mutations not previously seen in HPV-positive OPC tumours. Importantly, a number of these new mutations are found to be already present in several HPV-negative OPC tumours. This finding suggests that previously designated HPV-negative OPCs could possibly have begun its carcinogenic journey as an HPV positive tumour and over time lose key viral oncogene(s) to accumulate new mutations for its continual maintenance., Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Pharmacy & Med Sci, Griffith Health, Full Text

Objective To analyse mortality rate trends in Spain for oral cavity and oropharyngeal cancer (OCOPC) from 1979 to 2018, evaluating differences between oral cavity cancer (OCC) and oropharyngeal cancer (OPC). Materials and Methods Death certificates and mid-year population data were collected from the Spanish National Statistics Institute. Age-standardized mortality rates were calculated using the direct method. Joinpoint regressions were used to identify significant changes in mortality trends. Independent effects of age, period and cohort (APC) were estimated. Results A total of 52,057 deaths were registered from OCOPC, 38,988 from OCC and 13,069 from OPC between 1979 and 2018. While OCC mortality rates declined, OCOPC rates increased slightly and OPC significantly. OCC and OPC mortality reached their highest values between 1979 and 1992, when OCC rates began to decrease in males and OPC levelled off until 2018. Lip cancer suffered the highest drop. APC models showed a mortality increase in males and females from 40 to 45 and 50 to 55 years of age, respectively. Conclusions Favourable OCC mortality trends was plausibly influenced by decreased tobacco/alcohol consumption, while OPC rise was probably associated with increased human papillomavirus infection. The importance of closely monitoring these cancers by age group, sex and location, and continuing with preventive measures against known risk factors, is highlighted.

This study evaluated the effectiveness of an information pamphlet designed to address common information gaps that exist for human papillomavirus positive oropharyngeal cancer patients. The study has highlighted the complex psychosocial impacts of a human papillomavirus positive oropharyngeal cancer diagnosis and has provided insight into how an informational intervention could assist patients to manage these impacts. The results contribute to the growing evidence regarding the psychosocial and information needs of human papillomavirus positive oropharyngeal cancer patients.

In this real-world study, the aims were to prospectively evaluate the expression of inflammatory proteins in serum collected from head and neck cancer patients before and after treatment, and to assess whether there were differences in expression associated with treatment modalities. The mixed study cohort consisted of 180 patients with head and neck cancer. The most common tumor sites were the oropharynx (n = 81), the oral cavity (n = 53), and the larynx (n = 22). Blood tests for proteomics analysis were carried out before treatment, 7 weeks after the start of treatment, and 3 and 12 months after the termination of treatment. Sera were analyzed for 83 proteins using an immuno-oncology biomarker panel (Olink, Uppsala, Sweden). Patients were divided into four treatment groups: surgery alone (Surg group, n = 24), radiotherapy with or without surgery (RT group, n = 94), radiotherapy with concomitant cisplatin (CRT group, n = 47), and radiotherapy with concomitant targeted therapy (RT Cetux group, n = 15). For the overall cohort, the expression levels of 15 of the 83 proteins changed significantly between the pretreatment sample and the sample taken 7 weeks after the start of treatment. At 7 weeks after the start of treatment, 13 proteins showed lower expression in the CRT group compared to the RT group. The majority of the inflammatory proteins had returned to their pretreatment levels after 12 months. It was clearly demonstrated that cisplatin-based chemoradiation has immunological effects in patients with head and neck cancer. This analysis draws attention to several inflammatory proteins that are of interest for further studies.

To identify predictive/targetable markers in human papillomavirus positive (HPV+) ton-sillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metas-tases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.

In the recent years, the prevalence of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) has increased significantly. Currently, nearly 80-90% of all oropharynx tumors are HPV-positive. In addition, it is now recognized that HPV-positive tumor status is associated with good prognosis and improved response to chemoradiation. However, within this setting, there are still patients with HPV-positive OPSCC who will experience recurrence. With the increasing incidence of HPV-mediated OPSCC, recurrent HPV disease is also becoming more prevalent and there is an increasing need to understand the unique presentation and treatment of recurrent HPV-mediated disease. In this review, we will discuss epidemiology of recurrent HPV-positive OPSCC, role of surgical salvage, re-irradiation, and the role of upcoming novel treatments and immunotherapy. Historically, recurrent oropharyngeal disease has been associated with poor prognosis and high morbidity. However, recent advances have transformed the landscape for salvage treatment of HPV-mediated OPSCC. Liquid biomarkers offer potential for early detection of recurrence, robotic techniques may reduce morbidity of surgical salvage, improvements in re-irradiation approaches reduce toxicities, and novel immune based therapies on the horizon are offering promising results. These advances combined with the improved prognosis of HPV-positive disease offer to transform our approach to recurrent disease of the oropharynx.

The incidence of oropharyngeal cancer (OPC) has been rising, especially among middle-aged men. While Human Papillomavirus (HPV) has been irrevocably implicated in the pathogenesis of oropharyngeal cancer (OPC), the current HPV vaccination uptake rate remains low in the US. The aim of our study was to evaluate the impact of increased HPV vaccination coverage on HPV-associated OPC incidence and costs. A decision analytic model was constructed for hypothetical cohorts of 9-year-old boys and girls. Two strategies were compared: 1) Maintaining the current vaccination uptake rates; 2) Increasing HPV vaccination uptake rates to the Healthy People 2030 target (80%) for both sexes. Increasing HPV vaccination coverage rates to 80% would be expected to prevent 5,339 OPC cases at a cost of $0.57 billion USD. Increased HPV vaccination coverage would result in 7,430 quality-adjusted life year (QALY) gains in the overall population, and it is estimated to be cost-effective for males with an incremental cost-effectiveness ratio of $86,940 per QALY gained under certain conditions. Expanding HPV vaccination rates would likely provide a cost-effective way to reduce the OPC incidence, particularly among males.

Objectives: Base-of-tongue (BOT)/tonsillar cancer incidence is rising, primarily due to human papillomavirus; meanwhile, rates of the mainly smoking-associated laryngeal cancer is declining. Little is known about whether these trends are seen in all socioeconomic levels and age-groups. We describe incidence trends of BOT/tonsillar and laryngeal cancer in Denmark 1994-2018 by educational level and age. Methods: BOT/tonsillar and laryngeal cancer cases diagnosed 1994-2018 were identified from the Danish Cancer Registry. We obtained individual-level educational information from nationwide registries. We estimated agestandardized incidence rates of BOT/tonsillar and laryngeal cancer according to sex, education and age. Temporal incidence trends were evaluated by the average annual percentage change (AAPC) with corresponding 95% confidence intervals (CIs) using linear and Poisson regression models for age-standardized incidence rates. Results: We identified 4245 individuals with BOT/tonsillar cancer and 6123 with laryngeal cancer. BOT/tonsillar cancer incidence increased among men with short (AAPC:3.4, 95% CI 2.1;4.6) and long (AAPC:5.1, 95% CI 3.2;7.1) education, and all age-groups, while decreased from 2012 among men with medium education (AAPC:4.3, 95 %CI -7.6;-1.0). Laryngeal cancer incidence decreased from 2007 in men with medium (AAPC:-4.7, 95% CI -6.7;-2.7) and long (AAPC:-2.4, 95% CI -3.4;-1.4) education, and all age-groups, whereas increased in men with short education (AAPC:1.0, 95% CI 0.2;1.8). Similar trends were seen among women. Conclusions: Over the last 25 years, BOT/tonsillar cancer incidence in Denmark has generally increased in all agegroups and educational levels. In contrast, social inequality was seen in laryngeal cancer trends as incidence decreased in individuals with medium and long education, while incidence increased in individuals with short education.

Background: Evidence suggests that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have antineoplastic properties of potential importance for survival of head and neck cancer. Methods: We conducted a nationwide cohort study including all individuals with primary head and neck squamous cell carcinoma in Denmark during 2000–2016 at age 30–84 years, with no history of cancer (except non-melanoma skin cancer), and alive at 1 year after diagnosis. Nationwide registries provided information on drug use, causes of death and potential confounders, and additional clinical information was obtained for a subpopulation. We conducted Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between post-diagnosis non-aspirin NSAID use (defined as ≥1 filled prescription within first year after diagnosis) and cancer-specific mortality. Results: Among 10,770 head and neck cancer 1-year survivors, the HR for cancer-specific mortality with non-aspirin NSAID use was 1.68 at 1 year after diagnosis, but declined and stabilized around 1.15 (95% CI 1.02–1.29) at 2 years after diagnosis. Among 2-year survivors, the HRs for cancer-specific mortality with non-aspirin NSAID use remained slightly increased in analyses stratified by age, sex, stage, and pre-diagnosis non-aspirin NSAID use. Similar results were seen in the subpopulation (n = 1029) with additional clinical information, and among 5-year survivors with additional non-aspirin NSAID exposure assessment. Conclusion: In this nationwide cohort of patients with head and neck cancer, use of non-aspirin NSAIDs was associated with a slightly increased mortality risk, warranting further evaluation.

Purpose: Squamous cell carcinoma metastasis of the head and neck with unknown primary tumor (CUP) comprises a diagnostic challenge. Human papillomavirus (HPV) testing on cytologic specimens is gaining increasing focus as this may facilitate an early diagnosis of HPV-induced oropharyngeal carcinoma. This study aimed to prospectively assess PCR-based HPV-DNA testing on FNA smears in a clinical setting. Methods: Patients referred to a tertiary Head and Neck Cancer Center with suspected CUP were included from November 2016 to November 2018. Scraped cell material from FNA smears was analyzed for HPV-DNA with PCR using general primers (GP5 + /GP6 +) and correlated with the origin and histology of the primary tumor (oropharynx vs. outside oropharynx or benign tumor). The turn-around time reflecting the workflow for HPV-DNA testing by PCR was also calculated. Results: A total of 93 patients were enrolled in the study. The sensitivity and specificity were 86.7% [95% CI 75.4–94.1%] and 92.0% [95% CI 74.0–99.0%], and the positive and negative predictive values were 96.3% [95% CI 87.3–99.0%] and 74.2% [95% CI 59.9–84.7%], respectively. The turn-around time for HPV testing was a mean four calendar days. Conclusion: HPV-DNA testing on FNA smears can be performed within a reasonable timeframe and can guide for the detection of an HPV-positive oropharyngeal primary tumor in the clinical setting for patients presenting with CUP of the head and neck.

Background: Alcohol and tobacco are the major risk factors for oral and pharyngeal cancer, but diet is likely to have a role, too. Objective: The objective was to analyze the relationship between adherence to the 2015-2020 Dietary Guidelines for Americans (DGA), as measured by the Healthy Eating Index 2015 (HEI-2015), and oral and pharyngeal cancer risk. Moreover, this work aimed to quantify the number of avoidable cases under different scenarios of increased adherence to the DGA, with the use of the potential impact fraction. This estimates the proportion of cases that would occur if the distribution of the risk factor in the population followed an alternative distribution. Design: A multicenter, case–control study was conducted in Italy between 1991 and 2009. Participants’ usual diet for the 2 years preceding study enrolment was assessed using a food frequency questionnaire. Participants and setting: Cases were 946 patients admitted to major hospitals with incident, histologically confirmed oral and pharyngeal cancer. Controls were 2,492 patients admitted to the same hospitals for acute non neoplastic conditions. Main outcome measures: The adherence to the DGA was assessed using the HEI-2015 score (range = 0 to 100), based on 13 components. The outcome was oral and pharyngeal cancer. Statistical analyses performed: Odds ratios and the corresponding 95% CIs were estimated using multiple logistic regression models adjusted for tobacco, alcohol, and other relevant covariates. The potential impact fraction was estimated under different scenarios of adherence to the DGA. Results: In this Italian population the HEI-2015 score ranged from 33.4 to 97.5. A higher HEI-2015 score was associated with a lower risk of oral and pharyngeal cancer, with an odds ratio of 0.70 (95% CI 0.62 to 0.79) for a 10-point increment of the score. The estimated potential impact fraction was 64.8% under the maximum achievable reduction scenario, and it ranged from 9% to 27% following other more

The incidence of oropharyngeal cancers (OPSCCs) has continued to rise over the years, mainly due to human papillomavirus (HPV) infection. Although they were newly reclassified in the last TNM staging system, some groups still relapse and have poor prognoses. Based on their implication in oncogenesis, we investigated the density of cytotoxic and regulatory T cells, macrophages, and Langerhans cells in relation to p16 status, staging and survival of patients. Biopsies from 194 OPSCCs were analyzed for HPV by RT-qPCR and for p16 by immunohistochemistry, while CD8, FoxP3, CD68 and CD1a immunolabeling was performed in stromal (ST) and intratumoral (IT) compartments to establish optimal cutoff values for overall survival (OS). High levels of FoxP3 IT and CD1a ST positively correlated with OS and were observed in p16-positive and low-stage patients, respectively. Then, their associations with p16 and TNM were more efficient than the clinical parameters alone in describing patient survival. Using multivariate analyses, we demonstrated that the respective combination of FoxP3 or CD1a with p16 status or staging was an independent prognostic marker improving the outcome of OPSCC patients. These two combinations are significant prognostic signatures that may eventually be included in the staging stratification system to develop personalized treatment approaches., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Proton beam therapy (PBT) is a new-emerging cancer treatment in China but its treatment costs are high and not yet covered by Chinese public medical insurance. The advanced form of PBT, intensity-modulated proton radiation therapy (IMPT), has been confirmed to reduce normal tissue complication probability (NTCP) as compared to conventional intensity-modulated photon-radiation therapy (IMRT) in patients with oropharyngeal cancer (OPC). Herein, we evaluated the cost-effectiveness and applicability of IMPT versus IMRT for OPC patients in China, aiming at guiding the proper use of PBT. Methods A 7-state Markov model was designed for analysis. Base-case evaluation was performed on a 56-year-old (median age of OPC in China) patient under the assumption that IMPT could provide a 25% NTCP-reduction in long-term symptomatic dysphagia and xerostomia. Model robustness was examined using probabilistic sensitivity analysis, cohort analysis, and tornado diagram. One-way sensitivity analyses were conducted to identify the cost-effective scenarios. IMPT was considered as cost-effective if the incremental cost-effectiveness ratio (ICER) was below the societal willingness-to-pay (WTP) threshold. Results Compared with IMRT, IMPT provided an extra 0.205 quality-adjusted life-year (QALY) at an additional cost of 34,926.6 US dollars ($), and had an ICER of $170,082.4/ QALY for the base case. At the current WTP of China ($33,558 / QALY) and a current IMPT treatment costs of $50,000, IMPT should provide a minimum NTCP-reduction of 47.5, 50.8, 55.6, 63.3 and 77.2% to be considered cost-effective for patient age levels of 10, 20, 30, 40 and 50-year-old, respectively. For patients at the median age level, reducing the current IMPT costs ($50,000) to a $30,000 level would make the minimum NTCP-reduction threshold for "cost-effective" decrease from 91.4 to 44.6%, at the current WTP of China (from 69.0 to 33.5%, at a WTP of $50,000 / QALY; and from 39.7 to 19.1%, at a WTP of $100,000

Background: Patients with oral cavity cancer (OCC) and oropharyngeal cancer (OPC) are often seen with locoregionally advanced disease requiring complex multimodality treatments. These treatments may have detrimental effects on the oral microbiome, which is critical to maintaining physiological balance and health. Methods: The effects of different OCC and OPC treatment types on the oral microbiome and metabolomic profiles for 24-month post-treatment in patients with OCC and OPC were investigated using 16S rRNA gene amplicon next-generation sequencing and gas chromatography–mass spectrometry (GC–MS), respectively. Results: Chemoradiation resulted in oral dysbiosis with specific depletion of genera which regulate the enterosalivary nitrate–nitrite–nitric oxide pathway. These data also correlate with the oral metabolomic profiles with nitric oxide-related precursor, modulator, or catalyst significantly downregulated in saliva samples from patients' postchemoradiation. Conclusions: Together, we have shown that oral dysbiosis due to the effects of chemoradiation could potentially have an impact on OCC and OPC patient's quality of life post-treatment.

Background: Patients undergoing (chemo) radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) are at high risk of malnutrition during and after treatment. Malnutrition can lead to poor tolerance to treatment, treatment interruptions, poor quality of life (QOL) and potentially reduced survival rate. Human papillomavirus (HPV) is now known as the major cause of OPSCC. However, research regarding its effect on nutritional outcomes is limited. The aim of this study was to examine the relationship between HPV status and nutritional outcomes, including malnutrition and weight loss during and after patients’ (chemo) radiotherapy treatment for OPSCC. Methods: This was a longitudinal cohort study comparing the nutritional outcomes of HPV-positive and negative OPSCC patients undergoing (chemo) radiotherapy. The primary outcome was nutritional status as measured using the Patient Generated-Subjective Global Assessment (PG-SGA). Secondary outcomes included loss of weight, depression, QOL and adverse events. Results: Although HPV-positive were less likely to be malnourished according to PG-SGA at the beginning of treatment, we found that the difference between malnutrition rates in response to treatment was not significantly different over the course of radiotherapy and 3 months post treatment. HPV-positive participants had significantly higher odds of experiencing >10% weight loss at three months post-treatment than HPV-negative participants (OR = 49.68, 95% CI (2.7, 912.86) p ≤ 0.01). Conclusions: The nutritional status of HPV positive and negative patients were both negatively affected by treatment and require similarly intense nutritional intervention. In acute recovery, HPV positive patients may require more intense intervention. At 3- months post treatment, both groups still showed nutritional symptoms that require nutritional intervention so ongoing nutritional support is essential.

The rising incidence of oropharyngeal squamous cell cancers (OPSCC) in the United States is largely attributed to HPV. Prophylactic HPV vaccines have demonstrated effectiveness against oral infection of HPV 16 and HPV 18. We review the global epidemiology and biology of HPV-related cancers as well as the development of HPV vaccines and their use worldwide. We also review the various strategies and challenges in development of therapeutic HPV vaccines.

Background This exploratory, registry-based, cross-sectional study aimed to evaluate patients' health-related quality of life (HRQOL) in a subsite of oropharyngeal cancer: cancer of the base of the tongue (CBT). Methods CBT patients, treated with curative intent, completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 15 months after diagnosis. The HRQOL of CBT patients was compared to reference scores from the general population and to that of tonsillar carcinoma patients. Results The 190 CBT patients scored significantly worse than members of the general population on most scales. CBT patients with human papilloma virus (HPV)-positive tumors had significantly better HRQOL on 8 of 28 scales than HPV-negative patients. Compared to 405 tonsillar carcinoma patients, CBT patients had significantly worse HRQOL on 8 of the 28 scales, the majority local head and neck related problems. Conclusion One year after treatment, CBT patients' HRQOL was significantly worse in many areas compared to that of the general population and slightly worse than that of tonsillar carcinoma patients.

Introduction: Oropharyngeal cancer (OPC) is a highly prevalent malignancy worldwideaffecting the tonsils, the soft palette and the base of the tongue. OPC has a high risk ofrecurrence. Patients are offered a 5-year follow-up program in order to discover earlyrecurrences. However, there exists some controversy regarding the benefit of this follow-up indetecting early recurrences. Objective: The primary aim of this study was to investigate whether recurrences of OPC weredetected in patient-initiated appointments or during routine follow-up. The secondary aim wasto compare the survival between these groups. Method and materials: This study is a retrospective cohort study regarding recurrencedetection among patients diagnosed with OPC. The Örebro Head- and neck cancer registerwas used to identify patients with recurrence of OPC. Additional data was collected frommedical records. Results: A total of 75 patients were included. Routine follow-up detected 50.7% ofrecurrences while patient-initiated visits detected 42.7% of recurrences. No statisticallysignificant difference was found in survival between these groups Conclusion: In contradiction to our hypothesis most of the recurrences were detected atroutine follow-up. There was no statistically significant difference in survival between thetwo ways of detection. These results indicate that our current follow-up program has animportance in detecting early recurrences and should not be altered.

Human papillomavirus (HPV) imposes an increased risk of developing cervical, anal and oropharyngeal cancer. In the Western world, HPV infection is currently the major cause of oropharyngeal cancer. The effectiveness of HPV vaccines for oral or oropharyngeal HPV infection is yet to be determined. This study conducted a systematic literature search in Pubmed and Embase. Studies investigating the impact of HPV vaccines on oral or oropharyngeal HPV infection were enrolled. This review reports the relative prevention percentage (RPP), including a risk of bias assessment as well as a quality assessment study. Nine studies were included (48,777 participants): five cross-sectional studies; one randomized community trial study (RCT); one longitudinal cohort study; and two case-control studies. A significant mean RPP of 83.9% (66.6–97.8%) was calculated from the cross-sectional studies, 82.4% in the included RCT and 83% in the longitudinal cohort study. Further, two case-control studies that measured antibody response in participants immunized with HPV vaccines were included. Respectively, 100% and 93.2% of participants developed HPV-16 Immunoglobulin G (IgG) antibodies in oral fluids post-vaccination. Analysis of the studies identified a significant decrease in vaccine-type oral or oropharyngeal HPV infections in study participants immunized with HPV vaccines across study designs and heterogenous populations. Further, a significant percentage of participants developed IgG antibodies in oral fluid post-vaccination.

Significant variation in human papillomavirus (HPV) prevalence in oropharyngeal squamous cell carcinoma (OPSCC) across countries ranging from 11% in Brazil to 74% in New Zealand has been reported earlier. The aim of this study was to systematically review the most recently published studies on the occurrence of HPV in OPSCC globally. PubMed and Embase were systematically searched for articles assessing the occurrence of HPV+ OPSCC published between January 2016 and May 2021. Studies with a study period including 2015 and the following years were included. Both HPV DNA and/or p16 were accepted as indicators of HPV+ OPSCC. 31 studies were enrolled comprising 49,564 patients with OPSCC (range 12–42,024 patients per study) from 26 different countries covering all continents. The lowest occurrences of HPV+ OPSCC were observed in India (0%) and Spain (10%) and the highest occurrences were observed in Lebanon (85%) and Sweden (70%). We observed great variation in HPV prevalence in OPSCC worldwide varying from 0% to 85%. The highest occurrences of HPV+ OPSCC were found in general in Northern European countries, USA, Lebanon, China, and South Korea. We observed a trend of increase in HPV-positivity, indicating a mounting burden of HPV+ OPSCC.

The aim of the study was to evaluate the diagnostic accuracy of Human Papillomavirus (HPV) techniques in oropharyngeal cancer. PubMed, EMBASE, the Cochrane Library and clinicaltrials.org were systematically searched for studies reporting methods of HPV detection. Primary outcomes were sensitivity and specificity of HPV detection. In this case, 27 studies were included (n = 5488, 41.6% HPV+). In this case, 13 studies evaluated HPV detection in tumour tissue, nine studies examined HPV detection in blood samples and five studies evaluated HPV detection in oral samples. Accuracy of HPV detection in tumour tissue was high for all detection methods, with pooled sensitivity ranging from 81.1% (95% CI 71.9–87.8) to 93.1% (95% CI 87.4–96.4) and specificity ranging from 81.1% (95% CI 71.9–87.8) to 94.9% (95% CI 79.1–98.9) depending on detection methods. Overall accuracy of HPV detection in blood samples revealed a sensitivity of 81.4% (95% CI 62.9– 91.9) and a specificity of 94.8% (95% CI 91.4–96.9). In oral samples pooled sensitivity and specificity were lower (77.0% (95% CI 68.8–83.6) and 74.0% (95% CI 58.0–85.4)). In conclusion, we found an overall high accuracy for HPV detection in tumour tissue regardless of the HPV detection method used. HPV detection in blood samples may provide a promising new way of HPV detection.

Objective: To analyze the role of transoral robotic base-of-tongue mucosectomy in a cohort of patients with human papilloma virus negative unknown primary carcinoma. Study Design: Retrospective database analysis. Methods: A retrospective database review from 2012 to 2018 was performed at two large tertiary centers to study patients with human papilloma virus (HPV)-negative unknown primary carcinoma who underwent transoral robotic base-of-tongue mucosectomy. P16 testing was used as a surrogate for HPV status. Patients were included that had squamous cell carcinoma metastatic to the lateral neck based on fine needle aspiration or open biopsy. Preoperatively, all patients were classified as having an unknown primary based on normal clinical and flexible endoscopic exam, normal operative endoscopy, nonlocalizing imaging, and tonsillectomy. All patients underwent robotic base-of-tongue mucosectomy. The primary outcome measure was the incidence of pathologic identification of a mucosal primary. Results: Twenty-three patients with p16-negative unknown primary carcinoma were identified and studied. All patients underwent transoral robotic base-of-tongue mucosectomy. Median age was 60 years at the time of diagnosis, and 18 of 23 (78.2%) were male. Pathologic analysis of the base-of-tongue specimens showed a primary tumor in only three of 23 (13.0%) of patients. Conclusion: Despite prior evidence suggesting a high rate of primary site identification in HPV-related disease, robotic base-of-tongue mucosectomy may not be indicated for HPV-negative unknown primary carcinoma based on a low likelihood of finding the primary. Level of Evidence: 4 Laryngoscope, 131:78–81, 2021.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.

Background: To describe the frequency of patients returning to work after treatment for oropharyngeal cancer and to identify predictors and physical barriers that might interfere with the return to work process. Methods: Cross‐sectional study including 295 patients. Data were collected regarding work/sick leave situation at 1 month before diagnosis and 15 months after diagnosis. The situation before diagnosis was retrospectively recalled by the patients. Two subscales and two single items from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐H&N35 were used. Data were analyzed with multivariate logistic regression. Results: Fifteen months after diagnosis, 212 patients (72%) were working. To be working 15 months after diagnosis was associated with working before diagnosis. Swallowing difficulties, problems talking on the telephone, and physical appearance were negatively associated with returning to work. Conclusions: The large number of individuals returning to work is encouraging for patients diagnosed with oropharyngeal cancer.

Background: A large tumor volume negatively impacts the outcome of radiation therapy (RT). Altered fractionation (AF) can improve local control (LC) compared with conventional fractionation (CF). The aim of the present study was to investigate if response to AF differs with tumor volume in oropharyngeal cancer. Methods: Three hundred and twenty four patients with oropharyngeal cancer treated in a randomized, phase III trial comparing CF (2 Gy/d, 5 d/wk, 7 weeks, total dose 68 Gy) to AF (1.1 Gy + 2 Gy/d, 5 d/wk, 4.5 weeks, total dose 68 Gy) were analyzed. Results: Tumor volume had less impact on LC for patients treated with AF. There was an interaction between tumor volume and fractionation schedule (P = .039). This differential response was in favor of CF for small tumors and of AF for large tumors. Conclusion: AF diminishes the importance of tumor volume for local tumor control in oropharyngeal cancer.

Purpose: In automated treatment planning, configuration of the underlying algorithm to generate high-quality plans for all patients of a particular tumor type can be a major challenge. Often, a time-consuming trial-and-error tuning procedure is required. The purpose of this paper is to automatically configure an automated treatment planning algorithm for oropharyngeal cancer patients. Methods: Recently, we proposed a new procedure to automatically configure the reference point method (RPM), a fast automatic multi-objective treatment planning algorithm. With a well-tuned configuration, the RPM generates a single Pareto optimal treatment plan with clinically favorable trade-offs for each patient. The automatic configuration of the RPM requires a set of computed tomography (CT) scans with corresponding dose distributions for training. Previously, we demonstrated for prostate cancer planning with 12 objectives tha

BACKGROUND & AIMS: Chemoradiation and bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often comes with high toxicity rates, interfering with oral intake and leading to temporary tube feeding (TF) dependency. High-quality scientific evidence for indicators of prophylactic gastrostomy insertion is not available. The aim of this retrospective cohort study was to develop a prediction model to identify patients who need prophylactic gastrostomy insertion, defined as the expected use of TF for at least four weeks.METHODS: Four-hundred-fifty LAHNSCC patients receiving CRT/BRT with curative intent between 2013 and 2016 were included in the study. Primary outcome was TF-dependency for four weeks or longer. Patient, tumor, and treatment characteristics were extracted from the medical records and their effects on the use of TF were analyzed using univariable and multivariable analysis. The prediction model was internally validated using bootstrapping techniques.RESULTS: Sixty-five percent (294/450 patients) required TF for four weeks or longer. Variables included in the model were: body mass index and adjusted diet at start of CRT/BRT, percentage weight change at baseline, World Health Organization performance status, tumor subsite, TNM-classification, CRT/BRT, mean radiation dose on the contralateral submandibular and parotid gland. The corrected Area Under the Curve after internal validation was 72.3%, indicating good discriminative properties of the prediction model.CONCLUSIONS: We developed and internally validated a prediction model that is intended to estimate TF-dependency for at least four weeks in LAHNSCC patients treated with CRT/BRT. This model can be used as a tool to support personalized decision making on prophylactic gastrostomy insertion.

Human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a relatively new clinical entity that is dramatically on the rise globally. HPV+ OPSCC is thought to be a separate clinical entity compared to HPV- OPSCC with a distinct tumor biology. Patients with HPV associated disease have been shown to have a substantially better prognosis and overall survival than those patients with the HPV negative (HPV-) counterpart. The standard of care for OPSCC is definitive radiation therapy (RT) and concurrent chemoradiation therapy (CRT), for lower and higher stage disease, respectively. However, traditional CRT is also associated with severe acute and late toxicities affecting patient quality of life, such as severe mucositis, dry mouth and dysphagia. Considering that HPV+ OPSCC is on the rise in a younger, healthier patient population and the good prognosis of HPV-related disease, there has been a focus on reducing treatment toxicities and optimizing quality of life while maintaining favorable oncologic outcomes. A variety of such de-escalation regimens are currently being explored in recently completed and ongoing clinical trials. Alterations to the standard chemotherapy, radiation and surgical regimens are being explored. This review will provide an overview of the rationale for and available results of the major de-intensification strategies in the treatment of locally advanced HPV+ OPSCC.

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981-2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks.

BackgroundHuman papillomavirus (HPV)-positive oropharyngeal cancer (HPV-OPC) is distinct from HPV-unassociated head and neck cancer. However, whether risk factors for HPV-positive oropharyngeal and nonoropharyngeal squamous cell cancer are the same is unclear.MethodsIncident cases of HPV-positive head and neck cell cancer and matched non-cancer controls were enrolled in a multi-institutional, prospective study examining risk factors, biomarkers, and survival.ResultsHPV-nonOPC (n = 20) were more likely to be ever smokers than controls (n = 80, OR 3.49, 95%CI 1.11-10.9) and HPV-OPC (n = 185, OR 3.28, 95%CI 1.10-10.2). Compared with HPV-OPC, HPV-nonOPC were less likely to have had over 3 oral sexual partners (OR 0.29, 95%CI 0.06-0.9), more likely to have multimorbidity (OR 3.30, 95%CI 1.04-10.5), and less likely to have antibodies to HPV16 E6 (90% vs 28%, OR 0.05, 95%CI 0.02-0.2). HPV-nonOPC had worse 4-year OS (77% vs 96%, P = .001) and RFS (69% vs 94%, P < .001) than HPV-OPC.ConclusionsHPV-positive nonoropharyngeal are distinct from HPV-positive oropharyngeal cancers.

This study aimed to evaluate the effectiveness of an educational intervention at improving Oral Health Professionals (OHP's) knowledge of HPV and comfortability to discuss vaccination with their American Indian and Alaskan Native patients. OHP's attended an educational lecture covering HPV vaccination. Participants completed four validated questionnaires that encompassed a sociodemographic survey, a pre-lecture questionnaire (pre-Q), a post-lecture questionnaire (post-Q), and a follow-up questionnaire (follow-Q). The McNemar test was used to assess the significance of marginal probabilities in the responses between the pre-Q and post-Q and the Chi-square test to assess responses between the post-Q and follow-Q. A total of 122 OHP's completed the sociodemographic survey, pre-Q, and post-Q. Among these, 29 OHP's completed the eight-week follow-Q. The majority of all the participants were White/Caucasian (41%), 31 to 60 years of age (72%), females (64%), and held a graduate/professional degree (52%). Analysis of the pre-Q responses showed that only 6.8% of OHP's discuss the connection between HPV and oropharyngeal cancer with patients and a lack of information on the topic was the major barrier reported. After the educational intervention (post-Q), 86.5% of OHP's reported they were more likely to recommend the HPV vaccine and 69.8% felt more comfortable administering it. Comparison between the pre-Q and the post-Q showed a significant improvement in overall HPV knowledge. Similarly, a comparison between the post-Q and the follow-Q showed retained knowledge overtime. Our study suggests that the educational intervention was effective at improving OHP's knowledge of HPV and enhancing their comfortability and preparedness to discuss the vaccination with their patients.

Background. Human papillomavirus (HPV) infection has been recognized as an important risk factor in cancer. The purpose of this systematic review and meta-analysis was to determine the prevalence and effect size of association between salivary HPV DNA and the risk of developing oral and oropharyngeal cancer. Methods. A systematic literature search of PubMed, EMBASE, Web of Science, LILACS, Scopus and the Cochrane Library was performed, without language restrictions or specified start date. Pooled data were analyzed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). Quality assessment was performed using the Newcastle–Ottawa Scale (NOS). Results. A total of 1672 studies were screened and 14 met inclusion criteria for the meta-analysis. The overall prevalence of salivary HPV DNA for oral and oropharyngeal carcinoma was 43.2%, and the prevalence of salivary HPV16 genotype was 27.5%. Pooled results showed a significant association between salivary HPV and oral and oropharyngeal cancer (OR = 4.94; 2.82−8.67), oral cancer (OR = 2.58; 1.67−3.99) and oropharyngeal cancer (OR = 17.71; 6.42−48.84). Significant associations were also found between salivary HPV16 and oral and oropharyngeal cancer (OR = 10.07; 3.65−27.82), oral cancer (OR = 2.95; 1.23−7.08) and oropharyngeal cancer (OR = 38.50; 22.43−66.07). Conclusions. Our meta-analysis demonstrated the association between salivary HPV infection and the incidence of oral and oropharyngeal cancer indicating its value as a predictive indicator

Background: The main indication for transoral robotic surgery (TORS) has been the primary treatment of oropharyngeal squamous cell carcinoma (OPSCC). In the western world this is highly relevant due to the increasing incidence of human papillomavirus (HPV)-positive OPSCC. In Denmark, TORS was implemented in 2013 for use in the protocolled primary treatment of OPSCC. Aims/objectives: To perform a year-by-year comparative analysis of indications for TORS, hospitalization and complication rates to identify optimal future indications for TORS. Methods and materials: This is a retrospective single-centre case review from 2013-2017. Data were collected from patient files through electronic health care systems. Results: Since 2013, there has been a change of indications from performing benign and salvage surgery to mainly primary treatment of OPSCC and diagnostic use in patients with cancer of unknown primary (CUP). The overall complication rates have reduced considerably over time. Conclusions and significance: Lower complication rates may be explained by improved surgical experience, through better patient selection and changes in indications for TORS. Future applications of TORS will be in the management of CUP and as part of a Danish national randomized clinical trial aiming to compare long-term functional outcomes after treatment of early-stage OPSCC with TORS versus radiation treatment.

Background: The objectives of this study were to investigate the incidence of high-risk genotypes of human papillomavirus (HPV) in tumours of patients with oropharyngeal squamous cell carcinoma (OPSCC) during an 18-year period in Eastern Denmark. Methods: In this population-based, consecutive, semi-national registry study, all patients diagnosed with OPSCC from 2000 to 2017 in Eastern Denmark were evaluated at head and neck oncological departments at public university hospitals. Analyses included tumour characteristics (HPV-positive [HPV+] versus HPV-negative [HPV–]), age-adjusted incidence rates (AAIRs), average annual percentage change (AAPC) of OPSCC, and patient demographics. All HPV+ cases from 2011 to 2017 were genotyped. Results: In total, 55% of 2169 OPSCC cases were HPV+. HPV16, HPV33, HPV35 or other types were found in 86%, 7.4%, 3.4% and 3.2% of cases, respectively. The AAIR per 100,000 of all OPSCCs was 1.8 in 2000, which increased to 5.1 in 2017 (HPV+: threefold increase, HPV–: twofold increase). The AAPC from 2000 to 2017 increased by 7% (HPV+ increased by 10% and HPV– by 4%). The median age at diagnosis for all OPSCC cases increased during the 18-year study period (HPV+: 58–61 years, p < 0.001; HPV–: 60–65 years, p < 0.001). Conclusion: We report a threefold increase in OPSCC incidence during the 18-year observation period and a significant increase in median age at diagnosis. Over 93% of HPV genotypes in HPV+ OPSCC are included in current HPV vaccines except for HPV35 (4%). HPV vaccination of both sexes is advised to halt this emerging cancer epidemic.

Objectives/hypothesisDetermine the rate, diagnoses, and risk factors associated with 30-day nonelective readmissions for patients undergoing surgery for oropharyngeal cancer.Study designRetrospective cohort study.MethodsWe analyzed the Nationwide Readmissions Database for patients who underwent oropharyngeal cancer surgery between 2010 and 2014. Rates and causes of 30-day readmissions were determined. Multivariate logistic regression was used to identify risk factors for readmission.ResultsAmong 16,902 identified cases, the 30-day, nonelective readmission rate was 10.2%, with an average cost per readmission of $14,170. The most common readmission diagnoses were postoperative bleeding (14.1%) and wound complications (12.6%) (surgical site infection [8.6%], dehiscence [2.3%], and fistula [1.7%]). On multivariate regression, significant risk factors for readmission were major ablative surgery (which included total glossectomy, pharyngectomy, and mandibulectomy) (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.06-1.60), advanced Charlson/Deyo comorbidity (OR: 2.00, 95% CI: 1.43-2.79), history of radiation (OR: 1.58, 95% CI: 1.15-2.17), Medicare (OR: 1.34, 95% CI: 1.06-1.69) or Medicaid (OR: 1.82, 95% CI: 1.32-2.50) payer status, index admission from the emergency department (OR: 1.19, 95% CI: 1.02-1.40), and length of stay ≥6 days (OR: 1.57, 95% CI: 1.19-2.08).ConclusionsIn this large database analysis, we found that approximately one in 10 patients undergoing surgery for oropharyngeal cancer is readmitted within 30 days. Procedural complexity, insurance status, and advanced comorbidity are independent risk factors, whereas postoperative bleeding and wound complications are the most common reasons for readmission.Level of evidence4. Laryngoscope, 129:910-918, 2019.

The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is rising in high-income countries, including Australia. Increasing evidence suggests that accurate HPV testing is pivotal for clinical decision making and treatment planning in these patients. Recently, the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor–node–metastasis (TNM) staging system for OPC (based on the p16INK4a (p16) status) was proposed and has been implemented. However, the applicability of this new staging system is still far from clear. In our study, n = 127 OPC patients from Queensland, Australia were recruited, and the tumor p16 expression in these patients was examined using immunohistochemical (IHC) analysis. HPV-16 genotyping, viral load, and physical status (episomal versus integrated) in the saliva samples of OPC patients were determined using the qPCR method. A good inter-rater agreement (k = 0.612) was found between tumor p16 expression and oral HPV-16 infection in OPC. Importantly, according to the eighth edition staging system, HPV-16 DNA viral load (>10 copies/50 ng) was significantly associated with the advanced stages of OPC. In concordance with previous studies, a mixed HPV-16 form (partially or fully integrated) was predominately found in OPC patients. Taken together, our data support HPV-16 detection in saliva as a screening biomarker to identify people within the community who are at risk of developing OPC.