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Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16‐ and HPV testing covering a consecutive 21‐year period. Age‐adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional‐hazards model were employed. Two thousand eight hundred thirty‐four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV‐)/p16 negative (p16−), 4% HPV+/p16−, and 4.8% HPV−/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV−/p16− OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5‐year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16− OS: 50.4%; HPV−/p16+ OS: 49.4%; HPV−/p16− OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV−/p16− OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de‐escalating/escalating. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article responds to comments on a study about oropharyngeal cancer in a high HPV-prevalent area in Denmark from 2000 to 2020. The authors acknowledge the potential impact of HPV vaccination on changing epidemiological trends and emphasize the importance of further research on its long-term effects. They also highlight the significance of continuous education and communication to raise awareness about HPV-driven oropharyngeal cancer and the benefits of vaccination. Additionally, the authors discuss the potential of a minimally invasive liquid biopsy method for the follow-up of patients with HPV-positive oropharyngeal cancer, aiming to improve survival outcomes and enhance future diagnostic testing. [Extracted from the article]

The increases observed in incidence and survival of oropharyngeal squamous cell carcinoma (OPSCC) have been attributed to human papillomavirus (HPV) infection, but the survival‐impact of specific genotypes is poorly understood. We investigated the potential influence of HPV genotypes on survival in HPV‐positive (HPV+) OPSCC. All patients with HPV+/p16+ OPSCC and available genotype data within the period 2011 to 2017 in Eastern Denmark were included. Descriptive statistics on clinical and tumor data, as well as overall survival (OS) and recurrence‐free survival (RFS) with Cox hazard models and Kaplan‐Meier plots were performed. Overall, 769 HPV+/p16+ OPSCC patients were included of which genotype HPV16 accounted for 86% (n = 662). Compared to high‐risk non‐HPV16 genotypes (HR non‐HPV16), HPV16 patients were younger at diagnosis (median years, 60 vs 64), had a higher male to female ratio (3.7:1 vs 2.1:1), and lower performance scores of ≤1 (90%, n = 559, vs 81%, n = 74). Regarding 5‐year OS and RFS, no difference was observed between HPV16 and HR non‐HPV16 patients. Subgrouping the HR non‐HPV16 group into HPV33 (n = 57), HPV35 (n = 26) and "other genotypes" (n = 24) a significantly worse OS in the "other genotypes" group (hazard rate: 2.33, P =.027) was shown. With similar survival results between HPV16 and non‐HPV16 genotypes, genotyping in OPSCC is interesting from an epidemiological point of view as well as in vaccination programs, but not a necessary addition in prognostication of HPV+/p16+ OPSCC. [ABSTRACT FROM AUTHOR]

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: We aimed to review systematically the literature on locoregional recurrence rates in patients with HPV-positive and -negative oropharyngeal squamous cell carcinoma (OPSCC). Methods: PubMed and Embase databases were systematically searched using key words such as human papillomavirus, oropharyngeal squamous cell carcinoma with local, regional, and locoregional recurrence. Results: Nine studies (2974 patients with known HPV-status, 59% HPV-positive) were included. Among the HPV-positive and -negative patients, 69% and 58% had lymph node metastasis at diagnosis. At a median time to recurrence ranging from 8.4 to 13.2 months among the included studies, we found that a weighted average of 9% and 26% for HPV-positive and -negative patients experienced locoregional recurrence. Overall, the median follow-up time ranged from 21 to 83 months among the included studies. Conclusion: Recurrence rates for HPV-positive and -negative OPSCC patients were 9% and 26%, respectively, equating to an almost three times higher rate of locoregional recurrence among HPV-negative patients compared to HPV-positive patients. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. • The current largest register-based study in Eastern Denmark of HPV-tested Oropharyngeal Squamous Cell Carcinoma (OPSCC). • All confirmed OPSCC cases (n= 2169) from 2000-2017 were included and tested for HPV DNA and p16 expression. • HPV-positive tumours had the viral DNA genotyped (n= 770) to examine high-risk genotypes. • HPV16 was the most common genotype (86%) among HPV-positive cases. • The incidence rate of OPSCC increased threefold overall, especially for HPV-positive OPSCC of the tonsils. [ABSTRACT FROM AUTHOR]

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Comorbid conditions impact outcome for patients treated for oropharyngeal squamous cell carcinoma (OPSCC) and serve as competing risk factors for death. The purpose of this study was to examine differences in comorbidities in patients with OPSCC and known HPV-DNA.Material and Methods: We included patients diagnosed with OPSCC in Eastern Denmark in 2000-2014. Patients were linked to the Danish National Patient Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at time of diagnosis and following cancer treatment. Patients were age-and sex-matched in a 1:10 ratio with a reference group and stratified according to HPV-status.Results: In total 1,499 patients (55.0% HPV+) and 14,990 controls were included. Significantly more HPV+ patients had no comorbidities compared to HPV- patients at time of diagnosis (RR: 1.5 (1.3;1.6), n = HPV+: 522, HPV-: 302) and following treatment (RR 1.5 (1.4;1.6), n = HPV+: 342, HPV-: 142). Most prevalent comorbidity was malignancy not including OPSCCs. HPV+ patients had an increased risk of having AIDS before their OPSCC diagnosis compared to the reference population (OR: 4.8 (1.8;12.9)). HPV- patients had increased risk of multiple comorbidities including cerebrovascular disease (OR: 1.9 (1.4;2.5)), peripheral vascular disease (OR: 1.7 (1.9;3.7)), dementia (OR: 2.9 (1.4;5.8)), ulcer disease (OR: 2.6 (1.9;3.5)), liver disease, mild (OR: 9.5 (7.0;13.0)) and severe (OR: 13.9 (5.8;22.8)).Conclusion: This study showed that HPV- patients had more comorbidities than HPV+ patients at the diagnosis time and following treatment. Irrespective of HPV-status, OPSCC patients had a significant increased risk of (secondary) malignancy compared to the reference population. [ABSTRACT FROM AUTHOR]

Background: Persistent infection with high-risk genotypes of human papillomavirus (HPV) is the main risk factor in the development of uterine cervical precancerous lesions and cervical cancer (CC), and cases of HPV-induced oropharyngeal squamous cell carcinoma (OPSCC) is increasing in the Western world. We investigated the association between HPV and p16 status and previous results of cervical examinations, including cytological and histological tests, in females with OPSCC. Material and Methods: We included females diagnosed with an OPSCC in Eastern Denmark from 2000 to 2014. OPSCCs were assessed for p16-overexpression and HPV DNA PCR. History of cervical tests was obtained from the Danish Pathology Registry. The cytology and histological results were categorized in accordance with the 2014 Bethesda System (TBS) and WHO. Hence, we divide the cervical results into two groups. Group I were negative for intraepithelial lesion or malignancy and group II had epithelial cell abnormalities and subdivided after increasingly neoplastic severity from A-D. Chi2-tests and Fischer's exact tests were performed to compare the two groups. Results: A total of 417 women with OPSCC were identified; 203 with HPV-positive tumors (49%) of which cervical cytology or histology were available in 172 women (85%). Among these, 22 (13%) patients had a cervical history of ≥ IIC. A total of 171 out of 214 women in the HPV-negative group (80%) were examined with cytology and 17 had a history of ≥ IIC. No significant difference in diagnoses of (pre)cancerous lesions between the OPSCC HPV-positive and negative groups were observed (χ2 test p = .28, Fischer's exact test p = .29). Conclusion: HPV status in oropharyngeal tumors was not correlated with a history of ≥ IIC in cervical examinations. The effect on cervical dysplasia may be masked by a higher incidence of smoking among the OPSCC HPV-negative group. [ABSTRACT FROM AUTHOR]

Distant progression (DP) in oropharyngeal squamous cell carcinoma (OPSCC) has significant impact on morbidity and mortality. This study systematically reviewed the literature on studies reporting location and timing of DP after human papillomavirus (HPV)+ or HPV− OPSCCs. PubMed, EMBASE, and the Cochrane Library were systematically searched for studies reporting DP in patients treated with curative intend for an OPSCC. Outcome was site of and time to DP stratified on HPV‐status. Seven studies (n = 1564; 77% HPV+) were included in which 313 patients (20%) developed a DP (70% HPV+). The most common site of DP was the lungs (n = 232) regardless of HPV‐status. Patients with HPV+ tumors were more prone to dissemination involving multiple sites (risk ratio = 16.49). There was no difference in time to DP when stratified on HPV‐status (P = .10). The pattern of but not time to DP was significantly different in patients with OPSCC when stratified on HPV‐status. [ABSTRACT FROM AUTHOR]

Highlights • Therapeutic vaccines are seemingly safe with predominantly grade 1 and 2 toxicity. • Temporary results indicate a positive immune response to the vaccines. • Immunogenicity shows elevated antibody, IFN-γ and/or T-cell responses. • One study has demonstrated complete and partial tumour responses. Abstract Objectives This systematic review provides an overview of the current clinical trials investigating therapeutic vaccines for HPV+ head and neck cancer and discusses the future directions of therapeutic vaccine therapy. Materials and methods A systematic search was conducted in PubMed, EMBASE, Cochrane and clinicaltrials.gov for clinical trials involving therapeutic vaccines. We included studies initiated between 2000 and 2018 with patients diagnosed with HPV+ head and neck cancer and extracted data concerning type of vaccine therapy, adverse events, immunogenicity and clinical outcome measures (e.g. tumour response, progression-free survival and overall survival). Results We identified 11 studies (n = 376 patients) initiated between year 2005 and 2017. Four studies (n = 34) presented preliminary results in patients with incurable, recurrent loco-regional or distant metastatic disease indicating a positive immune response with 74% (n = 25/34 patients) having elevated antibody levels, IFN-γ and/or T-cell response. Five studies presented data on the vaccines' safety profile, demonstrating predominantly grade 1 and 2 toxicity. Three studies evaluated the clinical outcome – one study showed no complete or partial response, one study demonstrated stable disease as the best tumour response in 64% (n = 9/14 patients) and one study showed a 33% overall response rate: one patient with a complete response and seven patients with a partial response. Conclusions Treatment with therapeutic vaccines is a promising and seemingly safe strategy for patients with HPV+ head and neck cancer. However, there are not enough data to draw any further conclusions and clinical outcome measures and tumour responses to the vaccines are still missing. [ABSTRACT FROM AUTHOR]

Background: The purpose of the study was to determine trends in age-adjusted incidence rates (AAIR) and survival probability in head and neck cancers (HNCs) in the Danish population from 1980 to 2014. Material and methods: All patients registered with HNC in the nationwide Danish Cancer Registry from 1980 to 2014 were included. We evaluated the AAIR per 100,000 and the average annual percent change (AAPC). The relative survival probability at 5 years was calculated in relation to gender, anatomical location and histology, and we constructed age-period-cohort models of incidence. Results: About 34,606 patients were included (64.7% men). The AAIR increased from 9.1 per 100,000 in 1980 to 17.4 per 100,000 in 2014 with an AAPC of 2.1%. The greatest incidence increase was observed in oropharyngeal cancer (AAPC: 5.4%) followed by hypopharyngeal cancer (AAPC: 4.2%). Adenocarcinomas had the highest AAPC (5.0%) followed by squamous cell carcinomas (AAPC: 2.0%). The AAPC was significantly higher in women (2.4%) compared with men (1.6%). For all HNC patients, the relative survival at 5 years rose significantly from 49.0% in 1980-1984 to 62.4% in 2010-2014. Women had a significantly higher survival than men with a relative survival of 61.7% compared to 50.0% in men. Laryngeal cancer had the best survival probability of cancers in the upper aerodigestive tract with hypopharyngeal cancer having the poorest survival. Conclusion: This nation-wide study showed a significant rise in incidence of HNC for men and women along with a significant increase in relative survival. Oropharyngeal cancer had the highest increase in incidence followed by hypopharyngeal cancer which showed the poorest survival of HNCs. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Currently, data is sparse on the pattern and timing of recurrence. This long-term study concerning both HPV- and p16-status aimed to report predictive factors, pattern, timing of loco-regional recurrence (LRR) and distant recurrence (DR), and survival following recurrence in patients diagnosed with OPSCC.Material and Methods: We included patients diagnosed with OPSCC from 2000 to 2014 in Eastern Denmark, who were treated with curative intent. Tumors were defined as HPV-positive when they were both HPV-DNA and p16-positive. Time-to-failure and -death were estimated by the Kaplan-Meier method. Cox proportional hazards models were used to evaluate predictors of failure.Results: The cohort consisted of 1244 consecutive patients with OPSCC of which 288 patients (23%) experienced recurrence. Of these patients, the majority (n = 197/1244; 16%) experienced LRR and the remaining (n = 91/1244; 7%) DR. Significantly more HPV-negative patients experienced recurrence (n = 170/486; 35%) compared to HPV-positive patient (n = 112/726; 15%). DR occurred for both groups predominantly to the lung (n = 63/91; 69.2%) followed by the liver and bone. Factors influencing risk of LRR included gender, T-classification, and HPV-status. The same variables influenced risk of DR in addition to the UICC-8 classification, N-classification, pack years of smoking, and performance status. HPV-status was the strongest risk factor for LRR and DR.Conclusion: LRR and DR occur significantly less often in HPV-positive patients compared with HPV-negative patients. HPV-status is an independent and strong predictor of recurrence. DR most commonly occurs to the lungs, irrespective of HPV-status. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal carcinomas (OPCs) constitute a significant and increasing proportion of head and neck carcinomas and are an important global cause of morbidity and mortality. The purpose of this study was to determine trends in incidence and survival in OPC in the Danish population from 1980 to 2014. Methods: This study included all patients registered in the nationwide Danish Cancer Registry over the period 1980-2014. The age-adjusted incidence rates (AAIR) per 100,000, annual percentage change (APC) and average annual percent change (AAPC) were evaluated. Five-year relative survival (RS) was calculated with Cox regression analyses in relation to gender, anatomical location and histology. Results: A total of 6555 patients (69% male) were included, with a median age at diagnosis of 60 years. The AAIR of patients with OPC increased from 0.815 per 100,000 in 1980 to 4.51 per 100,000 in 2014 with an AAPC of 5.3. The 5-year RS increased significantly from 33.1% over the period 1980-1984 to 58.5% (25.4% points) over the period 2010-2014. With no significant difference stratified for gender. Tumors located at the palatine tonsils (n=3333) and salivary gland OPC (n=90) had significantly better survival compared with other sub-locations and histology subtypes. In the APC model the birth cohort effect rate ratio increased until 1925 and then decreased until 1935 from which point it increased in the last cohorts. Conclusions: In this population-based study, we observed a significant increase in the incidence of OPCs and in the RS for OPC. We also identified a profound birth cohort effect on the incidence. [ABSTRACT FROM AUTHOR]

Identifying the causes of death in head and neck cancer patients can optimize follow- up and therapeutic strategies, but studies in oropharyngeal squamous cell carcinoma (OPSCC) patients stratified by HPV status are lacking. We report cause- specific mortality in a population- based cohort of patients with OPSCC. Patients who had been diagnosed with OPSCC (n = 1541) between 2000 and 2014 in eastern Denmark were included in the study. Causes of death were collected through medical files and the Danish National Cause of Death registry. Deaths were grouped as (1) primary oropharyngeal cancer, (2) secondary malignancies, (3) cardiovascular and pulmonary disease, or (4) other/unspecified. The cumulative incidence of death and specific causes of death were determined using risk analysis. At follow-up, 723 (47.5%) patients had died. The median time to and cause of death were determined: oropharyngeal cancer (n = 432; 1.00 year), secondary malignancies (n = 131; 2.37 years), cardiovascular and pulmonary causes (n = 58; 3.48 years), and unspecified causes (n = 102; 3.42 years). HPV/p16 status was the strongest predictor of improved survival across all causes of death. The only cause of death to decrease in incidence over the 2 years after treatment was death from OPSCC. HPV/p16 positivity was an independent factor for improved survival across all causes of death in patients with OPSCC. In addition, both HPV-positive and HPV-negative OPSCC patients faced high 5- and 10-year mortality rates. Implementing secondary screening and prevention strategies for late toxicity and mortality are major goals in managing the treatment of these patients. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, but data on the incidence of synchronous, bilateral tonsillar squamous cell carcinomas (BiTSCCs) is sparse. In this study, we report the incidence and tumour characteristics of BiTSCCs in a population-based, consecutive cohort of OPSCCs.Methods: We identified all patients diagnosed with tonsillar squamous cell carcinoma (TSCC) in eastern Denmark during a 15-year period to detect the incidence of synchronous BiTSCCs. The tumours were assessed for p16Ink4a expression, the presence of HPV DNA and HPV genotypes. Furthermore, we systematically reviewed the literature examining BiTSCCs.Results: Of the total of 1119 TSCCs diagnosed in eastern Denmark from 2000 to 2014, we identified 12 BiTSCCs, nine of which initially presented as a cancer of unknown primary (CUP) in the neck. Nine cases were bilaterally HPV16 positive (HPV16+), while two cases were HPV16+ in one tonsil and respectively, HPV33 and HPV35 positive in the contralateral tonsil. One case was bilaterally HPV-negative. We also identified an increase in the incidence of BiTSCCs after 2012 when histological examination of the entire tonsil tissue became routine, suggesting that BiTSCCs might be underdiagnosed. In the literature, we identified 15 studies from six countries, encompassing 25 cases in total.Conclusions: BiTSCCs were primarily HPV16+ and were most often diagnosed as part of the diagnostic work-up for CUP. We found an incidence of 9% BiTSCCs in patients with TSCC after 2012 and we therefore recommend focusing on putative BiTSCC with total embedding and histological examination of tonsils harvested by bilateral tonsillectomies. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is rapidly increasing in incidence and has a favourable prognosis compared with HPV-negative disease. Current combined therapies include significant risks of morbidity for the growing group of survivors. This systematic review and meta-analysis investigates how treatment affects quality of life (QoL) in survivors of oropharyngeal cancer. PubMed, EMBASE and the Cochrane Library were systematically searched for all studies reporting patient-assessed QoL at least 1 year after treatment for OPC. In a meta-analysis, weighted average QoL scores from the four most commonly utilised QoL instruments were compared with baseline and reference group scores using the concept of minimal clinically important difference. The meta-analysis included data from 1366 patients from 25 studies and 12 countries. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) was answered by 704 patients, 644 patients answered the EORTC QLQ Head and Neck-35 (H&N-35), 474 patients answered the University of Washington Quality of Life Questionnaire, and 381 patients answered the M. D. Anderson Dysphagia Inventory. Moderate to large clinically important deteriorations in QoL were found in the domains dry mouth and sticky saliva for the EORTC QLQ-H&N35, saliva, chewing, swallowing, speech, taste, appearance and shoulder for the University of Washington Quality of Life Questionnaire, and the global, physical and emotional subscales for the M. D. Anderson Dysphagia Inventory. In conclusion, survivors of OPC face clinically important deteriorations in QoL that most markedly centre on xerostomia, dysphagia and chewing. These ailments indicate a potential for improvement in patient management. [ABSTRACT FROM AUTHOR]

Background: Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia.Methods: This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention.Discussion: The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials.Trial Registration: EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015. ClinicalTrials.gov, Identifier: NCT02513238 . First received on 2 July 2015. The trial is prospectively registered. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r =–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society. [ABSTRACT FROM AUTHOR]

The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis. • The study includes 7654 oropharyngeal cancer patients. • HPV impacts overall and disease-free survival, regardless of p16 status. • HPV exerts substantial influence on survival, regardless of stage. • Incorporating HPV in cancer staging, with p16, is crucial for precise prognosis.. [ABSTRACT FROM AUTHOR]

Uncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas. OPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015–2020, (n = 2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1–2N0M0) and high-risk patients (UICC8 III-IV). There were significantly more HPV-positive (88.2 % vs. 63.1 %), males (89.4 % vs. 74.1 %), never-smokers (52.1 % vs. 23.7 %), lower UICC8-stage (I/II: 79.3 % vs. 68 %), and fewer patients treated with radiotherapy (RT) alone (14.8 % vs. 30.3 %) in the UTMDACC cohort. No difference in the adjusted OS was observed (hazard ratio [HR] 1.21, p = 0.23), but a significantly increased RFI HR was observed for the Copenhagen cohort (HR: 1.74, p = 0.003). Subgroup analyses of low- and high-risk patients revealed significant clinical and treatment differences. No difference in prognosis was observed for low-risk patients, but the prognosis for high-risk patients in the Copenhagen cohort was worse (OS HR 2.20, p = 0.004, RFI HR 2.80, p = 0.002). We identified significant differences in clinical characteristics, treatment modalities, and prognosis between a Northern European and Northern American OPSCC population. These differences are important to consider when comparing outcomes and for patient stratification in clinical trials, as reproducibility might be challenging. • Significant clinical and treatment differences in two high HPV prevalence cohorts. • The Copenhagen cohort included more smokers, HPV-negative and higher stage. • The overall survival for patients with HPV-positive OPSCC was equally good. • The prognosis was equally good at both centers for low-risk T1T2N0M0 patients. • The UTMDACC Stage III-IV patients had a significantly better prognosis. [ABSTRACT FROM AUTHOR]