Human Papillomavirus-associated Head Research Articles

Prevalence of Human Papillomavirus-Associated Head and Neck Cancer in Rwanda: A 10-Year Review.

Head and neck cancer (HNC) is a significant global health burden, with late presentation leading to complex treatment. While human papillomavirus (HPV) infection has been implicated in HNC, data from low- and middle-income countries (LMICs) are limited. In this study, we investigated the prevalence and role of HPV in head and neck cancers diagnosed in Rwanda. A retrospective cross-sectional study was conducted using Rwanda Cancer Registry from January 2011 through December 2020. p16 immunohistochemistry as a surrogate for HPV was performed on a randomly selected case. p16-positive cases were genotyped. A total of 1001 patients with HNC were identified; 82% (n = 819) had squamous cell carcinoma. The mean age at diagnosis was 51.1 years, with a majority being males (58%). Oral cavity and lip (27%) were the most common primary cancer sites. Stage was unknown in most cases (75%, n = 747). HIV status was known in 33% (n = 334) of patients with 10% (n = 33) HIV-positive; 22% of 202 randomly selected cases were p16-positive; 34% of the p16-positive cases were oropharynx. PCR analysis of p16-positive cases showed 19% HPV positivity, and HPV16 was the most common high-risk HPV strain, and 55.5% were recorded HPV-positive by PCR. HNC cases in Rwanda have been increasing from 2011 to 2020, with a significant portion being HPV-positive. Strategies to implement routine testing for p16, especially in oropharynx cancer patients, improved preservation of tissue samples, collection of comprehensive information including cancer risk factors, staging, and treatment are needed in Rwanda.

Uncommon and Challenging Phenotypes of High-Risk Human Papillomavirus-Associated Head and Neck Carcinomas Revealed by High-Throughput Studies.

HPV- associated squamous cell carcinoma (SCC) is uncommon in non-oropharynx sites and not well characterized. This study aims to investigate uncommon phenotypes of HPV-associated head and neck carcinoma, the prevalence and morphologic spectrum of HPV-associated SCC in the oral cavity, larynx and hypopharynx. P16 immunostaining and HPV E6/7 in situ hybridization (ISH) were performed on tissue microarrays comprised of SCCs from different anatomic sites: oropharynx (n = 270), hypopharynx (n = 52), oral cavity (n = 95) and larynx (n = 123). Tumors were classified as HPV-associated based on a positive E6/7 ISH testing. RNA sequencing was performed on several selected cases. 66% oropharynx SCCs (OPSCCs) were HPV-associated; all were p16/HPV testing concordant except one which was p16 negative. The p16-/HPV + OPSCC resembled similar gene expression signature with p16+/HPV + OPSCCs by transcriptome analysis. 6/95 (6%) oral cavity SCCs were HPV-associated, all from male patients and 5/6 (83%) arose from the floor of mouth. Morphologically, 3/6 (50%) showed keratinizing SCC and 5/6 (83%) demonstrated HPV-associated squamous dysplasia in adjacent mucosa. 1/123 (less than 1%) larynx SCCs and 0/52 hypopharynx SCCs were HPV-associated. Although uncommon, p16 negative HPV-associated OPSCC can occur, emphasizing the importance of judicious HPV testing. The morphology of HPV-associated oral cavity SCCs may deviate from prototypic nonkeratinizing SCC, making them difficult to recognize. Presence of HPV-associated squamous dysplasia could serve as a morphologic clue.

Human papillomavirus-associated head and neck squamous cell carcinoma cells lose viability during triggered myocyte lineage differentiation

Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting strategies are desperately needed, and a previous report indicated the triggered differentiation of HPV-negative HNSCC cells to confer therapeutic benefits. Using patient-derived tumor cells, we created a similar HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-Seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. We are the first to report that carcinoma cells can undergo a triggered myocyte-like differentiation, and our study suggests that the targeted differentiation of HPV+ HNSCCs might be therapeutically valuable.

Multi-feature next-generation liquid biopsy for diagnosis and prognosis in HPV-associated head and neck cancer.

6064 Background: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+HNSCC) releases circulating tumor HPV DNA (ctHPVDNA) into the blood which is a highly accurate biomarker of disease status. Existing approaches based on droplet digital PCR (ddPCR) have limitations in sensitivity, genotype coverage, and do not annotate additional prognostic genomic features. In this study, we tested the diagnostic and prognostic performance of a custom HPV whole-genome next-generation sequencing (NGS) liquid biopsy, termed HPV-DeepSeek, at the time of diagnosis with HPV+HNSCC, compared to ctHPVDNA ddPCR, HPV serology, and clinical work-up. Methods: 304 participants (152 untreated HPV+HNSCC patients, 152 population-level controls) were prospectively enrolled in this single-center prospective cohort study. Plasma samples were analyzed using HPV-DeepSeek, a multiplexed serology assay, single-plex ddPCR, and a 5-genotype multiplexed ddPCR assay. We tested the hypothesis that HPV-DeepSeek would have the highest diagnostic accuracy. We secondarily examined the accuracy of HPV-DeepSeek for prognostic feature annotation including high-risk HPV16 single nucleotide polymorphisms (SNPs), integration events, and PIK3CA mutations. Results: Of 152 cases, 114 (75%) were AJCC stage 1 and 138/152 (91%) were oropharynx primary site cancers. The sensitivity (98.7%), specificity (98.7%), and diagnostic accuracy (0.974) of HPV-DeepSeek was superior (P<0.001) to singleplex ddPCR (94.2%, 98.6%, 0.928), multiplex ddPCR (90.6%, 96.3%, 0.869), HPV serology (86.4%, 96.3%, 0.827), and first attempt clinical diagnostic biopsy (78% sensitive). Utilizing HPV-DeepSeek, 8 different genotypes were detected. 4 patients were found to have multi-genotype infections. 137/152 cases were classified as HPV16, with A1 the most common sub-lineage (90/137). 21 of 137 HPV+HNSCC HPV16 cases (15%) displayed high risk SNPs. Head-to-head comparison of HPV SNP genotyping by HPV-DeepSeek, with the gold-standard tissue-based HPV whole genome sequencing assay, demonstrated 89% concordance in tissue and 85% in blood. The internal concordance rate for HPV-DeepSeek between tissue and blood was 91%. 48 of 152 cases (32%) had at least one viral integration event detected and 36 of 152 cases (24%) had a PIK3CA mutation detected by HPV-DeepSeek. Fragmentomic analysis demonstrated a mean ctHPVDNA fragment size of 148bp for ctHPVDNA versus 167bp for human cell free (cf)DNA from HPV+HNSCC patients and 168bp for control patient cfDNA. Baseline ctHPVDNA quantity was strongly correlated with viral integration status, T stage and N stage (P<0.001). Conclusions: HPV-DeepSeek has improved diagnostic accuracy relative to ddPCR, HPV serology and clinical work-up at the time of diagnosis and demonstrates detection of prognostic features including high-risk HPV16 SNPs, viral integration events, and PIK3CA mutations.

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy.

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

Human papillomavirus-associated head and neck squamous cell carcinoma cells rely on glycolysis and display reduced oxidative phosphorylation.

Head and neck squamous cell carcinoma (HNSCC) constitutes a heterogeneous group of cancers. Human papilloma virus (HPV) is associated with a subtype of HNSCC with a better response to treatment and more favorable prognosis. Mitochondrial function and metabolism vary depending on cancer type and can be related to tumor aggressiveness. This study aims to characterize the metabolism of HPV-positive and HPV-negative HNSCC cell lines. Oxidative phosphorylation (OXPHOS) and glycolysis were assessed in intact cells, in four HNSCC cell lines using Seahorse XF Analyzer. OXPHOS was further studied in permeabilized cells using high-resolution respirometry in an Oroboros O2K. Metabolomic analysis was performed using mass spectroscopy. The HPV-negative cell lines were found to display a higher OXPHOS capacity and were also able to upregulate glycolysis when needed. The HPV-positive cell line had a higher basal glycolytic rate but lower spare OXPHOS capacity. These cells were also unable to increase respiration in response to succinate, unlike the HPV-negative cells. In the metabolomic analysis, the HPV-positive cells showed a higher kynurenine/tryptophan ratio. HPV-positive HNSCC preferred glycolysis to compensate for lower OXPHOS reserves, while the HPV-negative HNSCC displayed a more versatile metabolism, which might be related to increased tumor aggressiveness. The higher kynurenine/tryptophan ratio of HPV-positive HNSCC might be related to increased indoleamine 2,3-dioxygenase activity due to the carcinoma's viral origin. This study highlights important metabolic differences between HPV-positive and HPV-negative cancers and suggests that future metabolic targets for cancer treatment should be individualized based on specific tumor metabolism.

Bayesian prognosis analysis of human papillomavirus-associated head and neck cancer using hierarchical Dirichlet process mixture models

The incidence and prognosis of Head and Neck Cancer (HNC) depend heavily on patients’ Human PapillomaVirus (HPV) status. Prognosis analysis of HPV-associated HNC is of clinical importance because in-depth understanding of the survival distribution is valuable for designing more informed treatment strategies. In this article, we develop a novel Hierarchical Dirichlet Process Weibull Mixture Model (HDP-WMM) to study the prognosis of HNC patients given their HPV status. The HDP-WMM is capable of simultaneously characterizing the survival distributions of grouped data and capturing the dependence among different groups. Moreover, the HDP-WMM can identify clusters of patients based on their outcomes, providing additional information for exploring patient subtypes. Effective Markov chain Monte Carlo sampling algorithms are designed for model inference and function estimation. The clustering structure is identified by summarizing the posterior samples of the data random partition using the Bayesian cluster analysis tool. A simulation study is designed to validate the performance of the proposed inference methods. The practical utility of the proposed HDP-WMM is demonstrated by a case study on prognosis analysis of HPV-associated HNC. Our results show that the Bayesian HDP-WMM achieves satisfactory performance on estimating the survival functions and clustering patients based on their outcomes.

Blood and saliva-derived ctDNA is a marker of residual disease after treatment and correlates with recurrence in human papillomavirus-associated head and neck cancer.

There is an alarming increase in human papillomavirus-associated head and neck cancer (HNC), reaching epidemic levels. While patient prognosis is generally good, off-target treatment effects are associated with decreased quality of life. Thus, non-invasive strategies to predict treatment response and risk of recurrence could help de-escalate treatment. In this study, we tested circulating tumor (ct)DNA in liquid biopsies (blood/saliva) of HPV-positive HNC patients to assess treatment response and disease progression. A total of 235 blood and saliva samples were collected from 60 HPV-positive and 17 HPV-negative HNC patients (control group) before and/or after treatment. Samples were analyzed using ddPCR for HPV16/18/31/33/35/45 and correlated with imaging and pathological examination. HPV-ctDNA detection was significantly higher prior to treatment (91%) than after treatment (8.0%) (χ2 p < 0.00001), with high concordance between saliva and blood (93%). In matched samples, all patients positive for ctDNA before treatment showed significant reductions in ctDNA levels post treatment (p < 0.0001). All but one patient with persistent ctDNA after treatment showed residual tumor and subsequent recurrence. Finally, fragmentomic analysis revealed shifts in cell-free DNA fragment size after treatment, suggesting a complementary biomarker for treatment response. Blood and saliva were found to be good sources of HPV-ctDNA. The presence of ctDNA strongly correlated with treatment response, demonstrating clinical utility as a non-invasive biomarker to monitor tumor progression in HPV-positive HNC. Liquid biopsy based ctDNA testing could be an effective approach to predict recurrence and stratify patients for de-escalation of treatment, thereby improving quality of life.

Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis.

Head and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended. Transcriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed. A total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031). Our findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.

Human Papillomavirus-Associated Head and Neck Cancers. Where are We Now? A Systematic Review.

Human papillomavirus targets the skin and mucous membranes, producing benign hyperplastic lesions and precancerous and cancerous lesions. An increasing number of head and neck cancersin particular, oropharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, and oral squamous cell carcinoma, are attributable to HPV infection. HPV-induced HNCs typically affect younger, nonsmoking patients with no prior history of heavy alcohol use, more extensive sexual history, and higher socioeconomic status. The purpose of the review is to present the most recent and well-established findings concerning HPV-induced head and neck cancers and consequently to provide medical specialists with essential information regarding the epidemiology, the role of HPV in HNC cancerogenesis, prevention, diagnosis, and treatment. All authors independently have searched The EMbase, Medline/Pubmed, and Cochrane databases by using the following keywords "head and neck cancer", "human papillomavirus", "HPV", "HPV biology", "oropharyngeal squamous cell carcinoma", "carcinogenesis", "transoral surgery", "robotic surgery". The last search was conducted in March 2022. The references of the publications of interest were also screened for relevant papers. There were no limitations in regard to the publication date. Aiming to avoid the epidemic of HPV-induced HNC, it is paramount to improve the access to vaccination as well as resolve parental concerns regarding vaccine safety. Physicians should rely on reduced-dose radiation and aim to reduce the overall treatment time. Thanks to a more elaborate understanding of the genomic background of HPV-induced HNC, precision medicine could become a relevant part of patients' management. In comparison to traditional techniques and non-operative treatment, transoral robotic surgery (TORS) offers similar oncologic and functional outcomes, with a possible benefit on long-term quality of life. However, more research is needed to establish clear guidelines indicating when TORS resections should be supported with adjuvant therapy.

A Clinically Translatable, Extensively Validated Immune-based Classification of Human Papillomavirus-Associated Head and Neck Cancer With Implications for Treatment Deintensification and Immunotherapy

<h3>Purpose/Objective(s)</h3> Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the fastest rising cancer in North America, with generally favourable prognosis. There is significant interest in treatment de-escalation for these patients, but 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to predict survival of patients with newly diagnosed HPV+ HNSCC. <h3>Materials/Methods</h3> We created an RNA-based prognostic score which was successfully validated in six cohorts comprising a total of 906 patients, including blinded external validations in a large retrospective cohort (n = 269) and in a prospective cohort (BD2Decide, NCT02832102, n = 286). We assessed the feasibility of using IHC to calculate the UWO3 score using an immunohistochemistry-based tissue microarray cohort (n = 197). Transcriptomic data from two aggressive treatment de-escalation cohorts were used to assess ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 score and outcomes, adjusting for potential confounders. <h3>Results</h3> Analysis of HPV+ HNSCC tumours revealed three distinct tumor microenvironment subtypes: immune rich, immune desert, and mixed. A three gene immune score (UWO3) classified patients into the three immune groups and was strongly associated with disease-free survival in six datasets, including blinded validation in a retrospective and a prospective dataset. Pooled analysis (n = 906) demonstrated that the immune rich group had superior disease-free survival at 5 years. The association between UWO3 immune class and time to recurrence was independent of patient age, sex, smoking status, alcohol intake status, and AJCC 8th edition clinical stage. Finally, UWO3 was able to identify patients who respond to aggressive treatment de-escalation to 30 Gy radiation in two treatment de-escalation cohorts. <h3>Conclusion</h3> The UWO3 immune score could inform clinical decision making for patients with HPV+ HNSCC based on robust outcome prediction across six independent cohorts. The superior survival of immune rich patients supports de-intensification strategies for this cohort, while the inferior outcomes of the immune desert patients suggest potential for intensification and/or immunotherapy. Prospective de-escalation and intensification clinical trials are currently being planned.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Simple SummaryA critical need for optimal management of human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) patients is the development of therapeutic strategies to exploit the inherent vulnerabilities of this unique disease. We identified fenofibrate, an FDA-approved drug, as a potent anti-cancer agent for HPV+ HNSCC. Fenofibrate induced the accumulation of the p53 tumor suppressor and re-programmed the tumor microenvironment to drive immune cell infiltration. We provide compelling evidence to reposition fenofibrate as a single agent or in combination with standard therapies for the HPV+ HNSCC setting.Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

Abstract P042: Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer

Abstract Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is a fast-growing health problem in the United States. By analyzing the transcriptomes of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC patient tissues, we previously revealed that expression of CXCL14, constitutively expressed in basal epithelial cells, is downregulated in HPV-positive HNSCC. In contrast, the expression of proinflammatory chemokines, particularly CXCL1, CXCL2, and CXCL8, are significantly upregulated in both HPV+ and HPV- HNSCCs. We further showed that restored expression of CXCL14 in HPV+ HNSCC cells leads to tumor-free survival in vivo by increasing MHC-I antigen presentation on the cancer cell surface and CD8+ T cell activation. Interestingly, high CXCL1, CXCL2, and CXCL8 expression levels significantly correlate to poor HNSCC patient survival, showing an exact opposite pattern of the clinical outcomes associated with the CXCL14 expression levels. To determine the roles of these chemokines in HPV+ HNSCC development, CXCL1 and CXCL2 genes (no murine CXCL8 ortholog) were deleted using a CRISPR-Cas9 knockout system in HPV+ murine HNSCC cells. Using these stably engineered HNSCC cells, we investigated tumor growth, immune cell infiltration, and metastasis in immunocompetent syngeneic mice. Interestingly, the deletion of CXCL1 and CXCL2 significantly delays in vivo tumor growth, decreases myeloid-derived suppressor cell (MDSC) infiltration in the tumor, and decreases lung metastasis. However, the numbers of natural killer (NK), CD4+, and CD8+ T cells in the tumor microenvironment were not affected by CXCL1 and CXCL2 knockout. Next, mice injected with the murine HNSCC cells were treated twice daily with AZD5068, a selective inhibitor of CXCR2, which is a common receptor of CXCL1, CXCL2, and CXCL8 expressed on myeloid cells. Our result showed that the treatment of CXCR2 suppresses in vivo tumor growth in a similar pattern with CXCL1 and CXCL2 knockout. These results suggest that the dysregulation of chemokine expression in HPV-infected cells plays an important role in regulating tumor growth, antitumor immune responses, and metastasis of HPV+ HNSCC. Our findings may provide promising strategies to develop novel immunotherapies for HPV+ HNSCC patients which can likely be extended to other non-viral cancers with immunosuppressive phenotypes. Citation Format: Daniel Vermeer, Joseph Westrich, Paul Colbert, Craig Welbon, John H. Lee, David Raben, William C. Spanos, Dohun Pyeon. Chemokine dysregulation creates the immunosuppressive tumor microenvironment and promotes human papillomavirus-associated head and neck cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P042.

Vaccine Strategies for Human Papillomavirus-Associated Head and Neck Cancers.

Simple SummaryHuman papillomavirus (HPV) is recognized as a significant risk factor for head and neck cancers worldwide, and it is the most common cause of oropharyngeal cancers in the United States. Here, we review the incidence and pathogenesis of HPV-related cancers, the development and approval of HPV prophylactic vaccines, and the use and effectiveness of HPV vaccines around the world. Furthermore, we discuss advances in the development of HPV therapeutic vaccines as well as its associated challenges.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.

Tumor detection with transoral use of flexible endoscopy for unknown primary head and neck cancer.

ObjectivesWith the advent of new optical technologies, early pharyngolaryngeal cancerous lesions can be better visualized. Although the conventional transnasal approach offers great views of the hypopharynx and larynx, the visualization of the oropharynx and palatine tonsils is limited. Through the transoral insertion of a flexible video‐laryngoscope, direct views of the oropharynx and oral cavity can be obtained. Thus, transoral examination may contribute to primary detection of cancers of unknown primary (CUP).MethodsEighty‐five CUP patients from Tokai University were included retrospectively in this study, from 2006 to 2017. Starting in 2010, we employed the transoral examination in addition to our conventional method. The primary detection rates were compared before and after 2010. Oropharyngeal primaries were further analyzed for tumor subsite and p16 status.ResultsThe overall primary detection rate did not improve with the addition of transoral examination. However, greater numbers of oropharyngeal primaries were detected. The oropharyngeal lesions detected by transoral examination were mainly p16 positive, located on the palatine tonsil.ConclusionTransoral examination is a noninvasive, easy method to adopt in an outpatient setting, and a promising technique to improve tumor detection in this era of human papillomavirus‐associated head and neck cancers.Level of Evidence3.

Human Papillomavirus-Associated Head and Neck Cancer.

Oropharyngeal squamous cell carcinoma (OPSCC) has historically been attributable to tobacco and alcohol exposure and saw a decline in incidence after societal norms shifted away from smoking. In recent decades, this disease has had a re-emergence due to human papillomavirus (HPV) infection, now surpassing cervical cancer as the number 1 cause of HPV-related cancer in the United States. HPV-positive OPSCC differs from HPV-negative disease in epidemiology, prognosis, treatment, and prevention. Additionally, there is a deficit in awareness of the causal relationship between HPV and OPSCC. This, coupled with low vaccination rates, puts primary care providers in a unique position to play a vital role in prevention and early diagnosis. In this review, we highlight the epidemiology, screening, patient presentation, diagnosis, prognosis, and prevention of HPV-positive OPSCC, with a focus on the primary care provider's role.

Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can...

CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers.

Genetic alterations of CYLD lysine 63 deubiquitinase (CYLD), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic CYLD alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma), CYLD alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function CYLD alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of CYLD somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor CYLD alterations are also discussed. IMPLICATIONS: Alterations in CYLD gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.

Barriers and facilitators to discussing HPV with head and neck cancer patients: A qualitative study using the theoretical domains framework

ObjectiveThe incidence of human papillomavirus-associated head and neck cancers (HPV-HNC) is increasing worldwide. Research in other clinical contexts has shown that healthcare professionals (HCPs) can find discussing HPV with patients challenging. However, limited research has been conducted in HNC. This study aimed to investigate barriers and facilitators to, discussing HPV among HCPs caring for patients with HNC in Ireland. MethodsSemi-structured telephone/face-to-face interviews were conducted with HCPs. Barriers and facilitators to discussing HPV with patients were identified using the Theoretical Domains Framework (TDF). Results20 HCPs (8 clinicians, 3 nurses, 9 allied healthcare professionals) were interviewed. Barriers to discussing HPV included professionals' lack of HPV knowledge, difficulties in talking about sexual issues with patients and lack of privacy to discuss HPV in busy clinic settings. Facilitators included increasing public and patient awareness of the link between HPV and HNC and professional education and skills development. ConclusionsThis is the first theoretically informed study to identify barriers and facilitators to discussing HPV with HNC patients. HCPs consider HPV discussions to be an essential part of HNC patient care. Practice implicationsUnderstanding the issues associated with patient-provider HPV communication will help develop effective interventions to support HCPs in their HPV discussions.

Long-read RNA-Seq of human papillomavirus-associated head and neck cancer reveals novel alternatively spliced viral RNA isoforms

Long-read RNA-Seq of human papillomavirus-associated head and neck cancer reveals novel alternatively spliced viral RNA isoforms