Currently, producing NPSH after HPV infection of cells has been confirmed. These NPSH-containing substances accumulate around the urethral opening and are subsequently washed out with urine. Therefore, indirect detection of HPV infection by assessing NPSH levels in urine is feasible, but it has not been reported in detail so far. Here, an assay using phosphotungstic acid to oxidise and produce colour changes by NPSH in urine was developed. This assay enabled the rapid, non-invasive identification of HPV infection by detecting the metabolic byproduct NPSH produced by HPV-infected cells. Employing a smartphone-based device, developed using an ambient light sensor, reduces the cost and simplifies the operation associated with the colourimetric assay. The colourimetric assay was used to detect L-cysteine and L-ascorbic acid standard substance (as NPSH mimics), the limited of detection were 0.12 mM and 31.25 μM, respectively, with high reproducibility and stability. When this colourimetric assay was used to evaluate urine samples from individuals suspected of HPV infection, along with other at-home self-screening methods for HPV nucleic acid detection in urine, showed comparable sensitivity and specificity. Compared with nucleic acid detection in urine, this colourimetric assay is cost-effective, user-friendly, amenable to self-sampling, and enables testing at one's convenience and location of choice, which is more suitable for home self-testing or population self-screening.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) are highly prone to malnutrition and sarcopenia due to the tumor's location and treatment-related toxicity. Human papillomavirus (HPV)-related and HPV-unrelated OPSCC represent two distinct biological entities. This study aimed to assess nutritional characteristics and body composition differences at diagnosis, as well as 3- and 6-months post- (chemo) radiation treatment, stratified by HPV status in OPSCC patients.

Retrospective data analysis of a prospective cohort of OPSCC patients diagnosed and treated with curative intent from 2016 to 2022 at our center. Sociodemographic, clinical, and nutritional data were retrieved from medical records from diagnosis to 6 months post-treatment. Body composition parameters were assessed by analyzing the cross-sectional area of the third lumbar vertebra (L3) using available positron emission tomography (PET) and computed tomography (CT) scans at baseline, 3- and 6-months post-treatment.

Seventy patients were included, 33 (47.1 %) of whom had HPV-related OPSCC. HPV-related patients had higher body mass index (27.3 vs 21.9 kg/m2; p < 0.001) and better baseline nutritional status (p = 0.023), but no differences in skeletal muscle index (SMI, p = 0.103) compared to HPV-unrelated patients. At 3- and 6-months post-treatment the two groups showed similar SMI and total adipose tissue index loss (p > 0.05 for both). HPV status was not independently associated with body composition changes over time (p = 0.624).

Although HPV-related patients were better nourished than HPV-unrelated patients at diagnosis, by the end of treatment, both groups exhibited similar nutritional deterioration.

Human papillomaviruses are causative agents in around 5 % of all cancers, and in a number of other human diseases. While prophylactic vaccines will alleviate the HPV disease burden on future generations, there are currently no therapeutic anti-viral strategies for combating HPV infections or lesions. HPV induce the proliferation of infected epithelial cells and modulate the host differentiation response, and both of these controls are required for a successful viral life cycle. Enhanced understanding of viral-host interactions during the viral life cycle will identify potential novel anti-viral strategies for therapeutic development. This minireview will summarize the critical role of the host enzyme CK2 in regulating the function of the viral proteins E1, E2 and E7; such control makes CK2 a critical enzyme for regulating HPV life cycles. Therapeutic strategies blocking CK2 function to combat HPV infections and treat HPV diseases will be described.

Youth are disproportionately affected by substance use and associated sexual risk behaviors, increasing STI and HIV susceptibility. This study analyzed the interplay between alcohol/drug use before sex (ABS/DBS), perceived sex approval (e.g., perceived familial or peer approval in engaging in sex), and HIV/STI risk perception among youth aged 13-21 (n = 150). We assessed how these factors influenced condomless vaginal/anal sex (VAS) and oral sex practices. Results showed significant interactions between perceived sex approval and lifetime ABS for lifetime condomless VAS, and between HIV/STI risk perception and lifetime ABS for current condomless oral sex. These findings underline the influence of perceived sex approval and HIV/STI risk perception on youth's sexual behaviors. Implications for targeted interventions are discussed.

Pathologic extranodal extension is a known predictor of poor outcomes in head and neck cancer. However, data on imaging-identified extranodal extension (iENE) in oropharyngeal cancer (OPC) outcomes are limited. This study aimed to evaluate the prognostic value of iENE for human papillomavirus-positive (HPV+) OPC patients.

This retrospective study included patients treated at a tertiary referral hospital. All eligible TNM eighth edition stage I to III HPV+ OPC patients treated with curative intent, including definitive or postoperative radiation therapy from 2009 to 2020, were included. The presence of iENE on pretreatment computed tomography or magnetic resonance imaging was assessed by 2 neuroradiologists masked to clinical characteristics. iENE grade (0, 1, 2, or 3) was based on standard definitions used in previous studies. Clinical outcomes were compared based on the presence of iENE and grade. χ2 and t tests were used for the univariate analysis of categorical and continuous variables. The Cox-proportional hazards model was used to assess time-to-event outcomes while controlling for N category, smoking history, chemotherapy type, and surgery use.

Of 421 patients, 134 were iENE-negative (iENE-) and 287 iENE-positive (iENE+), with 271 patients having grade 2 or 3 iENE. iENE+ patients were more likely to receive chemotherapy (96% vs 79%, respectively; p≤ .001) and less likely to have had surgery (7% vs 13%, respectively; p = .03). The iENE+ cohort had a higher number of positive lymph nodes (1.9 vs 4.8 nodes, p≤ .001) and a higher proportion of patients with low neck nodes (16% vs 1%, p≤ .001). At 3 years, the presence of iENE was associated with decreased progression-free survival (PFS) (85% vs 94%; hazard ratio (HR), 2.01; p = .007) and increased distant metastases (16% vs 7%; HR, 2.36; p = .031). Looking at individual grades, grade 3 iENE was associated with an increased risk of death or recurrence, ie, decreased PFS (HR, 3.56; p≤ .001) and increased distant recurrence (HR, 3.37; p = .007), and grade 2 iENE was associated with distant recurrence only (HR, 2.27; p = .041). Locoregional control was similar between the iENE+ and iENE- groups (HR, 1.35; p = .5).

HPV+ OPC patients with ENE evident on imaging, likely driven by grade 3 iENE, have an increased risk of distant metastases and decreased PFS. Incorporating iENE into HPV+ OPC staging may help improve prognostication and refine the clinical trial design.

Human-papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC) is a distinct disease characterized by unique clinical and molecular features compared to HPV-negative OPSCC. A comprehensive bibliometric analysis of HPV-positive OPSCC research was conducted in this study to identify key trends, research hotspots, and emerging frontiers in the field. Data were retrieved from the Web of Science Core Collection database. The distributions of contributors, including countries, institutions, authors, journals, and cooperative networks related to HPV-positive OPSCC, were analyzed and visualized using VOSviewer 1.6.20, CiteSpace 6.3.R1, and the R package Bibliometrix 4.0.0. In addition, the most influential publications and high-frequency keywords were identified and analyzed to discern key topics in this field. A total of 3895 articles and reviews on HPV-positive OPSCC were identified, involving 106 countries, 620 journals, and 18949 authors. The main contributors include the USA (1908 publications), Johns Hopkins University (310 publications), the journal Head and Neck (320 publications), and Erich M. Sturgis (94 publications). The top three keywords are "survival", "radiotherapy", and "p16". There has been a steadily increasing research interest in HPV-positive OPSCC over the last 23 years. Current studies focus on diagnosis, treatment strategies, prognosis, recurrence, and disease surveillance. This bibliometric analysis highlights key contributors and emerging themes, offering insights for future research directions.

Immunotherapy can treat cancer by boosting the immune system to mark and destroy cancer cells. Cancer vaccine is a promising therapeutic strategy in immunotherapy. Cancer vaccines are divided into four groups according to different preparation techniques: cell-based vaccine, virus-based vaccine, peptide-based vaccine, and nucleic acid-based vaccine. Cancer vaccines can be given with traditional treatments or another immunotherapy to give better results and overcome tumor resistance. The cancer vaccine is a promising immunotherapy that could stimulate the immune response to kill cancer cells and create immune surveillance. However, much work is still needed to identify neoantigens, optimize the vaccination platform, and develop combination therapy to improve the efficacy of immunotherapy. This review highlights the mechanism of action of cancer vaccines, the main four groups of cancer vaccines regarding their development, research progress, and clinical applications, and how to assess immune response following cancer vaccination.

Modality treatment including surgery, chemotherapy, radiation and immunotherapy was considered as standard strategy for tonsillar squamous cell carcinoma (TSCC). We reported a case of a 78-year-old man under severe underlying medical conditions who diagnosed with human papillomavirus (HPV)-positive and programmed death ligand 1 (PD-L1)-positive TSCC. He was administered camrelizumab combined with gemcitabine (GEM) for 8 cycles with partial response. Then, we gave him concurrent nanoparticle albumin-bound paclitaxel (nab-paclitaxel)-based chemoradiation. Eventually, this patient achieved complete response without severe adverse events. After a 12-month follow-up, he had no recurrence or metastasis.

Objective This study aims to analyze the trends in the incidence of human papilloma virus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPSCC) in relation to geographic rates of HPV vaccination in the United States.  Methods The US Cancer Statistics (USCS) database and the National Cancer Institute's (NCI's) Surveillance, Epidemiology and End Results (SEER) program were used for incidence and population data collection; the Centers for Disease Control and Prevention's (CDC) Teen National Immunization Survey provided vaccination data. Incidence of HPV-mediated OPSCC and the HPV vaccination rate were compared and analyzed using t-tests, ANOVA analyses, and linear regression analyses. Results Statistically significant differences between regions of the United States were observed when incidence and vaccination rates of OPSCC were analyzed. When incidence as a function of vaccination rate was analyzed, no significance was noted. Each region had an increase in the OPSCC incidence in the post-vaccine era compared to the pre-vaccine era. Conclusion We cannot conclude that any variance in OPSCC by region is due to HPV vaccination at this time. Because some regions show increased vaccination rates compared to others, it is likely that they will reach herd immunity first and be the first to see a decline in cases as the population ages. Because of the currently insignificant relationship between the vaccination rate over time and incidence rates, additional longitudinal analyses and cohort follow-up studies are needed to further assess the vaccine's impact.

Head and neck squamous cell carcinoma (HNSC) is a prevalent malignancy, with HPV-negative tumors exhibiting aggressive behavior and poor prognosis. Understanding the intricate interactions within the tumor microenvironment (TME) is crucial for improving prognostic models and identifying therapeutic targets. Using BulkSignalR, we identified ligand-receptor interactions in HPV-negative TCGA-HNSC cohort (n = 395). A prognostic model incorporating 14 ligand-receptor pairs was developed using random forest survival analysis and LASSO-penalized Cox regression based on overall survival and progression-free interval of HPV-negative tumors from TCGA-HNSC. Multi-omics analysis revealed distinct molecular features between risk groups, including differences in extracellular matrix remodeling, angiogenesis, immune infiltration, and APOBEC enzyme activity. Deep learning-based tissue morphology analysis on HE-stained whole slide images further improved risk stratification, with region selection via Silicon enhancing accuracy. The integration of routine histopathology with deep learning and multi-omics data offers a clinically accessible tool for precise risk stratification, facilitating personalized treatment strategies in HPV-negative HNSC.

Oropharyngeal carcinoma, a type of head and neck cancer (HNC), is an emerging malignancy associated with low survival rates. It typically affects older males and correlates with smoking, drinking, and lower socioeconomic conditions. Traditional treatments such as surgery have often yielded limited outcomes. However, recent insights, particularly those emphasized by Dr Teknos in his Keynote Conference at MedNews Week, have sparked a deeper exploration into alternative and more promising treatment methods. A comprehensive literature review was conducted to explore this subject further. One such approach, demonstrated by the UMCC 9921 trial, involves a comprehensive protocol starting with induction chemotherapy. This initial phase aims to reduce tumor burden and assess response to treatment. Based on the individual outcomes, patients then undergo concurrent chemoradiation or salvage surgery. This strategy has significantly improved survival rates, especially in human papillomavirus (HPV)-positive patients, showcasing the potential of tailored treatments. While these advancements are promising, long-term complications such as dysphagia and osteoradionecrosis remain a cause of concern. The rise of HPV-related head and neck squamous cell carcinoma has further changed how risk factors and treatment outcomes are viewed. HPV-positive cancers have unique characteristics and respond well to modern therapies. Researchers are investigating biomarkers such as circulating HPV DNA and immunoglobulin J polypeptide expression, which could provide valuable insights into disease progression and pave the way for more targeted and effective treatment strategies. In addition, the use of existing medications, such as fenofibrate, to combat HPV infections illustrates the resourcefulness in repurposing specific treatments. Challenges persist, especially in the need for reliable biomarkers for early disease progression detection and monitoring. Deeper insights into viral-host interactions shape promising immunotherapy strategies that could revolutionize treatment approaches. Collaborative efforts between researchers, healthcare providers, and policymakers play a vital role in translating these advancements into substantial clinical benefits, improving outcomes and quality of life for individuals affected by HPV-related diseases. While HPV-associated HNCs present significant challenges, continuous research and innovative treatments offer hope for a brighter future in combating this growing epidemic and improving patient care.

Human papillomavirus (HPV) is a leading cause of mucosal cancers, including the increasing incidence of HPV-related head and neck cancers. The oral microbiota-a diverse community of bacteria, fungi, and viruses-play a critical role in oral and systemic health. Oral microbiota dysbiosis is increasingly linked to inflammation, immune suppression, and cancer progression. Recent studies have highlighted a complex interaction between HPV and oral microbiota, suggesting this interplay influences viral persistence, immune response and the tumor microenvironment. These interactions hold significant implications for disease progression, clinical outcomes, and therapeutic approaches. Furthermore, the oral microbiota has emerged as a promising biomarker for HPV detection and disease progress assessment. In addition, probiotic-based treatments are gaining attention as an innovative approach for preventing or treating HPV-related cancers by modulating the microbial environment. In this review, current research on the interaction between HPV and oral microbiota is provided, their clinical implications are explored, and the future potential for utilizing microbiota for diagnostic and therapeutic innovations in HPV-associated cancers is discussed.

Approximately 70% of oropharyngeal squamous carcinomas (OPSCC) are associated with human papillomavirus (HPV). Although patients with HPV-positive (HPV+) tumors generally have better outcomes than those with HPV-negative tumors, a subset of HPV+ positive patients do have poor outcomes. Our previous work suggested that tumors with integrated virus exhibit significantly greater genome-wide genomic instability than those with only episomal viral genomes, and patients with HPV+ OPSCC with episomal viral genomes had better outcomes. To explore the causal relation between viral integration and genomic instability, we have examined the time course of viral integration and genetic instability in tonsillar keratinocytes transformed with HPV16. HPV-infected human tonsil keratinocyte cell lines were continuously passaged, and every fifth passage, some cells were retained for genomic analysis. Whole-genome sequencing and optical genomic mapping confirmed that virus integrated in five of six cell lines while remaining episomal in the sixth. In all lines, genome instability occurred during early passages but essentially ceased following viral integration; however, it continued to occur in later passages in the episomal line. To test tumorigenicity of the cell lines, cells were injected subcutaneously into the flanks of nude mice. A cell line with the integrated virus induced tumors following injection in the nude mouse whereas that with the episomal virus did not. Implications: Genomic instability in HPV OPSCC tumors is not the result of viral integration but likely promotes integration. Moreover, transformants with episomal virus seem to be less tumorigenic than those with integrated virus.

Human papillomavirus (HPV) is a significant driver of elevated risk for oropharyngeal squamous cell carcinoma (OPSCC). In 2018, HPV vaccination eligibility was expanded to men and women aged 27 to 45. We evaluated changes in awareness of HPV, its association with OPSCC, and HPV vaccination among all US adults between 2018 and 2020, focusing on those aged 27 to 45.

Cross-sectional survey cycles.

The Health Information National Trends Survey (HINTS).

The HINTS, a nationally representative survey of US adults, was queried. A total of 3504 adults in 2018 and 3865 adults in 2020 were assessed for knowledge of HPV, its vaccine, its association with OPSCC, and changes in awareness between 2018 and 2020. Statistical significance was set at P < .05.

Most respondents were aware of HPV (2018: 60.8%; 2020: 64.8%) and its vaccine (2018: 60.8%; 2020: 61.6%). A significant decrease in awareness of the association between HPV and cervical cancer was seen between 2018 and 2020 (75.0% vs 70.2%, P = .028). Knowledge of HPV+ OPSCC was poor and did not change over time (2018: 27.0%, 2020: 29.5%). Statistically significant increases in HPV awareness between 2018 and 2020 were found for individuals who reported completing high school as their highest level of education (P = .009), Caucasians (P = .013), males (P = .024), and those making more than $200,000 annually (P = .022).

Knowledge of the association between HPV and OPSCC remained poor despite expanded vaccine eligibility. Public health education on the association may increase awareness for groups likely to benefit from vaccination.

In the 8th edition of the TNM classification, extracapsular spread (ECS) became a factor in classifying the UICC stage of oropharyngeal carcinomas (OPSCC). We aimed to find genetic markers for ECS and to identify differences between HPV/p16-positive and HPV/p16-negative cases.

We performed targeted next-generation sequencing on 99 samples of operable OPSCC and a retrospective analysis of clinical data.

We included 55 HPV/p16-positive and 44 HPV/p16-negative patients. We found a significant difference between both groups, particularly in TP53 mutation (p < 0.001). Among other things, a small primary tumor (p < 0.001), no ECS (p = 0.026) were identified as predictors for survival. Multiple mutations were associated with an increased incidence of ECS, especially in HPV+/p16+ cases (p = 0.017). A mutation in PIK3CA occurred more frequently in nonsmokers, especially in HPV-/p16- patients (p = 0.027). A PTEN mutation-which only occurred in HPV+/p16+ tissues-reduced disease-free survival (DFS, p = 0.026).

The presence of multiple mutations in HPV+/p16+ OPSCC was associated with a higher risk of ECS.

3.

BackgroundAmong head and neck squamous cell carcinomas (HNSCCs), the incidence of oropharyngeal cancer (OPC) has been increasing in recent decades. Human papillomavirus (HPV) type 16 is associated with the majority of OPC. Circulating antibodies (Abs) to multiple HPV16 early antigens, including E2, E6, and E7, have been detected in patient sera, and are strongly associated with risk for OPC. However, HPV serology currently requires laboratory-based tests that are difficult to implement for large-scale cancer screening.ObjectiveThe goal of this study was to develop and validate a point-of-care assay for rapid detection of circulating IgG to HPV16 early antigens.MethodsWe measured Abs to HPV16 E2, E6, and E7 proteins using a lateral flow assay (LFA) in sera from 119 newly diagnosed OPC cases, 41 partners, and 81 healthy volunteers. The 119 patients with HPV-OPC were classified as HPV-positive based on in situ hybridization (ISH) or institutional p16 immunohistochemistry. The sensitivity and specificity of the LFA were determined by comparing to clinical diagnosis.ResultsThe specificity for each individual HPV16 E2, E6, and E7 antibodies was 95.1% (77/81), 96.3% (78/81), and 98.7% (80/81), respectively. The sensitivities of the individual HPV16 antibodies were as follows: E2, 47.9% (57/119), E6, 31.9% (38/119), and E7, 57.1% (68/119). The 3-biomarker panel (at least one positive for E2, E6, and E7 Abs) demonstrated a sensitivity of 76.5% (91/119) and a specificity of 92.6% (75/81).ConclusionsWe developed a multiplexed lateral flow assay for the rapid detection of serologic responses to HPV16. Further research is required to determine the utility of these tests for HPV + HNSCC cancer screening, as higher specificity, and an assessment of the benefits of positive test results have yet to be evaluated in this context.

The human papillomavirus (HPV) is a prevalent sexually transmitted infection that is a known cause of morbidities such as genital warts and cancers of the cervix, anus, and oropharynx. Non-cervical HPV-related cancers have been a developing problem in North America, increasing in incidence by up to 225% in some instances over a span of two decades.

This study investigated levels of awareness and knowledge of HPV, oropharyngeal cancer (OPC), and the HPV vaccine using a self-administered web-based survey designed specifically for this research. University students (n = 1005) aged 18-30 completed a 42-item questionnaire that included demographic information, awareness questions, and a series of "true/false/I don't know" knowledge questions.

The data gathered revealed that participants had relatively high levels of awareness. However, many respondents had significant gaps in their knowledge of HPV, OPC, and the HPV vaccine. Collectively, the data indicate that awareness and knowledge of HPV and the value of vaccination may place younger individuals at risk for HPV-related infections.

Although a relatively high level of awareness concerning HPV was observed, the gaps in knowledge suggest that further efforts are necessary to educate young adults. While all risk factors cannot be reduced, the present data may guide future efforts directed toward better education on HPV and related health concerns and associated risks.

Definitive chemoradiation is the primary treatment for locally advanced head and neck carcinoma (LAHNSCC). Optimising outcome predictions requires validated biomarkers, since TNM8 and HPV could have limitations. Radiomics may enhance risk stratification.

This single-centre observational study collected clinical data and baseline CT scans from 171 LAHNSCC patients treated with chemoradiation. The dataset was divided into training (80%) and test (20%) sets, with a 5-fold cross-validation on the training set. Researchers extracted 108 radiomics features from each primary tumour and applied survival analysis and classification models to predict progression-free survival (PFS) and 5-year progression, respectively. Performance was evaluated using inverse probability of censoring weights and c-index for the PFS model and AUC, sensitivity, specificity, and accuracy for the 5-year progression model. Feature importance was measured by the SHapley Additive exPlanations (SHAP) method and patient stratification was assessed through Kaplan-Meier curves.

The final dataset included 171 LAHNSCC patients, with 53% experiencing disease progression at 5 years. The random survival forest model best predicted PFS, with an AUC of 0.64 and CI of 0.66 on the test set, highlighting 4 radiomics features and TNM8 as significant contributors. It successfully stratified patients into low and high-risk groups (log-rank p < 0.005). The extreme gradient boosting model most effectively predicted a 5-year progression, incorporating 12 radiomics features and four clinical variables, achieving an AUC of 0.74, sensitivity of 0.53, specificity of 0.81, and accuracy of 0.66 on the test set.

The combined clinical-radiomics model improved the standard TNM8 and clinical variables in predicting 5-year progression though further validation is necessary.

Question There is an unmet need for non-invasive biomarkers to guide treatment in locally advanced head and neck cancer. Findings Clinical data (TNM8 staging, primary tumour site, age, and smoking) plus radiomics improved 5-year progression prediction compared with the clinical comprehensive model or TNM staging alone. Clinical relevance SHAP simplifies complex machine learning radiomics models for clinicians by using easy-to-understand graphical representations, promoting explainability.

We used our mouse papillomavirus (MmuPV1) model to test the hypothesis that two primary psychoactive ingredients of marijuana, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), promote papillomavirus persistence in the oral mucosa of infected mice. We conducted intraperitoneal (ip) injections of a moderate dose (3 mg/kg) of either CBD and/or THC in both male and female athymic nude mice and followed the mice up to 20 weeks post-infection. These doses are comparable to what is estimated for human conventional cannabis consumption. All mice were infected with MmuPV1 in the oral cavity at week 4 post-ip delivery of CBD, THC, or a combination of THC and CBD (T + C). THC and CBD were detected in the blood of treated mice for up to 72 h after ip injection. Significantly higher levels of viral DNA were detected in males from both CBD and T + C-treated groups compared to those in the control group at 9- 10-and 12-weeks post infection. A marginally increased viral RNA was also detected in the infected tongues of males in all tested groups compared to that in males in the vehicle control group; the opposite was observed in females. We detected significantly higher levels of dermal dendritic cells (CD205+CD11c+), granulocytes (Ly6G+), but macrophages (F4-80+) recruited to the infected tongues of CBD-treated females. Our findings suggest that CBD may play a role in promoting MmuPV1 persistence in the oral cavity.

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.

HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable in vivo responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.

The incidence of human papillomavirus (HPV) associated oropharyngeal cancer has increased to epidemic-like proportions in the United States and other industrialized nations. While significant progress has been made in the understanding of this disease with respect to its underlying biology and clinical behavior, numerous questions persist regarding treatment. It is now firmly established that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite radiosensitivity compared to their HPV-negative counterparts and thus can be targeted with de-escalated approaches using reduced doses of radiation and/or chemotherapy. The fundamental goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain the high rates of cure and preserve quality of life for appropriately selected patients with this disease. However, the selection criteria and specific means for de-escalation remain uncertain, and paradigms continue to evolve. Given that HPV-positive oropharyngeal cancer is increasingly recognized as a public health problem, the search for answers to many of these provocative questions has important societal implications and is the subject of this review.

Tumor vaccine is a promising immunotherapy for solid tumors. Therapeutic tumor vaccines aim at inducing tumor regression, establishing durable antitumor memory, and avoiding non-specific or adverse reactions. However, tumor-induced immune suppression and immune resistance pose challenges to achieving this goal. In this article, we review multiple challenges currently faced in the development of therapeutic tumor vaccines, with a particular focus on anonymous antigen vaccines in situ as a new direction. We summarize the research progress in this area, aiming to provide a reference for future studies on tumor vaccines.

Checkpoint inhibitors (ICIs) have demonstrated substantial efficacy in the treatment of numerous solid tumors, including head and neck cancer. Their inclusion in the therapeutic paradigm in metastatic lines of treatment has certainly improved the outcomes of these patients. Starting from this assumption, numerous studies have been conducted on ICIs in other earlier disease settings, including studies conducted in patients in neoadjuvant settings. However, how many and which studies are truly significant? Can they lay concrete foundations for further future studies and therefore allow us to continue to have this interesting future perspective? Through a review of the existing literature, coupled with insights gleaned from clinical practice and from the main recently published studies, we aim to examine the therapeutic potential of ICIs in patients affected by head and neck cancer in a neoadjuvant treatment setting and encourage researchers to set up successful future clinical trials.

Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.

Herein, we evaluated the attributable fraction (AF) of human papillomavirus (HPV)-mediated (HPV+) oropharyngeal carcinomas (OPCs) in Greece over a recent calendar period.

ORPHEAS, a retrospective, observational, multicenter, cross-sectional study with prospective recruitment, included adult patients with OPC in 2017-2022, each of them with a high-quality, treatment-naïve tumor specimen. The primary endpoint was the HPV-AF, defined as combined positivity for p16INK4a (p16) overexpression and HPV DNA presence by central laboratory testing, among included patients. Other endpoints evaluated the HPV+/HPV- patient/disease characteristics at OPC diagnosis and the HPV subtypes for HPV+ patients.

144/147 patients with available HPV status by central laboratory testing were analyzed [median age: 60.0 years; males: 111 (77.1%)]. The most common tumor anatomical sites were the tonsils (70/147, 48.6%) and the base of the tongue (51, 35.4%), and most patients were at the American Joint Committee on Cancer eighth edition TNM (tumor-node-metastasis) stages III (25, 22.7%) and IV (43, 39.1%). The HPV-AF was 52.1% (75/144; 95% confidence interval 43.6% to 60.5%). Most HPV+ patients were infected by an HPV type targeted by the 9-valent HPV vaccine (72/75, 96.0%), especially HPV16 (70/75, 93.3%). HPV+ compared with HPV- patients were younger (median age 58.0 versus 64.0 years; P = 0.003); more likely to have tumors in the tonsils (65.0% versus 30.4%; P < 0.001); less likely to have tumors in the base of the tongue (25.3% versus 46.4%; P = 0.008); and less frequently at TNM stage IV (20.4% versus 57.1%; overall P < 0.001).

In Greece, we observed a high HPV-AF (52.1%) in OPC, approximating the AFs reported for some Northern European countries. HPV+ versus HPV- patients were younger, more frequently with tonsillar tumors, and less frequently at TNM stage IV. Since most patients were infected by ≥1 HPV type targeted by the 9-valent vaccine, the HPV+ OPC burden could be mitigated through a routine HPV gender-neutral vaccination program.

Adolescent human papillomavirus (HPV) vaccination rates continue to remain lower than other adolescent vaccines, both nationwide and in Iowa. This study examined predictors of missed opportunities for first-dose HPV vaccine administrations in Iowa in order to conduct more targeted outreach and improve adolescent HPV vaccine uptake.

A retrospective study was conducted to identify predictors of missed opportunities for first-dose HPV vaccination in Iowa adolescents using Iowa's Immunization Registry Information System. The study population included 154,905 adolescents aged 11-15 years between 2019 and 2022. Missed opportunity for first-dose HPV vaccination was defined as a vaccination encounter where an adolescent received a Tdap and/or MenACWY vaccine but did not receive the first-dose HPV vaccine during the same encounter.

Over a third of the study population experienced a missed opportunity for HPV vaccination between 2019 and 2022. Missed opportunity for vaccination was most common among individuals living in a rural county (aOR = 1.36), underinsured adolescents (aOR = 1.74), males (aOR = 1.12), teens 13-15 years of age (aOR = 1.76), and White race and non-Hispanic ethnicity.

This study builds on previously reported predictors of missed opportunity for HPV vaccination in adolescents. Increased understanding of provider needs and barriers to administering HPV vaccination and further analysis of how the Vaccines for Children Program can play a role in HPV vaccination uptake is necessary to improve HPV vaccination rates among adolescents in Iowa and more specifically in rural communities.

Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC).

We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants.

There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels.

Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system, a groundbreaking innovation in genetic engineering, has revolutionized our approach to surmounting complex diseases, culminating in CASGEVY™ approved for sickle cell anemia. Derived from a microbial immune defense mechanism, CRISPR/Cas9, characterized as precision, maneuverability and universality in gene editing, has been harnessed as a versatile tool for precisely manipulating DNA in mammals. In the process of applying it to practice, the consecutive exploitation of novel orthologs and variants never ceases. It's conducive to understanding the essentialities of diseases, particularly cancer, which is crucial for diagnosis, prevention, and treatment. CRISPR/Cas9 is used not only to investigate tumorous genes functioning but also to model disparate cancers, providing valuable insights into tumor biology, resistance, and immune evasion. Upon cancer therapy, CRISPR/Cas9 is instrumental in developing individual and precise cancer therapies that can selectively activate or deactivate genes within tumor cells, aiming to cripple tumor growth and invasion and sensitize cancer cells to treatments. Furthermore, it facilitates the development of innovative treatments, enhancing the targeting efficiency of reprogrammed immune cells, exemplified by advancements in CAR-T regimen. Beyond therapy, it is a potent tool for screening susceptible genes, offering the possibility of intervening before the tumor initiative or progresses. However, despite its vast potential, the application of CRISPR/Cas9 in cancer research and therapy is accompanied by significant efficacy, efficiency, technical, and safety considerations. Escalating technology innovations are warranted to address these issues. The CRISPR/Cas9 system is revolutionizing cancer research and treatment, opening up new avenues for advancements in our understanding and management of cancers. The integration of this evolving technology into clinical practice promises a new era of precision oncology, with targeted, personalized, and potentially curative therapies for cancer patients.

The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

The treatment of stage I-III HPV+ oropharyngeal squamous cell carcinoma (HPV-OPSCC) is based on either surgery ± adjuvant therapy or exclusive radio±chemotherapy. We sought to compare these two therapeutic strategies in terms of efficacy, tolerance and quality of life (QoL).

Patients treated for stage I-III HPV-OPSCC from 2010 to 2021 in 3 academic centers were included and sorted according to the treatment strategy: surgery or exclusive radio±chemotherapy. Efficacy and tolerance were retrospectively assessed, and a transversal exploratory QoL assessment was performed using QoL instruments.

A total of 83 patients were included, with 21 undergoing non-minimally invasive surgery and 62 receiving definitive radio-±chemotherapy. 2-year progression-free survival (PFS) and overall survival (OS) were respectively 80% and 86% in the surgical group and 92% and 95% in the non-surgical group, with no significant difference. At the end of treatment, 64.5% of patients presented with a grade III toxicity, without significant difference between the two groups. No patient had late grade III toxicity at 24 months. Forty-five patients (11 in the surgical group, 34 in the non-surgical group) participated in an exploratory quality-of-life analysis. Patients reported significantly more fatigue and loss of appetite after surgery, whereas patients in the radio±chemotherapy group described significantly more salivary and oral problems and difficulty swallowing, but the median time between treatment completion and the response to the questionnaires.

There was no significant difference in efficacy, physician-reported toxicity and overall patient-reported quality of life was found between non-minimally invasive surgery and radio±chemotherapy in the treatment of stage I-III HPV-OPSCC.

The oncogenic protein E7 of the Human Papillomavirus (HPV) is constitutionally expressed in HPV-associated tumors and has the potential to be targeted in T cell receptor (TCR)-based immunotherapy. Adoptive transfer of TCR-engineered T (TCR-T) cells has shown promise as a therapeutic approach for HPV-induced tumors. This study aimed to identify HPV-E7 specific TCRs from HLA-A11:01 transgenic mice through single-cell sorting and sequencing facilitated by E789-97/HLA-A11:01 tetramer. Two dominant TCRs were identified, which exhibited specific binding to E789-97 presented in the context of HLA-A*11:01. TCR-T cells were prepared by infecting primary T cells with lentiviruses containing the TCR genes, and the two TCRs demonstrated substantial responsiveness and showed CD8+ dependent cytokine secretion characteristics. Further analyses of the cytokine profiles revealed that the two TCRs were capable of exerting polyfunctional responses upon specific stimulation. These findings suggest that the two TCRs represent promising candidates for the development of future therapeutic drugs targeting HPV-E7 in the context of HLA-A*11:01 for tumor immunotherapy.

We estimated the population-level incidence of human papillomavirus (HPV)-positive oropharyngeal, cervical, and anal cancers by smoking status. We combined HPV DNA genotyping data from the Centers for Disease Control and Prevention's Cancer Registry Sentinel Surveillance System with data from the Kentucky Cancer Registry and Behavioral Risk Factor Surveillance System across smoking status. During 2004-2005 and 2014-2015 in Kentucky, most cases of oropharyngeal (63.3%), anal (59.7%), and cervical (54.9%) cancer were among individuals who ever smoked. The population-level incidence rate was higher among individuals who ever smoked than among those who never smoked for HPV-positive oropharyngeal (7.8 vs 2.1; adjusted incidence rate ratio = 2.6), cervical (13.7 vs 6.8; adjusted incidence rate ratio = 2.0), and anal (3.9 vs 1.6; adjusted incidence rate ratio = 2.5) cancers. These findings indicate that smoking is associated with increased risk of HPV-positive oropharyngeal, cervical, and anal cancers, and the population-level burden of these cancers is higher among individuals who ever smoked.

Oral squamous cell carcinoma (OSCC) has been being one of the most malignant carcinomas featuring high metastatic and recurrence rates. The current OSCC treatment modalities in clinics severely deteriorate the quality of life of patients due to the impaired oral and maxillofacial functions. In the present work, we have engineered the single-atom Fe nanocatalysts (SAF NCs) with a NO donor (S-nitrosothiol, SNO) via surface modification to achieve synergistic nanocatalytic NO gas therapy against orthotopic OSCC. Upon near-infrared laser irradiation, the photonic hyperthermia could effectively augment the heterogeneous Fenton catalytic activity, meanwhile trigger the thermal decomposition of the engineered NO donor, thus producing toxic hydroxyl radicals (•OH) and antitumor therapeutic NO gas at tumor lesion simultaneously, and consequently inducing the apoptotic cell death of tumors via mitochondrial apoptosis pathway. This therapeutic paradigm presents an effective local OSCC therapeutics in a synergistic manner based on the nanocatalytic NO gas therapy, providing a promising antitumor modality with high biocompatibility.

We recently developed an immuno-oncotherapy against human papillomavirus (HPV)-induced tumors based on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18 genotypes, namely "Lenti-HPV-07". The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07 is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we first established that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy of a homologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of the T-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, we tracked T-cell clonotypes by deep sequencing of T-Cell Receptor (TCR) variable β and α chain mRNA, applied to whole peripheral blood cells (PBL) and a T cell population specific of an immunodominant E7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied by increased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification of clonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstrated that the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpoint inhibitory treatments by systemic administration of anti-TIM3 or anti-NKG2A monoclonal antibodies. While Lenti-HPV-07 is about to enter a Phase I/IIa clinical trial, these results will help better elucidate its mode of action in immunotherapy against established HPV-mediated malignancies.

Studies have demonstrated that tonsillectomy may alter the risk of oropharyngeal cancer (OPC). We systematically reviewed the evidence and pooled data to examine such an association.

PubMed, Embase, and Scopus were searched up to 25th April 2023. Studies reporting an association between tonsillectomy and oropharyngeal cancer risk at any site were included.

Five studies were eligible. All examined the risk of tonsillar and base of the tongue (BOT) cancer with prior history of tonsillectomy. On meta-analysis of the data, prior history of tonsillectomy was associated with a significantly decreased risk of tonsillar cancer. The second meta-analysis showed that history of tonsillectomy did not significantly alter the risk of BOT cancer. However, after exclusion of one study, the results showed an increased risk of BOT cancer with a history of tonsillectomy.

The scarce data available in the literature suggests that tonsillectomy may reduce the risk of tonsillar cancer but does not alter the risk of BOT cancer. Further studies are needed to explore the association between tonsillectomy and the risk of OPC.

Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations.

We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070).

The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer.

The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease.

National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.