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The role of certain viruses in the etiology of some tumors is today indisputable, but there is a lack, however, of annoverview of the relationship between viruses and cancer with amultidisciplinary approach. For this reason, the Health Sciences Foundation has convened a group of professionals from different areas of knowledge to discuss the relationship between viruses and cancer, and the present document is the result of these deliberations. Although viruses cause only 10-15% of cancers, advances in oncology research are largely due to the work done during the last century on tumor viruses. The clearest cancer-inducing viruses are: HPV, HBV, HCV, EBV and, depending on the geographical area, HHV-8, HTLV-1 and HIV. HPVs, for example, are considered to be the causative agents of cervical carcinomas and, more recently, of a proportion of other cancers. Among the Herpes viruses, the association with the development of neoplasms is well established for EBV and HHV-8. Viruses can also be therapeutic agents in certain neoplasms and, thus, some oncolytic viruses with selective tropism for tumor cells have been approved for clinical use in humans. It is estimated that the prophylaxis or treatment of viral infections could prevent at least 1.5 million cancer deaths per year.

Vaccines against human papillomavirus (HPV) are available in Europe since 2006. They have been highly effective in preventing infection and disease caused by the vaccine types. Clinical efficacy data are available for cervical, vulvovaginal and anal precancer and invasive cervical cancer. Disease reduction is best with early vaccination and a coverage of more than 70%. Gender-neutral vaccination provides direct protection for all men and improves the coverage. A good coverage is followed by herd protection of the unvaccinated men and women. School-based programs appear to be most effective; under the age of 15 years, two doses with an interval of 6-12 months are sufficient. From the age of 15 years, the standard regimen with three doses is recommended. A broad catch-up program for young adult women and men improves the effectiveness. The vaccines are also effective in sexually active women and men with previous but cleared infections. Vaccination in addition to local treatment of HPV-related disease appears to reduce recurrent or subsequent HPV-related disease. Combination of HPV vaccination and screening with HPV testing is the most effective approach to prevention of cervical cancer. The screening intervals may increase in the vaccinated cohorts. The upper age limit for vaccination remains to be evaluated, is country specific and depends on cost-effectiveness. The European Society of Gynaecologic Oncology and the European Federation for Colposcopy strongly support gender-neutral vaccination programs for children and young adolescents, with a catch-up program for young adults. (C) 2019 The Authors. Published by Elsevier Ltd.

HPV vaccination has been introduced in clinical practice in recent years and represents the most effective strategy of primary prevention of cervical carcinoma and of female genital preneoplastic conditions. One of the major issues of the subject is represented by vaccination coverage of the target population. Since its introduction, HPV vaccine efficacy has been progressively demonstrated also towards extragenital HPV-correlated conditions and in males too. Moreover, even subjects of older age groups or subjects who already had HPV infections have been demonstrated to received benefits from vaccination, due to improvements of their immunological response. Recently, vaccine efficacy has also been investigated in terms of adjuvant administration after treatments of preneoplastic or benign conditions of the female lower genital tract caused by HPVs; preliminary results indicate an interesting and promising field of application. On this basis, in this article an analysis of the state of the art has been performed, with specific regard to the Italian scenario and with the focus of future perspectives of implementation of the HPV vaccination policy. From the available evidences, the Italian HPV Study Group recommends the extension of systematic HPV vaccination to males too, to adult subjects and also after conservative treatment of genital HPV correlated conditions.

Objective To explore reasons for variations in anxiety in women testing positive for human papillomavirus (HPV) with normal cytology at routine HPV primary cervical cancer screening. Methods In‐depth interviews were conducted with 30 women who had tested HPV‐positive with normal cytology, including 15 with low‐to‐normal anxiety and 15 with high anxiety. Data were analysed using Framework Analysis to compare themes between low and high anxiety groups. Results Several HPV‐related themes were shared across anxiety groups, but only highly anxious women expressed fear and worry, fatalistic cognitions about cancer, fertility‐related cognitions, adverse physiological responses and changes in health behaviour(s). In comparison to those with low anxiety, women with high anxiety more strongly voiced cognitions about the 12‐month wait for follow‐up screening, relationship infidelity, a lower internal locus of control and HPV‐related symptom attributions. Conclusions Receiving an HPV‐positive with normal cytology result related to various emotional, cognitive, behavioural and physiological responses; some of which were specific to, or more pronounced in, women with high anxiety. If our observations are confirmed in hypothesis‐driven quantitative studies, the identification of distinct themes relevant to women experiencing high anxiety can inform targeted patient communications and HPV primary screening implementation policy., Highlights To our knowledge, this is the first qualitative study to explore anxiety in women testing human papillomavirus (HPV)‐positive with normal cytology at routine HPV primary screening.Our comparative qualitative design allowed thematic nuances to emerge between women who had experienced low versus high anxiety following their result.Only highly anxious women expressed fear and worry, fatalistic cognitions about cancer, fertility‐related cognitions, adverse physiological responses and changes in health behaviour(s).Highly anxious women also more strongly voiced cognitions about the 12‐month wait for follow‐up screen, reltionship infidelity, a lower internal locus of control and HPV‐related symptom attributions.These distinct themes can be used to minimise unnecessary anxiety through the development of evidence‐based patient communications at HPV primary screening.

Background The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA. Materials and methods Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics. Results The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96). Conclusions Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p

Introduction Human papillomavirus (HPV) is responsible for oral cavity lesions such as squamous papilloma, multiform epithelial hyperplasia, condylomata acuminata, giant cell fibroids or squamous cell carcinoma. Aim To assess the patients’ awareness of HPV infection’s impact on oral health. Material and methods This was a prospective study of dental patients who were treated in the Department of Oral Surgery at the Medical University of Gdańsk (Gdańsk, Poland) from January to February 2019. Inclusion criteria were as follows: Polish-speaking patients over 18 years old. Exclusion criteria were as follows: people with limited Polish language knowledge and under 18 years old. Participation was voluntary based on the written consent. Descriptive and bivariate statistics were computed and the p-value was set at ≤ 0.05. Results Three hundred and sixty-three people (58.13%: females; 41.87%: males; mean age 21 years, range: 18–65) were included in the study. Women were more aware what HPV was (p = 0.011), the fact that HPV infection could be latent (p = 0.018), responsible for the oral cancer (p = 0.032), there was an HPV vaccine (p < 0.001), and how to prevent infection (p < 0.001); relationship between age and the fact that HPV infection may be responsible for the oral cancer (p = 0.007), HPV infection methods (p < 0.001), characteristics of the lesions caused by the HPV on the mucous membrane (p < 0.001), and how to prevent infection (p = 0.044). Conclusions Our study suggests that patients’ awareness of the influence of HPV infections on oral health is limited. Therefore, more attention should be paid to the education of the patients and to prevention programs.

VGX-3100 is an investigational DNA-based immunotherapy being developed as an alternative to surgery and ablation for cervical High-Grade Squamous Intraepithelial Lesion (HSIL) with the aim of preserving reproductive health while treating precancerous disease. Response durability up to 1.5 y following dosing is now reported. Histologic regression and HPV16 and/or HPV 18 (HPV16/18) clearance were previously demonstrated in a randomized, placebo-controlled, double-blind trial and reported for 6 months after the last dose of VGX-3100 or placebo. The presence of HPV16/18, Pap smear diagnoses, and immunogenicity longer-term responses were assessed at 18 months after the last dose. 91% (32/35) VGX-3100-treated women, whose cervical HSIL regressed and avoided excision at 6 months following study treatment completion, had no detectable HPV16/18 at 18 months following treatment completion. These results were comparable to those for women who received placebo and then later underwent surgery. For VGX-3100 recipients who regressed at 6 months following study treatment completion and avoided excision during the trial, Pap testing showed no HSIL recurrence at 18 months following VGX-3100 treatment. VGX-3100-induced cellular immune responses specific for HPV 16/18 E6/E7 remained higher than for placebo control recipients at 18 months. In women with cervical HSIL who responded to VGX-3100 and were able to avoid surgery, clinical outcomes were comparable to the placebo control group which underwent conventional surgical treatment. These findings extend the understanding of the durability of the treatment effect of VGX-3100 up to 1.5 y and support that VGX-3100 could be used as an alternative to surgery.

Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.

High-risk human papillomaviruses (HPV) can be present and cooperate with Epstein-Barr virus (EBV) to promote the onset and/or progression of various cancers including cervical, breast, head and neck as well as colorectal. In this investigation, we explored the co-prevalence of high-risk HPV and EBV in 74 breast cancer tissues from Qatari women using polymerase chain reaction. We found that high-risk HPV and EBV are present in 48/74 (65%) and 36/74 (49%) of the cases, respectively. While we noted that the presence of HPV presence is associated with triple-negative breast cancer (TNBC) ( = .008), however, the presence of EBV did not correlate with any breast cancer subgroup. Moreover, our data revealed that high-risk HPV and EBV are co-present in 35/74 (47%) of the samples and their co-presence is significantly associated with tumor grade ( = .04) and tumor stage ( = .04). These data indicate that HPV and EBV are commonly co-present in breast cancer and their association could be linked with a more aggressive tumor phenotype. Thus, further investigations are essential to understand the underlying mechanisms of HPV and EBV cooperation in breast carcinogenesis. grants from Qatar University [QUCG-CMED-2018/2019-3, QUHI-CMED-19/20-1 and QUCG-CMED-20/21-2

Introduction Studies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively). Materials and methods Patients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups. Results 33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, p = 0.01; and 62% vs. 33%, p = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, p = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells. Conclusions Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.

Programs aimed at boosting human papillomavirus (HPV)-related awareness are considered one of the most effective strategies for increasing vaccination uptake and eliminating HPV-associated cancers. Several US states have made strong commitments to this effort through legislation and dedicated funds. However, it is not known if these efforts have resulted in population-level increments in HPV awareness overtime. Using the Health Information National Trends Survey data, we examined the awareness of HPV and HPV vaccine in the US, between 2008 and 2018. Prevalence estimates and confidence intervals were calculated for HPV and HPV vaccine awareness. Further, we assessed awareness after stratifying by key sociodemographic characteristics. Overall, the awareness of HPV and HPV vaccine declined over time. The lowest awareness was among racial minorities, rural residents, male respondents, those aged 65 years and older, as well as those with the lowest educational and socioeconomic standing. Between 2013 and 2018, the awareness of HPV and HPV vaccine declined by almost 10% among males, those with a high school level of education or lower, and those who earned less than USD 35,000 per annum. In 2018, the awareness of HPV and HPV vaccine was highest among non-Hispanic whites (65.8% and 66.5%) and female adults (70.5% and 71.4%); however, these figures represented declines of about 5% from rates observed in 2008. Amidst a background of sub-optimal HPV vaccination uptake and a growing incidence of HPV-associated cancers in the US, HPV-related awareness within the general US population has declined over time. This calls for stricter enforcement of legislation aimed at boosting HPV awareness, as well as frequent evaluation of government-funded HPV awareness programs.

Background: The vaccination uptake rates of the human papillomavirus (HPV) vaccine remain low despite the fact that the effectiveness of HPV vaccines has been established for more than a decade. Vaccine hesitancy is in part due to false information about HPV vaccines on social media. Combating false HPV vaccine information is a reasonable step to addressing vaccine hesitancy. Objective: Given the substantial harm of false HPV vaccine information, there is an urgent need to identify false social media messages before it goes viral. The goal of the study is to develop a systematic and generalizable approach to identifying false HPV vaccine information on social media. Methods: This study used machine learning and natural language processing to develop a series of classification models and causality mining methods to identify and examine true and false HPV vaccine-related information on Twitter. Results: We found that the convolutional neural network model outperformed all other models in identifying tweets containing false HPV vaccine-related information (F score=91.95). We also developed completely unsupervised causality mining models to identify HPV vaccine candidate effects for capturing risk perceptions of HPV vaccines. Furthermore, we found that false information contained mostly loss-framed messages focusing on the potential risk of vaccines covering a variety of topics using more diverse vocabulary, while true information contained both gain- and loss-framed messages focusing on the effectiveness of vaccines covering fewer topics using relatively limited vocabulary. Conclusions: Our research demonstrated the feasibility and effectiveness of using predictive models to identify false HPV vaccine information and its risk perceptions on social media. Technology Services and the Cancer Center at Illinois at the University of Illinois at Urbana-Champaign; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R21CA237483] Published version We thank Chieh-Li (Julian) Chin and Wen-Yuh Su for their assistance in the data collection and preparation for this study. We also thank the Technology Services and the Cancer Center at Illinois at the University of Illinois at Urbana-Champaign for their support of our study. This study was supported by a grant from the National Institutes of Health (#1R21CA237483). Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the National Institutes of Health.

Epigenetic alteration of host DNA is a common occurrence in both low- and high-risk human papillomavirus (HPV) infection. Although changes in promoter methylation have been widely studied in HPV-associated cancers, they have not been the subject of much investigation in HPV-induced warts, which are a temporary manifestation of HPV infection. The present study sought to examine the differences in promoter methylation between warts and normal skin. To achieve this, DNA was extracted from 24 paired wart and normal skin samples and inputted into the Infinium MethylationEPIC BeadChip microarray. Differential methylation analysis revealed a clear pattern of hyper- and hypomethylation in warts compared to normal skin, and the most differentially methylated promoters were found within the EIF3EP2, CYSLTR1, C10orf99, KRT6B, LAMA4, and H3F3B genes as well as the C9orf30 pseudogene. Moreover, pathway analysis showed that the H3F3A, CDKN1A, and MAPK13 genes were the most common regulators among the most differentially methylated promoters. Since the tissue samples were excised from active warts, however, this differential methylation could either be a cellular response to HPV infection or an HPV-driven process to establish the wart and/or promote disease progression. Conclusively, it is apparent that HPV infection alters the methylation status of certain genes to possibly initiate the formation of a wart and maintain its presence.

Oropharyngeal squamous cell carcinoma (OPSCC) represents the most common HPV-related malignancy in the United States with increasing incidence. There is heterogeneity between the behavior and response to treatment of HPV-positive oropharyngeal squamous cell carcinoma that may be linked to the tumor virome. In this prospective study, a pan-pathogen microarray (PathoChip) was used to determine the virome of early stage, p16-positive OPSCC and neck metastasis treated with transoral robotic surgery (TORS) and neck dissection. The virome findings of primary tumors and neck lymph nodes were correlated with clinical data to determine if specific organisms were associated with clinical outcomes. A total of 114 patients were enrolled in the study. Double-stranded DNA viruses, specifically Papillomaviridae, showed the highest hybridization signal (viral copies) across all viral families in the primary and positive lymph node samples. High hybridization signals were also detected for signatures of Baculoviridae, Reoviridae, Siphoviridae, Myoviridae, and Polydnaviridae in most of the cancer specimens, including the lymph nodes without cancer present. Across all HPV signatures, HPV16 and 18 had the highest average hybridization signal index and prevalence. To our knowledge, this is the first study that has identified the viral signatures of OPSCC tumors. This will serve as a foundation for future research investigating the role of the virome in OPSCC. Further investigation into the OPSCC microbiome and its variations may allow for improved appreciation of the impact of microbial dysbiosis on risk stratification, oncologic outcomes, and treatment response which has been shown in other cancer sites.

HPV remains the most common sexually transmitted disease worldwide, despite improvements in awareness, screening, prophylactic vaccination uptake, and surgical treatment. VGX-3100 is an immunotherapy that uses electroporation to introduce DNA encoding for modified HPV-16 and HPV-18, E6-and E7 proteins into myocytes to stimulate an effector T cell response. We now report immunogenicity and safety of VGX-3100 for a refrigeration-stable formulation, which improves patient-care setting usability. This multi-arm, double-blinded, randomized trial enrolled 235 healthy men and women to receive either a refrigerated (RF) or frozen formulation (FF) of VGX-3100. Three doses were administered intramuscularly with electroporation at 0, 4, and 12 weeks. Non-inferiority of RF to FF was assessed by comparing the proportion of subjects who achieved a ≥2-fold increase from baseline to Week 14 in Spot Forming Units/106 PMBCs using an interferon-γ enzyme-linked immunospot assay. There were no related SAEs. Injection site reactions were the most common adverse event (54%, RF; 66%, FF) the majority of which resolved within a few minutes following administration. The primary endpoint was met with 89.9% of RF recipients and 97.2% of FF recipients reaching a ≥2-fold rise in SFU/106 PBMC, 2 weeks following the last dose; RF was statistically non-inferior to FF (p = .022). A systemic, immunologic approach has the potential to fill a critical gap in the ability to treat men and women with high grade HPV diseases. These safety and immunogenicity data are supportive of the continued development of a refrigerated formulation of VGX-3100.

Background: The immune checkpoint, indoleamine 2,3-dioxygenase 1, is under investigation as target of novel immunotherapies for cancers, including head and neck squamous cell carcinomas (HNSCC). The aim of our study was to analyze DNA methylation of the encoding gene (IDO1) in HNSCC. Methods: Methylation of three CpG sites within the promoter, promoter flank, and gene body was investigated and correlated with mRNA expression, immune cell infiltration, mutational burden, human papillomavirus (HPV)-status, and overall survival in a cohort of N = 528 HNSCC patients obtained from The Cancer Genome Atlas. In addition, IDO1 immunohistochemistry and DNA methylation analysis was performed in an independent cohort of N = 138 HNSCC samples. Findings: Significant inverse correlations of IDO1 methylation and IDO1 mRNA expression were found in the promoter and promoter flank region (Spearman's ρ = −0.163 and ρ = −0.377, respectively) while a positive correlation was present in the gene body (ρ = 0.502; all P

There is limited data on the HPV immunization status of Latino/Hispanic youth in the USA. In Los Angeles County in 2015, 54,973 (34.3%) college students were of Latino/Hispanic background. We examined Los Angeles County college students’ awareness of HPV and HPV-related disease, HPV vaccine recommendations, and their vaccination status. This study surveyed 212 Los Angeles college students from January to April 2018. In a convenience sampling study, a 31-question, IRB-approved survey was administered face-to-face to college students 18 years and older at California State University settings in Los Angeles County. Almost two-thirds of the male (65%) and half of the female (51.6%) respondents did not know that the HPV vaccine is recommended through 26 years of age, and 47.6% did not know they can get the HPV vaccine at the college student health center or youth-friendly clinics. Ethnicity, family income, and the highest level of education in the family had a significant impact on immunization rates. Self-reported and actual HPV knowledge levels were significantly associated with vaccination status. Educational strategies focusing on the logistics of receiving the HPV vaccine and HPV vaccine catch-up eligibility for college students may be effective in decreasing racial disparities in vaccine receipt.

Vaccine confidence reflects social, individual, and political factors indicating confidence in vaccines and associated health systems. In Japan, the government ceased proactive recommendation of the human papillomavirus (HPV) vaccine in June 2013, only several months after the recommendation had begun. Seven years later, as of October 2020, the suspension persists and vaccine coverage has precipitously declined, resulting in many young women being continually exposed to the risk of preventable HPV-related diseases. Accordingly, understanding stakeholder opinions on HPV vaccination issues is critical for informing strategies to improve HPV vaccine confidence and acceptance. In October 2019, we performed a nationwide, web-based survey of 1646 mothers of HPV-vaccination-eligible girls, 562 female adolescents aged 15-19 years, and 919 healthcare professionals (HCPs) in Japan. This survey captured key elements of vaccine confidence (i.e., importance, effectiveness, and safety of the HPV vaccine), awareness, and the willingness to receive (in HPV-vaccination-eligible girls) or recommend (in HCPs) the HPV vaccine, and the factors responsible for these decisions. HPV vaccine confidence was generally higher among HCPs than among mothers or female adolescents. Nearly half of all stakeholders were neutral regarding their willingness to receive/recommend the HPV vaccine. The seriousness of cervical cancer and the HPV vaccine's effectiveness or safety were important deciding factors for receiving/recommending the HPV vaccine. Besides these factors, sufficient information and free vaccination were crucial. Our results suggest several factors that could help shape public policy and communication strategies to improve HPV vaccine confidence and acceptance in Japan. ispartof: HUMAN VACCINES & IMMUNOTHERAPEUTICS vol:17 issue:9 pages:3102-3112 ispartof: location:United States status: published

Persistent infection with high-risk human papillomavirus (HPV) is the main risk factor for cervical cancer. Our mass spectrometry data showed that the Ras-associated binding protein Rab31 was upregulated by HPV; however, little is known regarding the role of Rab31 in the metastasis of cervical cancer cells. In this study, we showed that Rab31 was highly expressed in cervical cancer tissues and cells, and both HPV E6 and E7 promoted the expression of Rab31. Rab31 knockdown inhibited while Rab31 overexpression promoted the migration and invasion capabilities of cervical cancer cells. Additionally, Rab31 knockdown inhibited the epithelial-mesenchymal transition (EMT) and cytoskeletal rearrangement in cervical cancer cells. Furthermore, Rab31 interacted with mitogen-activated protein kinase 6 (MAPK6), and Rab31 knockdown inhibited the expression of MAPK6, which was mainly localized in the cytoplasm. More importantly, Rab31 knockdown promoted and Rab31 overexpression inhibited MAPK6 degradation. Accordingly, MAPK6 overexpression restored the decreased migration potential caused by Rab31 knockdown. Finally, a xenograft mouse model showed that Rab31 knockdown in cervical cancer cells led to reduced tumor growth and impaired lung and liver metastasis in vivo. In conclusion, Rab31 plays a crucial role in cervical cancer metastasis by inhibiting MAPK6 degradation. Thus, Rab31 may serve as a novel therapeutic target to manage cervical cancer.

Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment of metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in the face of an ineffective therapy can lead to rapid death. Real-time biomarkers of response to therapy could improve outcomes by guiding early change of therapy in the metastatic setting. Herein, we developed and analytically validated a new droplet digital PCR (ddPCR)-based assay for HPV16 circulating tumor DNA (ctDNA) and evaluated plasma HPV16 ctDNA for predicting treatment response in metastatic HPV+ OPSCC. We found that longitudinal changes HPV16 ctDNA correlate with treatment response and that ctDNA responses are observed earlier than conventional imaging (average 70 days, range: 35-166). With additional validation in multi-site studies, this assay may enable early identification of treatment failure, allowing patients to be directed promptly toward clinical trials or alternative therapies.

The generation of successful anticancer vaccines relies on the ability to induce efficient and long-lasting immune responses to tumor antigens. In this scenario, dendritic cells (DCs) are essential cellular components in the generation of antitumor immune responses. Thus, delivery of tumor antigens to specific DC populations represents a promising approach to enhance the efficiency of antitumor immunotherapies. In the present study, we employed antibody-antigen conjugates targeting a specific DC C-type lectin receptor. For that purpose, we genetically fused the anti-DEC205 monoclonal antibody to the type 16 human papillomavirus (HPV-16) E7 oncoprotein to create a therapeutic vaccine to treat HPV-associated tumors in syngeneic mouse tumor models. The therapeutic efficacy of the αDEC205-E7 mAb was investigated in three distinct anatomical tumor models (subcutaneous, lingual and intravaginal). The immunization regimen comprised two doses of the αDEC205-E7 mAb coadministered with a DC maturation stimulus (Polyinosinic:polycytidylic acid, poly (I:C)) as an adjuvant. The combined immunotherapy produced robust antitumor effects on both the subcutaneous and orthotopic tumor models, stimulating rapid tumor regression and long-term survival. These outcomes were related to the activation of tumor antigen-specific CD8+ T cells in both systemic compartments and lymphoid tissues. The αDEC205-E7 antibody plus poly (I:C) administration induced long-lasting immunity and controlled tumor relapses. Our results highlight that the delivery of HPV tumor antigens to DCs, particularly via the DEC205 surface receptor, is a promising therapeutic approach, providing new opportunities for the development of alternative immunotherapies for patients with HPV-associated tumors at different anatomical sites.

INTRODUCTION: It is unclear what role daughters play in the decision-making process regarding HPV vaccination. Therefore, we explored the impact of HPV vaccination intention among parents and their 12–13 year-old daughters on HPV vaccination uptake. METHODS: In February 2014 parents/guardians and their 12–13 year-old daughters were invited to complete a questionnaire about socio-psychological determinants of the decision-making process regarding HPV vaccination. Vaccination status of the daughter was retrieved from the national vaccination database after the last possible vaccination date in 2014. The association between HPV vaccination uptake and intention, and determinants of intention, was jointly assessed using a generalized structural equation model, stratified by origin of parents (Dutch versus non-Dutch). RESULTS: In total, 273 Dutch parent-daughter dyads and 165 non-Dutch dyads were analyzed for this study. HPV vaccination uptake was 90% (246/273) and 84% (139/165) in the Dutch and non-Dutch group, respectively. In the Dutch group, high parental intention (β = 2.3, 95%CI 1.2–3.3) and high daughters’ intention (β = 1.5, 95%CI 0.41–2.6) were significantly associated with HPV vaccination uptake. In the non-Dutch group, high daughters’ intention (β = 1.2, 95%CI 0.16–2.2) was significantly associated with HPV vaccination, but high parental intention was not (β = 0.52, 95%CI −0.47–1.5). Attitude was the most prominent socio-psychological determinant associated with vaccination intention among all groups. CONCLUSION: In the non-Dutch group, only daughters’ intention was significantly associated with HPV vaccination uptake, whereas in the Dutch group both the parents’ and the daughters’ intention were significantly associated with uptake. The role of the child in the decision-making process might need to be taken into account when developing new interventions focused on increasing HPV vaccination uptake, especially among individuals of non-Dutch origin.