The data from the literature show that women undergoing a LEEP due to CIN3 have a greater risk of having subsequent high-grade anogenital intraepithelial neoplasia or cancer, and the risk is greater for vaginal cancer than for anal and vulvar cancers. It is hypothesized that the laparoscopic hysterectomy procedure may cause a higher incidence of VaIN in hysterectomized women. There are few studies addressing this issue, and they show mixed results. This study aimed to investigate the incidence of high-grade or severe VaIN in the population of women undergoing hysterectomy for CIN3 or benign uterine disease and illustrate the treatment options and follow-up.
METHODS: This retrospective study was conducted on 170 women who underwent a laparoscopic hysterectomy due to high-grade cervical intraepithelial neoplasia (CIN3) or benign gynecological disease. The follow-up strategy included performing a cotest and colposcopy with biopsy if necessary. The median time between primary treatment and a diagnosis of high-grade VaIN was 18 months.
RESULTS: High-grade or severe VaIN was found in eight patients after hysterectomy (4.7%). All cases of high-grade VaIN occurred in women with persistent HPV infection. The most frequent genotype was 16. Women hysterectomized due to CIN3 showed an eight-fold greater risk than women hysterectomized due to benign disease of developing high-grade VaIN. The risk of VaIN is low in women hysterectomized due to benign disease. The risk of developing VaIN is greater in women with viral persistence.
CONCLUSIONS: All these elements suggest that it is a history of HPV-related disease of the lower genital tract and viral persistence, rather than hysterectomy itself, that should be considered risk factors for the development of high-grade VaIN. After hysterectomy, patients with a history of CIN should undergo annual screening with vaginal dome cytology and HPV testing.

The persistence of the human papillomavirus type 16 (HPV16) infection on the cervical epithelium contributes to the progression of cervical cancer. Studies have demonstrated that HPV16 genetic variants may be associated with different risks of developing cervical cancer. However, the E5 oncoprotein of HPV16, which is related to several cellular mechanisms in the initial phases of the infection and thus contributes to carcinogenesis, is still little studied. Here we investigate the HPV16 E5 oncogene variants to assess the effects of different mutations on the biological function of the E5 protein. We detected and analyzed the HPV16 E5 oncogene polymorphisms and their phylogenetic relationships. After that, we proposed a tertiary structure analysis of the protein variants, preferential codon usage, and functional activity of the HPV16 E5 protein. Intra-type variants were grouped in the lineages A and D using in silico analysis. The mutations in E5 were located in the T-cell epitopes region. We therefore analyzed the interference of the HPV16 E5 protein in the NF-kB pathway. Our results showed that the variants HPV16E5_49PE and HPV16E5_85PE did not increase the potential of the pathway activation capacity. This study provides additional knowledge about the mechanisms of dispersion of the HPV16 E5 variants, providing evidence that these variants may be relevant to the modulation of the NF-κB signaling pathway.

HPV 16 integration is crucial for the onset and progression of premalignant lesions to invasive squamous cell carcinoma (ISCC) because it promotes the amplification of proto-oncogenes and the silencing of tumor suppressor genes; some of these are proteins with PDZ domains involved in homeostasis and cell polarity. Through a bioinformatics approach based on interaction networks, a group of proteins associated with HPV 16 infection, PDZ domains, and direct physical interaction with E6 and related to different hallmarks of cancer were identified. MAGI-1 was selected to evaluate the expression profile and subcellular localization changes in premalignant lesions and ISCC with HPV 16 in an integrated state in cervical cytology; the profile expression of MAGI-1 diminished according to lesion grade. Surprisingly, in cell lines CaSki and SiHa, the protein localization was cytoplasmic and nuclear. In contrast, in histological samples, a change in subcellular localization from the cytoplasm in low-grade squamous intraepithelial lesions (LSIL) to the nucleus in the high-grade squamous intraepithelial lesion (HSIL) was observed; in in situ carcinomas and ISCC, MAGI-1 expression was absent. In conclusion, MAGI-1 expression could be a potential biomarker for distinguishing those cells with normal morphology but with HPV 16 integrated from those showing morphology-related uterine cervical lesions associated with tumor progression.

Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1β to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.

High-risk human papillomaviruses are well-established drivers of several cancer types including cervical, head and neck, penile as well as anal cancers. While the E6 and E7 viral oncoproteins have proven to be critical for malignant transformation, evidence is also beginning to emerge suggesting that both host pathways and additional viral genes may also be pivotal for malignant transformation. Here, we focus on the role of host APOBEC genes, which have an important role in molecular editing including in the response to the viral DNA and their role in HPV-driven carcinogenesis. Further, we also discuss data developed suggesting the existence of HPV-derived miRNAs in HPV + tumors and their potential role in regulating the host transcriptome. Collectively, while recent advances in these two areas have added complexity to the working model of papillomavirus-induced oncogenesis, these discoveries have also shed a light onto new areas of research that will be required to fully understand the process.

BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy.
Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses.
BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response.
ClinicalTrials.gov, identifier NCT02866006.

The role of human papillomavirus 16 (HPV 16) in esophageal squamous cell carcinoma (ESCC) remains uncertain. Therefore, this study aimed to investigate the prevalence of HPV 16 in patients with ESCC and its impact on theirprognosis. HPV 16 was detected using FISH, and TP53 status was evaluated via immunohistochemistry. The factors influencing prognosis were ananalyzed using the Log-rank test and Cox regression analyses. Among 178 patients with ESCC, 105 and 73 patients were categorized into concurrent chemoradiotherapy (CCRT) and postoperative chemoradiotherapy (POCRT) cohorts, respectively. Among 178 patients, 87 (48.87%) tested positive for HPV 16. Log-rank tests revealed that the overall survival (OS) of patients with ESCC who were HPV 16-positive was longer than that of those who were HPV 16-negative (median OS: 57 months vs. 27 months, p < 0.01**). HPV 16 infection and TP53 mutation status were identified as independent events. The OS of patients with mutant TP53 who were HPV 16-positive was longer than that of those who were HPV 16-negative in both CCRT and POCRT cohorts (p = 0.002** for CCRT cohorts and p = 0.0023** for POCRT cohorts). Conversely, HPV 16 infection had no effect on OS in the wild-type TP53 subgroup (p = 0.13 and 0.052 for CCRT and POCRT cohorts, respectively). As a conclusion, the positive rate of HPV 16 in ESCC in this study was 48.87% (87/178). Among the patients with ESCC who had TP53 mutation, those who were HPV 16-positive exhibited a better prognosis than those who were HPV 16-negative.

BACKGROUND: Epstein-Barr virus, human papillomavirus (HPV), and herpes simplex virus type 1 (HSV-1) are examples of viruses that have been associated with the development of oral squamous cell carcinoma (OSCC). These viruses can infect various epithelial tissues in the human body. The use of incredibly accurate cellular biology techniques, such as the polymerase chain reaction (PCR), which permits the rapid identification of viruses following infection, has increased. The parameters of human head and neck oncology have been widened.
OBJECTIVE: In this study, using the PCR, the presence of HPV variants such as HPV 18 and HPV 16 in patients with OSCC was assessed.
METHODS: Tissue specimens were obtained from clinically presumed OSCC individuals taken as cases, and tissues from the retromolar region were obtained from people who experienced an operation for partially and completely impacted tooth and taken as controls. The study included 80 samples divided into two separate categories: case category (n = 40) = OSCC-diagnosed individuals; control category (n = 40) = controls with a comparable age. For verification of the diagnosis, a specimen of the tissue has been processed and sections have been stained and inspected for standard hematoxylin and eosin stain. Deoxyribonucleic acid (DNA) was extracted from the leftover histopathologically verified tissue specimens and then exposed to PCR for the assessment of HPV infiltration.
RESULTS: It was observed in this research that 22 cases out of 40 cases of OSCC were found positive for HPV-DNA. While 12 out of 40 age-matched healthy controls were found positive for HPV-DNA. Out of 40 cases of OSCC, 12 cases were found positive for HPV 16. While six out of 40 age-matched healthy controls were found positive for HPV 16. Six cases out of 40 cases of OSCC were found positive for HPV 16. While two out of 40 age-matched healthy controls were found positive for HPV 18. Four cases out of 40 cases of OSCC were found positive for HPV 16. While four out of 40 age-matched healthy controls were found positive for HPV 16 and HPV 18. On carrying out statistical analysis, the variation between the two categories was non-meaningful statistically (p = 0.662). However, the prevalence was greater in the case (OSCC) subgroup.
CONCLUSIONS: When evaluated against controls in the current investigation, OSCC cases had a greater level of HPV expression and a greater proportion of HPV 16 positives. However, there was no statistically noteworthy change.

Human papillomavirus (HPV) is the most common sexually transmitted infection, linked to several types of lesions. HPV, specifically HPV 16, accounts for most of anal cancer cases. In this study, we evaluated the proportion of samples tested positive for HPV and characterized genotypes distribution in anal specimens collected from individuals at risk of anal HPV infection attending from 2018 to 2022 a large Infectious Diseases Department in Italy. The presence of HPV DNA was investigated through a commercial kit detecting 12 HR-HPV, 8 probable/possible HR-HPV, and 8 LR-HPV genotypes. Among 1514 samples, 84% (1266/1514) resulted positive for any type of HPV. The prevalence of high-risk HPV types remained high during all the years of the study period, from 2018 to 2022, ranging from 65% to 73%. Most of HR-HPV, LR-HPV and HPV 16 positive samples were collected from men >45 years. HPV 16 was also the most frequent type in men and women. We did not observe significant variations between years in detection of HR-HPV, instead of LR-HPV, that significantly decreased. In conclusion, the high prevalence of oncogenic HPV genotypes underlines the necessity of clear anal HPV screening guidelines and, along with frequent HR-HPV coinfections, reinforces the urge to intensify the anti-HPV vaccination campaign.

BACKGROUND: Human papillomavirus (HPV) 16 and 18 cause approximately 70% of cervical cancer cases. The aim of this study was to evaluate whether co-infected with other HPV genotypes will affect the risk of cervical carcinogenesis in HPV16/18 positive-women.
METHODS: In this cross-sectional study, cervical cytology and histological classifications from women who tested positive for HPV 16/18 and underwent colposcopy within 6 months, between January 2010 and May 2021 were obtained from West China Second University Hospital of Sichuan University.
METHODS: Immediate risk of cervical intraepithelial neoplasia grade 3 or more diagnoses (CIN 3+).
RESULTS: A total of 7940 HPV 16/18-positive women were included, with a median age of 40 years (range 25-84 years). Among them, 2710 (34.1%) were infected with multiple genotypes, 6533 (82.28%) had cytology results and 2116 (26.65%) women were diagnosed with CIN 3+. The effects of HPV 16/18 coinfecting with other HPV on CIN3 + risk varied with specific HPV genotypes. After adjusting for cofactors, compared to single HPV 16 infection, the CIN 3 + risk was significantly reduced in women infected with HPV 16 + other high-risk HPV (hrHPV) [odds ratio (OR) = 0.621, 95% confidence interval (CI) 0.511-0.755], HPV 16 + low-risk HPV (lrHPV) (OR = 0.620, 95% CI 0.436-0.883), and HPV 16 + lrHPVs + other hrHPVs (OR = 0.248, 95% CI 0.157-0.391). The prevalence of CIN 3 + was associated with increased severity of cytologic abnormalities in HPV 16/18-positive women and peaked at cytology HSIL + (89.9% and 82.3%), which held a substantially greater risk than that of NILM (OR = 65.466, 95% CI 50.234-85.316).
CONCLUSIONS: In this cross-sectional study of HPV 16/18-positive women, the effects of multiple infection were likely complicated and varied with specific HPV genotypes. The coinfection of HPV 16 and other genotypes of HPV except HPV 18 was associated with decreased CIN 3 + risk. Cytologic results were informative when HPV 16/18 was positive. It might be reasonable to recommend expedited treatment for patients with HPV 16/18 positive and HSIL + cytology in the Chinese population.