HPV-associated Cervical Lesions Research Articles

Impact of human papillomavirus types on uterine cervical neoplasia.

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV-associated cervical lesions is HPV genotype-dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high-risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high-risk HPVs, HPV18 has some peculiar characteristics different from those of other high-risk HPV types; the detection rate in precancerous lesions is much lower than those of other high-risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell-like cells. In this context, this review outlines the natural history of HPV-infected cervical lesions and the characteristics of each HPV genotype.

Оценка эффективности применения активированной глицирризиновой кислоты у пациенток с ВПЧ-ассоциированными поражениями шейки матки с учетом уровня половых стероидных и гонадотропных пептидных гормонов

Background: the persistence of human papillomavirus (HPV) infection with oncogenic protein expression causes changes in the stratified squamous epithelium, which is the immediate cause of cervical cancer manifestation. The use of the activated glycyrrhizic acid (GA) for HPV-associated cervical lesions is pathogenetically justified. During an experimental study on a culture of human cervical adenocarcinoma cells (HeLa line), it was shown that the antiproliferative effect of GA is enhanced by low concentrations of estradiol and weakened by testosterone. Aim: to evaluate the efficacy of the activated GA in female patients with HPV-associated cervical pathology with respect to the level of sex steroid and gonadotropin-releasing hormones Patients and Methods: a prospective study was conducted with the inclusion of 51 female patients with HPV-associated cervical pathology (ASCUS — atypical squamous epithelial cells of undetermined significance, LSIL — low-grade squamous intraepithelial lesion, HSIL— high-grade squamous intraepithelial lesion according to the Bethesda classification) and the absence of clinical and/or laboratory signs of hyperandrogenism. The following studies were performed: clinical examination, colposcopy, microscopic examination, cytology and immunocytochemistry, as well as hormonal status was evaluated. All female patients received Epigen Intim spray 0.1%, 3 times a day, for 30 days from the moment of inclusion in the study. If indicated, cervical conization was also performed. The treatment efficacy was evaluated 90±7 days after the therapy initiation based on the liquid-based HPV-PAP test results with the determination of p16/Ki67 oncogenic protein co-expression in the cervical epithelium. Changes in the colposcopy results were also evaluated. Results: it was found that the level of estradiol in patients with HSIL was lower versus the patients with ASCUS and LSIL (32 [32.0; 36.0] pg/ml versus 40 [34.5; 45.5] and 40 [33.0; 44.0] pg/ml, respectively, but the difference did not reach statistical significance (p=0.453). 90 days after the follow-up start, according to the cytology results of the cervical epithelium, 50 (98.0%) patients showed the absence of cervical intraepithelial lesions and the absence of p16/Ki67 oncogenic protein co-expression, 48 (94.1%) patients showed no high-risk (HR) HPV DNA, whereas HPV-associated colposcopy signs (anogenital warts, chronic cervicitis signs) persisted only in 6 (11.8%) patients. Conclusion: the use of activated GA in female patients of reproductive age with HPV-associated cervical lesions without clinical and/or laboratory signs of hyperandrogenism allowed to achieve high efficiency indicators: 98.5% — according to the cytology results, 83.3% — in reducing the HR-HPV viral load, 85.7% — in terms of p16/Ki67 oncogenic protein co-expression. KEYWORDS: human papillomavirus, squamous intraepithelial lesion of the cervix, oncogenic protein co-expression, sex steroid hormones, activated glycyrrhizic acid FOR CITATION: Mandrykina Zh.A., Dobrokhotova Yu.E., Ibragimova D.M., Kazieva M.D., Filimonova M.S., Shimanovsky N.L., Akhmetgaliev A.R. Assessment of the activated glycyrrhizic acid efficacy in female patients with HPV-associated cervical lesions with respect to the level of sex steroid and gonadotropin-releasing hormones. Russian Journal of Woman and Child Health. 2024;7(2):127–134 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-7.

Genetic Modulation of HPV Infection and Cervical Lesions: Role of Oxidative Stress-Related Genes.

Human papillomavirus (HPV) infection is a necessary but not sufficient factor for the development of invasive cervical cancer (ICC) and high-grade intraepithelial lesion (HSIL). Oxidative stress is known to play a crucial role in HPV infection and carcinogenesis. In this study, we comprehensively investigate the modulation of HPV infection, HSIL and ICC, and ICC through an exploration of oxidative stress-related genes: CβS, MTHFR, NOS3, ACE1, CYBA, HAP, ACP1, GSTT1, GSTM1, and CYP1A1. Notably, the ACE1 gene emerges as a prominent factor with the presence of the I allele offering protection against HPV infection. The association of NOS3 with HPV infection is perceived with the 4a allele showing a protective effect. The presence of the GSTT1 null mutant correlates with increased susceptibility to HPV infection, HSIL and ICC, and ICC. This study also uncovers intriguing epistatic interactions among some of the genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the BB genotype (ACP1) and DD genotype (ECA1) were shown to increase the risk of HPV infection, and the interaction between BB (ACP1) and 0.0 (GSTT1) was associated with HPV infection and cervical lesions. These findings underscore the pivotal role of four oxidative stress-related genes in HPV-associated cervical lesions and cancer development, enriching our clinical understanding of the genetic influences on disease manifestation. The awareness of these genetic variations holds potential clinical implications.

Effect of activated glycyrrhizic acid on epithelial cell lipidome in HPV-associated cervical lesions: A prospective cohort study

Aim. To determine the change of lipid levels in the cervical epithelial cells during the treatment of chronic cervicitis and low-grade squamous intraepithelial lesions (LSIL) with 0.1% activated glycyrrhizic acid.
 Materials and methods. The prospective cohort study included 40 patients with chronic cervicitis and 40 patients with LSIL. Cytological evaluation of cervical smears was performed according to the Bethesda system (2014). All patients received Epigen Intim Spray for 18 months. Amplification of type-specific DNA fragments of human papillomavirus (HPV) and human DNA (sampling control SC) was done using a kit of reagents to detect, type, and quantitatively determine 21 HPV types by Quantum-21 HPV PCR. Lipid extract of a cervical epithelial scraping taken before and after therapy was analyzed by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Lipids were identified using the Lipid Match R-script and by characteristic MS/MS. Correlation analysis of the lipidome of cervicovaginal fluid and SC was performed using the Spearman test, and the Mann-Whitney test was used to compare lipid levels at the two time points.
 Results. During the treatment of chronic cervicitis, the levels of CL lipids 16:0_16:1_18:1_18:1, HexCer-NDS d20:0/26:0, PC 16: 0_18: 1 and 16: 0_20:4 were decreasing; during the treatment of LSIL, the levels of ceramides and glucosylceramides were decreasing. Chronic cervicitis is characterized by a positive correlation of SC smear with cardiolipins, glucosylceramides, and epithelial lipids with an ether bond; LSIL showed a negative correlation with phosphatidylcholines and phosphatidylethanolamines with an ether bond.
 Conclusion. As a result of treatment with activated glycyrrhizic acid, the lipid spectrum of epithelial cells significantly changed, depending on the type of lesion. It is also necessary to consider SC scrapings in further studies of epithelial cell lipidome and the type of HPV-associated lesions that affects the adjustments.

Current approaches in the diagnosis, treatment and prevention of HPV-associated cervical diseases: practical recommendations. A review

Papillomavirus infection is one of the most important infectious diseases of the reproductive system. The genome of human papillomavirus (HPV) transforms the cervical epithelial cells, leading to progressive changes: from cervical epithelial neoplasia to carcinoma in situ and further to invasive cancer. More than 550 000 cases of cervical cancer (CC) are reported yearly. In Russia, the incidence of CC in 2020 decreased for the first time in 20 years, and the average annual rate of increase in incidence was 1.27%. It became possible thanks to the introduction of a new system of diagnosis, treatment, and prevention of cervical cancer, in particular, the introduction of screening and a program of modern methods of diagnosis and treatment. Uniform for all countries, screening cervical diseases aims to diagnose changes in the cervical epithelium that occur due to HPV, which may be silent. Until now, the basis of screening programs was a cytological study (pap-test). Since 2018, most EU countries have switched to primary screening for HPV (HPV test) due to its greater sensitivity compared to the cytological method. No etiopathogenetic methods of HPV therapy have been developed yet. However, numerous studies have described the effective treatment of HPV-associated cervical lesions. It was shown that the most effective is a comprehensive approach involving treatment aimed at abnormal tissues and nonspecific antiviral and immunomodulatory therapy. The basis of the CC prevention strategy, of course, is primary prevention through vaccination. Studies are ongoing on the effectiveness of the new generation of vaccines based on the L2 viral protein and therapeutic vaccines against HPV.

Efficacy of HPV vaccine in preventing cervical cancer in the Tomsk region

Background. The age-standardized cervical cancer incidence rate in the Tomsk region in 2021 was consistently higher than the average for the Russian Federation (21.2 / 100,000 versus 13.6 / 100,000 women). Primary prevention of cervical cancer is best achieved by human papillomavirus (HPV) vaccination of girls. Aim. To evaluate HPV vaccine efficacy for the prevention of cervical cancer in the Tomsk region within the framework of implementation of two regional programs: “Prevention of gynecological cancer and rehabilitation of women diagnosed with gynecological cancer in 2008–2010” and “Urgent measures to improve cancer care for the population of the Tomsk region in 2011–2013”. Material and methods. We studied the tolerability and efficacy of HPV vaccination for the prevention of HPV-associated cervical cancer in 439 vaccinated girls aged 9–26 years during a follow-up time of 14-years. Results. The assessment of a 14-year follow-up study of the impact of HPV vaccination on HPV-associated cervical lesions has shown that HPV vaccine is safe and 100 % effective. Conclusion. Further prospects for primary prevention of cervical cancer before the introduction of vaccines against HPV infection in the national immunization schedule indicates the feasibility and real clinical effectiveness of the introduction of regional and regional programs with the development of a mathematical model for optimizing financial costs for primary prevention of cervical cancer, taking into account demographic parameters and socio-economic damage from cervical cancer in the study area.

Lymphocyte Subsets in Cervicovaginal Lavage Specimens of HIV-Infected Women: A Surrogate Risk Marker of HPV-Associated Cervical Lesions

Introduction: To better understand the role of mucosa immunity in the development of cervical carcinoma in HIV infection, cervical lymphocyte subsets were characterized in HIV+ and HIV− women, as well as their relation to HPV-associated cervical lesions. Methods: Eighty-three (52 HIV+, 31 HIV−) cell suspensions of cervicovaginal lavage (CVL) and 52 HIV+ peripheral blood (PB) samples were assessed by flow cytometry to evaluate lymphoid populations. High-risk (HR) HPV was assessed in liquid-based cytology and HIV mRNA in PB in the same patients. Results: Cervical CD4⁺ T cells and CD4⁺/CD8⁺ ratio were decreased (p < 0.0001) and cervical CD8⁺ T cells were increased (p = 0.0080) in HIV+ women. These patients had lower CD4⁺ T-cell percentages in CVL compared to PB (p = 0.0257), and the opposite was true for CD8⁺ T cells (p = 0.0104). They also had a higher prevalence of high-grade squamous intraepithelial lesions (SILs) with an increased prevalence of HR HPV. Cervical CD8⁺ T cells were increased in HR HPV+ patients (p = 0.0300) and related to higher prevalence of SILs (p = 0.0001). Discussion/Conclusion: Cervical lymphoid populations can be characterized by flow cytometry, showing a distinct cervical T-cell compartment in HIV+ women. This may represent a surrogate risk marker of HPV-associated cervical lesions in this population and prompt further research on this subject, contributing to improving patients’ management.

The prevalence of 30 HPV genotypes detected by EUROArray HPV in cervical samples among unvaccinated women from Vojvodina province, Serbia.

This study evaluates the pre-vaccination prevalence of HPV infection in women from Vojvodina, Serbia, according to age and cytological status. A total of 1,495 women, ranging from 18 to 65 years of age, with different cytological results were enrolled. The HPV genotyping assay was performed using the EUROArray HPV test in order to detect thirty genitally relevant HPV subtypes. In our study, the most prevalent genotypeswere HPV 16, 31, 51, and 53. Among these, HPV 16 was consistently present in all cytological subgroups. Twelve HPV genotypes classified as carcinogenic to humans (Group 1) were detected in 77.8.0% of HSIL/ASCH and 55.0% of NILM with abnormal colposcopy findings. Six possible carcinogens—HRs (group 2B) were often found in women with normal cytology (14.8%) and mild abnormalities (ASCUS and LSIL), but with lower frequence in HSIL/ASCH lesions (7.1%). HPVs 6 and 11(Group 3) were not found in the cases of HSIL/ASCH. Unclassified HPV types were equally distributed in all cytology groups: 20.7%, 19.1%, 16.3% and 13% of NILM, ASCUS, LSIL and HSIL/ASCH, respectively. Our findings highlight that majority of abnormal Pap test results are caused by Group 1 HPVs among women from our region. Low frequency HPVs of group 2A/2B, especially HSIL/ASCH, supports the conclusion that individual genotypes require consideration of each type as an individual agent. We expect a positive impact of HPV vaccine in reducing HPV-associated cervical lesions among women from Vojvodina province, after establishing vaccination programs in our country.

Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri.

BackgroundThe burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status.MethodsCervical cytobrush (n = 468: 253 HIV- and 215 HIV+; 71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, α4β7).ResultsCervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and α4β7 in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32; p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or α4β7+ CD4 T cells.ConclusionThe increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women.

Cervical screening for HIV-positive women in the transition to primary HPV testing in Ireland

Abstract Background CervicalCheck, Ireland's national cervical cancer screening programme, will transition to primary HPV testing in March 2020. CervicalCheck sought an evidence review to inform the screening pathway for HIV-positive women in this context, with regard to age of initiation and frequency of screening. Currently, HIV-positive women commence cervical screening at age 20 in Ireland with annual screening thereafter. Methods An electronic literature search was conducted to identify relevant peer-reviewed publications using the database Pubmed. A hand search of reference lists of suitable articles and international cervical screening guidelines was conducted to check for additional material. Publications pertaining to international cervical screening guidance and practice were sourced via internet searches using Google. The relevant grey literature was also explored. Results The prevalence of multiple and more persistent high-risk HPV types is higher among HIV-positive women compared to HIV-negative women. HIV-positive women are also at an increased risk of progression and post-treatment recurrence of HPV-associated cervical lesions. The degree of immunosuppression is a key factor in the relationship between HPV and HIV. There is significant heterogeneity internationally as regards cervical screening pathways for HIV-positive women. Many programmes commence screening at the time of diagnosis with HIV. Most developed countries screen HIV-positive women more frequently than HIV-negative women, although the screening interval varies. Conclusions HIV-positive women warrant special attention within an organised population-based cervical screening programme. The evidence synthesised in this review was used to inform change to the screening pathway for HIV-positive women as part of the planned transition to primary HPV testing. Cervical screening for these women using primary HPV testing will now commence at the time of diagnosis with HIV, with annual screening thereafter. Key messages HIV-positive women warrant special attention within an organised population-based cervical screening programme. The evidence synthesised in this review was used to inform change to the screening pathway for HIV-positive women as part of the planned transition to primary HPV testing in Ireland.

Experience of clinical use of diindolylmethane in the treatment of HPV-associated low-grade cervical lesions

Introduction. A genital human papillomavirus infection receives the sword-point attention of both researchers and practitioners, due to its large prevalence in the human population, high contagiousness and, in particular, the ability of some HPV strains to contribute to the development of malignancy. This is particularly so with cervical cancer (CC), one of the most common types of cancer both in the Russian Federation and most countries of the world. It ranked first among the causes of malignant tumour deaths of women aged over 30 years. Objective. To present the experience in using the 3,3’-diindolylmethane-containing drug in the treatment of patients with HPVassociated low-grade cervical intraepithelial lesion. Material and methods. 62 women with HPV-associated low-grade cervical intraepithelial lesion were examined and received treatment with the 3,3’-diindolylmethane-containing drug (Cervicon-DIM). The primary diagnosis and therapeutic outcomes monitoring included the following research methods: colposcopy, histological examination of biopsy cervical specimens, Pap test, RT-PCR of high carcinogenic risk (HCR) HPV. The therapy compliance was evaluated using the clinical psychological test method (Morisky Green scale): compliant patients 4 scores (noncompliant 2 scores or less, insufficiently compliant 3 scores). Results. The therapeutic outcomes using 3,3’-diindolylmethane-containing drug (Cervicon-DIM) in the form of vaginal suppositories (100 mg twice daily for 90 days) showed clinical (recovery of colposcopic status in 83.0% of patients), cytological (confirmed absence of LSIL in 98.3% of women) and microbiological (PCR-negative HCR HPV in 91.5% of women) efficacy with satisfactory tolerance of the drug. Сonclusions. The therapeutic outcomes obtained using 3,3’-diindolylmethane-containing drug in the treatment of patients with HPV-associated low-grade cervical intraepithelial lesion could be considered as satisfactory. The data presented may be of interest to practicing gynecologists and other specialists.

Impact of antiviral AV2 in the topical treatment of HPV-associated lesions of the cervix: Results of a phase III randomized placebo-controlled trial

BackgroundNon-surgical topical therapies have been assessed in the treatment of precancerous lesions of the cervix. Their use can offer logistical and feasibility advantages in low-resource settings. Antiviral AV2® is a mixture of natural essential oils (eugenol, carvone, nerolidol, geraniol) in olive oil, and has a broad spectrum anti-viral activity. In a phase II randomized controlled trial (RCT), AV2® proved effective in reducing the size of cervical lesions associated with human papillomavirus (HPV). The purpose of the present study was to further evaluate the efficacy of AV2 over placebo in the topical treatment of HPV-associated cervical lesions. MethodsWomen aged 25 years and older were included in this phase 3 RCT. Cytology screening, HPV testing and visual inspection of the cervix with 5% acetic acid (VIA) were performed on all participants. VIA-positive women were randomized to one of two groups to receive treatment by either AV2® or placebo. The treatment consisted of 2 puffs of spray of the investigational drug directed to the cervix. Participants were subjected to repeat examinations two months and six months later for assessment of outcomes. The primary outcome was the change of lesions on VIA at 2 months after application of the investigational drug. Secondary outcomes were: HPV clearance and cytologic regression at 2 months and 6 months, and number of participants with AEs. ResultsA total 327 VIA positive women were randomized in two groups (168 in AV2 group and 159 in placebo group). Women in the 2 groups were similar with respect to baseline demographics and clinical characteristics. At 2 months, regression of lesions on VIA was observed in 127 (89.4%) out of 142 women in AV2 group compared to 120 (91.6%) out of 131 women in placebo group (P = 0.7). On cytology, regression of lesions occurred in 14 (56%) out of 25 women in the AV2 arm and in 13 (48.1) out of 27 women in the placebo arm (p = 0.7), and HPV clearance rates were 34.1% and 35% in AV2 group and placebo group respectively (p = 0.8). At 6 months cytologic regression was observed in 64.7% of women in AV2 group and 45.8% in placebo group (p = 0.2), while HPV clearance occurred in 11 (51.9%) out of 17 women in AV2 arm versus 11 (34.4%) in placebo arm (p = 0.3).Some local side effects (burning, itching, irritation) were similarly noted in the 2 groups (p-values = 0.169, 0.623 and 0.172 respectively) but they were mild and transitory. ConclusionA topical application of AV2 onto the cervix can induce the regression of cervical precancerous lesions, but its efficacy does not significantly differ with that of placebo. The discrepancy between the expected and the recorded sample size as well as the huge number of lost to follow-up probably impeded the power of analyses, which could be one of the reasons for the lack of difference seen between AV2 and placebo. Further evaluation of the effects of AV2 with different diagnostic methods and treatment regimen and arms is warranted. Clinical trial registrationNCT02346227 registered on November 8, 2014;

Reduction in HPV 16/18 prevalence among young women following HPV vaccine introduction in a highly vaccinated district, Japan, 2008–2017

Objective: Human papillomavirus (HPV) vaccination was introduced in Japan in April 2013, as a national immunization program for girls aged 12–16 years, after an initial introduction in 2010 as a public-aid program for girls aged 13–16 years. The Yuri-Honjo district had the highest vaccine coverage among women aged 17–51 years in 2017, due to the original public-aid program. The aim of this study was to evaluate the differences in the vaccine types of HPV16/18 infections between 2008–2012 (pre-vaccine era) and 2013–2017 (vaccine era).Materials and Methods: We evaluated whether HPV vaccination was associated with a decrease in the prevalence of HPV16/18 and high-risk HPV and the incidence of HPV-associated cervical lesions. A total of 1,342 women aged 18–49 years, covering both the pre-vaccine and vaccine eras, who visited Yuri Kumiai General Hospital and underwent HPV genotype tests from June 2008 to December 2017 were compared.Results: Among women aged 18–24 years with higher vaccine coverage (68.2%), the prevalence of HPV16/18 and high-risk HPV decreased from 36.7% and 69.4%, respectively, in the pre-vaccine era to 5.8% and 50.0%, respectively, in the vaccine era (p=0.00013 and p=0.047, respectively). Among those with cervical intraepithelial neoplasia grade 2− and grade 2+, HPV16/18 prevalence decreased from 30.0% to 2.7% (p=0.0018) and from 81.8% to 36.4% (p=0.030), respectively. In this age group, the rate of HPV16/18 positivity decreased significantly. Among age groups with lower vaccine coverage, HPV prevalence did not significantly differ between the two eras.Conclusion: The prevalence of HPV16/18 and high-risk HPV significantly decreased in women aged 18–24 years, most of whom were vaccinated. HPV vaccination effectively reduced the prevalence of HPV16/18 infections in the Yuri-Honjo district.

Urogenital tract microbiocenosis and quantitative features of papillomavirus infection depending on the severity of HPV-associated cervical lesions

Urogenital tract microbiocenosis and quantitative features of papillomavirus infection depending on the severity of HPV-associated cervical lesions

Conisation as a marker of persistent human papilloma virus infection and risk of breast cancer.

Background:Human papillomavirus (HPV) infection may increase breast cancer (BC) risk.Methods:To examine this, we used nationwide medical registries to identify all Danish women who underwent conisation to remove HPV-associated cervical precancerous lesions (n=87 782) from 1978 to 2013. We computed the absolute risk of BC and standardised incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for breast cancer, based on national breast cancer incidence rates.Results:Conisation was associated with slightly increased BC incidence (SIR=1.1, 95% CI=1.0–1.1), and an absolute BC risk of 7.7% (95% CI=7.3–8.1%) in 35.9 years of follow-up. BC risk was elevated throughout follow-up, especially in the first 5 years (<1 year: SIR=1.2, 95% CI=0.92–1.5; 1–5 years: SIR=1.2, 95% CI=1.1–1.3; ⩾5 years: SIR=1.1, 95% CI=1.0–1.1). Women who underwent conisation and had autoimmune disease had elevated BC risk after 5 years of follow-up (SIR=1.4, 95% CI=1.0–1.8).Conclusions:BC risk is slightly elevated in women with persistent HPV infection, possibly due to detection bias.

Disc large 1 expression is altered by human papillomavirus E6/E7 proteins in organotypic cultures of human keratinocytes.

Loss of cell polarity is a fundamental process in cell transformation. Among polarity proteins, we focused on human disc large (DLG1), which is localized mainly at adherens junctions and contributes to the control of cell proliferation. We previously demonstrated that its expression is altered in HPV-associated cervical neoplastic lesions, but the mechanisms beyond this remain unknown. In this study, we analysed the contribution of HPV proteins to the changes in DLG1 expression in the squamous epithelium. We observed tissue and intracellular misdistribution of DLG1 when high-risk HPV-18 E7 or E6/E7 proteins were expressed in organotypic raft cultures. The viral oncoproteins induce the loss of DLG1 from the cell borders and an increase in the level of DLG1 protein, reflecting the pattern observed in cervical lesions. These findings were corroborated in cultures bearing the entire HPV-18 genome. Interestingly, changes in tissue distribution and abundance of DLG1 were also detected in organotypic cultures expressing the low-risk HPV-11 E7 or E6/E7 proteins, suggesting a conserved function among different HPV types. However, for low-risk HPVs, the subcellular localization of DLG1 at cell-to-cell contacts was predominantly maintained. This report offers new evidence, we believe, of the involvement of HPV proteins in DLG1 expression pattern and our data support previous observations regarding DLG1 expression in cervical lesions.

Prevalence of human papillomaviruses in the healthy oral mucosa of women with high-grade squamous intra-epithelial lesion and of their partners as compared to healthy controls.

Oral human papillomavirus (HPV) carriage rates were investigated in relation to genital HPV carriage in women with HPV-associated cervical lesions and male partner of such women, including several couples, in comparison with healthy individuals. Buccal and lingual mucosa of 60 males and 149 females with healthy oral mucosa and without known genital lesion, genital and oral mucosa of further 40 females with cervical high-grade squamous intraepithelial lesion (HSIL) and 34 male sexual partners of women with HSIL (including 20 couples) were sampled. HPV DNA was detected using MY/GP PCR. Genotype was determined by sequencing or restriction fragment length polymorphism. Virus copy numbers were determined by real-time PCR. Overall, oral HPV carriage rate was 5.7% (12/209) in healthy individuals; average copy number was 5.8 × 10(2) copies/1 μg DNA; male and female rates were comparable. Oral carriage in women with HSIL was significantly higher, 20.0% (8/40, P = 0.003); males with partners with HSIL showed a carriage rate of 17.6% (6/34), copy numbers were similar to the healthy controls. In contrast, genital carriage rate (52.9%, 18/34 vs. 82.5%, 33/40; P = 0.006) and average copy number were lower in males (5.0 × 10(5) vs. 7.8 × 10(5) copies/1 μg DNA; P = 0.01). Oral copy numbers in these groups and in healthy individuals were comparable. High-risk genotypes were dominant; couples usually had the same genotype in the genital sample. In conclusion, genital HPV carriage is a risk factor of oral carriage for the individual or for the sexual partner, but alone is not sufficient to produce an oral HPV infection in most cases.

Are Selective Estrogen Receptor Modulators (SERMs) a Therapeutic Option for HPV-Associated Cervical Lesions and Cancers?

This Commentary highlights the article by Spurgeon etal which evaluates oral SERM raloxifene as a potential therapeutic agent for HPV-associated cancer.

HPV-Based Screening, Triage, Treatment, and Followup Strategies in the Management of Cervical Intraepithelial Neoplasia

Cervical cancer is the second most common cause of death from cancer in women worldwide, and the development of new diagnostic, prognostic, and treatment strategies merits special attention. Many efforts have been made to design new drugs and develop immunotherapy and gene therapy strategies to treat cervical cancer. HPV genotyping has potentially valuable applications in triage of low-grade abnormal cervical cytology, assessment of prognosis and followup of cervical intraepithelial neoplasia, and in treatment strategies for invasive cervical cancer. It is known that during the development of cervical cancer associated with HPV infection, a cascade of abnormal events is induced, including disruption of cellular cycle control, alteration of gene expression, and deregulation of microRNA expression. Thus, the identification and subsequent functional evaluation of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information in understanding cervical carcinogenesis, identifying cervical cancer molecular markers, and developing specific targeting strategies against tumor cells. Therefore, in this paper, we discuss the main diagnostic methods, management strategies, and followup of HPV-associated cervical lesions and review clinical trials applying gene therapy strategies against the development of cervical cancer.

Expression of P-glycoprotein is Positively Correlated with p53 in Human Papilloma Virus Induced Squamous Intraepithelial Lesions of Uterine Cervix: Poor Prognosis Association

This study was conducted to assess the predictive value of p-glycoprotein (p-gp) and p53 immunoexpression in human papillomavirus (HPV) infected cases of cervical dysplasia. Expression of both p-gp and p53 proteins was detected in cervical smears from 177 squamous intraepithelial lesions (SIL) cases along with 183 "atypical squamous cells of unknown significance" (ASCUS) and 150 normal cases. HPV 16 and 18 infection was detected by polymerase chain reaction using type-specific primers for HPV sub-types. There were no significant detectable p53 and p-gp expression in the normal cervix smears (p>0.05). In the ASCUS group 10 cases were positive for both p53 and p-gp immunoreactivity. In cervical dysplasia cases, p53 was positive in 86 (48.58%) while p-gp was positive in 93 (52.54%) and the two markers showed a highly significant correlation (r=0.92, p<0.001). Expression of p53 and p-gp was associated with grade of SIL (p<0.001). A positive correlation between the presence of HPV and expression of proteins p53 and p-gp in smears of patients with cervical lesions was also noted (p<0.001). Thus, p53 and p-gp immunostaining in cervical smears may act as an auxiliary biomarker for detection of HPV-associated cervical lesions. Additionally, a significant positive correlation between ascending grades of SIL and labeling indices of markers suggests that p53 and p-gp can be used as an adjunct to cytomorphological interpretation of conventional cervical Pap smears.