Cervical HPV Infections, Sexually Transmitted Bacterial Pathogens and Cytology Findings-A Molecular Epidemiology Study.

Prevalent cervical HPV infection and high-risk HPV persistence consequences have been extensively investigated in the literature; nevertheless, any causative interrelations of other sexually transmitted bacterial infections (STIs) with cervical HPV infection have not yet been fully elucidated. This study aimed to investigate the possible association of STIs with cervical cytology aberrations and HPV genotyping results in a representative sample of predominantly young Greek women. Liquid-based cytology and molecular detection for bacterial STIs and HPV as well as extended HPV genotyping were simultaneously assessed in cervical samples from 2256 individuals visiting several urban outpatient Gynecology Departments for well-woman visits or cervical screening throughout a 20-month period. All specimens were centrally processed with validated molecular assays. The mean age of the studied women was 37.0 ± 11.7 years; 722 women (33.30%) tested positive for STI (mean age 34.23 ± 10.87 years). A higher mean age (38.34 ± 11.83 years (p < 0.05)) was associated with negative STI testing. Chlamydia trachomatis was detected in 59 individuals (8.2%), Mycoplasma hominis in 156 (21.6%), Mycoplasma genitalium in 14 (1.9%), and Ureaplasma spp. in 555 (76.9%); infections with two bacterial pathogens were identified in 73 samples (10.1%). Cervical HPV was detected in 357 out of 1385 samples with a valid HPV typing result (25.8%). The mean age of HPV-positive women was 32.0 ± 8.4 years; individuals testing HPV-negative were slightly older (N = 1028): 34.4 ± 9.2 (p < 0.05). Among the 1371 individuals with valid results both for bacterial STIs and cervical HPV detection, women with an HPV-positive sample were more likely to harbor an STI (OR: 2.69, 95% CI 2.10-3.46, p < 0.05). Interestingly, bacterial STI positivity illustrated significant heterogeneity between NILM and LSIL cases, with 28.88% of NILM and 46.33% of LSIL cases harboring an STI, respectively (p < 0.05). In brief, in a population with a high prevalence for STIs, especially Ureaplasma spp., an association was documented between bacterial pathogen detection and cervical HPV infection, as well as abnormal cytology; these findings merit further investigation.

The ErbB Signaling Network and Its Potential Role in Endometrial Cancer.

Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/ß-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.

HPV-Based Self-Sampling in Cervical Cancer Screening: An Updated Review of the Current Evidence in the Literature.

Identifying and reaching women at higher risk for cervical cancer is all-important for achieving the ambitious endpoints set in 2020 by the WHO for global cervical cancer control by 2030. HPV-based (vaginal) self-sampling (SS) represents a cost-effective screening strategy, which has been successfully implemented during the last decade both in affluent and constrained settings. Among other advantages, SS strategies offer convenience, diminished costs, flexibility to obtain a sample in the office or home, avoiding a pelvic exam and uncomfortable appointment with a healthcare professional, as well as social and cultural acceptability. SS implementation has been globally boosted during the COVID-19 pandemic. In pragmatic terms, social distancing, local lockdowns, discontinuation of clinics and reallocation of human and financial resources challenged established clinician-based screening; self-collection strategies apparently surpassed most obstacles, representing a viable and flexible alternative. With time, sufficient reassuring data has accumulated regarding specially designed SS devices, aspects of sample preparation, transport and storage and, importantly, optimization of validated PCR-based HPV testing platforms for self-collected specimens. Suboptimal rates of clinical follow-up post-SS screening, as well as overtreatment with reliance solely on molecular assays, have both been documented and remain concerning. Therefore, effective strategies are still required to ensure linkage to follow-up testing and management following positive SS results by trained health professionals with knowledge of HPV biology and management algorithms. Because of the prolonged SS screening intervals, implementation data are limited regarding subsequent screening rounds of SS-screened individuals; however, these are accumulating gradually. With further refinement of assays and validation of novel biomarkers in self-collected samples, there is a clear potential for increasing SS accuracy and PPV. The potential differentiation of self-collection protocols for vaccinated versus non-vaccinated individuals also represents an open issue. In conclusion, HPV-based self-collection techniques can effectively address limited uptake alongside other conventional cervical screening drawbacks; however, assays, logistics and infrastructures need further optimization to increase the efficacy, effectiveness and cost-effectiveness of SS approaches.

Effect of Condom Use after CIN Treatment on Cervical HPV Biomarkers Positivity: Prolonged Follow Up Study.

Background: Several factors contribute in the cervical healing process following local surgical treatment; in a previous work our group has documented a beneficial mid-term role of regular condom use immediately postoperatively in terms of CIN relapse prevention and expression of active viral biomarkers. Materials and Methods: Aiming to investigate whether the favorable contribution of consistent condom use could be extrapolated in the longer term, we conducted a prospective single center observational study including women scheduled to undergo conservative excisional treatment for CIN (LLETZ procedure). In all women a strong recommendation for consistent use for the first 6 months was given. For 204 women who underwent the procedure and completed successfully the two-year follow up a complete dataset of HPV biomarkers' results obtained six months and two years postoperatively was available. Patients were asked to complete a questionnaire to assess condom use compliance. A 90% compliance rate represented the threshold for consistent use. An LBC sample was obtained and tested for HPV genotyping, E6 & E7 mRNA by NASBA technique as well as flow cytometry, and p16 at 0 (pre-treatment), 6 and 24 months. HPV DNA and other related biomarkers status at 6 and 24 months, treatment failures at 24 months and condom use compliance rates represented study outcomes. Results: Six months post-operatively we documented a reduction in the rates of HPV DNA positivity, which was detected in only 23.2% of compliant condom users in comparison to 61.9% in the non-compliant group (p < 0.001, OR: 0.19, 95%CI: 0.1−0.36). For the HPV mRNA test, either assessed with the NASBA method or with flow cytometry, reduced positivity percentages were observed in the compliant group, in particular 1.6% vs. 8% for NASBA and 7.1% vs. 16.4% using flow cytometry, although these differences were not statistically significant (p = 0.1039 and 0.0791, respectively). Finally, reduced p16 positivity rates were documented in the compliant group. At the two year follow up, a more pronounced difference in HPV DNA positivity rates was observed, specifically only 13% positivity among the compliant women compared with 71% of the non-compliant (p < 0.0001); this illustrates a further decreasing trend compared with the 6th month in the compliant group as opposed to an increasing tendency in the non-compliant group, respectively (difference: 9.0%, 95% CI: 0% to 20.6%, p = 0.1523). At that time, 80% of the failed treatments were HPV mRNA positive compared to 10% positivity for the cases treated successfully (OR: 34, 95%CI: 6.8−173, p < 0.0001), a finding indicative that HPV mRNA E6 & E7 positivity accurately predicts treatment failure; p16 positivity was also observed at higher rates in cases with treatment failure. Conclusions: Consistent condom use following conservative excisional CIN treatment appears to significantly reduce rates of CIN recurrence and biomarkers of HPV expression. Additional HPV vaccination at the time of treatment could further enhance the positive effect of consistent condom use.

The Influence of Sexual Behavior and Demographic Characteristics in the Expression of HPV-Related Biomarkers in a Colposcopy Population of Reproductive Age Greek Women.

Despite the significant scientific evolution in primary and secondary cervical cancer prevention in the battle started by George Papanicolaou in the previous century, global cervical cancer mortality rates remain disappointing. The widespread implementation of HPV-related molecular markers has paved the way to tremendous developments in cervical cancer screening, with the transition from cytological approach to the more accurate and cost-effective HPV testing modalities. However, the academic audience and different health systems have not yet adopted a universal approach in screening strategies, and even artificial intelligence modalities have been utilized from the multidisciplinary scientific armamentarium. Combination algorithms, scoring systems as well as artificial intelligent models have been so far proposed for cervical screening and management. The impact of sexual lifestyle inherently possesses a key role in the prevalence of HPV-related biomarkers. This study aimed to investigate any possible influence of sexual behavior and demographic characteristics in the expression of HPV-related biomarkers in a colposcopy population from October 2016 to June 2017, and corroborated the determining role of age at fist intercourse; the older the age, the lower the probability for DNA positivity. Multivariate analysis illustrated additionally that a number of sexual partners exceeding 4.2 was crucial, with women with ≤5 partners being approximately four times less likely to harbor a positive HPV DNA test (p < 0.0001). Similarly, a reported partner change during the last year before HPV DNA assessment contributed to 2.5 times higher odds for DNA positivity (p = 0.0006). From this perspective, the further development and validation of scoring systems quantifying lifestyle factors that could reflect cervical precancer risk seems paramount.

Cervical Pathology Following HPV Vaccination in Greece: A 10-year HeCPA Observational Cohort Study.

BACKGROUND: In Greece the population-level impact of HPV vaccination is unknown due to lack of official registries. This study presents in a pragmatic frame the comparison of cervical pathology data between HPV-vaccinated and unvaccinated women referred for colposcopy. PATIENTS AND METHODS: This is an observational prospective cohort study performed in 7 academic Obstetrics and Gynaecology Departments across Greece between 2009-2019. Cases were women that had completed HPV vaccination before coitarche and were referred for colposcopy due to abnormal cytology. For each vaccinated woman an unvaccinated matched control was selected. RESULTS: A total of 849 women who had been vaccinated before coitarche and 849 unvaccinated controls were recruited. The combination of cytological, colposcopic and molecular findings necessitated treatment in only a single case among vaccinated (0.1%) and in 8.4% among unvaccinated. CONCLUSION: HPV vaccination at a proper age can markedly reduce development of severe cervical precancers and consequently the need for treatment, as well as their long-term related obstetrical morbidity.

Disruption of Boundary Encoding During Sensorimotor Sequence Learning: An MEG Study.

Music performance relies on the ability to learn and execute actions and their associated sounds. The process of learning these auditory-motor contingencies depends on the proper encoding of the serial order of the actions and sounds. Among the different serial positions of a behavioral sequence, the first and last (boundary) elements are particularly relevant. Animal and patient studies have demonstrated a specific neural representation for boundary elements in prefrontal cortical regions and in the basal ganglia, highlighting the relevance of their proper encoding. The neural mechanisms underlying the encoding of sequence boundaries in the general human population remain, however, largely unknown. In this study, we examined how alterations of auditory feedback, introduced at different ordinal positions (boundary or within-sequence element), affect the neural and behavioral responses during sensorimotor sequence learning. Analysing the neuromagnetic signals from 20 participants while they performed short piano sequences under the occasional effect of altered feedback (AF), we found that at around 150-200 ms post-keystroke, the neural activities in the dorsolateral prefrontal cortex (DLPFC) and supplementary motor area (SMA) were dissociated for boundary and within-sequence elements. Furthermore, the behavioral data demonstrated that feedback alterations on boundaries led to greater performance costs, such as more errors in the subsequent keystrokes. These findings jointly support the idea that the proper encoding of boundaries is critical in acquiring sensorimotor sequences. They also provide evidence for the involvement of a distinct neural circuitry in humans including prefrontal and higher-order motor areas during the encoding of the different classes of serial order.

An immunohistochemical analysis of sex-steroid receptors, tumor suppressor gene p53 and Ki-67 in the normal and neoplastic uterine cervix squamous epithelium.

INTRODUCTION: Malignant transformation of sex-steroid dependent tissues is associated with the loss of expression of sex steroid receptors as well as of the tumor suppression gene p53. The aim of this study is to evaluate the expression of sex-steroid receptors, p53 and Ki-67 in specimens from pre-malignant and malignant cervical epithelial lesions throughout the menstrual cycle. MATERIAL AND METHODS: Immunohistochemical staining was performed on formalin fixed, paraffin embedded tissue sections of normal squamous cervical epithelium, cervical intraepithelial neoplasia and invasive squamous cervical carcinoma, specimens utilizing antibodies against estrogen receptors, progesterone receptors, p53 protein and Ki-67 antigen. RESULTS: In the samples taken from the normal cervical tissue, basal cells were usually estrogen receptor-positive, progesterone receptor-negative, p53-negative and Ki-67-negative throughout the menstrual cycle. In contrast, para-basal cells were estrogen receptor-positive and progesterone receptor-negative in the follicular phase, but estrogen receptor-negative and progesterone receptor-positive and Ki-67 positive in the luteal phase. In cervical precancerous and cancer tissue samples (cervical intraepithelial neoplasia and squamous cervical carcinoma), the expression of estrogen receptors decreased. 31.15% of cervical intraepithelial neoplasia and 11.5% of squamous cervical carcinoma were positive for estrogen receptors. However, the expression of progesterone receptors increased. 29.5% of cervical intraepithelial neoplasia and 49.2% of squamous cervical carcinoma were positive for progesterone receptors. Positive staining for p53 was observed in 15 (24.59%) cases of cervical intraepithelial neoplasia and in 39 (64%) of squamous cervical carcinoma. The expression Ki-67 index in squamous cervical carcinoma cases (47.60%) was significantly higher than of cervical intraepithelial neoplasia cases (30.2%) (p = 0.041). CONCLUSION: The findings of this study suggest that tumor cervical cells evade normal growth control by sex steroid hormones while synchronously abnormal regulatory mechanisms acquire control of the cell cycle.