OBJECTIVE: To explore the effectiveness of HPV 16/18 E7 oncoprotein in detecting high-grade cervical intraepithelial neoplasia (CIN) and predicting disease outcomes in HPV 16/18-positive patients.
METHODS: The present study was a cross-sectional study with a 2-year follow up. We collected 915 cervical exfoliated cell samples from patients who tested positive for HPV 16/18 in gynecologic clinics of three tertiary hospitals in Beijing from March 2021 to October 2022 for HPV 16/18 E7 oncoprotein testing. Subsequently, 2-year follow up of 408 patients with baseline histologic CIN1 or below were used to investigate the predictive role of HPV 16/18 E7 oncoprotein in determining HPV persistent infection and disease progression.
RESULTS: The positivity rate of the HPV 16/18 E7 oncoprotein assay was 42.06% (249/592) in the inflammation/CIN 1 group and 85.45% (277/324) in the CIN2+ group. For CIN2+ detection, using the HPV 16/18 E7 oncoprotein assay combined with HPV 16/18 testing, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.45%, 57.94%, 52.57%, and 87.95%, respectively. During the 2-year follow up, the sensitivity, specificity, PPV, and NPV for predicting persistent HPV infection were 48.44%, 58.21%, 34.64%, and 71.18% in the baseline inflammation and CIN1 group.
CONCLUSIONS: As a triage method for high-grade CIN screening in HPV 16/18-positive patients, HPV 16/18 E7 oncoprotein demonstrated a relatively high NPV, making it suitable for clinical use in triaging HPV 16/18-positive cases and potentially reducing the colposcopic referral rate. HPV 16/18 E7 oncoprotein exhibited a preferably predictive value in determining HPV infection outcomes and disease progression.

Biomarkers including Forkhead/winged-helix transcription factor box P3 have been proposed in immunohistochemical techniques to diagnose cervical lesions, but can be objectively quantified and measured in blood using methods that can be standardised. In this study we quantified the serum FOXP3 concentrations and assessed their association with cervical lesions at the cervical cancer clinic of Mbarara Regional Hospital (MRRH) Southwestern Uganda. We performed secondary analysis on archived serum samples from a previous unmatched case control study in which we recruited 90 cervical cancer (CC) cases, 90 cervical intraepithelial neoplasia (CIN) cases before any form of treatment and 90 controls. Clinical and demographic data were recorded. We measured FOXP3 concentrations using quantitative ELISA. We performed descriptive statistics and logistic regression in STATA 17 and took P-values of < 0.05 as statistically significant. The mean concentration of FOXP3 was higher in serum samples from CC cases compared with CIN cases and controls, and this difference was statistically significant (P value < 0.001). More than half (52/90,58 %) of serum samples from CC cases had FOXP3 concentrations greater than 0.0545 ng/ml (P value < 0.001). Increase serum FOXP3 expression was not associated with CIN. Increase in serum FOXP3 concentrations were observed to increase the chances of CC by 2 times (OR: 2.094, P value 0.038, 95 % CI: 1.042---4.209). Serum FOXP3 is likely associated with cervical lesions especially CC in our study population. Serum FOXP3 testing may be useful in resource limited settings to aid detection of such lesions given the challenges associated with cytology and VIA. We recommend diagnostic utility studies for circulating FOXP3 as a biomarker for detection of cervical cancer.

UNASSIGNED: Altered lipid levels may be associated with the development of a number of malignancies, including cancer of the cervix. However, there is limited understanding of this relationship in the rural Ugandan context.
UNASSIGNED: We investigated the connection between dyslipidaemias and cervical intraepithelial neoplasia (CIN) among women attending the cervical cancer clinic at Mbarara Regional Referral Hospital in south-western Uganda.
UNASSIGNED: This unmatched case-control study was conducted between December 2022 and February 2023 and included women with CIN (cases) and women without intraepithelial lesions (controls) in a 1:1 ratio. Participants were selected based on cytology and/or histology results, and after obtaining written informed consent. Demographic data were collected, and venous blood was drawn for lipid profile analysis. Dyslipidaemia was defined as: total cholesterol > 200 mg/dL, low-density lipoprotein > 160 mg/dL, triglycerides > 150 mg/dL, or high-density lipoprotein < 40 mg/dL. At diagnosis, cases were categorised as either CIN1 (low grade) or CIN2+ (high grade).
UNASSIGNED: Among the 93 cases, 81 had CIN1, while 12 had CIN2+. Controls had a 13.9% (13/93) prevalence of high triglycerides and cases had a prevalence of 3.2% (3/93; p = 0.016). Reduced high-density lipoprotein was the most prevalent dyslipidaemia among cases (40.9%; 38/93). Statistically significant associations were found between high serum triglycerides and CIN (odds ratio: 1.395, 95% confidence interval: 0.084-1.851, p = 0.007).
UNASSIGNED: A notable association was observed between triglyceride dyslipidemia and CIN. Further studies into biochemical processes and interactions between lipids and cervical carcinogenesis are recommended through prospective cohort studies.
UNASSIGNED: This research provides additional information on the potential role of lipids in cervical carcinogenesis among women in rural Uganda. It also presents the possible prevalence of multimorbidity involving cervical cancer and cardiovascular diseases, particularly in low-resource settings lacking preventive measures against the increasing prevalence of dyslipidaemia.

BACKGROUND: In Denmark, where human papillomavirus (HPV) -based cervical cancer screening is being implemented, the aim of this pilot implementation study was to test a specific screening algorithm, assess follow-up examination attendance, and measure the proportion of precancer lesions found in relation to the number of women referred for colposcopy.
METHODS: From May 2017 to December 2020, 36 417 women in the uptake area of the Department of Pathology, Vejle Hospital, Region of Southern Denmark, were included in the HPV group. Women positive for HPV16/18 irrespective of cytology and women positive for other high-risk HPV (hrHPV) types having concomitant abnormal cytology were referred directly to colposcopy. Women positive for other hrHPV types and normal cytology were referred to repeat screening after 12 months, and hrHPV negative to routine screening after three years. We obtained information on screening results and subsequent histological diagnosis from the Danish Pathology Databank through September 2022.
RESULTS: 3.6% of the women were referred to colposcopy after primary screening, 5% to repeat screening after 12 months, and 91.4% back to routine screening. High follow-up rates were observed: 96% attended colposcopy after primary screening, with 91% attending colposcopy after repeat screening. CIN3+ was detected at colposcopy following the primary screening in 28.1% of HPV16/18-positive women and 18.2% of those positive for other hrHPV types with concomitant abnormal cytology. Of the women with other hrHPV and simultaneous ASCUS/LSIL, 8% had CIN3+. At the repeat screening, 43% had become hrHPV negative, 55% were persistently positive for other hrHPV, and 2% had turned positive for HPV16/18. At the colposcopy following repeat screening, 10.1% of the women positive for other hrHPV were diagnosed with CIN3+, in comparison with 11.1% of the HPV16/18-positive women.
CONCLUSIONS: In this pilot implementation study, an algorithm for HPV-based screening was evaluated in a Danish setting. The results demonstrated high attendance at follow-up examinations and provided insights into the number of colposcopy referrals and the detection of CIN2 and CIN3+ cases. The results suggest that women testing positive for other hrHPV in combination with ASCUS/LSIL at primary screening could potentially be referred to repeat screening instead of an immediate colposcopy.

BACKGROUND: Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) has been implemented recently in many countries, including the Nordic countries. In Denmark, the only eligibility criterion for active surveillance for CIN2 is that the woman should be of reproductive age. With this study, we aimed to evaluate clinical and socioeconomic characteristics in women with CIN2 managed by active surveillance or large loop excision of the transformation zone (LLETZ) and to evaluate temporal changes in the clinical management of CIN2.
METHODS: We conducted a Danish nationwide study using data from healthcare registries. All female residents aged 18-40 years, diagnosed with incident CIN2 from January 1, 1998, to February 29, 2020, were included. We collected data on age, index cytology result, year of CIN2 diagnosis, region of residence, civil status, HPV vaccination status, and socioeconomic position indicators. The variables were tabulated overall and by management group (active surveillance vs. LLETZ). To evaluate time trends, we used joinpoint regression to calculate the annual percentage change (APC), including 95% confidence intervals (CI).
RESULTS: Of the 27 536 women with CIN2 included, 12 500 (45.4%) underwent active surveillance, and 15 036 (54.6%) underwent a LLETZ. Women undergoing active surveillance were younger, more often HPV-vaccinated, and more likely to have a normal/low-grade index cytology result than women undergoing LLETZ. Socioeconomic position indicators did not differ. Over time, the proportion of women undergoing active surveillance increased from 21.7% in 2004 to 73.6% in 2019 (APC 9.7, 95% CI 8.1-11.4). The proportion of women undergoing active surveillance aged <30 declined over time (APC -2.2, 95% CI -2.9 to -1.5). The proportion of women with normal/low-grade index cytology increased slightly to 51.6% in 2019 (APC 0.8, 95% CI 0.4-1.3).
CONCLUSIONS: The use of active surveillance for CIN2 has increased over the past two decades in Denmark. Observed differences in characteristics between women undergoing active surveillance vs LLETZ are likely related to indications for clinical management.

OBJECTIVE: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle?
CONCLUSIONS: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis.
BACKGROUND: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses.
METHODS: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020.
METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income.
RESULTS: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group.
CONCLUSIONS: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1.
CONCLUSIONS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis.
BACKGROUND: This study was funded by The Danish Cancer Society (R167-A11036-17-S2). The overall cohorts were funded by the National Institute of Child Health and Human Development (R01-HD086742 and R03-HD094117). The authors report no competing interests.
BACKGROUND: N/A.

Human papillomavirus (HPV) is associated with cellular changes in the cervix leading to cancer, which highlights the importance of vaccination in preventing HPV infections and subsequent cellular changes. Women undergoing the loop electrosurgical excision procedure (LEEP), a treatment for high-grade cervical intraepithelial neoplasia (CIN2+), remain at risk of recurrence. This study assessed the effect of post-conization HPV vaccination on the viral status of women at six months post-conization, aiming to evaluate the vaccine\'s effectiveness in preventing recurrence of CIN2+. A retrospective cohort study was conducted among women in Troms and Finnmark who underwent conization in 2022. Using the SymPathy database and the national vaccination register (SYSVAK), we analyzed the vaccination statuses and HPV test results of women born before 1991, who had not received the HPV vaccine prior to conization. Out of 419 women undergoing conization, 243 met the inclusion criteria. A significant association was found between post-conization HPV vaccination and a negative HPV test at six months of follow-up (ARR = 12.1%, p = 0.039). Post-conization HPV vaccination significantly reduced the risk of a positive HPV test at the first follow-up, suggesting its potential in preventing the recurrence of high-grade cellular changes. However, the retrospective design and the insufficient control of confounding variables in this study underscore the need for further studies to confirm these findings.

BACKGROUND: Each high-risk HPV genotype has different oncogenic potential, and the risk of CIN3+ varies according to genotype. We evaluated the performance of different strategies of HPV-positivity triage combining cytology, p16/ki67 dual staining (DS), and extended genotyping.
METHODS: Samples from 3180 consecutive women from the NTCC2 study (NCT01837693) positive for HPV DNA at primary screening, were retrospectively analyzed by the BD Onclarity HPV Assay, which allows extended genotyping. Genotypes were divided into three groups based on the risk of CIN3+. HPV DNA-positive women were followed up for 24 months or to clearance.
RESULTS: Combining the three groups of genotypes with cytology or DS results we identify a group of women who need immediate colposcopy (PPV for CIN3+ from 7.8 to 20.1%), a group that can be referred to 1-year HPV retesting (PPV in those HPV-positive at retesting from 2.2 to 3.8), and a group with a very low 24-month CIN3+ risk, i.e. 0.4%, composed by women cytology or DS negative and positive for HPV 56/59/66 or 35/39/68 or negative with the Onclarity test, who can be referred to 3-year retesting.
CONCLUSIONS: Among the baseline HPV DNA positive/cytology or DS negative women, the extended genotyping allows to stratify for risk of CIN3+, and to identify a group of women with a risk of CIN3+ so low in the next 24 months that they could be referred to a new screening round after 3 years.
BACKGROUND: Italian Ministry of Health (grant number RF-2009-1536040). Hologic-Genprobe, Roche Diagnostics, and Becton & Dickinson provided financial and non-financial support.

The main aim of our study was to investigate the specific contribution of a 9-valent human papillomavirus vaccine (9vHPV) to the recurrence risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women vaccinated post-excision. Therefore, we conducted a retrospective monocentric cohort study in women aged 22-49 years undergoing conization between 2014 and 2023. The 9vHPV-vaccinated women were matched to unvaccinated women for age and follow-up duration in a 1:2 ratio to eliminate allocation bias. The risk of CIN2+ recurrence was estimated by the incidence rate ratio using Poisson regression with adjustment for comorbidities, smoking status, nulliparity, CIN grade, positive cone margin, and HPV genotypes. The CIN2+ recurrence rates in 147 women enrolled in the analysis were 18 and 2 cases per 100,000 person-days for unvaccinated and vaccinated women, respectively, during a mean follow-up period of 30 months (±22 months). A reduction in CIN2+ recurrences by 90% (95% confidence interval: 12-99%) was documented in 9vHPV-vaccinated participants compared to women undergoing only surgical excision. Moreover, vaccinated women with a positive cone margin showed a 42% (though non-significant) reduction in relapse (p = .661). Full post-conization vaccination with the 9vHPV contributed to an additional reduction in the risk of CIN2+ recurrence. This finding is consistent with current knowledge and suggests a high adjuvant effect of the 9vHPV vaccine.

UNASSIGNED: Tissue expression of P16ink4A is correlated with cervical lesions. In this study we determined the association between serum P16ink4A concentrations and cervical lesions among women attending the cervical cancer clinic at Mbarara Regional Hospital (MRRH) South Western Uganda.
UNASSIGNED: We recruited 90 cervical intraepithelial neoplasia (CIN) cases, 90 cervical cancer (CC) cases before treatment and 90 controls. Clinical and demographic data were recorded. Serum P16ink4A concentrations were measured by quantitative Elisa. Cases were confirmed with cytology and/or histology. Descriptive statistics and logistic regression were done with STATA 17 and P-values of <0.05 were considered statistically significant.
UNASSIGNED: The mean serum P16ink4A concentration among CIN cases, CC cases and controls was 1.11(+/-0.66) ng/ml, 1.45(+/-1.11) ng/ml and 1.13(+/-0.61) ng/ml respectively (p = 0.008). 50 % of CIN cases and controls as well as 60 % of CC cases had P16ink4A concentration above 0.946 ng/ml. There were increased odds of CIN for serum P16ink4A though statistically insignificant (AOR: 1.11, p-value: 0.70). There was also a statistically significant reduction in odds of CC for serum P16ink4A (AOR: 0.55, p-value: 0.01).
UNASSIGNED: Serum P16ink4A may likely be associated with cervical lesions especially CC in our study population and this may aid detection of such lesions. Diagnostic utility studies for circulating P16ink4A in detection of cervical cancer are recommended.