Risk of progression of cervical intraepithelial neoplasia grade 2 in human papillomavirus-vaccinated and unvaccinated women: a population-based cohort study.

BACKGROUND: Many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option among younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment increases the risk for preterm birth in subsequent pregnancies. However, early identification of women at increased risk for progression to cervical intraepithelial neoplasia grade 3 or worse is important to ensure timely treatment. Because women who have received a human papillomavirus vaccine have a lower risk for cervical cancer, they may have a lower risk for progression of untreated cervical intraepithelial neoplasia grade 2 to cervical intraepithelial neoplasia grade 3 or worse. OBJECTIVE: This study aimed to investigate if women who received a human papillomavirus vaccine and who are undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are less likely to progress to cervical intraepithelial neoplasia grade 3 or worse when compared with women who did not receive the vaccine. STUDY DESIGN: We conducted a population-based cohort study in Denmark using data from national health registers. We identified all women aged 18 to 40 years who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 from January 1, 2007, to December 31, 2020. Women with a previous record of cervical intraepithelial neoplasia grade 2 or worse, hysterectomy, or a loop electrosurgical excision procedure were excluded. Exposure was defined as having received ≥1 dose of a human papillomavirus vaccine at least 1 year before the cervical intraepithelial neoplasia grade 2 diagnosis. We used cumulative incidence functions to estimate the risk for progression to cervical intraepithelial neoplasia grade 3 or worse within 28 months using hysterectomy, emigration, and death as competing events. We used modified Poisson regression to calculate crude and adjusted relative risks of progression during the 28-month surveillance period. Results were stratified by age at vaccination and adjusted for index cytology, disposable income, and educational level. RESULTS: The study population consisted of 7904 women of whom 3867 (48.9%) were vaccinated at least 1 year before a diagnosis of cervical intraepithelial neoplasia grade 2. At the time of cervical intraepithelial neoplasia grade 2 diagnosis, women who were vaccinated were younger (median age, 25 years; interquartile range, 23-27 years) than those who were not (median age, 29 years; interquartile range, 25-33 years). The 28-month cumulative risk for cervical intraepithelial neoplasia grade 3 or worse was significantly lower among women who were vaccinated before the age of 15 years (22.9%; 95% confidence interval, 19.8-26.1) and between the ages of 15 and 20 years (31.5%; 95% confidence interval, 28.8-34.3) when compared with women who were not vaccinated (37.6%; 95% confidence interval, 36.1-39.1). Thus, when compared with women who were not vaccinated, those who were vaccinated before the age of 15 years had a 35% lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse (adjusted relative risk, 0.65; 95% confidence interval, 0.57-0.75), whereas women who were vaccinated between the ages of 15 and 20 years had a 14% lower risk (adjusted relative risk, 0.86; 95% confidence interval, 0.79-0.95). For women who were vaccinated after the age of 20 years, the risk was comparable with that among women who were not vaccinated (adjusted relative risk, 1.02; 95% confidence interval, 0.96-1.09). CONCLUSION: Women who were vaccinated and who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 had a lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse during 28 months of follow-up when compared with women who were not vaccinated but only if the vaccine was administered by the age of 20 years. These findings may suggest that the human papillomavirus vaccination status can be used for risk stratification in clinical management of cervical intraepithelial neoplasia grade 2.

Aerobic vaginitis is associated with carbonic anhydrase IX in cervical intraepithelial neoplasia.

The aim of this study was to analyze the association between vaginal microbiota, carbonic anhydrase IX (CAIX) and histological findings of cervical intraepithelial neoplasia (CIN). The study included 132 females, among them 66 were diagnosed with high-grade intraepithelial lesion (CIN2, CIN3, and cancer), 14 with low-grade disease, and 52 assigned to the control group. An interview focused on the behavior risk factors, together with vaginal fluid pH measurement, wet mount microscopy, detection of Chlamydia trachomatis, and Trichomonas vaginalis were performed. After colposcopy, high-grade abnormalities were detected via direct biopsies and treated with conization procedure. Conuses were immuno-stained with CAIX antibody. The histological findings were CIN1 (n = 14), and CIN2+ (included CIN2 (n = 10), CIN3 (n = 49), and cancer (n = 7; squamous cell carcinomas)). Prevalence of bacterial vaginosis (BV) was similar between the groups. Moderate or severe aerobic vaginitis (msAV) was diagnosed more often among CIN2+ (53.0%) than CIN1 (21.4%). Moderate or strong immunostaining of CAIX (msCAIX) was not detected among CIN1 cases. Thus, msAV was prevalent in CAIX non-stained group (p = 0.049) among CIN2 patients. Co-location of msAV and msCAIX was found in CIN3. Regression model revealed that msAV associated with high-grade cervical intraepithelial neoplasia independently from smoking and the number of partners.

Cervical Cancer Screening via Visual Inspection With Acetic Acid and Lugol Iodine for Triage of HPV-Positive Women.

Importance: Limited evidence supports the performance of human papillomavirus (HPV) DNA testing as a primary screening method, followed by triage with visual inspection with acetic acid, in areas with limited health care resources, as suggested by the 2021 World Health Organization guidelines. Objective: To evaluate the performance of visual inspection with acetic acid and Lugol iodine as a triage method for detecting cervical precancerous lesions among HPV-positive women in 1 visit. Design, Setting, and Participants: This cohort study examined the implementation of a government-led cervical cancer screening program conducted from January 1, 2016, to December 31, 2020, in Ordos City, China. Female residents, aged 35 to 64 years, who understood the screening procedures and voluntarily participated were included in the study. Women were excluded if they reported never having had sexual intercourse, were pregnant, had a hysterectomy, or had ever undergone treatment for cervical lesions. Statistical analysis was conducted from December 2022 to December 2023. Exposures: The program used the careHPV DNA assay as the primary screening method, and immediate triage was performed by visual inspection if HPV screening results were positive, with a 5-year screening interval. A colposcopy was performed for the women who had suspected cancer on visual inspection results or who were HPV positive and had abnormal visual inspection results, all in 1 visit. Main Outcomes and Measures: The rate of compliance with colposcopy and the detection rate of cervical intraepithelial neoplasia grade 2 or higher (CIN2+). Results: The study included 187 863 women (median age, 46 years [IQR, 40-52 years]) who participated in the program and had valid HPV test results. The overall prevalence of HPV positivity was 12.8% (24 070 of 187 863), and the adherence to triage with visual inspection among HPV-positive women was 93.9% (22 592 of 24 070). Among HPV-positive women, the rate of compliance with colposcopy was 65.6% (2714 of 4137), and the CIN2+ detection rate was 2.8% (643 of 22 592). Conclusions and Relevance: The findings of this cohort study suggest that the implementation of HPV testing, visual inspection, and colposcopy within 1 visit may mitigate losses to follow-up, detect precancerous lesions, and hold significant implications for screening in comparable areas with limited health care resources.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

OBJECTIVES: The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results. METHODS: Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group. RESULTS: For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier. CONCLUSIONS: Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.

Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion.

OBJECTIVE: Our aim was to evaluate the performance of different follow-up strategies after treatment for cervical intraepithelial neoplasia (CIN) 2 or 3, including human papillomavirus (HPV) detection, cytology, or colposcopy, as well as their combinations. Additionally, we compared the influence of the persistence of HPV 16/18 versus that of other high-risk HPV genotypes (HR-HPV) in the recurrence risk. METHODS: Retrospective register-based study, including women who had an excision of the transformation zone for CIN2 or CIN3 at our institution, between January 2011 and December 2022. The outcome assessed was histopathological recurrence/persistence of CIN2 or worse. RESULTS: Of the 721 women included, 6.8% (49/721) had recurrence/persistence. The sensitivity, specificity, and positive and negative predictive values of the HPV test were 97.4%, 80%, 22.3%, and 99.8%, respectively, whereas for cotesting (HR-HPV and cytology), 86.8%, 90.1%, 34.4%, and 99.1%, respectively. The referral rates for colposcopy were 24.3% and 14.2%, respectively. The sensitivity of colposcopy was low (40.0%).Women who were initially positive for non-16/18 genotypes at baseline who became HPV16/18 positive during follow-up, had a statistically significant increased risk of CIN2 or worse, compared with those who tested positive only for other HR-HPV genotypes during both stages (hazard ratio = 4.98; 95% CI = 1.66-14.91). CONCLUSIONS: Human papillomavirus testing is the best strategy for follow-up after treatment of cervical HSIL. The addition of cytology triage decreases by more than 40% the referrals for colposcopy, without significantly missing cases of recurrence/persistence. Human papillomavirus 16/18 in the follow-up, regardless of being previously positive, is associated with higher risk of recurrence/persistence of HSIL.

Correlation between P16/Ki67 in cervical cytology and diagnosis of cervical intraepithelial neoplasia 2-3 in Thai women infected with high-risk types of human papillomavirus.

OBJECTIVES: The addition of p16/Ki-67 dual immunostaining to human papilloma virus (HPV) screening tests has been shown to increase the detection rate of high-grade cervical intraepithelial neoplasia. Thus, the aim of this study was to evaluate the accuracy of p16/Ki67 dual staining in the detection of cervical intraepithelial neoplasia 2 (CIN2+) in women with high-risk HPV infection. MATERIALS AND METHODS: A cross-sectional study was conducted between August 2017 and August 2019 at the Chulabhorn Hospital in Bangkok, Thailand. Women aged 20-70 years who underwent co-testing and tested positive for high-risk (HR) HPV (N = 215) were invited to participate in the study. P16/Ki67 testing was performed on residual cytological materials. Colposcopic biopsies were performed on all patients, and the results were correlated with positive or negative p16/Ki-67 test results. RESULTS: The sensitivity and specificity of p16/Ki-67 dual staining in the detection of CIN2+ in the women with HR HPV infection were 74.4 % and 63.4 %, respectively. Compared with liquid-based cytology (LBC), p16/Ki67 cytology had similar sensitivity (p = 1.000) and specificity (p = 0.561) to LBC for detecting CIN2+. CONCLUSION: In this study, p16/Ki67 dual staining in HPV triage demonstrated a test performance similar to that of LBC.

Topical delivery of drugs in the treatment of high-grade cervical squamous intraepithelial lesions: A meta-analysis.

OBJECTIVE: The present study aims to evaluate the efficacy and effect of localized delivery of drugs in the treatment of high-grade squamous intraepithelial lesion (HSIL) based on a meta-analysis. STUDY DESIGN: Databases including Cochrane Library, PubMed, Embase, Scopus, CNKI, and Wanfang were searched from their inception till August 2022. Randomized controlled trials (RCTs) that compared the efficacy of drugs and surgery in the treatment of HSIL were collected. A meta-analysis was performed using the software of Review Manager (version 5.4.1). RESULTS: Eight RCTs involving 523 patients were included in the meta-analysis. For HSIL, the rate of cervical lesions histological regression was 69.85 % in the surgery group and 59.88 % in the drug group, there was no significant difference between the two groups [OR = 0.45, 95 % CI (0.07, 3.03), P = 0.41]. The histological regression rate of cervical lesions in the placebo group was 37.76 %, and the difference between the drug group and the placebo group was statistically significant [OR = 4.94, 95 % CI (2.65, 9.20), P < 0.00001]. CONCLUSION: A total of four drugs were involved in the eight RCTS included in this study, which were imiquimod, 5-fluorouracil (5-FU), cidofovir and interferon. The results showed that although drug administration was effective in the histological regression of HSIL, the efficacy was less than about 10% of surgical treatment. Considering the recurrence of the disease after surgery and the problems of abortion, premature delivery and premature rupture of membranes after cervical conization in reproductive women, drug therapy can be used as a supplement to surgery or conservative treatment to promote the histological regression of cervical lesions in patients with HSIL.

The importance of combined HPV and CINtec® PLUS genotyping testing for p16 in women with cervical squamous cell carcinoma.

INTRODUCTION: Immunohistochemistry (IHC) for p16INK4A (p16) is a reliable surrogate test for the presence of a high-risk, potentially transformative human papillomavirus (HPV) infection in precursor and malignant lesions of the cervix. The purpose of this study was to evaluate changes in cervical cells caused by persistent HPV infection, by IHC (p16 protein) by comparison with HPV genotyping. PATIENTS, MATERIALS AND METHODS: The study included female patients aged between 26 and 57 years who presented to a public hospital, with complaints related to the genital area, namely vaginal bleeding and dyspareunia. After selecting the patients, samples were subjected to cytological testing and IHC for p16 and for the determination of HPV types. RESULTS: The relationship between HPV status and p16 status was statistically significant (p=0.0001), of the 41 patients, 53.7% were HPV positive, respectively 56.1% were p16 positive, the agreement relationship between the two indicators was very high (weighted kappa: 0.951). The clinical performance of CINtec® PLUS triage for p16 shows a high positive predictive value (PPV) and a high negative predictive value (NPV) of 95.7% and 100%, respectively, as regards HPV. CONCLUSIONS: The p16 marker (CINtec® PLUS) can be used as a prognostic biomarker and provides clinical usefulness through increased sensitivity (Se) and specificity (Sp) in the triage of women at risk of developing precancerous lesions, compared to cytology that is based on morphology, but has a rather low Se and high Sp, while HPV testing is very sensitive but slightly more specific.

Escherichia coli and HPV16 coinfection may contribute to the development of cervical cancer.

Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers susceptibility and progression, recently attracting considerable attention. This study aimed to determine the infection status and relationship between high-risk HPV (HR-HPV) and lower genital tract infectious pathogens in cervical cancer and its precursors. From a retrospective and a prospective cohort analysis, Escherichia coli (E. coli) dominated the pathogens isolated from cervical discharges, and an isolation rate uptrend has been shown recently. HPV16 and E. coli's coinfection rate gradually increased with the severity of cervical intraepithelial neoplasia. The adhesion and invasion abilities of the isolated E. coli to HPV16-positive SiHa cells were evaluated in vitro. The TCGA database and cervical tissues samples analysis showed that IL-10 was upregulated in cervical cancer. IL-10 expression levels increased in tissue samples with the severity of cervical cancer and its precursors with HPV16 and E. coli coinfection. Although no significant changes in IL-10 production were observed in the co-culture supernatant, we hypothesized that Treg immune cells in the tumour microenvironment might be responsible for the local IL-10 upregulation, according to our data showing Foxp3 upregulation and an upward trend with the cervical intraepithelial neoplasia grading to cancer and tumours with E. coli and HPV16 coinfection. Our data provide insights into the possible role of E. coli in cervical cancer progression and suggest that the application of HPV and E. coli screening programs may be an effective strategy to relieve the burden of cervical cancer and its precursor lesions.

A retrospective study for long-term oncologic and obstetric outcomes in cervical intraepithelial neoplasia treated with loop electrosurgical excision procedure: focus on surgical margin and human papillomavirus.

BACKGROUND: The present study aimed to evaluate the long-term oncological and obstetric outcomes following the loop electrosurgical excision procedure (LEEP) in patients with cervical intraepithelial neoplasia (CIN) and investigate the risk factors for recurrence and preterm birth. METHODS: This retrospective cohort study included patients who underwent LEEP for CIN 2-3 between 2011 and 2019. Demographic information, histopathological findings, postoperative cytology, and human papillomavirus (HPV) status were collected and analyzed. The Cox proportional hazards model and Kaplan-Meier curves with the log-rank test were used for risk factor analysis. RESULTS: A total of 385 patients treated with the LEEP were analyzed. Treatment failure, including recurrence or residual disease following surgery, was observed in 13.5% of the patients. Positive surgical margins and postoperative HPV detection were independent risk factors for CIN1 + recurrence or residual disease (HR 1.948 [95%CI 1.020-3.720], p = 0.043, and HR 6.848 [95%CI 3.652-12.840], p-value < 0.001, respectively). Thirty-one patients subsequently delivered after LEEP, and the duration between LEEP and delivery was significantly associated with preterm-related complications, such as a short cervix, preterm labor, and preterm premature rupture of the membrane (p = 0.009). However, only a history of preterm birth was associated with preterm delivery. CONCLUSIONS: Positive HPV status after LEEP and margin status were identified as independent risk factors for treatment failure in patients with CIN who underwent LEEP. However, combining these two factors did not improve the prediction accuracy for recurrence.

Analysis of the Differences between Bethesda Groups according to Conventional Smear and Liquid-Based Cytology Methods in Cervicovaginal Cytology: A Single-Center Experience with 165,915 Cases.

INTRODUCTION: Liquid-based cytology (LBC) has replaced conventional smear (CS) in the world. In this study, through a series with a large number of cases, we aimed to make a comparison and general evaluation in all groups, primarily epithelial abnormalities, according to LBC and CS methods. This study was carried out in a private pathology laboratory located in a metropolitan city, where cytological materials sent from many clinics were examined. MATERIAL AND METHODS: There were 165,915 cases whose smears were examined between 2012 and 2020, most of them conventional (131,224 CS, 34,691 LBC). Cases were evaluated on the basis of the Bethesda 2014 classification and divided into sub-diagnostic categories after they were divided into two main groups as "with epithelial abnormalities" and "without." χ2 and Fischer's precision statistical tests were conducted using SPSS 23.0 package. In the CS process, cervical samples were obtained using an endocervical brush and a spatula. Cells were directly spread onto the slides and promptly fixed in 95% ethanol, followed by staining with the standard Papanicolaou stain. For LBC ThinPrep, cervical specimens were gathered using a cervix brush. The brush was washed in a vial and discarded. Finally, cells were isolated through vacuum filtration and transferred to the slide using air pressure. RESULTS: Squamous cell abnormalities (atypical squamous cells of undetermined significance [ASC-US], atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion [ASC-H], low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], squamous cell carcinoma, atypical glandular cells of undetermined significance) were reported in 5,696 (3.43%) cases. ASC (ASC-US + ASC-H)/SIL ratio (1.36/2.04) was found to be 0.67 (recommended Bethesda ratio is <3). ASC-US (p < 0.001), ASC-H (p < 0.001), and HSIL(p < 0.001) detection rate of LBC was found to be significantly higher than CS. ASC-US (1.8/1.2), ASC-H (0.08/0.008), and HSIL (0.6/0.3) case ratios of LBC/CS were found to be significantly higher in LBC. LSIL (1.72/1.66) rate was similar. CONCLUSION: LBC is superior to CS in detecting epithelial lesions. In addition to being used as a screening method, it is clear that it makes a great contribution to reducing cervical carcinomas due to HPV typing. Definitive comments regarding comparison of methods on reactive changes and microorganism detection are challenging. Preanalytical factors might account for these situations.

An audit of 1632 routinely collected cervical cancer screening smears from 398 women in Germany: Results from the TeQaZ Study.

OBJECTIVE: There is evidence in Germany that half of the cervical cancer (CC) cases had undergone screening frequently in the decade preceding their diagnosis, signaling cytology quality issues. This study investigates routine smear assessment accuracy in Germany. METHODS: Within a population-based case-control study in 9 German states, we recruited cases (women with a histologically confirmed diagnosis of CC) and population controls (women with no history of CC or hysterectomy). Two independent expert cytologists audited Pap smears taken within the 10 years preceding CC diagnosis (cases)/study entry (controls). We report the prevalence of positive results, as well as routine assessment's accuracy, as sensitivity, specificity, false-positive and false-negative rates along with 95% confidence intervals (95% CI). We also examined cases' smear history, to investigate possible false-positive recurrence. RESULTS: We audited 1632 smears of 392 women (18.9% cases, 81.1% controls). In the routine assessment, the overall prevalence of positive results was 4.5% (29.0% among cases). According to the expert audit, the overall prevalence of positive results was 7.7% (40.8% among cases). When restricting analyses to the 3 years preceding diagnosis/study entry, this prevalence increased to 11.9% overall (61.4% among cases). The overall sensitivity of the routine assessment was 54.9% (66.8% for cases). CONCLUSION: As cytology remains an important part of CC screening, quality issues must be urgently addressed in Germany. Shifting to objective methods such as primary high-risk HPV screening followed by triaging may help CC elimination in Germany.

Exploring conservative management for cervical intraepithelial neoplasia grade 2 in organised cervical cancer screening programmes: a multicentre study in Italy.

Cervical intraepithelial neoplasia grade 2 (CIN2) lesions may regress spontaneously, offering an alternative to immediate treatment, especially for women of childbearing age (15-45 years).We conducted a prospective multicentre study on conservative CIN2 management, with semiannual follow-up visits over 24 months, biomarkers' investigation and treatment for progression to CIN3+ or CIN2 persistence for more than 12 months. Here, we assess women's willingness to participate and adherence to the study protocol.The study was set in population-based organised cervical cancer screening.From April 2019 to October 2021, 640 CIN2 cases were diagnosed in women aged 25-64 participating in the screening programmes.According to our predefined inclusion and exclusion criteria, 228 (35.6%) women were not eligible; 93 (22.6%) of the 412 eligible refused, and 319 (77.4%) were enrolled. Refusal for personal reasons (ie, desire to become pregnant, anxiety, difficulty in complying with the study protocol) and external barriers (ie, residence elsewhere and language problems) accounted for 71% and 17%, respectively. Only 9% expressed a preference for treatment. The primary ineligibility factor was the upper age limit of 45 years. After enrolment, 12 (4%) women without evidence of progression requested treatment, 125 (39%) were lost to follow-up (mostly after 6-12 months) and 182 (57%) remained compliant. Remarkably, 40% of enrolees did not fully adhere to the protocol, whereas only 5% (20/412) of the eligible women desired treatment.Our study demonstrates a good acceptance of conservative management for CIN2 lesions by the women, supporting its implementation within cervical screening programmes.

A prospective clinical trial of diathermy ablation for patients with high-grade cervical intraepithelial neoplasia from a single institution in Japan.

Approximately 500,000 women are diagnosed with cervical cancer annually, with high-grade cervical intraepithelial neoplasia (CIN) estimated to be 20 times higher. The diathermy ablation is an inexpensive minimally invasive surgeries for CIN. However, little is known about the treatment outcomes. A prospective clinical trial was therefore conducted to evaluate ablation outcomes based on detailed colposcopy findings, cytology, and biopsy results over a two-year period. We enrolled CIN2 (n = 32) and CIN3 (n = 7) patients. Eligibility criteria included: aged between 29 and 49 (median: 36, mean: 36.3), visible transformation zone with high-grade lesions not entirely occupying the cervix, and histologically diagnosed with CIN2 or CIN3. Cytology and HPV genotyping were performed, and colposcopic findings were evaluated. Colposcopy-guided diathermy ablation was conducted by a certified gynecologic oncologist. The incidence of recurrent or residual disease was 5.1% (2/39, 95% confidence interval: - 0.02 to 0.12). The prevalence of HPV infection at 12 months decreased after surgery, as 67.6% (23/34, 0.52-0.83) of patients were HPV-negative. No severe adverse events were reported, while there were five pregnancies with full-term deliveries. The promising outcome was possibly due to selection of rigorous surgical indication and skilled surgical techniques. The study highlights the importance of experienced and skilled colposcopists.TrialRegistry This study was registered in the clinical trial registration system of the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR ID: UMIN000024483). Open for the trial to the public through the website: 01/11/2016. First registration of the patient: 30/01/2017.

Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies.

BACKGROUND AND OBJECTIVES: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). METHODS: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects. RESULTS: We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age. DISCUSSION: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.

Performance of BD Onclarity HPV assay on FLOQSwabs vaginal self-samples.

This study assessed the accuracy of high-risk human papillomavirus testing of BD Onclarity HPV (Onclarity) assay on vaginal self-collected FLOQSwab versus cervical samples to ensure similar accuracy to detect cervical intraepithelial neoplasia. Testing was performed on two automated platforms, BD Viper LT and BD COR, to evaluate the effect of machine and using two vaginal self-samples to analyze the influence of collection, transport, and freezing-unfreezing on the results. A cervical sample and two self-samples were collected from 300 women. The first collected vaginal and the cervical sample were tested on BD Viper LT, and the second swab was frozen and subsequently tested on both automated systems. Test results on vaginal and cervical specimens were considered the index and comparator, respectively; colposcopy and histology were reference standards. Relative sensitivity for ≥CIN2 on vaginal samples analyzed versus the cervical sample was 1.01 (0.97-1.06), 1.01 (0.97-1.06), and 1.00 (0.95-1.05), for the first, second self-collected sample tested on BD VIPER LT, and second self-collected sample tested on BD COR, respectively. Relative specificity was 0.83 (0.73-0.94), 0.76 (0.67-0.87), and 0.82 (0.73-0.92) using the three different workflows. Cut-off optimization for human papillomavirus (HPV) positivity defined at Ct ≤38.3 for HPV16, ≤ 34.2 for HPV18, and ≤31.5 for all other types showed an increased relative specificity with similar sensitivity. No significant difference was observed between self-samples tested with the two platforms and between first- and second-collected swabs. Onclarity assay on FLOQSwab using both platforms showed similar sensitivity but lower specificity to detect ≥CIN2 compared to cervical samples. By cut-off optimization, non-inferior specificity could be reached. IMPORTANCE: Human papillomavirus (HPV) testing on self-collected vaginal samples has been shown to improve women's participation to cervical cancer screening programs, particularly in regions with limited access to health care. Nevertheless, the introduction of self-sampling in cervical cancer screening programs requires prior clinical validation of the HPV assay in combination with a self-sample collection device, including also the laboratory workflow and automation required for high-throughput testing in screening. In this study, the performance of BD Onclarity HPV on FLOQSwab-collected vaginal self-samples has been compared to clinician-taken liquid-based cytology samples, to detect high-grade cervical intraepithelial neoplasia using two high-throughput platforms, BD Viper LT and BD COR. The study findings have shown a similar performance of BD Onclarity on testing self-collected samples, confirming the validation of the proposed pre-analytical and analytical protocols for their use in cervical cancer screening programs based on self-collected vaginal samples.

Single-cell RNA sequencing of cervical exfoliated cells reveals potential biomarkers and cellular pathogenesis in cervical carcinogenesis.

Cervical cancer (CC) is a common gynecological malignancy. Despite the current screening methods have been proved effectively and significantly decreased CC morbidity and mortality, deficiencies still exist. Single-cell RNA sequencing (scRNA-seq) approach can identify the complex and rare cell populations at single-cell resolution. By scRNA-seq, the heterogeneity of tumor microenvironment across cervical carcinogenesis has been mapped and described. Whether these alterations could be detected and applied to CC screening is unclear. Herein, we performed scRNA-seq of 56,173 cervical exfoliated cells from 15 samples, including normal cervix, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and malignancy. The present study delineated the alteration of immune and epithelial cells derived during the cervical lesion progression. A subset of lipid-associated macrophage was identified as a tumor-promoting element and could serve as a biomarker for predicting the progression of LSIL into HSIL, which was then verified by immunofluorescence. Furthermore, cell-cell communication analysis indicated the SPP1-CD44 axis might exhibit a protumor interaction between epithelial cell and macrophage. In this study, we investigated the cervical multicellular ecosystem in cervical carcinogenesis and identified potential biomarkers for early detection.

Prevalence of human papillomavirus infection and associated factors among women attending cervical cancer screening in setting of Addis Ababa, Ethiopia.

Human papillomaviruses (HPVs) are circular, nonenveloped small double-stranded DNA viruses that infect stratified epithelium and can cause a number of life-threatening diseases. HPV is the central risk factor for developing cervical cancer and is estimated that approximately 98% of this disease is associated with oncogenic types of HPV. HPV infection leads to an estimated 266,000 cervical cancer deaths annually. Therefore, the objective of this study was to determine the prevalence of HPV infection and risk factors associated with cervical lesion among women attending the cervical cancer screening clinic at the Ethiopian Family Guidance Association, Addis Ababa. A cross-sectional study was conducted to determine the prevalence of HPV infection. Data were collected using a questionnaire and samples leftover from cervical screening were taken. The leftover swab was air dried and DNA was extracted and amplified by using a PCR. A total of 247 women were included in the study. The prevalence of HPV was 9.72% among the population studied. Of all participants, 27.13% were positive for cervical intraepithelial neoplasia-1 (CIN1). CIN1 positivity was found in half of HPV positive women. Among HPV positive women, half of them had started sexual intercourse at ages 12-17 years and 41.66% were women who gave birth at ages 12-17 years. The high prevalence of HPV and the CIN1 positive group were ages 36-57 and women with multiple sexual partners. The other groups with the highest CIN1 positive were 22.39% grade (9-12) and 20.9% primary (1-8) and uneducated women. Among HPV positive women, 83.33% had an abortion history and 80% miscarried in the first trimester. Among the CIN1 positives, 53.73% had more than two sexual partners. Among HPV positive women, half of them were users of contraception methods. In conclusion, the highest prevalence of HPV is among women who began sexual intercourse earlier and who gave birth at 12-17 years of age, have an abortion history, with MSP and oral contraceptive methods users. In addition to HPV, early pregnancy and sexual intercourse at 12-17 years of age, abortion, MSP, and oral hormonal contraceptives are factors in cervical cancer. Finally, most women do not have enough knowledge and awareness about cervical cancer and the risk factor.

Factors associated with the persistence of human papillomavirus after surgery in patients with cervical cancer.

OBJECTIVE: To determine the rate of human papillomavirus (HPV) persistence after surgery in patients with cervical cancer, and to analyze the factors associated with HPV persistence and viral load after surgery. METHODS: Medical records of women who underwent surgery for treatment of cervical cancer between 1 January 2018 and 30 June 2019 at Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, were retrospectively analyzed. Patients with persistent HPV infection after 2 years of follow-up were identified. Univariate and multivariate analyses were employed to determine the impact of various factors including patient age, menopausal status, parity, and surgical margin status on HPV persistence. The Wilcoxon test was used to analyze the factors that influenced postoperative HPV viral load. RESULTS: Altogether, 607 women were eligible for the final analysis. The persistence rates of HPV at 6 months, 1 year, and 2 years after surgery were 17.3, 13.7, and 10.2 %, respectively. In univariate analysis, the factors that were predictive of the persistence of HPV infection were old age, postmenopausal status, and positive vaginal incision margin with cancer. In multivariate analysis, the significant independent predictive factors were postmenopausal status and positive vaginal incision margin with cancer (P < 0.05, odds ratio (OR) = 2.289, 95 % confidence interval (CI): 1.262-4.150 and OR = 3.271, 95 % CI: 1.253-8.537, respectively). A vaginal lesion with cancer or squamous intraepithelial lesion (SIL) and positive vaginal incision margin influenced HPV viral load at 6 months after surgery (P < 0.05). CONCLUSIONS: Postmenopausal patients and those with positive vaginal incision margin with cancer are at an increased risk of HPV persistence after surgical treatment for cervical cancer. Vaginal lesions with cancer or SILs and positive vaginal incision margin are risk factors for high HPV viral load after surgery.

Divergent effects of switching from cytology to HPV-based screening in the Nordic countries.

BACKGROUND: Cervical cytology has been the primary method of cervical cancer screening for decades. Tests that detect viral HPV are shown in several randomized trials to provide better protection against cancer compared with cytology. HPV-based screening has been implemented alongside cytology in the Nordic countries for several years. The aim of this study was to compare cytology and HPV-based screening in the colposcopy referrals and detection rates of cervical lesions. METHODS: Individual-level screening data from Finland, Iceland, Norway and Sweden were harmonized and aggregated locally. We utilized data for tests taken during years 2015-17 and biopsies taken during years 2015-19 to allow 24 months of follow-up. Age-standardized estimates and age-adjusted risk ratios for six different outcomes of screening management were calculated. RESULTS: The age-standardized colposcopy rates were higher in HPV-based testing compared with cytology in Finland (3.5% vs. 0.9%) and Norway (6.0% vs. 4.1%) but lower in Sweden (3.7% vs. 4.9%). The relative detection rate of cervical intraepithelial neoplasia grade 2 and above in HPV-based testing compared with cytology was highest in Finland (RR 2.37, 95% CI 2.13-2.63) and Norway (RR 1.66, 95% CI 1.57-1.72) while in Sweden the difference was not statistically significant (RR 0.98, 95% CI 0.95-1.00). CONCLUSIONS: The effects of implementing HPV screening varied by country as different screening algorithms were implemented. HPV-based screening increases colposcopy rates mainly through referrals from increased repeat testing and detection rate is therefore significantly higher compared with cytology. Monitoring of these indicators in subsequent rounds of HPV-based screening remains essential.