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Women living with HIV (WLWH) are at an increased risk of developing HPV-related high grade cervical dysplasia and cervical cancer. Prior World Health Organization (WHO) screening guidelines recommended starting screening at age 30. We assessed characteristics of women diagnosed with cervical cancer to further inform and refine screening guidelines. We prospectively enrolled women diagnosed with cervical cancer from January 2015 to March 2020 at two tertiary hospitals in Gaborone, Botswana. We performed chi-square and ANOVA analyses to evaluate the association between age upon diagnosis and HIV status, CD4 count, viral load, and other sociodemographic and clinical factors. Data were available for 1130 women who were diagnosed with cervical cancer and 69.3% were WLWH. The median age overall was 47.9 (IQR 41.2-59.1), 44.6 IQR: 39.8 - 50.9) among WLWH, and 61.2 (IQR 48.6-69.3) among women living without HIV. There were 1.3% of women aged <30 years old, 19.1% were 30-39 and 37.2% were 40-49. Overall, 20.4% (n = 231) of cancers were in women <40 years. Age of cervical cancer diagnosis is younger in countries with higher HIV prevalence, like Botswana. Approximately 20% of the patients presented with cancer at <40 years of age and would have likely benefited from screening 10 years prior to cancer diagnosis to provide an opportunity for detection and treatment of pre-invasive disease., Competing Interests: Declaration of Competing Interest Authors do not have any conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Various Human papillomavirus (HPV) types cause cervical cancer, and represent the primary cause of cancer death in Africa and the second cause of most common cancers in Cameroon. Herein, we determined the prevalence of high-risk HPV types in women and associated cervical cytologic abnormalities in Yaounde, Cameroon., Methodology: A cross-sectional study targeting HPV-positive women aged 20 and over was conducted between March and June 2020 at the Saint Martin de Porres' Health Centre in Yaounde. HPV tests were performed by PCR for detection of HPVs 16, 18, 33, and 45. The test was performed on 616 women using exfoliated cell specimens; then, we processed on cytological diagnosis with Pap smears on HPV positive specimens., Results: The HPV types tested were detected in 137 participants, of which 38.7% with multiple HPV infections, and the remaining part with single HPV infections of type HPV 16 (28.5%), HPV 18 (17.5%), HPV 33 (10.2%), and HPV 45 (5.1%). Cervical cytologic abnormalities were found in 69.34% of participants including: LSIL (49.63%), HSIL (15.32%), ASC-US (3.66%) and AGC (0.73%). Co-infections with HPV 16 and HPV 18 were significantly associated with HSIL (p = 0.001) lesions, while HPV 45 was more common in participants with normal cytology (p = 0.001). Cervical lesion occurrence was significantly associated with the number of sexual partners (p = 0.02) and history of oral contraceptive pill use (p = 0.001)., Conclusions: Our results suggest that HPV 16 and 18 are predominant in Yaounde, and are associated with more severe precancerous lesions., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Richard Tagne Simo, Arsene G Djoko Nono, Hervet Paulin Fogang Dongmo, Paul F Seke Etet, Bertrand Kiafon Fonyuy, Armel H Nwabo Kamdje, Nicolas Njintang Yanou, Phelix Bruno Telefo.)

Squamous intraepithelial lesions (SIL) and cervical cancer are primary due to suboptimal immune response against human papillomavirus (HPV). The FASL/FAS system is a trigger of extrinsic pathway apoptosis. The distribution of polymorphisms rs1800682 (-670 A > G) FAS and rs763110 (-844C > T) FASL was studied in cervical smears from 372 females (182 with stable or regressed low-grade SIL (LSIL) (groupI) and a group of 190 high-grade SIL (HSIL) (groupII). No significant differences were observed for rs1800682 in FAS between the study groups. In contrast, rs763110 CC genotype of FASL was found in 35.7% of group I females, and in 50.5% of group II (p = 0.0027; OR = 1.83 (95% CI = 1.21-2.79)). When only females infected with high-risk HPV were analysed, these differences were even higher (p = 0.0024; OR = 2.21 (95% CI = 1.30-3.75)). CC genotype in FASL seems to be associated with increased risk of LSIL to HSIL progression suggesting a role in HPV tolerance, persistent infection, and HSIL development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the real-life screening outcomes after cytology was replaced by human papillomavirus (HPV) testing for women aged 60-64 years., Methods: Using the Danish national pathology register, we compared screening outcomes during two consecutive calendar periods, one where women were screened with cytology and one where most women were screened with HPV testing. Our primary outcomes were the proportions of women with positive test results, high-grade cervical intraepithelial neoplasia (CIN 2 or worse), and cervical cancer., Results: Women screened during the HPV testing period were more likely to have a positive screening test result than were women screened during the cytology period (relative proportion 2.80, 95% CI 2.65-2.96). The detection of CIN 2 or worse was also increased (relative proportion 1.54, 95% CI 1.31-1.80), whereas there was no increase in screen-detected cervical cancer diagnoses (relative proportion 1.27, 95% CI 0.76-2.12). Within the first 4 years after a negative screening test result, including 168,477 woman-years at risk after a negative screen result in the HPV period and 451,421 woman-years after a negative screen result in the cytology period, the risk of a cervical cancer diagnosis was approximately 4 per 100,000 woman-years and was similar for both screening tests (relative risk 0.99, 95% CI 0.41-2.35)., Conclusion: Human papillomavirus testing led to more positive screening test results and diagnoses of high-grade CIN lesions. Few women were diagnosed with cervical cancer after a negative screening test result., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Cervical cancer is the fourth most common form of cancer among women. Smoking tobacco seems to be a risk factor for the development of cervical intra-epithelial neoplasia (CIN) and cervical cancer, but the exact role of smoking in the process of cervical carcinogenesis is not known. The aim of this study is to investigate the relationship between smoking and the development of CIN and cervical cancer. Areas covered: We searched Embase, Medline, Cochrane Central, Web of Science, and Google Scholar for studies on smoking and CIN and cervical cancer, published between 2009 and 2018. The following were the outcomes: CIN3 alone, CIN2 and CIN3 combined, CIN2+, CIN3+, and cervical cancer alone. We included 49 studies in our review and 45 in our meta-analyses. Expert opinion: Based on the available evidence it can be - cautiously - concluded that smoking increases the risk of cervical abnormalities. However, the high risk of bias indicates that for future studies, it will be important to adjust for relevant predictors, to separate CIN from cervical cancer as outcome measures, and to report research methods in detail.

Background: Persistent infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for the development of cervical cancer, but factors contributing to HR-HPV persistence are incompletely understood. The objective of this study was to test for associations of chronic stress and two aspects of diurnal cortisol secretion (i.e., the cortisol awakening response [CAR] and total cortisol output over the day [AUCgday]) with HR-HPV status at baseline and 12 months later (follow-up)., Methods: We evaluated 188 women (25 ± 3 years) at baseline. Follow-up investigation was restricted to HR-HPV infected women at baseline. Of the initial 48 HR-HPV positive participants, 42 completed the follow-up (16 HR-HPV positive and 26 HR-HPV negative). At baseline and follow-up, we determined HR-HPV status in cervical smears, assessed chronic stress, and repeatedly measured salivary cortisol over the day. At baseline, we analyzed salivary cortisol only in a subgroup of 90 participants (45 HR-HPV negative and 45 HR-HPV positive)., Results: At baseline, higher chronic stress (excessive demands at work: p = .022, chronic worrying: p = .032), and a higher CAR (p = .014) were related to baseline HR-HPV positivity. At follow-up, there was a statistical trend for a positive association between the CAR and HR-HPV positivity (p = .062). Neither the CAR nor the AUCgday mediated the associations between chronic stress and HR-HPV status., Conclusions: Our findings suggest that both chronic stress and diurnal cortisol are related to the presence of HR-HPV infection and may thus play a role in HPV-associated cervical carcinogenesis.

Human papillomavirus (HPV) DNA integration is a crucial event in cervical carcinogenesis. However, scarce studies have focused on studying HPV integration (HPVint) in early-stage cervical lesions. Using HPV capture followed by sequencing, we investigated HPVint in pre-tumor cervical lesions. Employing a novel pipeline, we analyzed reads containing direct evidence of the integration breakpoint. We observed multiple HPV infections in most of the samples (92%) with a median integration rate of 0.06% relative to HPV mapped reads corresponding to two or more sequence breakages. Unlike cancer studies, most integrations events were unique (supported by one read), consistent with the lack of clonal selection. Congruent to other studies, we found that breakpoints could occur, practically, in any part of the viral genome. We noted that L1 had a higher frequency of rupture integration (25%). Based on host genome integration frequencies, we found previously reported integration sites in cancer for genes like FHIT, CSMD1, and LRP1B and putatively many new ones such as those exemplified in CSMD3, ROBO2, and SETD3. Similar host integrations regions and genes were observed in diverse HPV types within many genes and even equivalent integration positions in different samples and HPV types. Interestingly, we noted an enrichment of integrations in most centromeres, suggesting a possible mechanism where HPV exploits this structural machinery to facilitate integration. Supported by previous findings, overall, our analysis provides novel information and insights about HPVint.

Background: In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification., Methods: We assessed the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after repeatedly testing positive for the same HPV type(s) in the randomized population-based screening study Amsterdam (POBASCAM). We compared 18-month CIN3+ risks in HPV-positive women (intervention, n = 1,066) to those in HPV-positive/cytology-negative women who tested HPV-positive in the next screening round (control, n = 111) five years later, stratified for HPV type concordance., Results: The 18-month CIN3+ risk was 15% in HPV-positive women in the intervention group, 40% in the control group after two-round type concordance (relative risk 2.6, 95% confidence interval 1.9-3.4), and 20% in the control group after a type switch (1.3, 0.5-3.2). The relative increase in CIN3+ risk after two-round type concordance was similar in <35-year-old (3.0, 2.0-4.4) and older women (2.2, 1.4-3.5), and was high in high-risk HPV-positive women who were HPV16/18/31/33/45-negative in both rounds (9.9, 4.4-21.9)., Conclusions: Five-year HPV type concordance signals high CIN3+ risk and warrants referral for colposcopy without additional cytology triage., Impact: HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years., (©2020 American Association for Cancer Research.)

Introduction: High-risk human papillomavirus (HR HPV) is found to be responsible for 4.5% of cancer in general, primarily cervical cancer. We aim here to highlight the prevalence and genotypes of HR HPV and correlate its association with Pap tests' results, which are still not well known in the Eastern Province of Saudi Arabia., Methods: Over 7 years (2013-2019), the results of 164 Saudi women coinvestigated for HR HPV along with Pap tests were collected from the archive of King Fahd University Hospital. Only women who had atypical squamous cells of undetermined significance (ASCUS) on the Pap test and those at elevated risk of infection were cotested for HR HPV; otherwise, the Pap test was the only screening modality for cervical cancer. Data were organized and statistically analyzed using IBM SPSS v26., Results: Out of 164 Saudi women, 14.5% (n = 24/164) showed positive results for HR HPV (8 patients had HPV16 and 2 had both HPV16 and HPV18/45, while the remaining 14 had other HR HPV); among them, 41.5% (n = 10/24) had an abnormal Pap test (5 ASCUS and 5 LSIL), while 58.5% (n = 14/24) had a negative Pap test. On the other hand, 21% (n = 35/164) of patients, in the study, had an abnormal Pap test (24 ASCUS, 8 low-grade squamous intraepithelial lesion [LSIL], and 3 atypical glandular cell [AGC]). In 80% (n = 19/24) of ASCUS cases, HR HPV was not detected; however, 20% (n = 5/24) were positive for other HR HPV. Concerning LSIL cases, 62.5% (n = 5/8) were positive for HR HPV (1 case showed HPV16 and HPV18/45, 2 cases showed HPV16, and 2 cases showed other HR HPV), while in the remaining 37.5% (n = 3/8) LSIL cases, HR HPV was negative; similarly, all AGC cases were negative for HR HPV. Statistical analysis showed a significant correlation between HPV status and Pap test findings (p value <0.001)., Discussion/conclusion: HR HPV frequency and genotype distribution, in this study, might reflect a different regional infection pattern. The high association of HR HPV with negative cytology emphasizes the need to add the HR HPV test to screening modalities of cervix cancer., (© 2020 S. Karger AG, Basel.)

Objective: To determine the prevalence and predictors of precancerous cervical lesions among HIV-positive women in Jos, Nigeria., Methods: A cross-sectional study was conducted from October 2017 to January 2018 among 326 HIV-positive women. Cervical smears were collected for examination at the AIDS Preventive Initiative of Nigeria clinics of Jos University Teaching Hospital (JUTH) and Bingham University Teaching Hospital (BhUTH), Jos, Nigeria. Demographic characteristics of participants were documented using a structured questionnaire. Data were entered and analyzed using SPSS version 21., Results: Of the 326 participants, precancerous cervical lesions were present in 40 (12.2%) women: 4 (1.2%) had atypical squamous cells of undetermined significance, 19 (5.8%) had low-grade squamous intraepithelial lesions, 1 (0.3%) had atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions, 13 (4.0%) had high-grade squamous intraepithelial lesions, and 3 (0.9%) had high-grade squamous intraepithelial lesions, suspected for invasion. The multivariate logistics regression model showed that parity (odds ratio 3.4, 95% confidence interval 1.3-9.5, P=0.043) was a significant predictor of precancerous cervical lesions., Conclusion: The prevalence of precancerous cervical lesions among HIV-infected women is relatively low compared to earlier reported prevalence in an HIV population in Jos. Increasing parity was a significant predictor., (© 2020 International Federation of Gynecology and Obstetrics.)

Background: The vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables., Methods: In total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software., Results: K-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036)., Conclusions: The vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.

Cervical carcinoma and cervical intraepithelial neoplasia (CIN) are associated with persistent infection by oncogenic subtypes of HPV (Human Papillomavirus). Factors linked to immunity, genetics and others like oral contraceptive use, sexual behavior, coinfections with other microorganisms and smoking seem to influence the mechanisms that determine regression or progression to CIN and cervical cancer. We investigated the effect of the MHC class I chain-related gene A (MICA) and Killer Cell Lectin Like receptor K1 (KLRK1) genes on cervical cancer and CIN lesions susceptibility in a group of 195 patients from southern Brazil. There were found a significantly higher number of ex-smokers in the control group (p = 0.005). There were more oral contraceptives (OC) users in the patient group. MICA*008:01/04 allele showed a significant difference between patient and control groups (p = 0.03; OR = 0.63, 95% CI 0.41-0.96), as well as MICA*018:01(p = 0.004, OR = 0.15, 95% CI 0.03-0.64) and MICA*002:01/020 (p = 0.01; OR = 0.60, 95% CI 0.40-0.88). We also analyzed cases and controls according to the MICA-129 genotypes (Met/Val). There was found a difference (p = 0.02) with the Met/Val genotype in a higher frequency in controls and Val/Val and Val/MICA del at a higher frequency in the patient group. For the KLRK1 gene there was no significant difference between groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

High-risk human papillomavirus (HR-HPV) infection is a major etiological agent in the progression of cervical intraepithelial neoplasia (CIN) and cervical cancer. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic pollutants that exist widely in the environment. We hypothesized that PAHs exposure was related to the progression of cervical cancer, and could increase the effect of HR-HPV on CIN. We investigated the effects of PAHs exposure combined with HR-HPV infection on CIN in community population in Shanxi Province, China. A total of 2,285 women were enrolled into the study. HR-HPV genotypes were detected by flow-through hybridization technology. 1-hydroxypyrene (1-OHP) was detected by high-performance liquid chromatography. The top three HR-HPV genotypes were 16, 58 and 52 in turn. With unconditional logistic regression analysis, we found that HR-HPV infection (adjusted odds ratio [aOR] = 4.08, 95% confidence interval [CI]: 3.00-5.54), HPV16 infection (aOR = 4.71, 95% CI: 3.39-6.53), HPV58 infection (aOR = 2.29, 95% CI: 1.41-3.73) and PAHs high exposure (aOR = 2.57, 95% CI: 1.82-3.62) increased the risk of CIN2/3, showing an increasing trend (p < 0.001) with the severity of cervical lesions. Compared to Q1 (<0.06 μmol/molCr) levels of 1-OHP, women with Q4 (>0.11 μmol/molCr) had a higher risk for CIN2/3 (aOR = 7.68, 95% CI: 4.83-12.22). Additionally, we observed that there was a synergic effect between high exposure to PAHs and HR-HPV infection in CIN2/3. Furthermore, the results from the generalized multifactor dimensionality reduction model showed that there were joint interactions of PAHs, HPV16, HPV58 and HPV52 on the risk of CIN2/3. Our study revealed that high exposure to PAHs could increase the risk for CIN, and it posed stronger risk when combined with HR-HPV infection., (© 2019 UICC.)

Aim: The aim of the study was to compare the diagnostic value of HPV testing and colposcopy in patients with abnormal cytology results., Patients and Methods: A total of 186 women with cytological abnormalities were included in the study. The patients underwent colposcopy examinations and DNA HPV testing of cervical smear with genotyping., Results: The HPV test was demonstrated to be more sensitive (79.4%) than specific (60.2%) and was more sensitive than colposcopy for detecting CIN changes (79.4% vs. 73.7%). Combined tests achieved a high sensitivity (90.9%) and negative predictive value (96.1%) in detecting patients with CIN2+ and demonstrated the highest positive predictive value (77.3%) for detecting CIN1+. Colposcopy had a very good specificity (83.5%) and positive predictive value (71.2%) in finding CIN1+ cases., Conclusion: HPV tests showed a higher sensitivity than colposcopy, but colposcopy results presented higher specificity. Combining HPV testing and colposcopy proved to be the most efficient method for detecting CIN lesions., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions., (© 2019 UICC.)

Background: About one-third of the cervical cancer cases in Sweden occur in women over the age of 60. The primary aim of this study was to analyze the incidence of HPV, and HPV related dysplasia, in elderly women who had an HPV negative test at the age of 60 years or older., Methods: From October 2004 to June 2019, 1784 women aged 60-90 years were sampled for an HPV test when attending an outpatient gynecology clinic. Of these women, 827 HPV-negative women had two or more HPV tests at intervals of three months to eleven years (mean 3.2 years). The women with positive results had a repeat HPV test and cytology after 2.5 months on average. Those with a positive repeat HPV test were examined by colposcopy and biopsy., Findings: The overall prevalence of HPV was 5.4%, (95%CI 4.4-6.6, 96/1784). The incidence of HPV in the 827 women, who were HPV negative in their first test, was 2.4% (95%CI 1.5-3.8, n = 20). At the repeat test 1.2% remained positive (95%CI 0.6-2.3, n = 10). HPV-related dysplasia diagnosed by histology was found in 1.2% (95%CI 0.6-2.3, n = 10) of the 827 women. CIN2+ was found in 0.5% (95%CI 0.2-1.3, n = 4). In the repeat HPV test 52.6% 10/19) were HPV positive. The time between an HPV negative test and an HPV positive test and CIN2+ was on average 45.5 months (range 10-85 months). The positive predictive value (PPV) for CIN2+ was 20.0% in the first positive HPV test and 40.0% in the repeat HPV test. The women with CIN2+ had normal cytology. No cancer or glandular dysplasia was detected., Interpretation: In this study older HPV-negative women were at risk of becoming HPV positive. Among the women who were HPV positive in a repeat test, there was a high risk of dysplasia., Competing Interests: The authors have declared that no competing interests exist.

Objective: To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN)., Design: Population-based national cohort study., Setting and Population: All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries., Methods: The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised., Main Outcome Measure: Vaginal cancer., Results: We identified 898 incident cases of vaginal cancer. Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100 000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15 years of follow up: 65.7 (95% CI 21.2-203.6)., Conclusions: Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening., Tweetable Abstract: High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery., (© 2019 Royal College of Obstetricians and Gynaecologists.)

The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

The Alinity m HR HPV assay (Alinity) is a novel human papillomavirus (HPV) assay that individually identifies genotypes HPV16, HPV18, and HPV45 while reporting on 11 other high-risk HPV (hrHPV) genotypes in two aggregates: HPV31/33/52/58 and HPV35/39/51/56/59/66/68. The clinical performance of Alinity for screening for cervical cancer was evaluated in population-based settings. For women aged ≥30 years, the clinical sensitivity ( n  = 68) and specificity ( n  = 3,077) for the detection of cervical intraepithelial neoplasia grade 2+ (CIN2+) of Alinity were 100.0% and 92.4%, respectively, and were not inferior to those of the Qiagen Digene Hybrid Capture 2 high-risk HPV DNA assay (hc2) ( P  = 0.0006 and P  < 0.0001, respectively). The intralaboratory reproducibility and interlaboratory agreement of Alinity were 96.7% (kappa, 0.92) and 98.7% (kappa, 0.97), respectively. In the group ≥30 years of age, women who were baseline hrHPV negative had a lower risk for CIN2+ at 3 years using Alinity (0.04%) than those with a normal baseline cytology (0.65%) and had a risk comparable to that determined by the Abbott RealTime High Risk HPV assay (0.04%), hc2 (0.08%), or the Roche Cobas 4800 HPV assay (0.04%). High-risk HPV16/18 infection was associated with a significantly higher baseline and 3-year CIN2+ and CIN3+ risk than the absence of HPV16/18 or the presence of hrHPVs at the baseline (all P values were <0.05). The baseline CIN2+ risk was 8.8% for those with HPV31/33/52/58 infection and 2.5% for those with HPV35/39/51/56/59/66/68 infection, while the 3-year CIN2+ risk was 17.0% and 4.9%, respectively (relative risk, 3.4 [ P  = 0.03] and 3.5 [ P  = 0.003], respectively), suggesting that extended genotyping by Alinity may be valuable in improving patient risk stratification. Alinity fulfills international consensus guideline criteria for primary cervical cancer screening and can be considered clinically validated, demonstrating safety comparable to that of other clinically validated HPV tests., (Copyright © 2019 American Society for Microbiology.)

Background: Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN)., Methods: We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates., Findings: 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8-92·2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0-74·1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3% (95%CI:6·5-16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5-8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (95%CI:63-87), specificity 64% (95%CI:55-71), area under the curve (0·73 (95%CI:0·69-0·77))., Interpretation: Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing., Funding: NIHR, Genesis Research Trust, Imperial Healthcare Charity, Wellcome Trust NIHR Imperial BRC, European Union's Horizon 2020., (Copyright © 2019. Published by Elsevier B.V.)

Aim: Prophylactic human papillomavirus (HPV) vaccines are highly effective at preventing pre-cancerous cervical lesions when given in a three-dose schedule. Some post-hoc trial data suggest that one dose prevents HPV infection. If one dose could prevent pre-cancerous cervical lesions, then global cervical cancer prevention would be greatly facilitated. We assessed the effectiveness of quadrivalent HPV vaccine by number of doses against cervical intraepithelial neoplasia (CIN) 2 or 3/adenocarcinoma-in-situ (AIS)/cancer in Australia up to seven years post vaccination., Methods: We linked registry data from all 8 jurisdictional cervical screening registers, with the national HPV vaccination register, death index and cancer registers for all Australian women aged 15 or under when eligible for vaccine who screened between April 2007 (when vaccination commenced) and 31 December 2014. We performed Cox proportional hazard regression, adjusted a priori for age, socioeconomic status, and area of residence, to estimate hazard ratios of histologically confirmed CIN2/CIN3/AIS/cancer., Results: We included 250,648 women: 48,845 (19·5%) unvaccinated, 174,995 (69·8%) had received three doses, 18,190 (7·3%) two doses and 8,618 (3·4%) one dose. The adjusted hazard ratio was significantly lower for all dose groups compared to unvaccinated women (1 dose 0·65 (95%CI 0·52-0·81), 2 doses 0·61 (0·52-0·72) and 3 doses 0·59 (0·54-0·65).) With adjustment for age at vaccination amongst the vaccinated group, the adjusted hazard ratios for one dose and two dose recipients were comparable to three dose recipients (one dose 1.01 (95%CI 0.81-1.26), two doses 1.00 (0.85-1.17).) Multiple sensitivity analyses, including use of different dose assignment methods, produced consistent findings. Comparison with a historical cohort of age matched women showed that the result was not due to herd protection alone., Conclusions: One dose had comparable effectiveness as two or three doses in preventing high-grade disease in a high coverage setting. These findings support the hypothesis that one dose vaccination may be a viable strategy when working towards the global elimination of cervical cancer., (Copyright © 2019. Published by Elsevier B.V.)

Background: Human papilloma viruses (HPVs) are recognized as the major etiological agents of most pre invasive and invasive cancer of the uterine cervix. Many cofactors in association with high-risk HPV (HR-HPV) trigger infection which leads to cervical carcinogenesis. The aim was to study various cofactors and their association with cervical cancer in women infected with HR-HPV., Methods: The present study screened a total of 156 subjects for the presence of HPV infection. Association of various cofactors with cervical cancer was estimated using binary logistic regression analysis., Results: The HR-HPV infection showed a very significant risk factor for cervical cancer. Among the cofactors, the education level, early sexual exposure and age at pregnancy had no significant association while low socioeconomic status (SES) and high parity showed significant association as risk factors for cervical cancer. Tobacco chewing with betel quid was not significantly associated with cervical cancer., Conclusions: The present study indicates that low SES is a major risk factor associated with cervical cancer. Bringing awareness about HPV infection and intensifying routine screening programs for cervical cancer will help reduce the risk of cervical cancer among women with low SES in this region.

Human papillomavirus (HPV) infection can lead to the development of productive epithelial lesions and cervical cancer. Most cervical HPV infections are solved by cell-mediated immunity within 1-2 years, and it is known that chronic inflammation predisposes to lesions progression and tumour development. In this context, we highlight the CC chemokine receptor 5 (CCR5) which is involved in leucocytes chemotaxis to sites of inflammation, controlling the immune response. The CCR5 rs333 genotyping of 164 HPV infected women and 185 non-infected women was performed using polymerase chain reaction (PCR). HPV infection was more frequent among women under 34 years old (p < 0.001), single (p = 0.001), that received 1 minimum wage or less (p = 0.002), tobacco smokers (p = 0.007), who had the first sexual intercourse before 17 years old (p = 0.038) and that had 4 or more sexual partners during lifetime (p = 0.001). No significant difference regarding genotypes and alleles distribution according to HPV infection was observed. CCR5/CCR5 genotype was observed in 94.1% of HPV non-infected women and in 89% of infected ones, CCR5/Δ32 in 5.9% of HPV infected and in 10.4% of non-infected women, and Δ32/Δ32 was observed in only one (0.6%) infected patient. CCR5 genotypes were also not associated with cervical lesions development among HPV infected women (p = 0.167). Since CCR5 may control the antitumour immune response and cervical lesions and the studied rs333 polymorphism is not very frequent, other studies are necessary, in order to establish CCR5 role on HPV infection and squamous intraepithelial lesions development., (© 2019 John Wiley & Sons Ltd.)

Self-sampling for human papillomavirus (HPV) testing is an alternative to physician sampling particularly for cervical cancer screening nonattenders. The GRECOSELF study is a nationwide observational cross-sectional study aiming to suggest a way to implement HPV-DNA testing in conjunction with self-sampling for cervical cancer screening in Greece, utilizing a midwifery network. Women residing in remote areas of Greece were approached by midwives, of a nationwide network, and were provided with a self-collection kit (dry swab) for cervicovaginal sampling and asked to answer a questionnaire about their cervical cancer screening history. Each sample was tested for high-risk (hr) HPV with the Cobas HPV test. HrHPV-Positive women were referred to undergo colposcopy and, if needed, treatment according to colposcopy/biopsy results. Between May 2016 and November 2018, 13,111 women were recruited. Of these, 12,787 women gave valid answers in the study questionnaire and had valid HPV-DNA results; hrHPV prevalence was 8.3%; high-grade cervical/vaginal disease or cancer prevalence was 0.6%. HrHPV positivity rate decreased with age from 20.7% for women aged 25-29 years to 5.1% for women aged 50-60 years. Positive predictive value for hrHPV testing and for HPV16/18 genotyping ranged from 5.0% to 11.6% and from 11.8% to 27.0%, respectively, in different age groups. Compliance to colposcopy referral rate ranged from 68.6% (for women 25-29) to 76.3% (for women 40-49). For women residing in remote areas of Greece, the detection of hrHPV DNA with the Cobas HPV test, on self-collected cervicovaginal samples using dry cotton swabs, which are provided by visiting midwives, is a promising method for cervical cancer secondary prevention., (©2019 American Association for Cancer Research.)

Introduction: The aim of this qualitative study was to describe the motivation and experiences of women with cervical dysplasia and associated diagnoses who used electronic cigarettes (ECs) to reduce the number of cigarettes they smoked., Methods: Qualitative interviews were conducted with 26 women aged 18-65 years with cervical dysplasia and associated diagnoses who smoked at least three cigarettes daily for the past year or more and who enrolled in an intervention designed to substitute regular cigarettes with ECs. At the 12-week follow-up, patients were contacted by telephone. Semi-structured interviews were recorded, then transcribed, coded and analysed for themes., Results: When confronted with a new diagnosis associated with smoking, women in this study were eager to try ECs to help them reduce their intake of cigarettes. Women reported that physical cues similar to smoking, delivery of nicotine sufficient to assist with smoking reduction and the security of having the device available to use in instances where temptations to smoke may occur were all positive experiences in trying the device. Other women in the study reported negative experiences, such as a lack of sufficient nicotine to eliminate cravings, heaviness of the device and the need to keep it charged. Depression, nicotine addiction and habit were factors that made it difficult to decrease cigarette consumption., Conclusions: Findings suggest that ECs may help with smoking substitution in patients who must reduce smoking due to medical conditions or diagnoses., (© 2019 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Purpose: Investigating the effects of active smoking, passive smoking and semen of tobacco smoking sexual partners on the carcinogenesis of uterine cervix., Introduction: It is now well-established that persistence of Human Papillomavirus (HPV) infection is the strongest epidemiologic factor associated with intraepithelial neoplasia and cancer of cervix, as well as in other related locations such as in the vagina, vulva, anus, oral cavity, etc. A 1999 study indicates that the worldwide HPV prevalence in cervical carcinomas is 99,7 per cent. Multiple factors seem to intervene on cervical carcinogenesis, many of them related to tobacco, especially by direct local carcinogenic effect and local immunosuppression. Many studies have also shown that active or passive smoking in women (family-work environment, meeting places, etc.) greatly affects the occurrence, progression and degree of malignancy of carcinogenesis. Furthermore, particularly increased levels of nicotine and cotinine in the cervical mucus as well as prostate sperm fluids and urinary cotinine:creatinine ratios in smokers and passive smokers indicate that tobacco constituents do indeed reach the uterine cervix and lead to increased modification of DNA in cervical epithelium, suggesting biochemical evidence consistent with smoking as a cause of cervical cancer. The research presented today, though it took place over 30 decades ago (1975-1986 at the University Gynecological and Obstetric Clinic of Homburg ad Saar), we hope will serve as a reminder and contributing factor for further examination of the increased risk of cervical cancer in non-smoking women living with smoking partners., Study: The study analyzed a total of one thousand five-hundred and forty (1,540) medical history sheets (krankenblätter) of women aged from eighteen to seventy-four (18-74) years old that were admitted, treated, examined (PAP TEST) or referred for further tests by their family physicians to the Homburg ad Saar Clinic between 1975-1986. The study evaluated the general medical history of the 1,540 women with a special focus on gynecological and obstetric related data and gathered additional information from patients through written questionnaires completed via phone, mail or personal interviews. Among a range of factors and data studied during the research, our current presentation and discussion will focus on the development of cervical neoplasms in women, examining results from three different study groups: smokers, passive-smokers and women with smoking sexual partners., Results: Five hundred and forty-four cases (544) out of the overall study sample of one thousand five-hundred and forty (1,540) women, were identified as cases with pathological cell abnormalities (35.32%). Following diagnosis and treatment of transient lesions due to various inflammations (vaginitis, cervicitis etc.) one hundred and twelve (112) cases (20.59%) showed varying degrees of mild/reversible up to CIN 1-3 intraepithelial lesions. From the above sample of one hundred and twelve 112 cases, nineteen cases (19) were smoke free women who never smoked themselves, were not exposed to passive smoking and had non-smoker partners (16.96%). Forty-four (44) cases (39.29%) were female smokers, twenty-two (22) cases (19.64%) were women exposed to regular passive smoking (family-work environment) with a smoke-free partner and twenty-seven (27) cases (24.11%) were women non-smokers with a smoker partner. From the above findings, intraepithelial lesions were found to be higher (and with a progressive malign ratio) on the study groups that were associated with tobacco use either active or passive and therefore, the synergistic harmful effect of smoking, progressively from passive smokers to active smokers, is clearly evident on the occurrence and progression of cervical malignancies. As already mentioned above, the presence of HPV has been widely proven to be almost exclusively the cause of different degrees of neoplasia in the cervix for more than 99.7% of cervical carcinogenesis. However, the harmful effects of a) active smoking, b) passive smoking and c) the exposure to tobacco constituents through an active smoker partner, in women, should be sought and possibly attributed to the catalytic reduction of cervical self-defense and overall cervical immunity disruption which results to the exposure of cervix to elevated levels of nicotine-cotinine and cancer-causing chemicals related to smoking, may work together with certain types of HPV limiting the natural ability of the cervix to defend against carcinogenesis and therefore increase the likelihood of developing cancer., Conclusion: Since the almost exclusively cause of cervical neoplasms is due to the presence and carcinogenic activity of HPV, the harmful/synergistic effect of smoking, passive smoking and partner smoking cannot be attributed to the direct carcinogenic effect of nicotine but to the overall damage of the immune system as we as the reduction of cervical self-defense making it more vulnerable to the carcinogenic nature of HPV, in particular the increased pathogenic types 16 and 18. Lastly, another potential correlation that could be further examined is the potential effects of tobacco constituents in cervical fluids on the self-defense system of the male reproductive system.

Objective: To examine the incidence of lower genital tract dysplasia in women after solid organ transplantation, to evaluate risk factors associated with development of dysplasia, and to assess the timeline of disease development., Methods: This was a retrospective study of female patients who underwent solid organ transplantation at a large-volume tertiary care center between 2000 and 2015. Demographic and clinicopathologic factors were extracted from electronic medical records. Cumulative incidence of lower genital tract dysplasia was calculated, and univariate and multivariable logistic regression were performed to identify risk factors for the development of dysplasia., Results: Among 394 female solid organ transplant recipients, the median age was 41 years (interquartile range 29-53). Forty-seven (11.9%; 95% CI 8.8-15.9%) women developed lower genital tract dysplasia over a median follow-up of 7.8 years (interquartile range 4.6-12.9). Thirty-eight (9.6%) developed cervical intraepithelial neoplasia (CIN), with 14 (3.6%) diagnosed with CIN 2 or worse (one was cervical carcinoma). Nineteen (4.8%) developed noncervical lower genital tract dysplasia, including vulvar, vaginal, or anal dysplasia, with 13 (3.3%) diagnosed with high-grade dysplasia or worse (five were lower genital tract carcinoma [three anal, one vulvar, and one vaginal]). Ten (2.5%) developed both cervical and noncervical lower genital tract dysplasia. Black race was significantly associated with developing dysplasia (odds ratio [OR] 2.86; 95% CI 1.33-6.13) as was hydroxychloroquine use (OR 5.95; 95% CI 1.96-18.09). High-grade cervical dysplasia was diagnosed at a median interval of 3.18 years after transplant; noncervical high-grade lower genital tract dysplasia was diagnosed at a median interval of 3.94 years., Conclusions: One in eight transplant recipients developed lower genital tract dysplasia and approximately half were high-grade dysplasia or cancer. Black race and hydroxychloroquine use were associated with an increased risk of dysplasia. Yearly cervical screening and comprehensive lower genital examination beyond the cervix is indicated in this population.

Background: Incidence of high-grade cervical lesions (HGCL) has declined in the U.S following the introduction of the human papillomavirus (HPV) vaccine in 2006. However, many women continue to be diagnosed with HGCLs, including those eligible to receive the vaccine but did not. We determined self-reported barriers to and correlates of HPV vaccination in vaccine-eligible women diagnosed with cervical intraepithelial neoplasia grades 2, 2/3, 3 and adenocarcinoma in situ (CIN2+)., Methods: Data from a statewide surveillance system in Connecticut for CIN 2+ during 2008-2015 were used for this analysis. Enhanced surveillance data were collected for women residing in New Haven County, including HPV vaccine history and demographic factors, through chart review and patient interviews. Women who reported being unvaccinated were asked why they did not receive the vaccine. We evaluated trends in reasons for not receiving the vaccine using a two-sided Cochran Armitage trend test. Log-binomial analysis was used to assess associations between sociodemographic characteristics and vaccination status., Results: Between 2008 and 2015, 1625 vaccine-eligible women were diagnosed with CIN2+, with 882 of these women reporting never receiving the HPV vaccine. The proportion of unvaccinated vaccine-eligible women did not significantly change from 2008 to 2015 (p = 0.18, range 49.1% to 60.0%). The most commonly reported reason for being unvaccinated was age/too old, followed by previous HPV diagnosis and no provider recommendation. Women who had public or no insurance were significantly more likely than privately insured women to report being unvaccinated (p = <0.001, p = 0.0034)., Conclusions: Commonly cited barriers to vaccination, such as age/too old and previous HPV diagnosis, are not contraindications for vaccination. Furthermore, frequent reporting of no provider recommendation underscores the important role providers play in the immunization of their patients. These results indicate the need for greater efforts by providers to dispel myths about HPV vaccine eligibility and to promote vaccination for all of their eligible patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction : Validated molecular assays for the detection of high risk (hr) Human Papillomavirus (HPV) DNA underpin the screening protocols against cervical cancer. New molecular assays based on real-time PCR also display the genotype of hrHPV. Areas covered : Recently, the BD Onclarity™ HPV assay (Onclarity), extended HPV genotyping test, for use on the BD Viper™ LT Instrument, has been developed. Onclaritys application for the detection and genotyping of hrHPV has been validated for the identification of women at high risk for cervical intraepithelial neoplasia of grade 2 or more in accordance with European Guidelines and FDA specifications. Expert opinion : Onclarity displays good sensitivity and specificity performance for HR-HPV detection and offers the possibility for genotype-specific reporting: the latter could provide risk-stratification for high-grade cervical disease during screening and facilitate surveillance for persistent genotypes in women at follow-up visits.

Introduction: Cervical cancer remains an important public health problem in Chinese women owing to the lack of a national screening program. The aim of the present study was to evaluate human papillomavirus (HPV) and Papanicolaou (Pap) test results preceding the histologic diagnosis of cervical intraepithelial neoplasia 2/3 (CIN2/3) in China's largest College of American Pathologists-certified clinical laboratory., Materials and Methods: All cases of CIN2/3 histologically diagnosed from January 2011 to August 2016 were retrieved from the pathology department records. The Pap cytology and HPV test results from the 6 months before the CIN2/3 diagnoses were analyzed., Results: A total of 5699 patients with histologically diagnosed CIN2/3 had previous Pap and/or HPV Hybrid Capture 2 testing results within the previous 6 months. The average age was 39.5 years (range, 16-82 years). Of these patients, 4288 had Pap test findings (average, 1.5 months) available. The results were high-grade squamous intraepithelial lesion in 44.1%, low-grade squamous intraepithelial lesion in 20.0%, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, in 16.0%, atypical squamous cells of undetermined significance, in 12.3%, atypical glandular cells in 0.7%, and negative in 6.9%. Of the 5699 patients, 2546 had HPV Hybrid Capture 2 test results (average, 1.4 months) available. Of these, 91.7% had positive results and 8.3% had negative results. Of 1135 patients with both previous Pap and HPV results, 7.1% had negative HPV results and 8.0% had negative Pap results (P = 0.38). Only 21 patients (1.9%) had double negative results., Conclusions: The present study has reported the previous results of HPV testing and Pap cytology for patients with high-grade cervical squamous precursor lesions in a population of women in China who had not undergone intensive previous screening. Both high-risk HPV and Pap cytology had similar negative testing rates for these women, although double negative results were less common. These results support the value of combined testing in the detection of cervical cancer precursors., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Background : Genotyping for the most carcinogenic human papillomavirus (HPV) types (HPV16/HPV18) can identify high risk of underlying cervical precancer and guide further management. Research design and methods : A pooled analysis was performed of the clinical accuracy of high-risk HPV (hrHPV) testing and HPV16/18 genotyping in triage of women with low-grade squamous intraepithelial lesions (LSIL). Data regarding 24 assays evaluated in four VALGENT validation panels were used. Results : In women with LSIL, hrHPV had a pooled sensitivity for CIN2+ of 95.5% (95% CI: 91.0-97.8%) and a specificity of 25.3% (95% CI: 22.2-28.6%). HPV16/18 genotyping had a sensitivity and specificity for CIN2+ of 52.9% (95% CI: 48.4-57.4%) and 83.5% (95% CI: 79.9-86.5%), respectively. The average risk of CIN2+ was 46.1% when HPV16/18-positive, 15.5% in women who were HPV16/18-negative but positive for other hrHPV types and 4.3% for hrHPV-negative women. Conclusions : Triage of women with LSIL with HPV16/18 genotyping increases the positive predictive value compared to hrHPV testing but at the expense of lower sensitivity. Arguably, women testing positive for HPV16/18 need further clinical work-up. Whether colposcopy referral or further surveillance is recommended for women with other hrHPV types may depend on the post-test risk of precancer and the local risk-based decision thresholds.

Background This study aimed to evaluate the clinical performance of p16/Ki-67 dual staining in the detection of cervical intraepithelial neoplasia grade 2 or 3 or worse (CIN2+/CIN3+) in Chinese women. Methods Cervical exfoliated cells were collected from 537 eligible women and were used for liquid-based cytology (LBC), p16/Ki-67 dual staining, and human papillomavirus (HPV) DNA testing. All women received colposcopy with biopsies taken at abnormal sites. Histopathological diagnoses were used as the gold standard. Results p16/Ki-67 staining had a positivity rate of 43.58% overall; the rate increased significantly with histological severity (p <0.001). The sensitivities of p16/ki-67 for detecting CIN2+ and CIN3+ were 88.10% and 91.30%, respectively. Compared with high-risk HPV (HR-HPV), sensitivity of p16/Ki-67 was lower for detecting CIN2+ (88.10% versus 95.71%), but similar for detecting CIN3+ (91.30% versus 96.27%). Specificities of p16/Ki-67 were 85.02% for detecting CIN2+ and 76.86% for detecting CIN3+, values similar to those for LBC (84.71% for CIN2+, 80.05% for CIN3+) but higher than those for HR-HPV (62.77% for CIN2+, 71.25% for CIN3+). All the tests performed better in women>30 years. With respect to the performance of triage for women with ASC-US, sensitivities of p16/Ki-67 were 86.36% for detecting CIN2+ and 83.33% for detecting CIN3+, values similar to those of HR-HPV. However, specificities of p16/Ki-67 were both higher than those of HR-HPV (85.96% versus 67.54% for CIN2+, 79.84% versus 62.90% for CIN3+). Conclusion P16/Ki-67 dual staining could probably provide an optional method for China's national cervical cancer screening, and could also be considered as an efficient method of triage for managing women with ASC-US., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We investigated the infection status and genotype distribution of human papillomavirus (HPV) in women of different ages and various ethnic groups in the Yili region, Xinjiang, China. We checked the HPV genotypes of 3,445 samples of exfoliated cervical cells using the PCR-reverse dot blot method. The total infection rate of HPV was 25.60% (882/3,445). The ethnic stratification showed that the infection rates were 22.87% (196/857) in Uygur, 21.55% (122/566) in Kazak, and 27.89% (564/2,022) in Han individuals. The most prevalent high-risk genotypes were HPV16, HPV52, and HPV53 in Uygur and Kazak and HPV16, HPV52, and HPV58 in Han ethnic groups. The age stratification showed that the infection rates in Han, Uygur, and Kazak women were up to 40.9% (61/149) in those aged 26-30 years, 41.5% (22/53) in those over 61 years old, and 30.2% (29/96) in those 46-50 years old, respectively. Therefore, HPV infection and HPV genotype distribution varied among the different age groups of the three ethnic groups.

We report the incidence of cervical intraepithelial neoplasia (CIN) among HIV-infected women who did not have any colposcopic or histopathological evidence of CIN at baseline. Of the 1,023 women without any CIN at baseline, 855 (83.6%) have been followed up to a maximum of 6.4 years contributing 2,875 person years of observation (PYO). Among these 855 women, 54 cases of any CIN were observed resulting in incidence rate of any CIN of 1.9 per 100 PYO. The median time for follow-up for women with any CIN was 3.0 (IQR 1.6-3.7) years. The cumulative incidence rate per 100 PYO of CIN 2 or worse lesion in women with HPV-18 infection at baseline was 13.3% (95% CI 5.1-26.8); in women with HPV-16 infection was 10.8% (95% CI 4.4-20.9); in women with HPV-31 infection was 4.2% (95% CI 0.9-11.7); and in women with other high-risk HPV infections was 5.4% (95% CI 2.6-9.7). HPV-18 infection at baseline contributed highest frequency of incident CIN 2 or worse lesions followed by HPV-16 infection; however, other high-risk HPV types were also responsible for substantial number of incident CIN. The elevated risk of CIN2+ disease in the study cohort was non-significant in women with CD4 count <200, possibly because of the small number of cases. Our results emphasize the need for regular cervical cancer screening of HIV-infected women and urgent implementation of cervical cancer screening services in HIV programs in India and other low and middle-income countries., (© 2018 UICC.)

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124-2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV-positive women. To date, longitudinal data on the cancer risk of methylation test-negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124-2 methylation analysis in an HPV-positive screening cohort with 14 years of follow-up. Archived HPV-positive cervical scrapes of 1,040 women (age 29-61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124-2 methylation. By linkage with the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow-up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124-2 methylation, including 24 women with cervical cancer in follow-up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow-up. Within screening round capability of FAM19A4/mir124-2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5-100). Kaplan-Meier estimate of 14-year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66-3.0) among baseline methylation-negative and 2.4% (95% CI: 1.4-3.6) among baseline cytology-negative women (risk difference: 0.71% [95% CI: 0.16-1.4]). In conclusion, a negative FAM19A4/mir124-2 methylation test provides a low cervical cancer risk in HPV-positive women of 30 years and older. FAM19A4/mir124-2 methylation testing merits consideration as an objective triage test in HPV-based cervical screening programs., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Human papillomavirus (HPV) vaccines protect against HPV types 16/18, but do not eliminate the need to detect pre-cancerous lesions. Australian women vaccinated as teenage girls are now entering their mid-thirties. Since other oncogenic HPV types have been shown to be more prevalent in women ≥30 years old, understanding high grade cervical lesions in older women is still important. Hormonal contraceptives (HC) and smoking are recognised cofactors for the development of pre-malignant lesions., Methods: 886 cases with cervical intraepithelial neoplasia (CIN) 2/3 and 3636 controls with normal cytology were recruited from the Pap Test Register of NSW, Australia. All women were aged 30-44 years. Conditional logistic regression was used to quantify the relationship of HC and smoking to CIN 2/3 adjusted for various factors., Results: Current-users of HC were at higher risk for CIN 2/3 than never-users [odds ratio (OR) = 1.50, 95%CI = 1.03-2.17] and risk increased with increasing duration of use [ORs:1.13 (0.73-1.75), 1.51 (1.00-2.72), 1.82 (1.22-2.72) for <10, 10-14, ≥15 years of use; p-trend = 0.04]. Ex-users had risks similar to never-users (OR 1.08, 95%CI = 0.75-1.57) regardless of duration of use. Current smoking was significantly associated with CIN 2/3 (OR = 1.43, 95%CI = 1.14-1.80) and risk increased with increasing number of cigarettes/day (p-trend = 0.02). Among ex-smokers, the risk of CIN 2/3 decreased with increasing time since quitting (p-trend = 0.04)., Conclusions: In this benchmark study, current, long term users of HC and current smokers of ≥5 cigarettes/day were each at increased risk of developing CIN 2/3. Findings support smoking cessation in relation to decreasing the risk of pre-cancerous lesions and reinforce the continuing need for cervical screening for cancer prevention in vaccinated and unvaccinated populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: This study aimed to provide more information for cancer prevention strategies by determining the distribution of human papilloma virus (HPV) genotype prevalence in invasive cervical carcinoma (ICC) and precancerous lesion patients in the Yangtze River Delta area in China., Methods: This multi-centre descriptive cross-sectional study involves four university hospitals in the Jiangzhehu area. Women with histologically confirmed cervical intraepithelial neoplasia (CIN) 1, CIN2, CIN3 or ICC who were diagnosed and treated in the four selected hospitals between February 2012 and April 2014 were eligible for recruitment. The average age of the patients was 40.93 ± 11.87 years old, among whom the youngest was 17 years old and the oldest was 76 years old.Those with immunodeficiency diseases or a previous history of cancer or CIN were excluded. HPV genotyping was performed by a central laboratory. The distribution and age and disease specificity of the HPV genotype prevalence were analysed., Results: Of the 2181 collected samples, 251 were ICC and 1930 were CIN. The mean age of cervical cancer and CIN patients was 40.93 ± 11.8 years (range, 17-76 years). The five most commonly identified HPV types in each lesion class were as follows: CIN1: 52, 58, 16, 33, and CP; CIN2: 16, 58, 52, 33, and 31; CIN3: 16, 58, 33, 52, and 31; and ICC: 16, 58, 18, 52, and 33. CIN1 had an earlier age of onset (30-40 years) than CIN2, CIN3, and cervical cancer. The age of onset of cervical cancer exhibited two peaks at 40-44 and 50-54 years of age. In all infected patients, the frequency of HPV infection with a single type was 62.9%, and with multiple types, it was 38.1%. There was no difference in the frequencies of multiple types amongst the different cervical lesions., Conclusions: The most prevalent genotypes in the investigated area (52, 58, 16 and 18) justify the necessity of anti-HPV vaccination in teenagers and young girls under 24 years old in the Yangtze River Delta area in China. Infection with multiple high-risk HPV types versus single infection does not increase the risk for ≥ CIN2 in ICC development.

Background: The total direct cost of screening and treating all human papillomavirus-related diseases (HPV-RD) has not been measured in a single study. Accurate cost estimates are needed to inform decisions on intervention priorities and evaluate the cost-effectiveness of existing programs. We used province-wide clinical, administrative, and accounting databases to measure direct medical costs of HPV infection in Manitoba (Canada)., Methods: All persons 9 years or older with health insurance coverage in Manitoba between April 2000 and March 2015 were eligible. We identified all persons with an incident HPV-RD and aggregated all medical costs (in 2014 Canadian dollars) related to that condition, including prescription drugs, diagnostic procedures, in-hospital and outpatient treatment, and physician visits., Results: We found that the median cost of treating a case of anogenital warts was $130. An episode of cervical dysplasia had a median cost of $220, compared to $1300 for an episode of cervical carcinoma in situ. The cost of treating HPV-related invasive cancer varied from $15,000 for cervical cancer to $33,000 for oral cavity cancer. Overall, 80% ($145 million) of the total cost was attributable to HPV infection. Cervical screening and follow-up accounted for $96 million (66%) of all costs and this cost component has declined following the introduction of new screening guidelines., Conclusions: Overall, the average direct medical cost of HPV infection was $720 per newborn. The economic burden of HPV remains significant, although changes in cervical screening guidelines, prompted by the introduction of a public HPV vaccine program, appear to have promoted a promising trend towards lower costs.

Human papillomavirus (HPV) testing is used in the triage of women with a borderline smear result. The efficiency of testing women with a low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells of undetermined significance (ASCUS) is less clear. For this reason we used a new HPV test that detects E6/E7 messenger RNA (mRNA), which might have a higher specificity. The objective of this prospective study was to assess whether HPV E6/E7 mRNA positivity in women with ASCUS and LSIL at baseline, is able to predict those women who have a high risk of developing a histological cervical intraepithelial neoplasia (CIN2) or worse lesion. We took into consideration the women's age and HPV DNA genotype and followed them up for 3 years. Cervical samples from women with high-risk HPV (HR-HPV) DNA-positive ASCUS (n = 90) or LSIL (n = 222) were tested for the presence of HR-HPV E6/E7 mRNA and the women were monitored for the development of histopathologically verified CIN2+. Thirteen patients with ASCUS and 17 with LSIL did not complete follow-up. All patients with LSIL and ASCUS, enrolled in this study, had confirmed lesions at the colposcopic examination. Follow-up was available for 312 women, 193 were positive in the HR-HPV DNA test and 93 had a HPV E6/E7 mRNA positive test. Finally, 22 women positive in the HPV DNA test for high-risk genotypes and with positive E6/E7 mRNA had a histologically confirmed CIN2+. Only two cases with negative HPV E6/E7 mRNA had CIN2+. The study shows that women positive in the HPV E6/E7 mRNA test have a greater risk of malignant progression of cervical lesions and therefore deserve greater attention and earlier check-ups.

Background: Persistent infection with high-risk human papillomavirus (HPV) strains, especially HPV 16 and HPV 18, is associated with the onset of various malignant diseases, including cervical carcinoma in women. HPV DNA testing is thus being implemented as a complementary method to standard cytological examination, mainly due to its increased sensitivity., Aim: This review outlines the role of HPV in cervical carcinogenesis, with a focus on the formation of cervical intraepithelial neoplasias (CIN1-3) and the molecular mechanism underlying cellular transformation. Current biomarkers used to screen premalignant lesions are described, including mRNA transcripts of the E6 and E7 genes, protein p16 (a cyclin-dependent kinase inhibitor that regulates cell cycle progression from G1 to S phase), altered DNA methylation patterns, and actions of specific microRNAs (short (18-22 bp), non-coding, single-stranded RNA molecules that regulate gene expression at the post-transcriptional level). This review also describes the advantages and drawbacks of commercial HPV tests, and depicts novel methods for more cost-effective and faster HPV diagnostics based on optical or electrochemical detection., Conclusion: Although great progress has been made, the incidence and mortality rates of cervical malignancies remain relatively high, especially in developing countries. Incorporation of HPV testing into routine screening programs could help to decrease mortality rates; however, the cost of such testing must be reduced if it is to compete with current cytology-based examinations.Key words: HPV - cervical carcinoma - HPV testing - nucleic acid hybridization - mRNA - DNA methylation - microRNA This work was supported by MEYS-NPS I-LO1413 and GAČR 17-08971S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 25. 9. 2017Accepted: 26. 1. 2018.

Objective: To evaluate the prevalence of anal intraepithelial lesions and associated risk factors in women with cervical neoplasia., Methods: The present cross-sectional study enrolled patients with intraepithelial or invasive cervical neoplasia who had been referred to the lower genital tract pathology outpatient department of the Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil, between December 1, 2008, and December 31, 2009; patients with HIV infections were excluded. All participants underwent anal cytology and high-resolution anoscopy; sociodemographic and clinical risk factors were identified using multivariate analysis., Results: There were 324 patients included and 37 (11.4%) had anal intraepithelial neoplasia. Factors associated with anal intraepithelial neoplasia in the multivariate analysis were being older than 35 years of age (P=0.002), having completed no more than 4 years of education (P=0.012), anomalous anal cytology (P=0.003), and anomalous high-resolution anoscopy findings (P<0.001); subclinical HPV lesions on vulvoscopy (P=0.057) were not associated with anal intraepithelial neoplasia., Conclusion: The prevalence of anal intraepithelial neoplasia was high among patients with cervical neoplasia who did not have HIV, particularly patients older than 35 years., (© 2017 International Federation of Gynecology and Obstetrics.)

Purpose: The aim of this study was to investigate the clinical performance of high risk (HR) HPV E6/E7 mRNA assay in detecting cervical high-grade intraepithelial neoplasia and cancer among women with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou (Pap) smears., Methods: A total of 160 patients with ASCUS who underwent HR-HPV DNA assay, HR-HPV E6/E7 mRNA assay and colposcopy biopsy at Third Affiliated Hospital of Zhengzhou University, China, from December 2015 to March 2017, were enrolled. Logistic regression analysis was used to evaluate the relationship between pathological results with clinical biologic factors., Results: Univariate analysis showed that the qualitative results of HR-HPV DNA, qualitative results of HR-HPV E6/E7 mRNA and expression levels of HR-HPV E6/E7 mRNA were risk factors of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (all P < 0.05). Multivariable analysis found that only the expression levels of HR-HPV E6/E7 mRNA was associated with high-grade CIN and cervical cancer (OR = 8.971, 95% CI = 2.572-31.289, P = 0.001). An optimal cut-off value of ≥ 558.26 copies/ml was determined using receiver operating characteristic curve, and specificity of cut-off value were higher than E6/E7 mRNA qualitative assay and DNA qualitative assay., Conclusion: HPV E6/E7 mRNA quantitative assay may be a valuable tool in triage of ASCUS pap smears. A high specificity of E6/E7 mRNA quantitative assay as a triage test in women with ASCUS can be translated into a low referral for colposcopy.

Purpose: As previously reported, treatment of high-grade cervical dysplasia with VGX-3100 resulted in complete histopathologic regression (CR) concomitant with elimination of HPV16/18 infection in 40.0% of VGX-3100-treated patients compared with only 14.3% in placebo recipients in a randomized phase IIb study. Here, we identify clinical and immunologic characteristics that either predicted or correlated with therapeutic benefit from VGX-3100 to identify parameters that might guide clinical decision-making for this disease. Experimental Design: We analyzed samples taken from cervical swabs, whole blood, and tissue biopsies/resections to determine correlates and predictors of treatment success. Results: At study entry, the presence of preexisting immunosuppressive factors such as FoxP3 and PD-L1 in cervical lesions showed no association with treatment outcome. The combination of HPV typing and cervical cytology following dosing was predictive for both histologic regression and elimination of detectable virus at the efficacy assessment 22 weeks later (negative predictive value 94%). Patients treated with VGX-3100 who had lesion regression had a statistically significant >2-fold increase in CD137 + perforin + CD8 + T cells specific for the HPV genotype causing disease. Increases in cervical mucosal CD137 + and CD103 + infiltrates were observed only in treated patients. Perforin + cell infiltrates were significantly increased >2-fold in cervical tissue only in treated patients who had histologic CR. Conclusions: Quantitative measures associated with an effector immune response to VGX-3100 antigens were associated with lesion regression. Consequently, these analyses indicate that certain immunologic responses associate with successful resolution of HPV-induced premalignancy, with particular emphasis on the upregulation of perforin in the immunotherapy-induced immune response. Clin Cancer Res; 24(2); 276-94. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: We aimed, in the present study, to measure the risk related to the high-grade cervical intraepithelial neoplasia grade 3 (CIN3) or worse (CIN3+) or worse/high-grade squamous intraepithelial lesions with respect to changes in human papillomavirus (HPV) and smoking status., Materials and Methods: A structured interview underwent for 7129 women. Then, we obtained their cervical cells and subjected to HPV testing. High-risk HPV infected and "no prevalent" cervical disease infected women were followed for cervical lesions up to 12 years (at baseline; n = 1531). Hazard ratios (HRs) for diagnosis of CIN3 (or worse) or worse/high-grade intraepithelial lesions were calculated along with the corresponding 95% confidence intervals (CIs)., Results: Among high-risk HPV-positive women, the conditions of long-term (more than 8 years) smokers and heavy (18 or more cigarettes/day) smokers are highly responsible for the increased risk for CIN3 or CIN3+. In the cases of persistent HPV-infected women, heavy smoking led to a higher risk for CIN3+ than those women who never smoked (HR, 2.31; 95% CI, 1.12-4.16)., Conclusion: We concluded here that smoking leads to an enhanced risk of high-grade cervical lesions in persistent high-risk HPV-infected women. This makes a good understanding of smoking's role in cervical cancer., Competing Interests: There are no conflicts of interest

Background: Long Interspersed Nuclear Elements-1 (LINEs-1) methylation from white blood cells (WBCs) DNA has been proposed as biomarker associated with different types of cancer. The aim of the present study was to investigate the degree of WBCs LINE-1 methylation, according to high-risk Human Papilloma Virus (hrHPV) status in a healthy population, and the association with high-grade Cervical Intraepithelial Neoplasia (CIN2+) in hrHPV positive women., Methods: Women with abnormal cervical cells were enrolled and classified by histological diagnosis and hrHPV infection. A structured questionnaire was used to obtain information on socio-demographic variables and lifestyle factors. LINE-1 methylation level in WBCs was measured by pyrosequencing-based methylation analysis after bisulfite conversion., Results: Among 252 women diagnosed with normal cervical epithelium, with regard to LINE-1 methylation level no significant difference was observed between hrHPV positive and hrHPV negative women, also adjusting for known risk factors of infection. The association between WBCs LINE-1 methylation and CIN2+ status was analyzed in hrHPV positive women. The median value of LINE-1 methylation levels was higher in cases (CIN2+) than in controls (75.00% versus 73.17%; p = 0.002). For a one-unit increase in LINE-1 methylation level, the odds of being diagnosed with CIN2+ increased by 10%, adjusting for known factors related to LINE-1 methylation (adjOR: 1.10; 95% CI:1.01-1.20; p = 0.032). The Receiver-Operating Characteristic (ROC) curve analysis identified the cut-off value of 73.8% as the best threshold to separate cases from controls (sensitivity: 63.4% and specificity: 61.8%)., Conclusions: LINE-1 methylation status in WBCs DNA may represent a cost-effective and tissue-accessible biomarker for high-grade CIN in hrHPV positive women. However, LINE-1 hypermethylation cannot be considered specific for cervical cancer (CC) and a model based solely on LINE-1 methylation levels has limited performance. Further investigations are necessary to propose and validate a novel methylation biomarker panel, based on LINE-1 methylation and other differentially methylated regions, for the screening of women at risk of CC.