Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

HPV DNA Testing and Mobile Colposcopy for Cervical Precancer Screening in HIV Positive Women: A Comparison Between Two Settings in Ghana and Recommendation for Screening.

INTRODUCTION: Women living with HIV (WLHIV) have higher prevalence and persistence rates of high-risk human papillomavirus (hr-HPV) infection with a six-fold increased risk of cervical cancer. Thus, more frequent screening is recommended for WLHIV. OBJECTIVES: This retrospective descriptive cross-sectional study was conducted to investigate and compare the prevalence of hr-HPV infection and abnormal findings on mobile colposcopy in two cohorts of WLHIV following cervical screening in rural and urban settings in Ghana. METHODS: Through the mPharma 10 000 Women Initiative, WLHIV were screened via concurrent hr-HPV DNA testing (MA-6000; Sansure Biotech Inc., Hunan, China) and visual inspection (Enhanced Visual Assessment [EVA] mobile colposcope; MobileODT, Tel Aviv, Israel) by trained nurses. The women were screened while undergoing routine outpatient reviews at HIV clinics held at the Catholic Hospital, Battor (rural setting) and Tema General Hospital (urban setting), both in Ghana. RESULTS: Two-hundred and fifty-eight WLHIV were included in the analysis (rural, n = 132; urban, n = 126). The two groups were comparable in terms of age, time since HIV diagnosis, and duration of treatment for HIV. The hr-HPV prevalence rates were 53.7% (95% CI, 45.3-62.3) and 48.4% (95% CI, 39.7-57.1) among WLHIV screened in the rural vs urban settings (p-value = .388). Abnormal colposcopy findings were found in 8.5% (95% CI, 5.1-11.9) of the WLHIV, with no significant difference in detection rates between the two settings (p-value = .221). Three (13.6%) of 22 women who showed abnormal colposcopic findings underwent loop electrosurgical excision procedure (LEEP), leaving 19/22 women from both rural and urban areas with pending treatment/follow-up results, which demonstrates the difficulty faced in reaching early diagnosis and treatment, regardless of their area of residence. Histopathology following LEEP revealed CIN III in 2 WLHIV (urban setting, both hr-HPV negative) and CIN I in 1 woman in the rural setting (hr-HPV positive). CONCLUSIONS: There is a high prevalence of hr-HPV among WLHIV in both rural and urban settings in this study in Ghana. Concurrent HPV DNA testing with a visual inspection method (colposcopy/VIA) reduces loss to follow-up compared to performing HPV DNA testing as a standalone test and recalling hr-HPV positive women for follow up with a visual inspection method. Concurrent HPV DNA testing and a visual inspection method may also pick up precancerous cervical lesions that are hr-HPV negative and may be missed if HPV DNA testing is performed alone.

Prevalence of high-risk human papillomavirus infection among women with diabetes mellitus in Accra, Ghana.

BACKGROUND: There is increasing evidence of a higher risk and poorer prognosis of cervical cancer among women with diabetes mellitus (DM) compared to the general population. These are mediated by higher susceptibility to persistent high-risk human papillomavirus (hr-HPV) infection due to dysfunctional clearance in an immunocompromised state. We aimed to determine the prevalence of hr-HPV infection and cervical lesions in a cohort of women with DM in Ghana. We further disaggregated the prevalence according to DM type and explored factors associated with hr-HPV infection. METHODS: This retrospective descriptive cross-sectional study assessed 198 women with DM who underwent cervical screening via concurrent hr-HPV DNA testing and visual inspection with acetic acid in an outpatient department of the National Diabetes Management and Research Centre in Korle-Bu Teaching Hospital, Accra from March to May 2022. Univariate and multivariable binary logistic regression were used to explore factors associated with hr-HPV positivity. RESULTS: Among 198 women with DM (mean age, 60.2 ± 12.1 years), the overall hr-HPV prevalence rate was 21.7% (95% CI, 16.1-28.1), disaggregated as 1.5% (95% CI, 0.3-4.4) each for HPV16 and HPV18 and 20.7% (95% CI, 15.3-27.0) for other HPV genotype(s). Respective hr-HPV prevalence rates were 37.5% (95% CI, 15.2-64.6) for type 1 DM, 19.8% (95% CI, 13.9-26.7) for type 2 DM, and 25.0% (95% CI, 8.7-49.1) for unspecified/other DM types. Past use of the combined contraceptive pill independently increased the risk of hr-HPV infection by approximately three times (adjusted odds ratio [aOR] = 2.98; 95% CI, 1.03 - 8.64; p-value = 0.045), whereas each unit increase in FBG level increased the odds of hr-HPV infection by about 15% (aOR = 1.15; 95% CI, 1.02 - 1.30; p-value = 0.021). CONCLUSION: Our study points to a high prevalence of hr-HPV among women with DM and highlights a need for glycemic control among them as this could contribute to lowering their odds of hr-HPV infection. The low overall rates of HPV vaccination and prior screening also indicate a need to build capacity and expand the scope of education and services offered to women with DM as regards cervical precancer screening.

Expanding management strategies for cervical precancerous lesions in resource-limited settings: insights from a training center in a district hospital in Ghana.

BACKGROUND: Cervical cancer continues to disproportionately burden women in low/middle-income countries like Ghana. We examined treatment patterns and histopathological outcomes among women screened using visual inspection with acetic acid (VIA) and/or mobile colposcopy who subsequently underwent thermal ablation, large loop excision of the transformation zone (LLETZ), or cold knife conization at the Cervical Cancer Prevention and Training Centre, Battor. We also assessed the prevalence of cervical intraepithelial neoplasia 2+ (CIN2+) or micro-invasive disease and their associated factors for women who underwent excisional treatments. The treatment choices for cervical precancerous lesions suitable for resource-limited settings have also been described from the perspective of a center that manages a heterogenous population. METHODS: We conducted an analysis of secondary data collected between June 2016 and June 2023 among women with positive findings on VIA or mobile colposcopy who subsequently underwent thermal ablation or large loop excision of the transformation zone (LLETZ). The prevalence of histopathology outcomes, including no dysplasia, CIN1 - 3, and micro-invasive disease, were estimated with 95% confidence intervals (CIs). Factors associated with histopathological findings were modeled using multinomial logistic regression. RESULTS: For the study period, 14 (10.6%) of the total 132 participants underwent cervical lesion treatment at outreach locations, all via thermal ablation. The remaining 118 (89.4%) were treated at the Catholic Hospital, Battor using LLETZ (n = 66, 55.9%), thermal ablation (n = 51, 43.2%), and cold knife conization (n = 1, 0.9%). Among 65 women with histopathology reports, the most frequent histopathological finding was no dysplasia (47.7%; 95% CI, 35.1 - 60.5), followed by CIN2 and CIN3 (20.0%; 95% CI, 11.1 - 31.8 each), CIN1 (7.7%; 95% CI, 2.5 - 17.0) and micro-invasion (4.6%; 95% CI, 1.0 - 12.9). Those with micro-invasive disease were significantly older than those with CIN1, CIN2, and CIN3 (p = 0.036, 0.022, 0.009, respectively), but not significantly older than those who showed no dysplasia (p = 0.088). For each unit increase in age, the likelihood of CIN3 was relatively significantly reduced compared to no dysplasia (crude relative risk ratio [RRR] = 0.93; 95% CI, 0.86 - 0.99). This association was neither observed with the remaining histopathological groups nor for parity and persisted after controlling for parity (adjusted RRR = 0.92; 95% CI, 0.85 - 0.99; p = 0.025). CONCLUSION: This paper largely demonstrates treatment options available to women and practitioners in LMICs. The high combined prevalence of high-grade precancerous lesions and micro-invasive disease underscores the need to increase cervical cancer awareness that would enhance screening attendance and hasten efforts at moving from opportunistic to organized screening in Ghana. This will enhance early cervical lesion detection and treatment, while simultaneously re-evaluating and cutting down on unnecessary treatment.

Community cervical cancer screening and precancer risk in women living with HIV in Jos Nigeria.

BACKGROUND: High HIV prevalence, and lack of organized screening for the indigent population receiving care and treatment within HIV clinics in low-resource settings increases cervical cancer incidence. We sought to determine predictors of cervical precancer in women living with HIV and receiving cervical cancer screening in Jos, Nigeria. METHODS: A cross-sectional study of women living with HIV and receiving care and treatment in adult HIV/AIDS clinics in Jos-Metropolis, Nigeria between June 2020 and April 2023. Ethical approvals were obtained from the ethics committee in Jos, Nigeria and Northwestern University IRB, USA. Informed consent was obtained from eligible participants, and data on socio-demographics, cancer risk factors, and cytology reports were collected. The outcome variables were cervical precancer lesions. The independent variables were prior Pap smear status, socio-demographics, income, educational, and other reproductive health factors. Descriptive statistics was done to obtain means ± sd, frequencies, and percentages for the variables. Univariate and bivariate analyses were done to determine predictors of cervical dysplasia. Analyses were performed using R software. RESULTS: Of 957 women screened, 570 were living with HIV and 566 women had cytology report and were included in the final analysis. The mean age was 45.08 ± 8.89 years and 81.6% had no prior evidence of Pap test (under-screened). Prevalence of cervical dysplasia was 24% (mild and severe dysplasia were 12.9% and 11.1%, respectively). Age above 45 years (aOR = 3.48, p = 0.009), postmenopausal status (aOR = 7.69, p = 0.000), and women with no history of prior IUCD use (aOR = 5.94, p = 0.0001), were predictors for severe dysplasia. Women who had history of STI (aOR = 0.17, p = 0.000), prior use of IUCD (aOR = 0.32, p = 0.004), prior use of condom (aOR = 2.50, p = 0.003) and had co-morbidities (aOR = 0.46, p = 0.009) were more likely to have had a Pap test in the past. CONCLUSIONS: The majority of indigent women receiving care at HIV clinics had their first Pap test screening, and lack of organized screening among older and post-menopausal women with HIV, puts women at a higher risk of developing severe cervical precancer lesions.

Developing a predictive nomogram for colposcopists: a retrospective, multicenter study of cervical precancer identification in China.

BACKGROUND: Colposcopic examination with biopsy is the standard procedure for referrals with abnormal cervical cancer screening results; however, the decision to biopsy is controvertible. Having a predictive model may help to improve high-grade squamous intraepithelial lesion or worse (HSIL+) predictions which could reduce unnecessary testing and protecting women from unnecessary harm. METHODS: This retrospective multicenter study involved 5,854 patients identified through colposcopy databases. Cases were randomly assigned to a training set for development or to an internal validation set for performance assessment and comparability testing. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to reduce the number of candidate predictors and select statistically significant factors. Multivariable logistic regression was then used to establish a predictive model which generates risk scores for developing HSIL+. The predictive model is presented as a nomogram and was assessed for discriminability, and with calibration and decision curves. The model was externally validated with 472 consecutive patients and compared to 422 other patients from two additional hospitals. RESULTS: The final predictive model included age, cytology results, human papillomavirus status, transformation zone types, colposcopic impressions, and size of lesion area. The model had good overall discrimination when predicting HSIL + risk, which was internally validated (Area Under the Curve [AUC] of 0.92 (95%CI 0.90-0.94)). External validation found an AUC of 0.91 (95%CI 0.88-0.94) across the consecutive sample, and 0.88 (95%CI 0.84-0.93) across the comparative sample. Calibration suggested good coherence between predicted and observed probabilities. Decision curve analysis also suggested this model would be clinically useful. CONCLUSION: We developed and validated a nomogram which incorporates multiple clinically relevant variables to better identify HSIL + cases during colposcopic examination. This model may help clinicians determining next steps and in particular, around the need to refer patients for colposcopy-guided biopsies.

Vaginal microbiome community state types and high-risk human papillomaviruses in cervical precancer and cancer in North-central Nigeria.

BACKGROUND: High risk human papillomaviruses (HR-HPV) have a causal role in cervical oncogenesis, and HIV-mediated immune suppression allows HR-HPV to persist. We studied whether vaginal microbiome community state types (CSTs) are associated with high-grade precancer and/or invasive cervical cancer (HSIL/ICC). METHODS: This was a cross-sectional study of adult women with cervical cancer screening (CCS) at the Jos University Teaching Hospital (JUTH) in Jos, Nigeria, between January 2020 and February 2022. Cervical swabs underwent HPV genotyping (Anyplex™ II HPV28). Cervico-vaginal lavage (CVL) sample was collected for 16 S rRNA gene amplicon sequencing. We used multivariable logistic regression modelling to assess associations between CSTs and other factors associated with HSIL/ICC. RESULTS: We enrolled 155 eligible participants, 151 with microbiome data for this analysis. Women were median age 52 (IQR:43-58), 47.7% HIV positive, and 58.1% with HSIL/ICC. Of the 138 with HPV data, 40.6% were negative for HPV, 10.1% had low-risk HPV, 26.8% had single HR-HPV, and 22.5% had multiple HR-HPV types. The overall prevalence of any HR-HPV type (single and multiple) was 49.3%, with a higher proportion in women with HSIL/ICC (NILM 31.6%, LSIL 46.5%, HSIL 40.8%, and 81.5% ICC; p = 0.007). Women with HIV were more likely to have HSIL/ICC (70.3% vs. 29.7% among women without HIV). In crude and multivariable analysis CST was not associated with cervical pathology (CST-III aOR = 1.13, CST-IV aOR = 1.31). However, in the presence of HR-HPV CST-III (aOR = 6.7) and CST-IV (aOR = 3.6) showed positive association with HSIL/ICC. CONCLUSION: Vaginal microbiome CSTs were not significantly associated with HSIL/ICC. Our findings suggest however, that CST could be helpful in identifying women with HSIL/ICC and particularly those with HR-HPV. Characterization of CSTs using point-of-care molecular testing in women with HR-HPV should be studied as an approach to improve early detection and cervical cancer prevention. Future longitudinal research will improve our understanding of the temporal effect of non-optimal CST, HR-HPV, and other factors in cervical cancer development, prevention, and control.

Association between obesity and cervical intraepithelial neoplasia: results from a case control study in south western Uganda.

BACKGROUND: Though obesity has been said to be associated with a number of malignancies including cervical cancer, its association with cervical intraepithelial neoplasia (CIN) is still a contentious issue. This study was designed to determining the prevalence and association between obesity and CIN. METHODS: This was an unmatched case control study, involving women with cervical intraepithelial neoplasia (cases) and those negative for intraepithelial lesions or malignancy (controls) at the cervical cancer clinic of Mbarara Regional Referral Hospital, in south-western Uganda, between April and November 2022. Cases and controls provided written informed consent and were recruited in a ratio of 1:1. Cases were identified by visual inspection with acetic acid (VIA) and subsequent confirmation with cytology and/or histology. Demographic information was collected using an enrolment form and height, weight and waist circumference were recorded. We calculated body mass index (BMI) and identified obese women as those with body mass index of ≥ 30 kg/m2 from both case and control groups. Central obesity was defined as waist: height ration of ≥ 0.5. Data was analysed using STATA version 17. Categorical variables were analysed using proportions, chi-square and logistic regression analysis to determine association between obesity and CIN. Our level of statistical significance was set at ≤ 0.05. RESULTS: The prevalence of general and central obesity among cases was 25.5% (24/94) and 0% (0/94) respectively while the prevalence of general and central obesity among controls was 33.3% (37/111) and 0% (0/111) respectively. There was an increased prevalence of general obesity among women with low grade squamous intraepithelial lesions (LSIL). However, there was no statistically significant association between general obesity and CIN. Factors associated with general obesity included residing in Mbarara city (AOR 2.156, 95%CI 1.085-4.282, P-value 0.028), age group of 31-45 years (AOR 2.421, 95%CI 1.577-9.705, P-value 0.003) and ≥ 46 years (AOR 1.971, 95%CI 1.022-11.157, P-value 0.046). CONCLUSION: We observed an increased prevalence of general obesity among women with LSIL. However, there was no association between obesity and CIN. Factors associated with general obesity included residing in Mbarara city, and being in the age groups of 31-40 and ≥ 46 years. This highlights the need to rethink management of CIN to control other non-communicable diseases that could arise due to general obesity.

Role of HPV in the Prediction of Persistence/Recurrence After Treatment for Cervical Precancer.

OBJECTIVES: (1) To determine the role of human papillomavirus (HPV) testing after excisional treatment of cervical precancer. (2) To determine clinical factors associated with persistence of cervical precancer post-treatment. METHODS: A retrospective chart review was conducted including patients who had a loop electrosurgical excision procedure (LEEP) for cervical precancer (cervical intraepithelial neoplasia 3/adenocarcinoma in situ/high-grade squamous intraepithelial lesions [HSIL]). All patients treated between 2016 and 2018 at a tertiary centre colposcopy unit were included. Persistence/recurrence of disease was defined as high-grade cytology or histology identified during the time of follow-up. Univariate and multivariate regression models were performed to identify factors associated with persistence/recurrence and HPV positivity at exit testing. RESULTS: A total of 284 patients were included. The median follow-up time was 19 months. Of the LEEP specimens, 90.8% (n = 258) demonstrated HSIL and 3.9% (n = 11) had adenocarcinoma in situ. 28.5% (n = 81) of the LEEP specimens had positive margins. In follow-up, 72.9% had negative cytology, 17.6% had atypical squamous cells of undetermined significance/low-grade SIL, 1.8% had atypical squamous cells, HSIL cannot be excluded/low-grade SIL-H, and 6.7% had HSIL. At the final follow-up, 27.8% (n = 79) were HPV+. Overall rate of persistence/recurrence was 11.3% (n = 32); median time to persistence/recurrence was 6.5 months. Multivariate regression models demonstrated that follow-up HPV positivity (OR = 22.0) and positive margins (OR = 3.7) were significantly associated with persistence/recurrence. Similarly, in univariate regression models, positive margins were significant (OR = 2.2) for predicting HPV positivity in exit testing. CONCLUSIONS: Persistence/recurrence of precancer can occur due to incomplete treatment of lesions by local excision and by the persistence of HPV infection. Surveillance strategies for women treated for cervical precancer require a risk-based approach and should rely on HPV testing.

PAX1 and SEPT9 methylation analyses in cervical exfoliated cells are highly efficient for detecting cervical (pre)cancer in hrHPV-positive women.

Studies have investigated PAX1 and SEPT methylation were closely associated with cervical cancer. For this study, we verified the expressions of PAX1 and SEPT9 methylation in 236 hrHPV women cervical exfoliated cells by using quantitative methylation-specific PCR and we further explored their diagnostic value in cervical (pre)cancer detection. Our results identified that the methylation rates and levels of PAX1 and SEPT9 increased with cervical lesion severity. For a diagnosis of cervical (pre)cancer, the area under the curve (AUC) of PAX1 methylation was 0.77 (95% CI 0.71-0.83) and the AUC of SEPT9 methylation was 0.86 (95% CI 0.81∼0.90). Analyses of the PAX1 and SEPT9 methylation statuses alone or combined with commonly used tests can efficiently identify cervical (pre)cancer. In particular, SEPT9 methylation might serve as an effective and powerful biomarker for the diagnosis of cervical (pre)cancer and as an alternative triage test in HPV-based cervical (pre)cancer screening programs.Impact StatementWhat is already known on this subject? This subject showed that PAX1 and SEPT9 methylation were closely associated with cervical cancer. The methylation rates and levels of PAX1 and SEPT9 increased with cervical lesion severity and reached a peak in cervical cancer exfoliated cells. We further assessed the diagnostic performances of PAX1 and SEPT9 methylation in cervical cancer screening. In detecting cervical (pre)cancer, the sensitivity values of PAX1 and SEPT9 methylation were up to 61.18% and 82.35%, respectively, and the specificity values of PAX1 and SEPT9 methylation were up to 95.36% and 86.75%, respectively. Moreover, the ROC curve analysis showed AUC values of 0.77 for PAX1 methylation and 0.86 for SEPT9 methylation tests, which were significantly superior to other commonly used tests. These findings suggest that PAX1 and SEPT9 methylation detection may have great clinical potential in cervical cancer screening.What the results of this study add? The rates and levels of PAX1 and SEPT9 methylation increased with the severity of the cervical lesions. For a diagnosis of cervical (pre)cancer, the area under the curve (AUC) of PAX1 methylation was 0.77 (95% CI 0.71-0.83), and the sensitivity and specificity values were 61.18% and 95.36%, respectively. The AUC value of the SEPT9 methylation was 0.86 (95% CI 0.81 ∼ 0.90), and the sensitivity and specificity values were 82.35% and 86.75%, respectively. Compared with the various tests we conducted, the PAX1 methylation showed the highest specificity (95.36%), and the SEPT9 methylation demonstrated the highest accuracy(86.00%).What the implications are of these findings for clinical practice and/or further research? The methylation levels of PAX1 and SEPT9 had a certain predictive effect on the severity of cervical lesions in hrHPV-positive women. In addition, SEPT9 methylation analysis performs better than PAX1 methylation analysis and commonly used tests in cervical exfoliated cells for detecting cervical (pre)cancer in hrHPV-positive women. SEPT9 methylation analysis merits consideration as an effective and objective, alternative triage test in HPV-based cervical (pre)cancer screening programs.

Low rates of HPV vaccination and cervical cancer screening: Challenges and opportunities in the context of the COVID-19 pandemic.

This invited commentary discusses the article by Richards et al. describing differences in rates of on-time HPV vaccination and cervical cancer screening in 2018 among enrollees in different insurance plans. The commentary focuses on the larger problem of low vaccination HPV rates and decreasing cervical cancer screening rates seen across all sectors. We outline challenges posed by the COVID-19 pandemic on HPV vaccination and cervical cancer screening, and discuss opportunities to improve cervical cancer prevention.

Support for lowering cervical cancer screening age to 25 for women living with HIV: retrospective cross-sectional programmatic data from Botswana.

BACKGROUND: Women living with human immunodeficiency virus (HIV) tend to develop cervical cancer at a younger age than women without HIV. The World Health Organization's (WHO) 2021 guidelines for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention include a conditional recommendation for initiating screening at age 25 for women living with HIV (WLWH). This recommendation is based on low-certainty evidence, and WHO calls for additional data. We describe the association of age and HIV status with visual inspection with acetic acid (VIA) positivity and cervical intraepithelial neoplasia grade two or higher (CIN2+) in Botswana. METHODS: This was a retrospective cross-sectional study of 5714 participants aged 25 to 49 years who underwent VIA screening in a clinic mainly serving WLWH. VIA-positive women received cryotherapy if eligible or were referred for colposcopy and excisional treatment. Known cervical cancer risk factors, screening outcome, and histological results were extracted from the program database. We compared the proportions and association of VIA positivity and CIN2+ by age and HIV status. RESULTS: The median age was 35 years [IQR 31-39], and 18% of the women were aged 25-29. Ninety percent were WLWH; median CD4 count was 250 cells/µL [IQR 150-428], and 34.2% were on anti-retroviral treatment (ART). VIA-positivity was associated with younger age (OR 1.48, CI 1.28, 1.72 for 25-29 years vs. 30-49 years), and HIV-positivity (OR 1.85, CI 1.51, 2.28). CIN2+ was only associated with HIV-positivity (OR 6.12, CI 3.39, 11.10), and proportions of CIN2+ were similar for both age groups in WLWH (69.1% vs. 68.3%). CONCLUSIONS: Younger WLWH in Botswana had a significant burden of CIN2+. This finding further supports lowering the screening age for WLWH from 30 to 25.

Acting on the call for cervical cancer elimination: Planning tools for low- and middle- income countries to increase the coverage and effectiveness of screening and treatment.

INTRODUCTION: Accessible planning tools tailored for low-and middle-income countries can assist decision makers in comparing implementation of different cervical cancer screening approaches and treatment delivery scenarios in settings with high cervical cancer burden. METHODS: The Cervical Precancer Planning Tool (CPPT) was developed by PATH for users to explore and compare the accuracy of screening approaches, what treatment equipment to procure, and how best to deploy treatment equipment in a given country. The CPPT compares four screening approaches: 1) visual inspection with acetic acid (VIA), 2) HPV testing, 3) HPV testing followed by a VIA triage, and 4) HPV testing followed by an enhanced triage test. Accuracy of screening outcomes (e.g., true positives, false positives) is based on published sensitivity and specificity of tests to detect cervical precancerous lesions. The CPPT compares five scenarios for deploying ablative treatment equipment: 1) cervical precancer equipment at every location a woman is screened (single visit approach), 2) equipment only at a hospital level, 3) a single unit of equipment in each district, 4) allowing two districts to share a single unit of equipment, and 5) equipment placed at select district hospitals paired with mobile outreach. Users can customize the CPPT by adjusting pre-populated baseline values and assumptions, including population estimates, screening age range, screening frequency, HPV and HIV prevalence, supply costs, and health facility details. RESULTS: The CPPT generates data tables and graphs that compare the results of implementing each of the four screening and five treatment scenarios disaggregated by HIV status. Outputs include the number and outcomes of women screened, cost of each screening approach, provider time and cost saved by implementing self-sampling for HPV testing, number of women treated, treatment equipment needed by type, and the financial and economic costs for each equipment deployment scenario. CONCLUSION: The CPPT provides practical information and data to compare tradeoffs of patient access and screening accuracy as well as efficient utilization of equipment, skilled personnel, and financial resources. Country decision makers can use outputs from the CPPT to guide the scale-up of cervical cancer screening and treatment while optimizing limited resources.

The Dysregulation of MicroRNAs in the Development of Cervical Pre-Cancer-An Update.

Globally in 2020, an estimated ~600,000 women were diagnosed with and 340,000 women died from cervical cancer. Compared to 2012, the number of cases increased by 7.5% and the number of deaths increased by 17%. MiRNAs are involved in multiple processes in the pathogenesis of cervical cancer. Dysregulation of miRNAs in the pre-stage of cervical cancer is the focus of this review. Here we summarize the dysregulated miRNAs in clinical samples from cervical pre-cancer patients and relate them to the early transformation process owing to human papillomavirus (HPV) infection in the cervical cells. When HPV infects the normal cervical cells, the DNA damage response is initiated with the involvement of HPV's E1 and E2 proteins. Later, cell proliferation and cell death are affected by the E6 and E7 proteins. We find that the expressions of miRNAs in cervical pre-cancerous tissue revealed by different studies seldom agreed with each other. The discrepancy in sample types, samples' HPV status, expression measurement, and methods for analysis contributed to the non-aligned results across studies. However, several miRNAs (miR-34a, miR-9, miR-21, miR-145, and miR-375) were found to be dysregulated across multiple studies. In addition, there are hints that the DNA damage response and cell growth response induced by HPV during the early transformation of the cervical cells are related to these miRNAs. Currently, no review articles analyse the relationship between the dysregulated miRNAs in cervical pre-cancerous tissue and their possible roles in the early processes involving HPV's protein encoded by the early genes and DNA damage response during normal cell transformation. Our review provides insight on spotting miRNAs involved in the early pathogenic processes and pointing out their potential as biomarker targets of cervical pre-cancer.

Classification of high-grade cervical intraepithelial neoplasia by p16ink4a , Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management.

High-grade cervical intraepithelial neoplasia (CIN2 and CIN3) represents a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16ink4a , Ki-67 and host-cell DNA methylation) could provide guidance for clinical management in women with high-grade CIN. This study evaluates the cumulative score of immunohistochemical expression of p16ink4a (Scores 0-3) and Ki-67 (Scores 0-3), referred to as the "immunoscore" (IS), in 262 CIN2 and 235 CIN3 lesions derived from five European cohorts in relation to immunohistochemical HPV E4 expression and FAM19A4/miR124-2 methylation in the corresponding cervical scrape. The immunoscore classification resulted in 30 lesions within IS group 0-2 (6.0%), 151 lesions within IS group 3-4 (30.4%) and 316 lesions within IS group 5-6 (63.6%). E4 expression decreased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). Methylation positivity increased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). E4 expression was present in 9.8% of CIN3 (23/235) and in 12.0% of IS group 5-6 (38/316). Notably, in a minority (43/497, 8.7%) of high-grade lesions, characteristics of both transforming HPV infection (DNA hypermethylation) and productive HPV infection (E4 expression) were found simultaneously. Next, we stratified all high-grade CIN lesions, based on the presumed cancer progression risk of the biomarkers used, into biomarker profiles. These biomarker profiles, including immunoscore and methylation status, could help the clinician in the decision for immediate treatment or a "wait and see" policy to reduce overtreatment of high-grade CIN lesions.

Treatment approaches for women with positive cervical screening results in low-and middle-income countries.

The primary goal of cervical screening is to identify women with cervical precancers who need treatment to prevent invasive cervical cancer. Cervical cancer screening programs in high-resource settings rely on a multi-step process to reassure the majority of women of low cancer risk and treat the small number of women at high risk of precancer and cancer. The requirement of major resource investment for training and capacity building of multi-step cervical cancer screening programs prevents their introduction in low- and middle-income countries (LMICs). Screen-and-treat programs have been evaluated and introduced in some countries that use mainly ablative treatment as primary treatment options. Ablative treatment with cryotherapy and thermal ablation has a favorable tradeoff of benefits and harms and can be introduced more widely than excisional treatment in LMICs. While most women below 40 are eligible for ablative procedures, fewer than 50% are eligible by age 50 and ablative treatment is not appropriate over age 50. Excisional treatment is required for women ineligible for ablative treatment. Since screening programs in LMICs necessarily detect invasive cancers, cancer treatment and palliative care needs to be considered as well.

Impact of COVID-19 on cervical cancer screening: Challenges and opportunities to improving resilience and reduce disparities.

The COVID-19 pandemic has a major impact on a wide range of health outcomes. Disruptions of elective health services related to cervical screening, management of abnormal screening test results, and treatment of precancers, may lead to increases in cervical cancer incidence and exacerbate existing health disparities. Modeling studies suggest that a short delay of cervical screening in subjects with previously negative HPV results has minor effects on cancer outcomes, while delay of management and treatment can lead to larger increases in cervical cancer. Several approaches can mitigate the effects of disruption of cervical screening and management. HPV-based screening has higher accuracy compared to cytology, and a negative HPV result provides longer reassurance against cervical cancer; further, HPV testing can be conducted from self-collected specimens. Self-collection expands the reach of screening to underserved populations who currently do not participate in screening. Self-collection and can also provide alternative screening approaches during the pandemic because testing can be supported by telehealth and specimens collected in the home, substantially reducing patient-provider contact and risk of COVID-19 exposure, and also expanding the reach of catch-up services to address backlogs of screening tests that accumulated during the pandemic. Risk-based management allows prioritizing management of patients at highest risk of cervical cancer while extending screening intervals for those at lowest risk. The pandemic provides important lessons for how to make cervical screening more resilient to disruptions and how to reduce cervical cancer disparities that may be exacerbated due to disruptions of health services.

Thermo-coagulation versus cryotherapy for treatment of cervical precancers: A prospective analytical study in a low-resource African setting.

AIMS: To evaluate the outcomes of cryotherapy and thermo-coagulation in the treatment of cervical precancers. METHOD: Prospective analytical study. Women who screened positive to visual inspection with acetic acid and confirmed by colposcopy using the Swede's score were randomized to receive either cryotherapy or thermo-coagulation. Participants were re-evaluated 6 months later. RESULTS: A total of 11 124 women were screened. Only 1023 of the 1294 colposcopically confirmed positive cases were eligible for ablative therapy. Five hundred and twelve women received cryotherapy while 511 women received thermo-coagulation. Cryotherapy had similar cure rate with thermo-coagulation (85.5 vs 89.2%, P = 0.09). The mean patient satisfaction score for thermo-coagulation was higher than that for cryotherapy (3.9 ± 1.3 vs 2.8 ± 1.7; P < 0.0001). The mean duration of treatment per patient was higher for cryotherapy than thermo-coagulation (660.0 ± 0.0 vs 50.9 ± 15.3 s, P < 0.0001). The mean cost of treatment per patient was significantly higher for cryotherapy than for thermo-coagulation (2613.1 ± 254.9 vs 533.2 ± 45.2 Nigerian Naira, P < 0.0001). Higher proportion of women who had thermo-coagulation reported no side effect (55.2 vs 12.5%, P < 0.0001). CONCLUSION: Cryotherapy and thermo-coagulation have similar efficacy in the treatment of cervical precancers. Thermo-coagulation offers lower cost and lower duration of treatment, less side effects and higher patient satisfaction than cryotherapy. Thermo-coagulation should be the recommended ablative treatment method for low-resource settings of the world.

[Performance of high-risk HPV typing test in early diagnosis of cervical cancer].

Objective: To evaluate the performance of High-risk HPV typing detection in cervical cancer screening. Methods: A total of 3 231 women were recruited as the subjects of cervical cancer screening from Jiyuan city of Henan provinces from June to July 2017. All women underwent HPV DNA test. The women with cytological examination ≥ASCUS or cytological examination negative and HPV 16/18 positive underwent colposcopy biopsy and pathological examination. Pathological diagnosis was used as the gold standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value(NPV) as well as corresponding 95% confidence interval (CI) of HR-HPV and HPV 16/18 were calculated. Results: The mean age of 3 231 subjects selected in this study was 46.84±10.00 (21-64) years old. 524 subjects had the positive results of HR-HPV, including 91 of HPV16 and 15 of HPV18. Pathological test result CIN2+ was the gold standard. The sensitivity and specificity of HR-HPV for cervical precancer lesions screening were 93.75 (95%CI: 79.85-98.27) and 84.56% (95%CI: 83.26-85.77), respectively. To compared with HR-HPV, HPV16/18 had low sensitivity (65.63%, 95%CI: 48.31-79.59)and higher specificity (97.44%, 95%CI: 96.83-97.93). After age stratification by age 30 and 45, the sensitivity of HPV 16/18 was same with HR-HPV (100%, 95%CI: 34.24-100.00), the specificity of HPV 16/18 was higher than HR-HPV (98.71%, 95%CI: 96.27-99.56 vs 84.48%, 95%CI: 79.27-88.58) in<30 age group.The sensitivity of HR-HPVin 30-45 and ≥45 age group were higher than HPV16/18 (85.71%, 95%CI: 48.69-97.43 vs 71.43%, 95%CI: 35.89-91.78, 95.65%, 95%CI: 79.01-99.23 vs 60.87%, 95%CI: 40.79-77.84), but the specificity werelower than HPV16/18 (86.89%, 95%CI: 84.58-88.90 vs 98.51%, 95%CI: 97.51-99.11、83.49%, 95%CI: 81.81-85.04 vs 96.80%, 95%CI: 95.94-97.48). Conclusions: HR-HPV detection has relatively high sensitivity and specificity in cervical cancer screening. For >30 years old women, HR-HPV is more recommended in cervical cancer screening. Therefore, HR-HPV detection is an effective method for cervical cancer screening.

Impact of human papillomavirus vaccination on the clinical meaning of cervical screening results.

Women previously vaccinated against human papillomavirus (HPV) type 16 and 18 are now reaching the age (21 years) at which cervical-cancer screening is recommended in the U.S. The impact of HPV vaccination on risks of cervical precancer following a positive and negative screen among women aged 21-24 years who just started routine cervical screening are not well described. Therefore, three-year absolute and relative (RR) cumulative risks of cervical intraepithelial neoplasia grade 2 or more severe diagnoses (≥CIN2) and grade 3 or more severe diagnoses (≥CIN3) were estimated for women undergoing cervical screening at Kaiser Permanente Northern California. Risks were estimated in women aged 21-24 years (n = 75,008) undergoing cervical screening since late 2006, 6 months after HPV vaccination became available; women were categorized vaccinated at ages <18, 18-20, and 21-24 years and compared to those who were unvaccinated. Three-year risks were estimated for normal, low-grade, and high-grade cytology results. Three-year risks of ≥CIN2 and ≥CIN3 for unvaccinated women following low-grade cytology were 10.89% for and 3.70%, respectively. By comparison, Three-year risks of ≥CIN2 and ≥CIN3 were 5.26% (RR = 0.48, 95%CI = 0.24-0.99) and 0.99% (RR = 0.27, 95%CI = 0.06-1.13), respectively, for women vaccinated under the age of 18 years. Three-year ≥CIN2 and ≥CIN3 risks were lower for those HPV vaccinated at younger age for any screening result (ptrend ≤ 0.01 for all comparisons). These data support initiating cervical screening at an older age or changing the management of a low-grade cytology result in women aged 21-24 years who were vaccinated against HPV younger than age of 18 years.