Karin Sundström

Low-dose aspirin use and risk of ovarian cancer: a combined analysis from two nationwide studies in Denmark and Sweden

Studies on association between low-dose aspirin use and ovarian cancer risk were mostly based on self-reported medication use and few had large enough sample size to investigate the potential modification effect by ovarian cancer risk factors. In these two nationwide nested case-control studies among the Danish and Swedish female population, 11,874 women with ovarian cancer (30-84 years old) (Denmark: 7328 diagnosed in 2000-2019, Sweden: 4546 diagnosed in 2010-2018) were randomly age- matched with 473,960 female controls (293,120 from Denmark, and 181,840 from Sweden). We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and combined the estimates based the fixed-effect assumption. Effect modification by inflammation-related risk factors and by indication (cardiovascular disease, CVD) were also investigated. Ever use of low-dose aspirin was not strongly associated with the overall risk of ovarian cancer (OR = 0.97; 95%CI: 0.92-1.03). However, the association differed according to parity (nulliparous: OR = 0.80, 95%CI: 0.70-0.92; parous: OR = 1.00, 95%CI: 0.94-1.07; p-interaction = 0.0024), and according to history of CVD (no CVD: OR = 0.91, 95%CI: 0.82-1.00; ever CVD: OR = 1.05, 95%CI: 0.97-1.13; p-interaction =0.0204). Low-dose aspirin use was associated with a decreased ovarian cancer risk especially in nulliparous women and in women without CVD diagnosis.

The WID‐EC test for the detection and risk prediction of endometrial cancer

AbstractThe incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID‐EC (Women's cancer risk IDentification‐Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid‐based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID‐EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID‐EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88‐0.97) in the external set and of 0.82 (95% CI: 0.74‐0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID‐EC test can identify women with or at risk of endometrial cancer.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets

PURPOSE Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS We describe the Women's cancer risk IDentification – quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.

Predicting optimal impact interventions in the post‐ HPV vaccination world

Abstract Prophylactic vaccination is a powerful tool that changes exposure to infections and associated morbidity of preventable diseases. We discuss the impact of pneumococci and human papillomavirus (HPV) vaccination on the population biology of the two micro‐organisms and related public health effects. Data on HPV type‐replacement in communities where vaccine‐covered HPVs are almost eliminated, and interactions of the remaining HPV types on the risk of cervical cancer are reviewed. Results of comprehensive models for European country‐specific conduction of cervical screening among HPV‐vaccinated and unvaccinated women, assuming different HPV‐vaccination coverage and strategies, are discussed in our policy‐oriented review. An acceptable balance of benefits and harms of cervical cancer screening in HPV vaccinated populations requires an understanding of cancer risks in differently vaccinated birth cohorts. Finally, the challenges are complex but can be met if strategies are applied that (i) as fast as possible achieve herd effect and (ii) use a risk‐based design of HPV screening.

Mental disorders and socioeconomic outcomes in women with cervical cancer, and their children and co-parents

Abstract Background Cervical cancer often affects women who are in the middle of life and may carry substantial mental and socioeconomic impact also on families. We performed a generation-spanning study to elucidate this burden. Methods We used nationwide registers during 1991-2018 in Sweden to perform 2 matched cohort studies based on a source population of more than 5 million women. The individual sub-study included 6060 cases of cervical cancer diagnosed during 2006-2018 and 5 population comparators individually matched to each case by age, birth year, and region (n = 30 300). The family sub-study included 9332 cases of cervical cancer diagnosed during 1991-2016 and 45 674 matched population comparators and all their children and co-parents. Results We found an increased risk for mental disorders in cases compared with comparators, particularly during the first 2 years postdiagnosis (HR = 3.74, 95% CI = 3.45 to 4.06). Socioeconomic status changed negatively in cases after their diagnosis: a decreased income and increased need for financial aid appeared within 2 years, whereas unemployment escalated from 2 years after cancer diagnosis. We further found an increased risk of mental disorders in both children and co-parents of the cases, compared with the children and co-parents of the comparators. Furthermore, we observed negative socioeconomic trajectories in the co-parents and lower educational attainment in the children of the cases, especially if the case had died. Conclusions Women with cervical cancer, and their close family members, display increased risk of negative mental health and socioeconomic outcomes after diagnosis. The lower educational attainment in children appears particularly worrying.

Evaluation of primary HPV-based cervical screening among older women: Long-term follow-up of a randomized healthcare policy trial in Sweden

Background Evidence on invasive cervical cancer prevention among older women is limited, especially with the introduction of human papillomavirus (HPV)-based screening and longer interval. We conducted a long-term follow-up of the first phase of a randomized healthcare policy trial in cervical screening, targeting women aged 56 to 61 years old, to investigate the effectiveness of primary HPV-based screening in preventing invasive cervical cancer (ICC) and the safety of extending screening interval. Methods and findings The randomized healthcare policy trial of primary HPV-based cervical screening targeted women residing in Stockholm-Gotland region during 2012 to 2016, aged 30 to 64 years. The trial aimed to investigate the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) within 24 months and long-term protection against invasive cervical cancer, comparing primary HPV-based screening to primary cytology-based screening. The initial phase of the trial, which was the focus of this study, targeted women aged 56 to 61 years old in 2012 to 2014 who were randomized to primary cytology arm (n = 7,401) or primary HPV arm (n = 7,318). We used national registries to identify the subsequent cervical tests and all histopathological diagnoses including ICC before December 31, 2022. We calculated cumulative incidence, incidence rate (IR) and IR ratio (IRR) of ICC, by baseline test result. Furthermore, we calculated longitudinal sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by receipt of primary cytology or primary HPV test for the recommended screening intervals in this age group. We found that the IR of ICC among women in the primary HPV arm was 7.2/100,000 person-years (py) and 3.0 for women who tested HPV negative, compared to 18.4/100,000 py among women in the primary cytology arm and 18.8 for women who tested cytology negative. We further found that the overall point estimate for the risk of ICC over 10 years of follow-up among women in the primary HPV arm was 0.39 compared to women in the primary cytology arm, but this was not statistically significant (IRR: 0.39; 95% confidence interval, CI [0.14, 1.09]; p = 0.0726). However, among women with a negative test result at baseline, women in the primary HPV arm had an 84% lower risk of ICC compared to women in the primary cytology arm (IRR: 0.16; 95% CI [0.04, 0.72]; p = 0.0163). Moreover, primary HPV testing had a higher sensitivity for detecting CIN2+ within a 7-year interval than primary cytology testing within a 5-year interval (89.6% versus 50.9%, p < 0.0001). We were limited by a partial imbalance of invitations during the follow-up between the 2 arms which may have led to an underestimation of the effectiveness of primary HPV-based screening. Conclusions In this study, we observed that women over 55 years of age who received a primary negative HPV test result had substantially lower risk of CIN2+, and ICC, compared to women who received a primary negative cytology result. This should apply even if the screening interval were prolonged to 7 years. Trial Registration NCT01511328.

Cervical cancer screening using DNA methylation triage in a real-world population

AbstractCervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology’s low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women.

Deep sequencing detects human papillomavirus (HPV) in cervical cancers negative for HPV by PCR

Abstract Background Human papillomavirus (HPV) is a necessary cause of cervical cancer, although some invasive cervical cancers may test negative by HPV PCR. We previously requested all invasive cervical cancers in Sweden during 10 years and subjected them to PCR. We also optimised methods for deep sequencing of formalin-fixed paraffin-embedded samples. Methods Using Novaseq 6000, we simultaneously sequenced total DNA and cDNA from 392 HPV PCR-negative cervical cancers. Non-human reads were queried against all known HPVs. The complete database now contains PCR and/or deep sequencing data on 2850 invasive cervical cancers. Results HPV sequences were detected in 169/392 of HPV PCR-negative cervical cancers. Overall, 30 different HPV types were detected, but only 5 types were present in proportions above 3% of cancers. More than 92% of tumours were HPV-positive in PCR and/or sequencing (95% confidence interval: 91.1–93.1%). Exploring possible reasons for failure to previously detect HPV suggest that more sensitive type-specific PCRs for HPV 31, 33, 45 and 73 targeting retained regions of HPV would have detected most of these (117/392). Conclusions Unbiased deep sequencing provides comprehensive data on HPV types in cervical cancers and appears to be an important tool for quality assurance of HPV screening.

HPV Vaccination and the Risk of Invasive Cervical Cancer

The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking. We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history. During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years. Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).

Using machine learning for predicting cervical cancer from Swedish electronic health records by mining hierarchical representations

Electronic health records (EHRs) contain rich documentation regarding disease symptoms and progression, but EHR data is challenging to use for diagnosis prediction due to its high dimensionality, relative scarcity, and substantial level of noise. We investigated how to best represent EHR data for predicting cervical cancer, a serious disease where early detection is beneficial for the outcome of treatment. A case group of 1321 patients with cervical cancer were matched to ten times as many controls, and for both groups several types of events were extracted from their EHRs. These events included clinical codes, lab results, and contents of free text notes retrieved using a LSTM neural network. Clinical events are described with great variation in EHR texts, leading to a very large feature space. Therefore, an event hierarchy inferred from the textual events was created to represent the clinical texts. Overall, the events extracted from free text notes contributed the most to the final prediction, and the hierarchy of textual events further improved performance. Four classifiers were evaluated for predicting a future cancer diagnosis where Random Forest achieved the best results with an AUC of 0.70 from a year before diagnosis up to 0.97 one day before diagnosis. We conclude that our approach is sound and had excellent discrimination at diagnosis, but only modest discrimination capacity before this point. Since our study objective was earlier disease prediction than such, we propose further work should consider extending patient histories through e.g. the integration of primary health records preceding referral to hospital.

Advances in cervical cancer prevention: Efficacy, effectiveness, elimination?

With major advances in understanding the infectious etiology of cervical cancer, preventive medicine has obtained highly promising new tools. Human papillomavirus (HPV) vaccines, together with a growing arsenal of HPV-based screening tests, have the potential to radically change public health but require diligent, large-scale implementation to reach the final goal: the elimination of cervical cancer. We reflect here upon the state of cervical cancer prevention globally as there have been several recent developments that will inform this implementation process.

Sequencing detects human papillomavirus in some apparently HPV-negative invasive cervical cancers

Cervical cancer case–control audit: Results from routine evaluation of a nationwide cervical screening program

Our study used a refined case–control cervical cancer Audit framework to investigate effectiveness of cervical screening, with measures of three screening failures: irregular‐participation, cervical cancer developed after cytological abnormalities and after normal screening results. The register‐based study included 4,254 cervical cancer cases diagnosed in Sweden during 2002–2011, and 30 population‐based controls per case. We used conditional logistic regression models to examine relative risks of cervical cancer in relation to screening participation and screening results in the past two screening rounds from 6 months before cancer diagnosis. We found that women unscreened in past two screening rounds showed four times increased risk of cervical cancer compared to women screened in time (OR = 4.1, 95% CI = 3.8–4.5), and women unscreened in the previous round but screened in the most recent round also showed a statistically significantly elevated risk (OR = 1.6, 95% CI = 1.5–1.8). Women having abnormality in previous two rounds exhibited higher risk of cervical cancer compared to women screened with normal results, while having normal results in the subsequent round after the abnormality also yielded an increased risk (OR = 4.0, 95% CI = 3.2–5.1). Being screened with only normal results was associated with 89% risk reduction for squamous cell cancer, compared to women unscreened, but only 60% reduction for adenocarcinoma. Our findings emphasize the importance of routine participation in cervical screening and suggest that management of abnormalities, as well as sensitivity of the test, warrants improvement especially for preventing cervical adenocarcinoma. The Audit framework serves as routine evaluation model and the findings benchmark for future evaluation of changes in screening practice.

Human Papillomavirus Infection Determines Prognosis in Cervical Cancer

PURPOSE Detection of human papillomavirus (HPV) by polymerase chain reaction in invasive cervical cancer is strongly associated with prognosis but previous studies have not considered sequencing efforts. We aimed to assess the association when also including comprehensive analysis of HPV infection by deep sequencing and a longer follow-up period. MATERIALS AND METHODS We subjected all 392 of 2,845 invasive cervical cancer cases that were polymerase chain reaction–negative for HPV to RNA sequencing on the NovaSeq 6000 platform (Illumina) and identified an additional 169 cases as HPV-positive. We followed all women from date of diagnosis to December 31, 2016, emigration, or death, whichever occurred first. The main outcome was all-cause mortality by December 31, 2016. We calculated 5-year cumulative relative survival ratios compared with the female general population and used Poisson regression to estimate excess hazard ratios of all-cause mortality by infection with any of the 13 most oncogenic (high-risk [hr]) HPV types in the tumor. All models were adjusted for age, time since diagnosis, stage, histology, and education level. RESULTS The 5-year cumulative relative survival ratio was 0.45 (95% CI, 0.39 to 0.51) in the hrHPV-negative group, and 0.74 (95% CI, 0.72 to 0.75) in the hrHPV-positive group. This translated to a statistically significantly 43% lower excess mortality in the hrHPV-positive group compared with the hrHPV-negative (corresponding to an excess hazard ratio 0.57; 95% CI, 0.48 to 0.69). There was no association between HPV risk group, clade, or number of HPV infections and prognosis. CONCLUSION hrHPV status is a strong determinant of cervical cancer prognosis over 15 years after diagnosis, above and beyond other established factors.

Impact of cervical screening by human papillomavirus genotype: Population-based estimations

Background Cervical screening programs use testing for human papillomavirus (HPV) genotypes. Different HPV types differ greatly in prevalence and oncogenicity. We estimated the impact of cervical screening and follow-up for each HPV type. Methods and findings For each type of HPV, we calculated the number of women needed to screen (NNS) and number of women needing follow-up (NNF) to detect or prevent one cervical cancer case, using the following individual level input data (i) screening and cancer data for all women aged 25 to 80 years, resident in Sweden during 2004 to 2011 (N = 3,568,938); (ii) HPV type-specific prevalences and screening histories among women with cervical cancer in Sweden in 2002 to 2011(N = 4,254); (iii) HPV 16/18/other HPV prevalences in the population-based HPV screening program (N = 656,607); and (iv) exact HPV genotyping in a population-based cohort (n = 12,527). Historical screening attendance was associated with a 72% reduction of cervical cancer incidence caused by HPV16 (71.6%, 95% confidence interval (CI) [69.1%, 73.9%]) and a 54% reduction of cancer caused by HPV18 (53.8%, 95% CI [40.6%, 63.1%]). One case of HPV16-caused cervical cancer could be prevented for every 5,527 women attending screening (number needed to screen, NNS). Prevention of one case of HPV16-caused cervical cancer required follow-up of 147 HPV16–positive women (number needed to follow-up, NNF). The NNS and NNF were up to 40 to 500 times higher for HPV types commonly screened for with lower oncogenic potential (HPV35,39,51,56,59,66,68). For women below 30 years of age, NNS and NNF for HPV16 were 4,747 and 289, respectively, but >220,000 and >16,000 for HPV35,39,51,56,59,66,68. All estimates were either age-standarized or age-stratified. The primary limitation of our study is that NNS is dependent on the HPV prevalence that can differ between populations and over time. However, it can readily be recalculated in other settings and monitored when HPV type-specific prevalence changes. Other limitations include that in some age groups, there was little data and extrapolations had to be made. Finally, there were very few cervical cancer cases associated with certain HPV types in young age group. Conclusions In this study, we observed that the impact of cervical cancer screening varies depending on the HPV type screened for. Estimating and monitoring the impact of screening by HPV type can facilitate the design of effective and efficient HPV-based cervical screening programs. Trial registration ClinicalTrials.gov with numbers NCT00479375, NCT01511328.

Use of statins and risk of ovarian cancer: evidence on effect modification by parity, menopause and endometriosis from nationwide nested case-control studies

Previous results on the association between statin use and risk of ovarian cancer (OC) are inconsistent, warranting further investigation. This study aims to examine the association between statin use and risk of OC in a large study population. Based on two nationwide nested case-control studies utilizing data from Danish and Swedish high-quality registries, we identified 11,874 OC cases who were individually matched on age to 474,960 controls using risk-set sampling. Conditional logistic regression was performed separately on the country-specific data to calculate odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for the association between statin use and risk of OC. Country-specific estimates were combined based on a fixed-effect assumption. Furthermore, we examined potential effect modifications by a priori selected OC risk factors on the association between statin use and OC risk. We found no overall association between statin use and risk of OC (OR = 0.96; 95 % CI: 0.91-1.01); neither with duration nor intensity of use. However, statin use was associated with a decreased risk of OC in subsets of women with endometriosis (OR = 0.70; 95 % CI: 0.53-0.91), and nulliparous women (OR = 0.86; 95 % CI: 0.79-0.93). We found an effect modification of some known ovarian cancer risk factors on the association between statin use and risk of OC. In women with endometriosis, and in nulliparous women, respectively, statin use was associated with a decreased risk of OC, suggesting statins may have potential as a preventive measure.

Evaluation of DNA Methylation Markers for Endometrial Cancer Risk-stratification Using Patient-collected Urine and Vaginal Samples and Clinician-collected Cervical Samples From Women With Postmenopausal Bleeding

The goal of this observational study is to investigate the clinical utility of DNA-methylation testing in urine and vaginal samples collected by patients and cervical samples collected by clinicians, to determine the risk of endometrial cancer in symptomatic women with postmenopausal bleeding. The study aims to answer the following research questions: * What is the diagnostic accuracy of DNA methylation testing in urine, vaginal and cervical samples compared to traditional TVUS for endometrial cancer detection? * What is the 2-year risk of EC among women testing negative on TVUS and/or DNA methylation tests or those testing positive on methylation only? Researchers will compare DNA methylation testing in patient-collected urine and vaginal samples as well as in clinician-collected cervical samples, with the traditional diagnostic pathway for women with PMB, which includes TVUS evaluation, and when indicated by abnormal TVUS findings, endometrial biopsy according to clinical guidelines. Participants will * take a urine and vaginal sample * have a cervical sample collected by a clinician * undergo TVUS evaluation according to clinical guidelines * If TVUS shows thickened endometrium (≥ 5 mm) and/or irregularity, an endometrial biopsy will be collected according to clinical guidelines * fill out a questionnaire regarding acceptability and preferences of sampling methods and complete a lifestyle questionnaire.

The Clinical Utility of DNA Methylation Testing in Patient-collected Urine and Vaginal Samples to Detect Endometrial Cancer: a Case-control Study

The goal of this observational case-control study is to investigate the use of DNA-methylation testing in patient-collected urine and vaginal samples to detect endometrial cancer. The study aims to answer the following questions: * Can DNA methylation testing in vaginal and full-void urine samples distinguish endometrial cancer cases from healthy controls? Researchers will compare patient-collected urine and vaginal samples from patients with diagnosed endometrial cancer (cases) to gynaecologically and oncologically healthy controls (controls). Participants will * take a urine and vaginal sample at the hospital. * answer a questionnaire regarding acceptability and preferences of self-sampling methods. * answer a lifestyle questionnaire.

Clinical Studies of Endometrial Cytology and Cervical Methylation Assays in Endometrial Cancer Screening and Fertility-Preservation Evaluation

The current study aims to assess high-risk patients using both liquid-based cytology and cervical methylation testing. The results will be compared with the traditional hysteroscopic pathological findings to determine the sensitivity and specificity of these methods for early detection of endometrial cancer, thereby evaluating their potential application in early screening. Primary Objectives： 1. To evaluate the sensitivity, specificity, and accuracy of endometrial cytology for screening endometrial cancer. 2. To assess the sensitivity, specificity, and accuracy of methylation testing for screening endometrial cancer. 3. To perform further molecular testing on tissue samples obtained from endometrial cytology and cervical methylation tests, aiming to explore early screening-sensitive indicators. Secondary Objectives： 1. To determine the value of endometrial cytology in evaluating the efficacy of fertility-sparing treatments for endometrial cancer. 2. To assess the value of methylation testing in evaluating the efficacy of fertility-sparing treatments for endometrial cancer.

Faster Elimination of HPV Infection and Cervical Cancer Using Concomitant HPV Vaccination and HPV Screening: A Demonstration Project in Rwanda

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020. Rwanda is among countries with a high burden cervical cancer, with an annual incidence of 28.2/100,000 women (1,229 new cases in 2020) and a mortality rate of 20.1/100,000 (829 deaths in 2018) according to WHO (IARC 2020). Cervical cancer is almost completely preventable because of the highly effective primary (HPV vaccine) and secondary (HPV screening) prevention measures. However, these measures have not been equitably implemented across and within LMICs countries. Given the current situation, where the screening coverage is still low due to financial and operational challenges, it will take many years to achieve the elimination targets as included in the global elimination strategy. We are proposing to implement an innovative strategy to accelerate the elimination of cervical cancer in Rwanda consisting of concomitant HPV vaccination and HPV screening for young women aged 23-29 years old. HPV screening and vaccination are complementary preventive options often implemented as separate public health programs. This project proposal aims to address this disconnect by combining both strategies with the ultimate purpose of accelerating the reduction of cervical cancer incidence and mortality in Rwanda and making the programs both cost-effective and sustainable. Primary objective The study aims to evaluate whether organized, concomitant HPV vaccination and HPV screening offered to girls and women aged 23-29 years will result in more rapid elimination of HPV infections in the target districts in Rwanda. The study design is a before-after study design of the intervention, where the projected incidences and prevalence at the 2-year follow-up visit are modeled using the data from the baseline visit, with evaluation using Observed/expected numbers. Secondary objectives The study will evaluate whether concomitant vaccination and cervical screening result in an improved efficiency and/or safety of the cervical cancer screening program. These objectives will be examined among women who participated in the combined screening and vaccination study. i) Protection of Gardasil 9 against HPV infection and against CIN2+ by Gardasil 9 HPV vaccine types in 23 to 29-year-old women from the study districts. This analysis will be performed every 2 years, and the first analysis will determine the effectiveness of one-dose vaccination (incident infections of HPV vaccine types at 2 years), whereas all subsequent analysis will determine the effect of 2-dose vaccinations. The study will be powered to detect a decline in invasive cervical cancer among the study participants, using the cervical cancer incidence in the surrounding districts of Rwanda as the reference. ii) Efficiency will also be measured by the yield of histopathologically confirmed high-grade cervical cancer precursors or cancer (cervical intraepithelial neoplasia grade 2, 3, or cervical cancer) in relation to the consumption of resources and convenience for the women, using the yield at the baseline visit (10% of women tested) as the comparator. The hypothesis is that 2 years after vaccination, there will be only a few incident infections (only some old, persistent infections) resulting in high PPV and high yield of CIN2+ at modest consumption of resources. End of the study One screening interval (2 years) after the last visit of the last subject, defined as the day the last study subject receives her second vaccination. The study will be implemented in 4 districts of Rwanda covering 100,000 women aged 23 to 29 years old. We will use Gardasil 9, the HPV the second generation HPV Vaccine manufactured by Merck.

Screening for Early Cervical Cancer Detection

This study is to audit results and adherence to Cervical Screening program before and after the implementing awareness of the WHO guidelines of screening among the multidisciplinary healthcare workers and patients.

Strategies for Endocervical Canal Investigation in Women With Abnormal Screening Cytology and Negative Colposcopy

cervical cancer is the fourth most frequent cancer in women worldwide and in Brazil, it occupies the third position for the triennium 2020/2022, with a high mortality rate and maintained in the last 10 years. It is associated with persistent human papillomavirus (HPV) infection. Primary prevention can be accomplished through vaccines that prevent HPV infection of the epithelial cells of the cervix. Secondary prevention in screening for precursor lesions through periodic repeat cervical sampling in a population of asymptomatic women. Women with abnormal cytology are more likely to have pre-invasive or invasive lesions and are referred for further testing, colposcopy. Colposcopy identifies suspicious areas and guides the best site for biopsy. In the situation of negative colposcopy and abnormal cytology, suspicion for high-grade lesion (HSIL). It recommends further investigation of the endocervical canal before the possible excisional procedure and obtaining an additional canal sample by brushing or curettage. However, to date, there is no consensus and studies lack consistent results on which is the best method for further investigation of the endocervix. Objectives: To compare the performance of additional strategies in the investigation and detection of precursor or invasive lesions in the endocervical canal in women with abnormal cytology (ASC H+) and with initial colposcopy without suspicious images.

Randomized Implementation of Primary HPV Testing in the Organized Screening for Cervical Cancer in Stockholm

The purpose is to evaluate whether implementation of primary human papillomavirus (HPV) screening in the screening programme for cervical cancer improves the programme in terms of better cancer protection and better cost efficiency.

Randomized Controlled Trial of Human Papillomavirus Testing in Primary Cervical Cancer Screening

Human papillomavirus (HPV)-based cervical screening is known to increase sensitivity for detection of high-grade cervical intraepithelial neoplasia (CIN). Randomized trials of longitudinal efficacy are required to assess whether these gains represent overdiagnosis or a protective effect. Methods: A total of 12527 women, aged 32-38, attending population-based invitational screening in Sweden were randomized 1:1 to HPV test and cytology (intervention arm) or cytology only (control arm). HPV-positive women were invited for a second HPV test at least one year later and women with type-specific persistent infections were then invited to colposcopy. A similar number of random double-blinded procedures are performed in the control arm. Women are followed with comprehensive registry-based follow-up. Primary outcome is the relative rates of CIN grade 2 or worse (CIN2/CIN3+) found in subsequent screening. Secondary outcomes are the relative rates of CIN2/CIN3+ found in the aseline screening and outcomes stratified by grade of CIN (CIN 2 or CIN3+).