Global burden and economic impact of vaccine-preventable cancer mortality.

BACKGROUND: Infections are responsible for approximately 13% of cancer cases worldwide and many of these infections can be prevented by vaccination. Human papillomavirus (HPV) and hepatitis B virus (HBV) are among the most common infections that cause cancer deaths globally, despite effective prophylactic vaccines being available. This analysis aims to estimate the global burden and economic impact of vaccine-preventable cancer mortality across World Health Organization (WHO) regions. METHODS: The number of deaths and years of life lost (YLL) due to five different vaccine-preventable cancer forms (oral cavity, liver, laryngeal, cervical, and oropharyngeal cancer) in each of the WHO regions (African, Eastern Mediterranean, European, the Americas, South-East Asia Pacific, and Western Pacific) were obtained from the Institute for Health Metrics Evaluation global burden of disease dataset. Vaccine-preventable mortality was estimated considering the fraction attributable to infection, to estimate the number of deaths and YLL potentially preventable through vaccination. Data from the World Bank on GDP per capita were used to estimate the value of YLL (VYLL). The robustness of these results was explored with sensitivity analysis. Given that several Epstein-Barr virus (EBV) vaccines are in development, but not yet available, the impact of a potential vaccine for EBV was evaluated in a scenario analysis. RESULTS: In 2019, there were 465,740 potentially vaccine-preventable cancer deaths and 14,171,397 YLL across all WHO regions. The estimated economic impact due to this mortality was $106.3 billion globally. The sensitivity analysis calculated a range of 403,025-582,773 deaths and a range in productivity cost of $78.8-129.0 billion. In the scenario analysis EBV-related cancer mortality increased the global burden by 159,723 deaths and $32.4 billion. CONCLUSION: Overall, the findings from this analysis illustrate the high economic impact of premature cancer mortality that could be potentially preventable by vaccination which may assist decision-makers in allocating limited resources among competing priorities. Improved implementation and increased vaccination coverage of HPV and HBV should be prioritized to decrease this burden.

Antidepressant use and ovarian cancer risk: Evidence from nationwide studies with >14,000 cases from Denmark and Sweden.

OBJECTIVE: Given that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. METHODS: Altogether, 14,121 women with epithelial ovarian cancer (30-84 years old) (Denmark: 8976 diagnosed 2000-2019, Sweden: 5145 diagnosed 2010-2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. RESULTS: Antidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88-0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86-0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82-0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. CONCLUSIONS: Use of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden.

BACKGROUND: Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. METHODS AND FINDINGS: Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. CONCLUSIONS: Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Low-dose aspirin use was associated with a decreased ovarian cancer risk especially in nulliparous women and in women without CVD diagnosis.

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.

Overall and Cervical Cancer Survival in Patients With and Without Mental Disorders.

Importance: Individuals with a mental disorder experience substantial health disparity and are less likely to participate in cervical screening and human papillomavirus vaccination. Additionally, this population may benefit less from tertiary cancer prevention. Objective: To compare clinical characteristics and survival patterns between patients with cervical cancer with and without a preexisting diagnosis of a mental disorder at the time of cervical cancer diagnosis. Design, Setting, and Participants: This cohort study obtained data from Swedish population-based (Swedish Cancer Register, Swedish Cause of Death Register, Swedish Total Population Register, Swedish Patient Register, and Swedish Longitudinal Integration Database for Health Insurance and Labor Market Studies) and quality registries (Swedish Quality Register of Gynecologic Cancer and Swedish National Cervical Screening Register) on patients with cervical cancer. Patients who were included in the analysis were identified using the Swedish Cancer Register and were diagnosed with cervical cancer between 1978 and 2018. The Swedish Patient Register was used to identify patients with mental disorders using codes from the International Classification of Diseases, Eighth Revision and Ninth Revision and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Because data on clinical characteristics at the time of cancer diagnosis were available for only for part of the study population, 2 patient groups were created: those with cervical cancer diagnosed from 2002 to 2016 and all patients diagnosed with cervical cancer (1978-2018). Data analyses were carried out between March and September 2022. Exposure: Clinical diagnoses of a mental disorder, including substance abuse, psychotic disorders, depression, anxiety, stress-related disorders, attention-deficit/hyperactivity disorder, autism, and intellectual disability, prior to cervical cancer. Main Outcomes and Measures: Death due to any cause or due to cervical cancer as ascertained from the Swedish Cause of Death Register. Results: The sample included 20 177 females (mean [SD] age, 53.4 [17.7] years) diagnosed with cervical cancer from 1978 to 2018. In a subgroup of 6725 females (mean [SD] age, 52.2 [18.0] years) with cervical cancer diagnosed from 2002 to 2016, 893 (13.3%) had a preexisting diagnosis of a mental disorder. Compared with patients with no preexisting mental disorder diagnosis, those with a preexisting mental disorder had a higher risk of death due to any cause (hazard ratio [HR], 1.32; 95% CI, 1.17-1.48) and due to cervical cancer (HR, 1.23; 95% CI, 1.07-1.42). These risks were lower after adjustment for cancer characteristics at the time of cancer diagnosis (death due to any cause: HR, 1.19 [95% CI, 1.06-1.34] and death due to cervical cancer: HR, 1.12 [95% CI, 0.97-1.30]). Risk of death was higher for patients with substance abuse, psychotic disorders, or mental disorders requiring inpatient care. Among patients with cervical cancer diagnosed from 1978 to 2018, the estimated 5-year survival improved continuously during the study period regardless of preexisting diagnosis of a mental disorder status. For example, in 2018, the estimated 5-year overall survival proportion was 0.66 (95% CI, 0.60-0.71) and 0.74 (95% CI, 0.72-0.76) for patients with and without a preexisting diagnosis of a mental disorder, respectively. Conclusions and Relevance: Findings of this cohort study suggest that patients with cervical cancer and a preexisting diagnosis of a mental disorder have worse overall and cervical cancer-specific survival than patients without a preexisting mental disorder diagnosis, which may be partly attributable to cancer and sociodemographic characteristics at diagnosis. Hence, individuals with mental disorders deserve special attention in the tertiary prevention of cervical cancer.

[Conditions for performing CT and MRI scans in pregnant and lactating patients]. / Att tänka på vid neuroradiologisk diagnostik av gravida och ammande.

Many women are pregnant during several percent of their lives. Occasionally, there is a need for neuroradiological examinations during pregnancy or lactation. In our clinical work, we regularly see that female patients are being withheld relevant diagnostic scans during pregnancy, due to insufficient knowledge or an unbalanced comparison between benefits and risks. This article describes the current knowledge regarding conditions for performing CT and MRI scans in pregnant and lactating patients, including the use of contrast media. PET scans and reactions to contrast media are briefly mentioned, but interventional radiology is not discussed.

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012-2019.

Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden's childhood immunization program and provide an estimate on dose timing compliance. Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000-2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001-2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004-2005, and 56.3% in birth cohorts 2000-2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6-12 months after dose one. Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination.

Factors associated with teenage pregnancy in the Scandinavian countries.

AIMS: Teenage pregnancy may have negative consequences for the mother and the infant. The aim of the study was to examine whether selected individual factors occurring early in life were associated with teenage pregnancy. METHODS: In a population-based, cross-sectional questionnaire study among 34,455 women from Denmark, Norway, and Sweden aged 20-45 years, who had first sexual intercourse (FSI) at age 13-19 years, we assessed the association between early smoking and drinking initiation (i.e., before the age of 13), contraceptive use at FSI, and teenage pregnancy. Log-linear binary regression models were fitted to estimate the relative risk (RR) with 95% confidence intervals (CIs) of teenage pregnancy according to the three exposure variables, overall and by age at FSI. Furthermore, the outcomes of the teenage pregnancies were examined according to age at FSI. RESULTS: Teenage pregnancy occurred in 11% of the population. Both early smoking initiation (RR: 1.6; 95% CI: 1.4-1.8), early drinking initiation (RR: 1.2; 95% CI: 1.0-1.4), and non-use of contraceptives at FSI (RR: 1.9; 95% CI: 1.8-2.0) were associated with teenage pregnancy. The associations for early smoking initiation and non-use of contraceptives remained when analyses were stratified by age at FSI. Almost 60% of all teenage pregnant women had an induced abortion and less than 30% gave birth. CONCLUSIONS: Individual factors, including early smoking and drinking initiation, and non-use of contraceptives at FSI, were associated with teenage pregnancy regardless of age at FSI. This emphasizes the necessity of focusing on early risk-taking behavior as a potential modifier to prevent teenage pregnancy.

Invasive cervical cancer, precancerous lesions, and cervical screening participation among women with mental illness in Sweden: a population-based observational study.

BACKGROUND: WHO aims to eliminate cervical cancer. Whether women with mental illness constitute a group at high-risk and require targeted prevention initiatives remains unknown. We aimed to assess whether women with severe mental illness, psychiatric or neurodevelopmental disorders, have an increased risk of invasive cervical cancer, and an increased risk of precancerous lesions and a lower degree of participation in cervical screening compared with women without severe mental illness. METHODS: In this population-based observational study, 4 112 598 women from 1973 to 2018 in Sweden were included to compare the risk of invasive cervical cancer, high-grade precancerous cervical lesions (CIN2+), and degree of participation in cervical screening (defined as the proportion of time covered by screening during a period when cervical screening is recommended) between women with and without mental illness. We focused on severe mental illness (ie, diagnosed in specialised psychiatric care) and also investigated milder mental illness (ie, use of psychotropic medications prescribed in primary care without specialist diagnosis) as secondary exposure. In two nested case-control studies, we defined the cases as women who have a diagnosis of invasive cervical cancer or CIN2+, and randomly selected individually matched controls from women who did not have these diagnoses. FINDINGS: Women with a specialist diagnosis of mental illness had a higher risk of invasive cervical cancer (hazard ratio 2·39, 95% CI 2·22-2·57) and CIN2+ (2·22, 2·18-2·26) and a 5·0% (4·8-5·2) lower cervical screening participation compared with matched controls. The risk increment of invasive cervical cancer and CIN2+ was greatest for substance misuse, whereas the screening reduction was greatest for intellectual disability and autism. In contrast, women who used prescribed psychotropic medications without specialist diagnosis had slightly higher screening participation and higher risk of CIN2+ but lower risk of invasive cervical cancer than women with neither specialist diagnosis nor medication use. INTERPRETATION: Women with severe mental illness participate less in screening and experience a higher risk of cervical neoplasia. Refined approaches are needed to better target these women in the elimination agenda of cervical cancer. FUNDING: Swedish Cancer Society.

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia.

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.

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

The 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 review of data systems for assessing the impact of HPV vaccination in selected high-income countries.

INTRODUCTION: The introduction of effective human papillomavirus (HPV) vaccination, screening, and treatment programs has led the World Health Organization to call for the global elimination of cervical cancer. Assessing progress toward this goal is supported through monitoring vaccination coverage and its impact. AREAS COVERED: We performed a targeted review to assess the characteristics of HPV-related data systems from seven high-income countries (HICs) that represented varied approaches, including Australia, Canada, France, Italy, Scotland, Sweden, and the United States (US). Included data systems focused on preventive and early detection measures: HPV vaccination and cervical screening programs, as well as HPV-related disease outcomes. Differences were observed in approach to development of data systems, along with variation in geographical scope and methods of data collection. EXPERT OPINION: A challenge exists in how to best follow-up the ongoing global-scale elimination efforts in a comprehensive manner. These sources provide a wealth of information regarding the strengths and limitations of, and notable variation among, current data systems used in HICs. This review can inform improvements to existing prevention programs and the implementation of new programs in other countries, and thus support optimization of cervical cancer prevention policy.

DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test.

BACKGROUND: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. RESULTS: The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case-control) and predictive setting (nested case-control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt-) index sample who were diagnosed with CIN3 1-4 years after sample donation. CONCLUSION: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case-control settings and future studies will assess performance and generalisability in a randomised controlled trial.

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer.

BACKGROUND: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. METHODS: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free. RESULTS: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and <30-year-old women, at a specificity of 75%. CONCLUSIONS: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.

Real-world impact and effectiveness of the quadrivalent HPV vaccine: an updated systematic literature review.

INTRODUCTION: Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination. AREAS COVERED: We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints. EXPERT OPINION: The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

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.

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples.

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

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.

Real-world impact and effectiveness assessment of the quadrivalent HPV vaccine: a systematic review of study designs and data sources.

INTRODUCTION: Vaccine effectiveness and impact studies are typically observational, generating evidence after vaccine launch in a real-world setting. For human papillomavirus (HPV) vaccination studies, the variety of data sources and methods used is pronounced. Careful selection of study design, data capture and analytical methods can mitigate potential bias in such studies. AREAS COVERED: We systematically reviewed the different study designs, methods, and data sources in published evidence (1/2007-3/2020), which assessed the quadrivalent HPV vaccine effectiveness and impact on cervical/cervicovaginal, anal, and oral HPV infections, anogenital warts, lesions in anus, cervix, oropharynx, penis, vagina or vulva, and recurrent respiratory papillomatosis. EXPERT OPINION: The rapid growth in access to real-world data allows global monitoring of effects of different public health interventions, including HPV vaccination programs. But the use of data which are not collected or organized to support research also underscore a need to develop robust methodology that provides insight of vaccine effects and consequences of different health policy decisions. To achieve the WHO elimination goal, we foresee a growing need to evaluate HPV vaccination programs globally. A critical appraisal summary of methodology used will provide timely guidance to researchers who want to initiate research activities in various settings.