Clinical Validation of the Vitro HPV Screening Assay for Its Use in Primary Cervical Cancer Screening.

Many scientific societies have issued guidelines to introduce population-based cervical cancer screening with HPV testing. The Vitro HPV Screening assay is a fully automatic multiplex real-time PCR test targeting the L1 GP5+/GP6+ region of HPV genome. The assay detects 14 high risk (HR) HPV genotypes, identifying individual HPV16 and HPV18 genotypes, and the HPV-positive samples for the other 12 HR HPV types are subsequently genotyped with the HPV Direct Flow Chip test. Following international guidelines, the aim of this study was to validate the clinical accuracy of the Vitro HPV Screening test on ThinPrep-collected samples for its use as primary cervical cancer screening, using as comparator the validated cobas® 4800 HPV test. The non-inferiority analysis showed that the clinical sensitivity and specificity of the Vitro HPV Screening assay for a diagnosis of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were not inferior to those of cobas® 4800 HPV (p = 0.0049 and p < 0.001 respectively). The assay has demonstrated a high intra- and inter-laboratory reproducibility, also among the individual genotypes. The Vitro HPV Screening assay is valid for cervical cancer screening and it provides genotyping information on HPV-positive samples without further sample processing in a fully automated workflow.

Assessing the Potential of HPV16 E6 Seroprevalence as a Biomarker for Anal Dysplasia and Cancer Screening-A Systematic Review and Meta-Analysis.

Elevated rates of human papillomavirus (HPV)-related anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) in populations like men who have sex with men (MSM) living with HIV underscore the need for effective screening. While high-resolution anoscopy-guided biopsy is the gold standard, limited provider availability poses a challenge. This has spurred interest in identifying biomarkers for improved AC prevention. Antibodies against HPV16 oncoprotein E6, known as markers for cervical and oropharyngeal cancers, are the focus of the current study. The systematic review and meta-analysis included six studies meeting inclusion criteria, assessing HPV16 E6 seroprevalence in individuals with anal HSIL or AC. A two-step meta-analysis estimated pooled odds ratios and 95% confidence intervals (CI) for HPV16 E6 seroprevalence and HSIL or AC. Pooled prevalence, sensitivity, specificity, and diagnostic odds ratios were also calculated. This meta-analysis revealed a 3.6-fold increased risk of HSIL for HPV16 E6 seropositive individuals, escalating to a 26.1-fold risk increase for AC. Pooled specificity and sensitivity indicated a high specificity (0.99; 95%CI: 0.99, 0.99) but lower sensitivity (0.19; 95%CI: 0.10, 0.34) for HPV16 E6 serostatus as an AC biomarker. In conclusion, while HPV16 E6 seroprevalence demonstrates specificity as a potential biomarker for HPV-related AC, its utility as a standalone screening tool may be limited. Instead, it could serve effectively as a confirmation test, particularly in high-risk populations, alongside other diagnostic methods. Further research is imperative to explore HPV16 E6 seroconversion dynamics and alternative screening algorithms.

Total Effective Xenoestrogen Burden in Serum Samples and Risk of Endometrial Cancer in the Spanish Screenwide Case-Control Study.

BACKGROUND: Endometrial cancer is a hormone-dependent cancer, and estrogens play a relevant role in its etiology. However, little is known about the effects of environmental pollutants that act as xenoestrogens or that influence estrogenic activity through different pathways. OBJECTIVE: We aimed to assess the relationship between the combined estrogenic activity of mixtures of xenoestrogens present in serum samples and the risk of endometrial cancer in the Screenwide case-control study. METHODS: The total effective xenoestrogen burden (TEXB) attributable to organohalogenated compounds (TEXB-α) and to endogenous hormones and more polar xenoestrogens (TEXB-ß) was assessed in serum from 156 patients with endometrial cancer (cases) and 150 controls by combining chemical extraction and separation by high-performance liquid chromatography with the E-SCREEN bioassay for estrogenicity. RESULTS: Median TEXB-α and TEXB-ß levels for cases (0.30 and 1.25 Eeq pM/mL, respectively) and controls (0.42 and 1.28 Eeq pM/mL, respectively) did not significantly differ (p=0.653 and 0.933, respectively). An inverted-U risk trend across serum TEXB-α and TEXB-ß levels was observed in multivariate adjusted models: Positive associations were observed for the second category of exposure in comparison to the lowest category of exposure [odds ratio (OR)=2.11 (95% CI: 1.13, 3.94) for TEXB-α, and OR=3.32 (95% CI: 1.62, 6.81) for TEXB-ß], whereas no significant associations were observed between the third category of exposure and the first [OR=1.22 (95% CI: 0.64, 2.31) for TEXB-α, and OR=1.58 (95% CI: 0.75, 3.33) for TEXB-ß]. In mutually adjusted models for TEXB-α and TEXB-ß levels, the association of TEXB-α with endometrial cancer risk was attenuated [OR=1.45 (95% CI: 0.61, 3.47) for the second category of exposure], as well as estimates for TEXB-ß (OR=2.68; 95% CI: 1.03, 6.99). Most of the individual halogenated contaminants showed no associations with both TEXB and endometrial cancer. CONCLUSIONS: We evaluated serum total xenoestrogen burden in relation to endometrial cancer risk and found an inverted-U risk trend across increasing categories of exposure. The use of in vitro bioassays with human samples may lead to a paradigm shift in the way we understand the negative impact of chemical mixtures on human health effects. These results are relevant from a public health perspective and for decision-makers in charge of controlling the production and distribution of chemicals with xenoestrogenic activity. https://doi.org/10.1289/EHP13202.

Occupational exposure to pesticides and endometrial cancer in the Screenwide case-control study.

BACKGROUND: Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms. OBJECTIVE: This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain. METHODS: The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp). RESULTS: Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88, OR = 4.40; 95% CI = 1.65-13.33, and OR = 5.25; 95% CI = 1.84-17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59-12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55-2.67). CONCLUSIONS: Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour.

Night shift work, sleep duration and endometrial cancer risk: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.

Evaluation of somatic mutations in cervicovaginal samples as a non-invasive method for the detection and molecular classification of endometrial cancer.

BACKGROUND: The incidence of endometrial cancer is increasing worldwide. While delays in diagnosis reduce survival, case molecular misclassification might be associated with under- and over-treatment. The objective of this study was to evaluate genetic alterations to detect and molecularly classify cases of endometrial cancer using non-invasive samples. METHODS: Consecutive patients with incident endometrial cancer (N = 139) and controls (N = 107) from a recent Spanish case-control study were included in this analysis. Overall, 339 cervicovaginal samples (out of which 228 were clinician-collected and 111 were self-collected) were analysed using a test based on next-generation sequencing (NGS), which targets 47 genes. Immunohistochemical markers were evaluated in 133 tumour samples. A total of 159 samples were used to train the detection algorithm and 180 samples were used for validation. FINDINGS: Overall, 73% (N = 94 out of 129 clinician-collected samples, and N = 66 out of 90 self-collected samples) of endometrial cancer cases had detectable mutations in clinician-collected and self-collected samples, while the specificity was 80% (79/99) for clinician-collected samples and 90% (19/21) for self-collected samples. The molecular classifications obtained using tumour samples and non-invasive gynaecologic samples in our study showed moderate-to-good agreement. The molecular classification of cases of endometrial cancer into four groups using NGS of both clinician-collected and self-collected cervicovaginal samples yielded significant differences in disease-free survival. The cases with mutations in POLE had an excellent prognosis, whereas the cases with TP53 mutations had the poorest clinical outcome, which is consistent with the data on tumour samples. INTERPRETATION: This study classified endometrial cancer cases into four molecular groups based on the analysis of cervicovaginal samples that showed significant differences in disease-free survival. The molecular classification of endometrial cancer in non-invasive samples may improve patient care and survival by indicating the early need for aggressive surgery, as well as reducing referrals to highly specialized hospitals in cancers with good prognosis. Validation in independent sets will confirm the potential for molecular classification in non-invasive samples. FUNDING: This study was funded by a competitive grant from Instituto de Salud Carlos III through the projects PI19/01835, PI23/00790, and FI20/00031, CIBERESP CB06/02/0073 and CIBERONC CB16/12/00231, CB16/12/00234 (Co-funded by European Regional Development Fund. ERDF: A way to build Europe). Samples and data were provided by Biobank HUB-ICO-IDIBELL, integrated into the Spanish Biobank Network, and funded by the Instituto de Salud Carlos III (PT20/00171) and by Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d'Oncologia de Catalunya. This work was supported in part by the AECC, Grupos estables (GCTRA18014MATI). It also counts with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya, and grants to support the activities of research groups 2021SGR01354 and 2021SGR1112.

Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer.

PURPOSE: Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate patients with endometrial cancer from controls. EXPERIMENTAL DESIGN: Overall, 72 samples were analyzed using next-generation sequencing (NGS) with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n = 19) and age-matched controls (n = 20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples. RESULTS: Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF) ≥ 2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAF in urine supernatants than in urine cell pellets and blood samples. CONCLUSIONS: Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multicenter evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer.

Cost-effectiveness analysis of molecular testing in minimally invasive samples to detect endometrial cancer in women with postmenopausal bleeding.

INTRODUCTION: New approaches are being developed to early detect endometrial cancer using molecular biomarkers. These approaches offer high sensitivities and specificities, representing a promising horizon to develop early detection strategies. OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of introducing molecular testing to detect endometrial cancer in women with postmenopausal bleeding compared to the current strategy using the national healthcare service perspective. METHODS: A Markov model was developed to assess the two early detection strategies. The model predicts the number of hysterectomies, lifetime expectancy, quality-adjusted life-years, endometrial cancer prevalence and incidence, mortality from endometrial cancer and the lifetime cost of screening, diagnosis, and treatment. Strategies were compared using the incremental cost-effectiveness ratio. RESULTS: The molecular strategy reduces 1.9% of the overall number of hysterectomies and the number of undetected cancer cases by 65%. Assuming a molecular test cost of 310€, the molecular strategy has an incremental cost of -32,952€ per QALY gained, being more effective and less expensive than the current strategy. CONCLUSIONS: The introduction of molecular testing to diagnose endometrial cancer in women presenting postmenopausal bleeding provides more health benefit at a lower cost, and therefore has the potential to be cost-effective.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Highly Sensitive Microsatellite Instability and Immunohistochemistry Assessment in Endometrial Aspirates as a Tool for Cancer Risk Individualization in Lynch Syndrome.

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS.

Everything causes cancer? Beliefs and attitudes towards cancer prevention among anti-vaxxers, flat earthers, and reptilian conspiracists: online cross sectional survey.

OBJECTIVE: To evaluate, using an online non-probability sample, the beliefs about and attitudes towards cancer prevention of people professing vaccination scepticism or conspiracy theories. DESIGN: Cross sectional survey. SETTING: Data collected mainly from ForoCoches (a well known Spanish forum) and other platforms, including Reddit (English), 4Chan (English), HispaChan (Spanish), and a Spanish language website for cancer prevention (mejorsincancer.org) from January to March 2022. PARTICIPANTS: Among 1494 responders, 209 were unvaccinated against covid-19, 112 preferred alternative rather than conventional medicine, and 62 reported flat earth or reptilian beliefs. MAIN OUTCOME MEASURES: Cancer beliefs assessed using the Cancer Awareness Measure (CAM) and Cancer Awareness Measure Mythical Causes Scale (CAM-MYCS) (both validated tools). RESULTS: Awareness of the actual causes of cancer was greater (median CAM score 63.6%) than that of mythical causes (41.7%). The most endorsed mythical causes of cancer were eating food containing additives or sweeteners, feeling stressed, and eating genetically modified food. Awareness of the actual and mythical causes of cancer among the unvaccinated, alternative medicine, and conspiracy groups was lower than among their counterparts. A median of 54.5% of the actual causes was accurately identified among each of the unvaccinated, alternative medicine, and conspiracy groups, and a median of 63.6% was identified in each of the three corresponding counterparts (P=0.13, 0.04, and 0.003, respectively). For mythical causes, medians of 25.0%, 16.7%, and 16.7% were accurately identified in the unvaccinated, alternative medicine, and conspiracy groups, respectively; a median of 41.7% was identified in each of the three corresponding counterparts (P<0.001 in adjusted models for all comparisons). In total, 673 (45.0%) participants agreed with the statement "It seems like everything causes cancer." No significant differences were observed among the unvaccinated (44.0%), conspiracist (41.9%), or alternative medicine groups (35.7%), compared with their counterparts (45.2%, 45.7%, and 45.8%, respectively). CONCLUSIONS: Almost half of the participants agreed that "It seems like everything causes cancer," which highlights the difficulty that society encounters in differentiating actual and mythical causes owing to mass information. People who believed in conspiracies, rejected the covid-19 vaccine, or preferred alternative medicine were more likely to endorse the mythical causes of cancer than their counterparts but were less likely to endorse the actual causes of cancer. These results suggest a direct connection between digital misinformation and consequent erroneous health decisions, which may represent a further preventable fraction of cancer.

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.

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.

An Integrated Approach for the Early Detection of Endometrial and Ovarian Cancers (Screenwide Study): Rationale, Study Design and Pilot Study.

Screenwide is a case-control study (2017−2021) including women with incident endometrial and ovarian cancers (EC and OC), BRCA1/2 and MMR pathogenic variant carriers, and age-matched controls from three centers in Spain. Participants completed a personal interview on their sociodemographic factors, occupational exposure, medication, lifestyle, and medical history. We collected biological specimens, including blood samples, self-collected vaginal specimens, cervical pap-brush samples, uterine specimens, and, when available, tumor samples. The planned analyses included evaluation of the potential risk factors for EC/OC; evaluation of molecular biomarkers in minimally invasive samples; evaluation of the cost-effectiveness of molecular tests; and the generation of predictive scores to integrate different epidemiologic, clinical, and molecular factors. Overall, 182 EC, 69 OC, 98 BRCA pathogenic variant carriers, 104 MMR pathogenic variant carriers, and 385 controls were enrolled. The overall participation rate was 85.7%. The pilot study using 61 samples from nine EC cases and four controls showed that genetic variants at the variant allele fraction > 5% found in tumors (n = 61 variants across the nine tumors) were detected in paired endometrial aspirates, clinician-collected cervical samples, and vaginal self-samples with detection rates of 90% (55/61), 79% (48/61), and 72% (44/61) by duplex sequencing, respectively. Among the controls, only one somatic mutation was detected in a cervical sample. We enrolled more than 800 women to evaluate new early detection strategies. The preliminary data suggest that our methodological approach could be useful for the early detection of gynecological cancers.

Night work, chronotype and risk of endometrial cancer in the Screenwide case-control study.

BACKGROUND: Circadian disruption caused by night work has been associated with hormonal-related cancers such as breast and prostate cancer. Data on the role of circadian factors in the aetiology of endometrial cancer, an oestrogen-associated cancer, are scarce. METHODS: We examined the association between endometrial cancer and night shift work, chronotype (a characteristic correlating with preference for morning or evening activity) and sleep duration, in 180 incident cases and 218 hospital controls. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical, occupational history (including work shifts), sleep duration and chronotype, and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate ORs and 95% CIs. RESULTS: After adjustment by potential confounders, we found an inverse not statistically significant association between ever worked in night shifts and endometrial cancer (OR=0.64; 95% CI=0.35 to 1.16). Associations were irrespective of shift type (permanent or rotating nights) or duration of night work. We did not observe any statistically significant association between endometrial cancer and sleep duration, while inconsistent patterns were observed for chronotype and endometrial cancer risk. CONCLUSIONS: These data do not support a role for circadian disruption in the carcinogenesis of endometrial cancer.

Predicting Ovarian-Cancer Burden in Catalonia by 2030: An Age-Period-Cohort Modelling.

Ovarian cancer is the most lethal gynaecological cancer in very-high-human-development-index regions. Ovarian cancer incidence and mortality rates are estimated to globally rise by 2035, although incidence and mortality rates depend on the region and prevalence of the associated risk factors. The aim of this study is to assess changes in incidence and mortality of ovarian cancer in Catalonia by 2030. Bayesian autoregressive age-period-cohort models were used to predict the burden of OC incidence and mortality rates for the 2015-2030 period. Incidence and mortality rates of ovarian cancer are expected to decline in Catalonia by 2030 in women ≥ 45 years of age. A decrease in ovarian-cancer risk was observed with increasing year of birth, with a rebound in women born in the 1980s. A decrease in mortality was observed for the period of diagnosis and period of death. Nevertheless, ovarian-cancer mortality remains higher among older women compared to other age groups. Our study summarizes the most plausible scenario for ovarian-cancer changes in terms of incidence and mortality in Catalonia by 2030, which may be of interest from a public health perspective for policy implementation.

The Isothermal Amplification AmpFire Assay for Human Papillomavirus (HPV) Detection and Genotyping in Formalin-Fixed, Paraffin-Embedded Oropharyngeal Cancer Samples.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) represent a distinct clinical entity compared with HPV-negative tumors with particular regard to treatment response and survival outcome. The aim of this study was to assess the AmpFire Multiplex HR-HPV tests, for the detection and genotyping of 15 high-risk (HR) HPV types in formalin-fixed, paraffin-embedded (FFPE) samples and identify HPV-driven OPSCC. DNA from 160 OPSCC FFPE specimens plus 23 samples from other head and neck primary sites was tested. Results were compared with those obtained using Linear Array HPV-DNA Genotyping Test. Linear Array and AmpFire Multiplex HR-HPV tests showed, for all samples and specifically for OPSCCs, an overall concordance agreement of 98.9% and 99.4% and a Cohen κ coefficient of 0.972 and 0.984, respectively. A concordance of 100% for HPV16 and HPV18 was observed. The overall agreement between p16INK4a overexpression and HPV detection by the AmpFire Multiplex HR-HPV assay in 145 OPSCC samples was 93.8%, with a Cohen κ coefficient of 0.848. The AmpFire HPV Tests are simple assays for detection and genotyping of HPV-DNA in OPSCC FFPE samples and can be easily implemented in the clinical practice setting for HPV-DNA detection.

Sensitivity of cervical cytology in endometrial cancer detection in a tertiary hospital in Spain.

INTRODUCTION: Cervical cytology is a well-stablished cervical cancer screening method. However, due to the anatomical continuity of the genital tract, it can also detect signs of endometrial disease. Our aim was to estimate the sensitivity of cervical cytology in endometrial cancer detection and prognosis in a large population over a 30-year period in a large academic tertiary hospital in Spain. METHODOLOGY: We performed a search for women diagnosed with endometrial cancer from 1990 to 2020, who were surgically treated and had a previous cervical cytology result. Information Technologies Department databases from Bellvitge University Hospital and the Screenwide case-control study's database were used. Cervical cytology results were classified as abnormal when squamous lesions, glandular atypia or malignant cells were identified. RESULTS: Overall, we evaluated 371 women with endometrial cancer and a documented cervical cytology performed within 3 years previous to surgical treatment. Overall, the sensitivity of cervical cytology for endometrial cancer detection was 25.6%. Several clinico-pathological characteristics, such as non-endometrioid histology and a higher stage, were correlated with higher sensitivity. DISCUSSION: We observed a low sensitivity of cervical cytology to effectively diagnose endometrial cancer. However, recent technological advances using genomics and epigenomics may offer a promising perspective to detect endometrial cancer with high sensitivity in these cervical specimens.

New perspectives on screening and early detection of endometrial cancer.

Due to the anatomical continuity of the uterine cavity with the cervix, genomic exploitation of material from routine Pap smears and other noninvasive sampling methods represent a unique opportunity to detect signs of disease using biological material shed from the upper genital tract. Recent research findings offer a promising perspective in the detection of endometrial cancer, but certain questions need to be addressed in order to accelerate the implementation of novel technologies in a routine screening or clinical setting. We discuss here new perspectives on detection of endometrial cancer using genomic and other biomarkers in minimally invasive sampling methods with a special focus on public health classic screening criteria, highlighting current gaps in knowledge.

The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism.

Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.