The epidemiology of multiple primary cancers in Belgium (2004-2017): Incidence, proportion, risk, stage and impact on relative survival estimates.

BACKGROUND: As both life expectancy and cancer survival improve, the incidence of multiple primary cancer has augmented and is expected to further increase. This study describes for the first time the epidemiology of multiple invasive tumours in Belgium. METHODS: This nationwide study, based on all cancers diagnosed between 2004 and 2017 in Belgium, describes the proportion of multiple primary cancer, its evolution over time, the impact of inclusion or exclusion of multiple primary cancer on relative survival estimates, the risk of developing a second primary cancer, and the difference in stage between first and second primary cancer for the same patient. RESULTS: The proportion of multiple primary cancer increases with age, varies across cancer sites (from 4% for testis cancer to 22.8% for oesophageal cancer), is higher in men than in women, and has linearly increased over time. The inclusion of multiple primary cancer resulted in smaller 5-year relative survival and this impact is more pronounced in cancer sites with high relative survival. Patients with a first primary cancer have an increased risk to develop a new primary cancer compared to the population without a previous cancer history (1.27 and 1.59 times higher in men and women, respectively) and this risk depends on cancer site. Second primary cancers are associated with more advanced stages and more unknown stages than the corresponding first cancer diagnosis. CONCLUSIONS: This study describes multiple primary cancer according to several measures (proportion, standardised incidence ratio for an second primary cancer, impact of multiple primary cancer on relative survival and differences according to stage) for the first time in Belgium. The results are based on data of a population-based cancer registry with a relatively recent onset (2004).

Non-aspirin NSAID use and mortality of endometrial cancer. A nationwide cohort study.

PURPOSE: Laboratory studies have shown anti-neoplastic properties of non-aspirin NSAID; however, no studies have examined the influence of non-aspirin NSAIDs as potential adjuvant cancer therapy in women with endometrial cancer. We therefore examined the association between post-diagnostic use of non-aspirin NSAIDs and endometrial cancer mortality in Denmark. METHODS: We identified all women with a primary endometrial cancer diagnosis between 2000 and 2012, who were alive one year after the diagnosis. Information on drug use, cause-specific mortality and potential confounders was obtained from nationwide health- and demographic registries. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic non-aspirin NSAID use and endometrial cancer mortality. RESULTS: Among 6 694 endometrial cancer patients with a maximum follow-up of 13 years, 753 women died from endometrial cancer. Post-diagnostic non-aspirin NSAID use (≥ 1 filled prescription) was associated with an overall HR of 1.15 (95% CI; 0.97-1.36) for endometrial cancer mortality, with higher HRs for the highest intensity of use (HR; 1.40, 95% CI; 1.11-1.77) and largest cumulative amount (HR; 1.56, 95% CI; 1.14-2.14). CONCLUSION: Our findings yielded no evidence that use of non-aspirin NSAIDs was associated with reduced endometrial cancer. Rather, we observed that high-intensity and large cumulative amount of non-aspirin NSAID use may be associated with increased endometrial cancer mortality.

Low-dose aspirin use and risk of head and neck cancer-A Danish nationwide case-control study.

Results concerning a potential preventive effect of aspirin on head and neck cancer (HNC) are conflicting. We examined the association between low-dose aspirin use and HNC risk overall and by degree of human papillomavirus association in a nested case-control study using nationwide registries. Cases (n = 12 389) were all Danish residents diagnosed with primary HNC (2000-2015). Age- and sex-matched population controls (n = 185 835) were selected by risk-set-sampling. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios and 95% confidence intervals for HNC associated with low-dose aspirin use (≥2 prescriptions). No association was observed between low-dose aspirin ever-use and overall HNC (odds ratio: 1.03, 95% confidence interval: 0.97-1.10). Estimates remained neutral according to patterns of use. Low-dose aspirin use appeared to slightly decrease HNC risk among the eldest (71-84 y), independently of human papillomavirus association, while slightly increase HNC risk among younger age groups (30-60, 61-70 y), driven by an increased risk of oral cancer. However, no consistent patterns in risk estimates were found according to duration and consistency of low-dose aspirin use in the age-stratified analyses.

Dose-related Effectiveness of Quadrivalent Human Papillomavirus Vaccine Against Cervical Intraepithelial Neoplasia: A Danish Nationwide Cohort Study.

BACKGROUND: A reduced, 2-dose schedule of human papillomavirus (HPV) vaccination has been endorsed for preadolescent women on the basis of immunogenicity data from randomized trials, and limited data suggest that even 1 dose may provide sufficient protection. Surveillance of the impact of <3 vaccine doses on clinical endpoints in the targeted age group is warranted. METHODS: We conducted a nationwide cohort study of all women aged 17-25 years, living in Denmark between 2006 and 2016. From nationwide registries, we extracted individual-level data on vaccination with the quadrivalent HPV (qHPV) vaccine at 16 years or younger, number of doses administered, diagnoses of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+), and potential confounders. Using Poisson regression, we estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for CIN2+ and CIN3+, according to vaccination status. RESULTS: The cohort comprised 590 083 women, of which 215 309 (36%) women were vaccinated at ≤16 years, and among these, 40 742 (19%) received <3 vaccine doses. A total of 5561 women had a diagnosis of CIN3+. We found considerable vaccine effectiveness against CIN3+ after 1 (IRR, 0.38 [95% CI, .14-.98]), 2 (IRR, 0.38 [95% CI, .22-.66]), or 3 (IRR, 0.37 [95% CI, .30-.45]) vaccine doses, compared to unvaccinated women. Results were similar for CIN2+. CONCLUSIONS: We find substantial effectiveness of qHPV vaccination against high-grade cervical precancerous lesions, among women vaccinated with 1, 2, or 3 doses at ≤16 years of age. One-dose vaccination appeared to provide similar protection as 3-dose vaccination.

Use of nonaspirin nonsteroidal anti-inflammatory drugs and risk of head and neck cancer: A nationwide case-control study.

Head and neck cancer (HNC) is the sixth most frequent malignancy with high mortality and substantial morbidity and hence there is a need for identification of preventive factors. Preclinical and observational studies have reported antineoplastic effects of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), but studies of nonaspirin NSAID use and risk of HNC are sparse and with inconsistent results. We therefore conducted a register-based case-control study nested in the entire Danish population. Cases (n = 12,389) comprised all Danish residents aged 30-84 years with a histologically verified primary HNC diagnosis during 2000-2015. Based on the literature, cases were categorized into four groups of anticipated association with human papillomavirus (HPV): strong, potential, no/weak and uncertain. Age- and sex-matched population controls (n = 185,835) were selected by risk-set-sampling. We obtained information on filled prescriptions of nonaspirin NSAIDs, other drug use, comorbid conditions and socioeconomic parameters from nationwide Danish registries. Ever-use (≥2 prescriptions) of nonaspirin NSAIDs was not associated with the overall risk of HNC after adjustment for potential confounders (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.95-1.03). However, long-term consistent use (≥5 years) was associated with a 25% reduction in HNC risk (OR: 0.75, 95% CI: 0.62-0.90). Stratified analyses by anticipated HPV-association showed no material differences in estimates. In conclusion, ever-use of nonaspirin NSAIDs was not associated with the risk of HNC with no apparent influence on the estimates by the anticipated HPV-association. However, long-term consistent use may be associated with a reduced risk of HNC and merits further investigation.

Human papillomavirus and p16 in squamous cell carcinoma and intraepithelial neoplasia of the vagina.

We estimated the overall and type-specific prevalence of human papillomavirus (HPV) and p16 overexpression in vaginal cancer and vaginal intraepithelial neoplasia (VaIN). We conducted a systematic search of PubMed, Embase and Cochrane Library to identify studies published between 1986 and 2017 using PCR-based or Hybrid Capture 2 tests to evaluate the presence of HPV DNA and/or using any method to detect p16 overexpression in VaIN, vaginal squamous cell carcinoma (VaSCC), or other types of vaginal cancer. Applying a random effects model, we estimated the pooled prevalence of HPV and p16 overexpression along with 95% confidence intervals (CIs). The I2 statistic was used to assess heterogeneity. We included 26 studies, reporting HPV prevalence and six studies evaluating p16 overexpression. The pooled HPV prevalences in VaSCC (n = 593) and VaIN (n = 1,374) were 66.7% (95% CI = 54.7-77.8) and 85.2% (95% CI = 78.2-91.0), respectively. Substantial inter-study heterogeneity was observed, and analyses stratified on geographic region, type of tissue, HPV detection method or PCR primer type did not fully explain the observed heterogeneity. The most predominant HPV type among the HPV positive VaSCC and VaIN cases was HPV16, followed by HPV33, and HPV45 (in VaIN) and HPV18, and HPV33 (in VaSCC). In pooled analyses, 89.9% (95% CI = 81.7-94.6) of HPV positive and 38.9% (95% CI = 0.9-90.0) of HPV negative vaginal cancers were positive for p16 overexpression. Our findings suggest that vaccination against HPV might prevent a substantial proportion of vaginal neoplasia and highlight the need for further studies of the possible clinical value of p16 testing in these patients.

Statin use and mortality among endometrial cancer patients: a Danish nationwide cohort study.

Statin use has been linked to improved prognosis of some cancer types, however, for endometrial cancer, the results are equivocal. We therefore examined the effect of statin use on endometrial cancer mortality. From the Danish Cancer Registry, we identified all women in Denmark aged 30-84 years with primary endometrial cancer during 2000-2012. Data on drug use, mortality outcomes and potential confounders were retrieved from nationwide registries. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer-specific and other-cause mortality associated with statin use. Among 6,694 endometrial cancer patients, 753 died from endometrial cancer and 765 from other causes during a median follow-up of 4.5 year (interquartile range: 1.9-8.1). We observed an inverse association between time-varying postdiagnosis statin use (≥2 prescriptions) and endometrial cancer mortality (HR: 0.61, 95% CI: 0.48-0.77) compared to non-use (<2 prescriptions). The associations did not differ substantially by intensity or cumulative amount of statin use. In secondary analyses including prediagnosis statin use, we observed reduced mortality among both continuing (pre- and postdiagnosis) users (HR 0.70, 95% CI 0.53-0.92) and new (postdiagnosis only) users (HR 0.43, 95% CI 0.29-0.65) compared to "never users." In sensitivity analyses with fixed exposure periods after the endometrial cancer diagnosis, the inverse association was more pronounced more than 5 years after the diagnosis. Our findings suggest that statin use may be associated with improved survival in endometrial cancer patients.

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study.

BACKGROUND: Increasing data suggest that aspirin use may improve cancer survival; however, the evidence is sparse for ovarian cancer. METHODS: We examined the association between postdiagnosis use of low-dose aspirin and mortality in a nationwide cohort of women with epithelial ovarian cancer between 2000 and 2012. Information on filled prescriptions of low-dose aspirin, dates and causes of death, and potential confounding factors was obtained from nationwide Danish registries. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer-specific or other-cause mortality associated with low-dose aspirin use. RESULTS: Among 4117 patients, postdiagnosis use of low-dose aspirin was associated with HRs of 1.02 (95% CI: 0.87-1.20) for ovarian cancer mortality and 1.06 (95% CI: 0.77-1.47) for other-cause mortality. Hazard ratios remained neutral according to patterns of low-dose aspirin use, including prediagnosis use or established mortality predictors. CONCLUSIONS: Low-dose aspirin use did not reduce mortality among ovarian cancer patients.

Non-aspirin NSAID use and ovarian cancer mortality.

OBJECTIVE: Preclinical studies suggest that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) may improve survival of ovarian cancer. We examined the association between non-aspirin NSAID use and ovarian cancer mortality. METHODS: All women in Denmark with a first diagnosis of epithelial ovarian cancer between 2000 and 2012 were identified. We obtained information on drug use, mortality outcomes, and potential confounding factors from nationwide registries. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between postdiagnosis non-aspirin NSAID use (≥1 prescription) and ovarian cancer-specific or other-cause mortality compared with non-use (no prescriptions). The influence of competing risks was evaluated using the sub-distribution hazards model proposed by Fine and Gray. RESULTS: Among 4117 patients, any postdiagnosis use of non-aspirin NSAIDs was not associated with either ovarian cancer (HR = 0.97, 95% CI = 0.87-1.08) or other-cause (HR = 0.99, 95% CI = 0.77-1.27) mortality, however, inverse associations for ovarian cancer mortality were observed with high cumulative (HR = 0.75, 95% CI = 0.60-0.94) or high-intensity (HR = 0.86, 95% CI = 0.72-1.03) postdiagnosis use of non-aspirin NSAIDs. The associations differed substantially with histological subtype of ovarian cancer, with only inverse associations observed for serous ovarian cancer (HR = 0.87, 95% CI = 0.77-0.99). Among a smaller number of patients with a non-serous tumor, postdiagnosis non-aspirin NSAID use was associated with increased ovarian cancer mortality. CONCLUSIONS: Any postdiagnosis use of non-aspirin NSAIDs did not influence ovarian cancer mortality overall, however, more intensive use was associated with improved survival of serous ovarian cancer.

Use of prescription drugs among women diagnosed with epithelial ovarian cancer in Denmark.

INTRODUCTION: Epithelial ovarian cancer patients often suffer from chronic diseases requiring drug treatment. We assessed temporal patterns of drug use among women with ovarian cancer. MATERIAL AND METHODS: We identified all postmenopausal women with epithelial ovarian cancer in Denmark 2005-2012 and a comparison cohort of age-matched women without cancer. We calculated rates of new drug treatment and total drug use and examined use of new and prevalent drugs before and after diagnosis. Analyses were stratified by histological type and stage of epithelial ovarian cancer. RESULTS: We identified 2742 patients. The rate of new drug treatment increased from 3 to 5 months before diagnosis and peaked in the first month after diagnosis at 99 new types of drug therapy per 100 individuals (mainly antiemetics, proton-pump inhibitors, hypnotics, and opioids). Although declining, the rate of new drug use remained substantially higher among epithelial ovarian cancer patients than among controls throughout the 3-year postdiagnosis follow-up period. The number of prevalent drugs increased slightly from a median of 4 drugs (interquartile range 2-7) before diagnosis to 5 drugs (interquartile range 2-8) shortly after the diagnosis. The use of preventive drugs decreased only slightly after diagnosis. In stratified analyses, we found limited variation according to histological type, whereas patterns were slightly more pronounced among women with nonlocalized disease compared with localized disease. CONCLUSIONS: Drug use among postmenopausal women with epithelial ovarian cancer was substantial and varied considerably in relation to the time of cancer diagnosis, although only limited changes were seen in the use of preventive medicines.

Genotyping for Human Papillomavirus Types 16 and 18 in Women With Minor Cervical Lesions: A Systematic Review and Meta-analysis.

BACKGROUND: High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals. PURPOSE: To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions. DATA SOURCES: Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016. STUDY SELECTION: Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+]). DATA EXTRACTION: Independent study selection, extraction of data, and quality assessment by 2 reviewers. DATA SYNTHESIS: Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL. LIMITATION: Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays. CONCLUSION: Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots. PRIMARY FUNDING SOURCE: 7th Framework Programme of the European Commission.

Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis.

BACKGROUND: Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure. METHODS: We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models. FINDINGS: 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free. INTERPRETATION: The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status. FUNDING: European Federation for Colposcopy and Institut national du Cancer (INCA).

Statin use and mortality among ovarian cancer patients: A population-based cohort study.

Statin use has been suggested to improve prognosis in cancer patients, however, for ovarian cancer, the evidence is sparse. From the Danish Cancer Registry, we identified patients aged 30-84 years with a histologically verified first diagnosis of epithelial ovarian cancer between 2000 and 2013. Data on filled prescriptions, death, and potential confounding factors were obtained from nationwide registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic statin use and all-cause or ovarian cancer-specific mortality. Among 4,419 patients with epithelial ovarian cancer, post-diagnostic statin use was not statistically significantly associated with all-cause (HR: 0.90, 95% CI: 0.78-1.04) or ovarian cancer-specific mortality (HR: 0.90, 95% CI: 0.76-1.08). There was little evidence of a dose-response relationship and the neutral associations persisted in sensitivity analyses. In women with endometrioid or clear cell tumour histology, cancer-specific mortality was reduced by 30-40% among statin users compared to non-users, however the analyses were limited by small numbers. Significantly reduced mortality with statin use was observed in subcohorts of new users of statins and of patients not using low-dose aspirin. In conclusion, we found no strong evidence of an association between post-diagnostic statin use and reduced mortality in ovarian cancer patients. However, our finding of potential differential susceptibility to statins among patients with different histologic types of ovarian cancer warrants further evaluation.

Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva.

In this updated systematic review and meta-analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta-regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1-44.4%). Overall, 76.3% (95% CI: 70.1-82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5-95.5%) and 2.0% (95% CI: 0-10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases, the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.

Statin use and risk of endometrial cancer: a nationwide registry-based case-control study.

INTRODUCTION: Laboratory and epidemiological evidence have suggested that statin use may protect against the development of certain cancers, including endometrial cancer. In a nationwide registry-based case-control study, we examined the association between statin use and risk of endometrial cancer. MATERIAL AND METHODS: Cases were female residents of Denmark with a primary diagnosis of endometrial cancer during 2000-2009. For each case, we selected 15 female population controls matched on date of birth (±one month) using risk-set sampling. Ever use of statin was defined as two or more prescriptions on separate dates. Conditional logistic regressions were used to estimate age-matched (by design) and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for endometrial cancer associated with statin use. The multivariable-adjusted models included parity, hormone replacement therapy (HRT), obesity, diabetes, chronic obstructive pulmonary disease and education. We evaluated whether the association between statin use and endometrial cancer varied with duration and intensity of statin use, type of endometrial cancer or patient characteristics. RESULTS: The study population comprised 5382 endometrial cancer cases and 72 127 population controls. We observed no association between ever use of statins and endometrial cancer risk (OR 1.03, 95% CI 0.94-1.14). In addition, endometrial cancer risk did not vary substantially with duration or intensity of statin use. Stratification by type of endometrial cancer also yielded neutral ORs. CONCLUSIONS: In our nationwide case-control study, we found no association between statin use and risk of endometrial cancer.

High-risk HPV testing in the management of atypical glandular cells: A systematic review and meta-analysis.

Whereas the utility of high-risk HPV (hrHPV) testing is widely accepted in triage of women with atypical squamous lesions, its role in managing atypical glandular cells (AGC) is not fully elucidated. A systematic review and meta-analysis were performed to evaluate the accuracy of hrHPV testing in the management of women with AGC to detect underlying high-grade intraepithelial neoplasia or worse, and adenocarcinoma in situ or worse (AIS+). Additionally, the diagnosis of extra-cervical cancer was considered as an outcome in this review. A bibliographic database search (PubMed, EMBASE, CENTRAL) identified twelve eligible studies. The occurrence of cervical intraepithelial neoplasia grade two or worse including AIS+ (CIN2+/AIS+), was 19.8% among women with AGC, and 55.7% among women with AGC and concurrent squamous lesions (atypical squamous cells of undetermined significance or worse, ASC-US+). The pooled sensitivity and specificity of hrHPV-testing with Hybrid Capture 2 (HC2) to detect CIN2+/AIS+ in women with AGC was 90.0% (95% CI = 85.1-93.4%) and 75.1% (95% CI = 64.8-83.2%), respectively. Women who were hrHPV-negative, demonstrated an increased risk for extra-cervical malignancy (endometrium, fallopian tube, ovary). In women of 50y and older, a hrHPV-negative result was linked with a 18.0% chance of extra-cervical malignancy, while the chance of cervical pre-cancer and cancer was 0.4 and 0.0%, respectively. In conclusion, given the high risk of underlying CIN2+/AIS+, women with AGC should be referred directly to colposcopy. However, hrHPV test results in combination with the age, appears to improve the diagnostic process by distinguishing the risk for cervical versus non-cervical lesions.

Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: A systematic review and meta-analysis of observational studies.

OBJECTIVE: Non-steroidal anti-inflammatory drug (NSAID) use has been linked to a reduction in the risk of several cancer types. For endometrial cancer, however, results have been inconsistent. To summarize the available evidence on the risk of endometrial cancer associated with use of aspirin or non-aspirin (NA-) NSAIDs, we performed a systematic review and meta-analysis of observational studies. METHODS: We conducted a bibliographic database search in PubMed, Embase and Cochrane Library. Relative risk estimates were extracted from eligible case-control and cohort studies and pooled using a random effects model. RESULTS: Six case-control and seven cohort studies were found eligible for our meta-analysis. We observed risk reductions in endometrial cancer associated with regular use of aspirin (case-control: 11%, cohort: 8%) and NA-NSAIDs (case-control: 9%, cohort: 6%), compared to non-use. However, the pooled risk ratios were not statistically significant. Higher risk reductions were seen with high frequency of notably aspirin use (case-control: 37%, cohort: 20%). The inverse association between regular aspirin use and endometrial cancer risk was strongest among women with a body mass index above 30 (case-control: 44%, cohort: 20%). CONCLUSIONS: Regular use of aspirin or NA-NSAIDs was associated with a marginally reduced risk of endometrial cancer. Larger risk reductions were linked with high frequency of NSAID use and high BMI.

Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis.

BACKGROUND: Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians. METHODS: We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models. FINDINGS: We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69-82) of CIN2 or worse and 84% (72-92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83-89) and 87% (84-90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85-0·91] for CIN2 or worse and 0·89 [0·83-0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95-0·97] for CIN2 or worse and 0·96 [0·93-0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples. INTERPRETATION: In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs. FUNDING: The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology.

Correction: Evaluating the health and health economic impact of the COVID-19 pandemic on delayed cancer care in Belgium: A Markov model study protocol.

[This corrects the article DOI: 10.1371/journal.pone.0288777.].

Impact of the COVID-19 Pandemic on Incidence and Observed Survival of Malignant Brain Tumors in Belgium.

(1) Background: This study evaluates the impact of the COVID-19 pandemic on the incidence, treatment, and survival of adults diagnosed with malignant brain tumors in Belgium in 2020. (2) Methods: We examined patients aged 20 and older with malignant brain tumors (2004-2020) from the Belgian Cancer Registry database, assessing incidence, WHO performance status, vital status, and treatment data. We compared 2020 incidence rates with projected rates and age-standardized rates to 2015-2019. The Kaplan-Meier method was used to assess observed survival (OS). (3) Results: In 2020, there was an 8% drop in age-specific incidence rates, particularly for those over 50. Incidence rates plunged by 37% in April 2020 during the first COVID-19 peak but partially recovered by July. For all malignant brain tumors together, the two-year OS decreased by four percentage points (p.p.) in 2020 and three p.p. in 2019, compared to that in 2015-2018. Fewer patients (-9 p.p.) with glioblastoma underwent surgery, and the proportion of patients not receiving surgery, radiotherapy, or systemic therapy increased by six percentage points in 2020. (4) Conclusions: The COVID-19 pandemic profoundly impacted the diagnosis, treatment strategies, and survival of brain tumor patients in Belgium during 2020. These findings should guide policymakers in future outbreak responses, emphasizing the need to maintain or adapt (neuro)-oncological care pathways and promote informed decision making when care capacity is limited.