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Background: Long-term use of aspirin has been shown to reduce colorectal cancer risk, but the association remains inconclusive for individual noncolorectal cancers. We examined the association between long-term aspirin use and cancer risk in Denmark., Methods: Using nationwide registries, we followed individuals aged 40-70 years at baseline (January 1, 1997) for cancer diagnoses through 2018. We assessed low-dose (75-150 mg) aspirin use according to continuity, duration, and cumulative amount. In addition, we explored associations with consistent high-dose (500 mg) aspirin use. Using Cox regression, we estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with aspirin use for overall and site-specific cancer., Results: Among 1 909 531 individuals, 422 778 were diagnosed with cancer during mean follow-up of 18.2 years. Low-dose aspirin use did not reduce the hazard ratio for cancer overall irrespective of continuity and duration of use (continuous use: HR = 1.04, 95% CI = 1.03 to 1.06). However, long-term (≥5 or ≥10 years) use was associated with at least 10% reductions in hazard ratios for several cancer sites: colon, rectum, esophagus, stomach, liver, pancreas, small intestine, head and neck, brain tumors, meningioma, melanoma, thyroid, non-Hodgkin lymphoma, and leukemia. Substantially elevated hazard ratios were found for lung and bladder cancer. In secondary analyses, consistent high-dose aspirin use was associated with reduced hazard ratios for cancer overall (HR = 0.89, 95% CI = 0.85 to 0.93) and for several cancer sites., Conclusion: Long-term low-dose aspirin use was associated with slight to moderately reduced risks for several cancers but not for cancer overall owing to increased risk for some common cancers. Similar or slightly stronger inverse associations were observed for consistent use of high-dose aspirin., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) vaccination has shown high efficacy against anal HPV infection and lesions in clinical trials, and the HPV prevalence and type distribution in anal precancers and cancer predict a high preventable potential for HPV vaccination. However, the real-world effectiveness of HPV vaccination against anal high-grade lesions and cancer is yet to be shown., Methods: We investigated HPV vaccine effectiveness against anal high-grade squamous intraepithelial lesion (HSIL) or worse in a nationwide cohort including all Danish women aged 17-32 years during October 2006 to December 2021 (n = 968 881). HPV vaccinations and first occurrence of anal HSIL or worse were retrieved from nationwide registries. Women were considered vaccinated after first dose and classified by age at vaccination. Using Cox regression, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for anal HSIL or worse according to vaccination status., Results: During follow-up, the number of incident histological anal HSIL or worse cases was 37 in unvaccinated women, and less than 5 and 26 in women vaccinated at ages younger than 17 years and 17-32 years, respectively. The overall number of cancers was less than 5. Compared with unvaccinated women, the risk of histological anal HSIL or worse was reduced for women vaccinated at age younger than 17 years (HR = 0.30, 95% CI = 0.10 to 0.87). For women vaccinated at age 17-32 years, the hazard rate of anal HSIL or worse was 1.21 (95% CI = 0.73 to 2.03)., Conclusion: This is the first study to demonstrate that HPV vaccination at a younger age is associated with substantially reduced risk of anal HSIL or worse in the general population., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims/hypothesis: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to possess antineoplastic properties against prostate cancer. We examined the association between GLP-1RA use and prostate cancer risk in a real-world setting., Methods: We performed a nationwide register-based cohort study using an active-comparator, new-user design. We included all men in Denmark aged ≥50 years who commenced use of GLP-1RAs or basal insulin during 2007-2019. HRs and 95% CIs for incident prostate cancer were estimated using multivariable Cox regression in 'intention-to-treat' (ITT)- and 'per-protocol'-like analyses., Results: Among 14,206 initiators of GLP-1RAs and 21,756 initiators of basal insulin, we identified 697 patients with prostate cancer during a mean follow-up period of about 5 years from initiation of the study drugs. In comparison with basal insulin use, GLP-1RA use was associated with an adjusted HR of 0.91 (95% CI 0.73, 1.14) in the 'ITT' analysis and 0.80 (95% CI 0.64, 1.01) in the 'per-protocol' analysis. Stronger inverse associations were seen among older men (≥70 years) ('ITT' HR 0.56; 95% CI 0.38, 0.82; 'per-protocol' HR 0.47; 95% CI 0.30, 0.74), and in patients with CVD ('ITT' HR 0.75; 95% CI 0.53, 1.06; 'per-protocol' HR 0.60; 95% CI 0.39, 0.91)., Conclusions/interpretation: GLP-1RA use was inversely associated with prostate cancer risk compared with use of basal insulin in the 'per-protocol' analysis. Older men and patients with CVD exhibited stronger inverse associations in both the 'ITT' and 'per-protocol' analyses. Our results may indicate that GLP-1RA use could protect against prostate cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Proton Pump inhibitors (PPIs) are frequently prescribed to cancer patients to prevent gastric mucosal damage. Post-diagnostic PPI use in patients with solid tumors may be associated with increased cancer mortality. However, the hazardous impact of PPIs in patients with hematologic malignancies remains unknown. This association was investigated in a large, retrospective cohort study using data from the Danish nationwide health registries. The outcomes were cancer-specific or non-cancer deaths. We identified 15,320 patients with hematologic malignancies and of these 1811 were identified as post-diagnostic PPI users. PPI users had significantly increased HRs for cancer-specific mortality (HR 1.31; 95% CI, 1.18-1.44) and 1-year cancer-specific mortality (HR 1.50, 95% CI 1.29-1.74) as compared to nonusers. The association between PPI use and increased cancer-specific mortality in Danish patients with hematologic malignancies supports the raised concerns regarding the frequent use of PPIs in cancer patients.

Background: This nationwide, register-based case-control study investigated the association between hysterectomy and risk of epithelial ovarian cancer according to histology and by history of endometriosis and menopausal hormone therapy (MHT) use., Methods: From the Danish Cancer Registry, all women registered with epithelial ovarian cancer at age 40-79 years during 1998-2016 were identified (n = 6738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT., Results: Hysterectomy was not associated with risk of epithelial ovarian cancer overall (OR=0.99; 95% CI 0.91 -1.09) but was associated with reduced risk of clear cell ovarian cancer (OR=0.46; 95% CI 0.28-0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR=0.74; 95% CI 0.50-1.10) and in non-users of MHT (OR=0.87; 95% CI 0.76-1.01). In contrast, among long-term MHT users, hysterectomy was associated with increased odds for ovarian cancer (OR=1.20; 95% CI 1.03-1.39)., Conclusion: Hysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users. Interestingly our data pointed to an increased ovarian cancer risk associated with hysterectomy among long-term users of MHT., Competing Interests: Declaration of Competing Interest Lene Mellemkjær has an immediate family member employed at Novo Nordisk, and has an immediate family member who owns stocks in Novo Nordisk. All other authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Oncologist-led follow-up after breast cancer (BC) is increasingly replaced with less intensive follow-up based on higher self-management, which may overburden the less resourceful patients. We examined whether socioeconomic factors measured recently after the implementation of a new follow-up program for BC patients were associated with health-related quality of life (HRQoL) and self-management 12 months later., Methodology: Between January and August 2017, we invited 1773 patients in Region Zealand, Denmark, to participate in baseline and 12 months follow-up questionnaires. The patients had surgery for low- and intermediate risk BC 1-10 years prior to the survey, and they had recently been allocated to the new follow-up program of either patient-initiated follow-up, or in-person or telephone follow-up with a nurse, based on patients' preferences. We examined associations between socioeconomic factors (education and cohabitation) at baseline and two outcomes: HRQoL (EORTC QLQ-C30 and QLQ-BR23) and self-management factors (health care provider, confidence in follow-up, contact at symptoms of concern, and self-efficacy) at 12 months follow-up. Sensitivity analyses were performed according to time since diagnosis (≤ 5 > 5 years). Furthermore, we investigated whether treatment and self-management factors modified the associations., Results: A total of 987 patients were included in the analyses. We found no statistically significant associations between socioeconomic factors and HRQoL, except in patients ≤ 5 years from diagnosis. For self-management patients with short education were more likely to report that they had not experience relevant symptoms of concern compared to those with medium/long education (OR 1.75 95% CI: 1.04; 2.95). We found no clear patterns indicating that treatment or self-management factors modified the associations between socioeconomics' and HRQoL., Conclusion: Overall socioeconomic factors did not influence HRQoL and self-management factors except for experiencing and reporting relevant symptoms of concern. Socioeconomic factors may, however, influence HRQoL in patients within five years of diagnosis.

Prediagnostic use of menopausal hormone therapy (MHT) has been suggested to be associated with improved survival of epithelial ovarian cancer (EOC). We investigated the potential long-term survival benefit of prediagnostic MHT use in women ≥50 years with nonlocalized EOC using the Extreme study including all women in Denmark registered with nonlocalized EOC during 2000 to 2014 (N = 3776). We obtained individual-level information on prediagnostic use of systemic estrogen therapy (ET) and estrogen plus progestin therapy (EPT) from the National Prescription Registry and estimated absolute and relative 5- and 10-year survival probabilities with 95% confidence intervals (CIs) using pseudo-values, taking into account histology, comorbidity, income and residual disease. Among women not having used prediagnostic MHT, 5- and 10-year absolute survival probabilities were 19% and 11%, respectively. Compared to MHT nonusers, prediagnostic systemic ET use for 3 to 4 years and ≥ 5 years was associated with 1.43 (95% CI: 1.01-2.02) and 1.22 (95% CI: 0.96-1.55) times higher 5-year survival probabilities, respectively. Ten-year survival probabilities were also increased but not statistically significantly. Among prediagnostic EPT users, increased 5-year (1.14, 95% CI: 0.85-1.53) and 10-year (1.38, 95% CI: 0.91-2.08) survival probabilities were observed after use for 3 to 4 years compared to MHT nonuse, whereas EPT use for ≥5 years was not associated with long-term survival of nonlocalized EOC. Our findings may suggest a better long-term survival of nonlocalized EOC in women having used long-term prediagnostic ET. However, the statistical precision of our results did not allow firm conclusions and more studies are needed., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors., Patients and Methods: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www., Clinicaltrial: gov (NCT02991209) and ended June 2019., Results: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18))., Conclusion: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Symptoms and treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) may lead to prostate cancer workup, and patterns of prescriptions before diagnosis may affect findings of pharmacoepidemiological studies. Usage of BPH and ED drugs after diagnosis may be related to prostate cancer treatment. We investigated differences in prescription rates of BPH and ED drugs among prostate cancer patients and cancer-free comparisons and between patients with localized and non-localized disease., Material and Methods: A nationwide register-based study, including all Danish men aged 50-85 years diagnosed with prostate cancer during 1998-2015 and an age-matched comparison cohort without cancer. We calculated rates of new and total prescriptions in 1-month intervals from 3 years before to 3 years after cancer diagnosis for drugs used to treat BPH and ED, overall and stratified by clinical stage., Results: We identified 54,286 men with prostate cancer and a comparison cohort of 249,645 age-matched men. The new prescription rate for BPH drugs increased for men with prostate cancer in the year before diagnosis and peaked 1 month before diagnosis with an 18-fold higher rate. Men with prostate cancer had a higher total prescription rate of BPH drugs 3 years before diagnosis, notably among men with localized disease. Before diagnosis, the new prescription rates for ED drugs were similar among men with prostate cancer and comparisons. After diagnosis, men with prostate cancer had a 7-fold higher rate of new prescriptions for ED drugs. Among men with localized disease, the total prescription rate of ED drugs increased in the months following diagnosis., Conclusion: Differences in prescription rates suggest increased prostate cancer surveillance among men receiving BPH drugs, whereas the post-diagnostic increase in ED drugs among men with localized disease is compatible with the increased risk of ED following prostate cancer treatment.

Background: Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combination with borderline low testosterone, is unknown. To clarify if TRT improves symptoms of depression and anxiety, sexual function, fatigue, and quality of life in TC survivors with mild Leydig cell insufficiency., Materials and Methods: In total, 69 men aged between 18 and 65 years with mild Leydig cell insufficiency after TC treatment were randomized 1:1 to 12 months daily transdermal testosterone (maximum dose 40 mg/daily) vs. placebo. Patient reported anxiety, depression, sexual function, fatigue, and overall quality of life were assessed at baseline, after 6- and 12 months treatment, and 3 months post-treatment using validated questionnaires., Results: After 12 months of treatment, median luteinizing hormone and median free testosterone were normalized in the testosterone group. Compared to placebo, TRT was not associated with statistically significant improvement of symptoms of anxiety and depression, sexual function, fatigue, and overall quality of life. Testosterone replacement therapy did not improve anxiety, depression, sexual function, fatigue, or overall quality of life in patients with mild Leydig cell insufficiency compared to placebo., Conclusion: Routine TRT in TC survivors with mild Leydig cell insufficiency to improve sexual function and quality of life cannot be generally recommended. The findings should preferably be validated in a larger cohort., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Preclinical studies have suggested that antidepressant drugs may possess antineoplastic properties. In a nationwide case-control study, we examined the association between use of antidepressants and endometrial-cancer risk with a particular focus on selective serotonin reuptake inhibitors (SSRIs)., Methods: From the Danish Cancer Registry, we identified all women with a histologically verified diagnosis of endometrial cancer between 2000 and 2016, and, for each woman, 15 age-matched controls. We obtained information on use of SSRIs, tricyclic antidepressants (TCAs) and other antidepressants based on records of filled prescriptions from the National Prescription Register. Using conditional logistic regression, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between use of antidepressants and endometrial-cancer risk compared with non-use. In active comparator analyses, SSRI use was compared with TCA use., Results: The study population comprised 8164 cases and 122 432 controls. Compared with non-use, SSRI use was associated with an OR of 0.88 (95% CI 0.82-0.96) for endometrial cancer, whereas the association with TCA use was close to unity (OR 1.05, 95% CI 0.90-1.22). Use of other antidepressants yielded an OR of 0.86 (95% CI 0.71-1.03). We observed no apparent trends in associations according to cumulative amount. The inverse association with SSRI use persisted when compared with TCA use (OR 0.81, 95% CI 0.66-0.99)., Conclusions: Use of SSRIs was associated with a decreased risk of endometrial cancer, whereas no inverse association appeared with use of TCAs. The antineoplastic potential of SSRIs should be investigated in future studies., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: To describe the use of hormonal contraceptives in Danish breast cancer patients., Methods: Nationwide drug utilization study in Danish women diagnosed with breast cancer at ages 13-50 years during 2000-2015. User proportions were estimated in 6-months intervals from 2 years before to 2 years after diagnosis., Results: Use of hormonal contraceptives declined sharply after breast cancer diagnosis. Still, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis., Conclusions: The majority of premenopausal breast cancer patients discontinues hormonal contraception at diagnosis. All prescribers of hormonal contraceptives should acknowledge that hormonal contraception is contraindicated for breast cancer patients., Plain Language Summary: Use of hormonal contraception is contraindicated among women with breast cancer. In this nationwide study, we assessed the use of hormonal contraceptives among all Danish premenopausal women diagnosed with breast cancer during 2000-2015. Hormonal contraceptive use was assessed within 2 years before and 2 years after breast cancer diagnosis. The majority of patients discontinued hormonal contraception at breast cancer diagnosis. However, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis., (© 2022 John Wiley & Sons Ltd.)

Objective: Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT)., Methods: A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations., Results: During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (Pinteraction≥0.60)., Conclusions: Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Background: Evidence suggests that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have antineoplastic properties of potential importance for survival of head and neck cancer., Methods: We conducted a nationwide cohort study including all individuals with primary head and neck squamous cell carcinoma in Denmark during 2000-2016 at age 30-84 years, with no history of cancer (except non-melanoma skin cancer), and alive at 1 year after diagnosis. Nationwide registries provided information on drug use, causes of death and potential confounders, and additional clinical information was obtained for a subpopulation. We conducted Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between post-diagnosis non-aspirin NSAID use (defined as ≥1 filled prescription within first year after diagnosis) and cancer-specific mortality., Results: Among 10,770 head and neck cancer 1-year survivors, the HR for cancer-specific mortality with non-aspirin NSAID use was 1.68 at 1 year after diagnosis, but declined and stabilized around 1.15 (95% CI 1.02-1.29) at 2 years after diagnosis. Among 2-year survivors, the HRs for cancer-specific mortality with non-aspirin NSAID use remained slightly increased in analyses stratified by age, sex, stage, and pre-diagnosis non-aspirin NSAID use. Similar results were seen in the subpopulation (n = 1029) with additional clinical information, and among 5-year survivors with additional non-aspirin NSAID exposure assessment., Conclusion: In this nationwide cohort of patients with head and neck cancer, use of non-aspirin NSAIDs was associated with a slightly increased mortality risk, warranting further evaluation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Several recent observational studies have linked low-dose aspirin use to improved survival in patients with head and neck cancer. However, studies of patterns of aspirin use and risk of cancer-specific mortality are lacking. This nationwide cohort study included all patients in the Danish Cancer Registry with a primary diagnosis of head and neck squamous cell cancer (HNSCC) during 2000 to 2016, aged 30 to 84 years, without prior cancer (except nonmelanoma skin cancer) and alive 1 year after diagnosis. Nationwide registries provided information on filled prescriptions, mortality and potential confounding factors. For a subpopulation, a clinical database provided additional information, including human papillomavirus (HPV) tumor status. We used Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between postdiagnostic low-dose aspirin use (≥1 prescription within first year after diagnosis) and risk of cancer-specific mortality. We identified 10 770 patients with HNSCC during a median follow-up of 3.9 years. Of these, 1799 (16.7%) were low-dose aspirin users. Postdiagnostic use of low-dose aspirin was associated with a HR of 0.97 (95% CI 0.82-1.15) for cancer-specific mortality. Similar neutral associations were found according to patterns of aspirin use. No apparent trends emerged according to age, sex, topography or stage. A tendency towards a decreased cancer-specific mortality risk with low-dose aspirin use was observed among HPV-positive patients; however, the statistical precision was low. In conclusion, we did not observe an association between postdiagnostic low-dose aspirin use and cancer-specific mortality in a nationwide cohort of patients with HNSCC., (© 2021 UICC.)

Purpose: To investigate differences in prescription rates of commonly used drugs among prostate cancer patients and cancer-free comparisons and between patients diagnosed with localized and non-localized disease., Methods: We conducted a register-based study including all men aged 50-85 years diagnosed with prostate cancer in Denmark from 1998 to 2015 and an age-matched cancer-free comparison cohort. We calculated the number of new and total prescriptions from three years before to three years after the date of diagnosis of the case for selected drug classes divided by the number of person-months and stratified by stage at diagnosis., Results: We included 54,286 prostate cancer patients and 249,645 matched comparisons. 30,712 patients were diagnosed with localized disease and 12,884 with non-localized disease. The rates of new prescriptions increased considerably among patients within the year before the diagnosis. Hereafter the rates varied between drug classes. For most drug classes, total prescription rates for patients and comparisons increased similarly in the study period. Total prescription rates varied between men with localized and non-localized disease for all drug classes apart from statins., Conclusion: Our findings indicate that a large proportion of prostate cancer cases are likely diagnosed during medical work-up for other reasons than prostate cancer. Increased rates occur within the last year before diagnosis and future studies on the interaction between drug use and prostate cancer should at least include a one year pre-diagnostic lag-time. Post-diagnostic prescription rates demonstrated an increased use of drugs most likely associated with the consequences of the disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Depression is a leading cause of disability globally and affects more women than men. Ovarian sex steroids are thought to modify depression risk in women and interventions such as bilateral oophorectomy that permanently change the sex steroid milieu may increase the risk of depression. This study aimed to investigate the associations between unilateral and bilateral oophorectomy and depression over a 25-year period (1993-2018) and whether this varied by age at oophorectomy or use of menopausal hormone therapy., Methods: Twenty-five thousand one hundred eighty-eight nurses aged ≥45 years from the Danish Nurse Cohort were included. Nurses with depression prior to baseline were excluded. Poisson regression models, with log-transformed person-years as offset, were used to assess the associations between oophorectomy and incident depression. Nurses who retained their ovaries were the reference group., Results: Compared with nurses with retained ovaries, bilateral oophorectomy was associated with a slightly higher rate of depression (rate ratio [RR], 1.08; 95% confidence interval [CI], 0.95-1.23), but without statistical significance. However, when stratified by age at oophorectomy, compared with nurses with retained ovaries, bilateral oophorectomy at age ≥51 years was associated with higher rates of depression (RR 1.16; 95% CI, 1.00-1.34), but not bilateral oophorectomy at age <51 years (RR 0.86; 95% CI, 0.69-1.07); P value for difference in estimates = 0.02. No association between unilateral oophorectomy and depression was observed., Conclusions: In this cohort of Danish female nurses, bilateral oophorectomy at age ≥51 years, but not at younger ages, was associated with a slightly higher rate of depression compared with those who retained their ovaries., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Background: Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment., Methods: Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register., Results: We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities., Conclusions: The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy., (© 2021 UICC.)

Background: Road traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution., Methods: Twenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (L den [dB]) and air pollutants (particulate matter with diameter < 2.5 μm and < 10 μm [PM 2.5 and PM 10 ], nitrogen dioxide [NO 2 ], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of L den preceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government's maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential L den thresholds., Results: Of 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of L den and overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98-1.14) per 10 dB, which attenuated to 1.01 (0.93-1.09) and 1.00 (0.91-1.09) in models further adjusted for PM 2.5 or NO 2 , respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between L den and stroke., Conclusions: Long-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution., (© 2021. The Author(s).)

Background: Increasing evidence suggests that 1-dose human papillomavirus (HPV) vaccination may protect significantly against HPV-related disease. We provide nationwide, real-world data on the risk of genital warts (GWs) after <3 vaccine doses., Methods: All Danish women born in 1985-2003 were identified, and individual-level vaccination data were retrieved. The cohort was followed up for first occurrence of GWs until 31 December 2016. Using Poisson regression, we calculated incidence rates (IRs) of GWs per 100 000 person-years and IR ratios (IRRs) with corresponding 95% confidence intervals (CIs) for GWs, according to vaccination status, age at first dose, and calendar time., Results: The cohort comprised 1 076 945 girls and women, of whom 485 408 were vaccinated. For girls initiating vaccination at age 12-14 years and 15-16 years, 1-dose vaccine effectiveness (VE) was 71% (IRR = 0.29; 95% CI, .22-.38) and 62% (0.38; .29-.49), respectively, compared with unvaccinated girls. In the same age groups, 2-dose VE was 78% (IRR, 0.22; 95% CI, .18-.26) and 68% (0.32; .26-.38), respectively. After 2009, the IRRs for 3 versus 1 dose and 2 versus 1 dose increased towards unity over calendar time, being 0.69 (95% CI, .57-.84) and 0.86 (.68-1.08) in 2016, respectively., Conclusions: In this study, 1 or 2 doses of quadrivalent HPV vaccine was associated with substantial protection against GWs in girls vaccinated at age ≤16 years. The 1-dose VE approached that of 3 or 2 doses over calendar time, probably reflecting the impact of herd protection., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry., Methods: A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset., Results: A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed., Conclusion: Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2021 by The North American Menopause Society.)

Background: The primary goal of human papillomavirus (HPV) vaccination is to reduce morbidity and mortality from HPV-associated disease, especially cervical cancer. We determined the real-world effectiveness of HPV vaccination against cervical cancer., Methods: The study included women aged 17-30 years living in Denmark October 2006-December 2019. From nationwide registries, information on HPV vaccination and cervical cancer diagnoses were retrieved. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cervical cancer according to vaccination status were estimated using Poisson regression with HPV vaccination treated as a time-varying variable and stratified by age at vaccination. We adjusted for attained age, education, and ethnicity. To address the effect of prevalent disease, different buffer periods were used, with 1-year buffer period as primary analysis., Results: The cohort comprised 867 689 women. At baseline, 36.3% were vaccinated at age 16 years and younger, and during follow-up, 19.3% and 2.3% were vaccinated at ages 17-19 years and 20-30 years, respectively. For women vaccinated at ages 16 years and younger or 17-19 years, the IRRs of cervical cancer were 0.14 (95% CI = 0.04 to 0.53) and 0.32 (95% CI = 0.08 to 1.28), respectively, compared with unvaccinated women. In women aged 20-30 years at vaccination, the incidence rate was higher than among unvaccinated women (IRR = 1.19, 95% CI = 0.80 to 1.79) but slightly decreased with increasing buffer period (IRR = 0.85, 95% CI = 0.55 to 1.32, with 4-year buffer period)., Conclusion: HPV vaccine effectiveness against cervical cancer at the population level is high among girls vaccinated younger than age 20 years. The lack of immediate effect in women vaccinated at age 20-30 years points to the importance of early age at vaccination., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)