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The severity of the COVID-19 pandemic and subsequent mitigation strategies have varied across the Nordic countries. In a joint Nordic population-based effort, we compared patterns of new cancer cases and notifications between the Nordic countries during 2020. We used pathology notifications to cancer registries in Denmark, the Faroe Islands, Finland, Iceland, Norway and Sweden to determine monthly numbers of pathology notifications of malignant and in situ tumours from January to December 2020 compared to 2019 (2017-2019 for Iceland and the Faroe Islands). We compared new cancer cases per month based on unique individuals with pathology notifications. In April and May 2020, the numbers of new malignant cases declined in all Nordic countries, except the Faroe Islands, compared to previous year(s). The largest reduction was observed in Sweden (May: −31.2%, 95% CI −33.9, −28.3), followed by significant declines in Finland, Denmark and Norway, and a nonsignificant decline in Iceland. In Denmark, Norway, Sweden and Finland the reporting rates during the second half of 2020 rose to almost the same level as in 2019. However, in Sweden and Finland, the increase did not compensate for the spring decline (annual reduction −6.2% and −3.6%, respectively). Overall, similar patterns were observed for in situ tumours. The COVID-19 pandemic led to a decline in rates of new cancer cases in Sweden, Finland, Denmark and Norway, with the most pronounced reduction in Sweden. Possible explanations include the severity of the pandemic, temporary halting of screening activities and changes in healthcare seeking behaviour. What's new? The severity of the COVID-19 pandemic and subsequent mitigation strategies have varied across the Nordic countries. This is the first international comparison of cancer notification rates during the first year of the COVID-19 pandemic, including six countries with similar tax-funded healthcare systems and population-based cancer reporting. The findings suggest that, despite differences in pandemic mitigation efforts, the severity of the pandemic may have had a larger effect on cancer detection than strict societal restrictions. In all countries, it will be of importance to monitor future trends in late-stage cancer incidence and survival.

Beta-blockers have shown anti-neoplastic effects in laboratory studies but epidemiologic evidence in relation to contralateral breast cancer (CBC) is sparse. We investigated post-diagnosis beta-blocker use and risk of CBC in a cohort of 52 723 women with breast cancer by using nationwide Danish health registers and the Danish Breast Cancer Group database. We defined post-diagnosis beta-blocker use as a time-varying covariate starting one year after a second prescription was redeemed. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with beta-blocker use compared with non-use. We identified 1444 women with CBC of whom 209 women were beta-blocker users. We found an overall HR of 1.08 (95% CI: 0.93-1.27) for beta-blocker use and risk of CBC with no substantial variation according to cumulative amount, intensity or selectivity of beta-blocker use. Hence, our cohort study of women with breast cancer did not sustain a protective effect of beta-blocker use on risk of CBC, irrespective of beta-blocker type.

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.

Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by use of specific antibiotics, and risk of SCC of the bladder. We conducted a Danish nationwide case-control study and identified histologically verified bladder cancer cases (2000-2015; n=12,271) and age- and sex-matched cancer-free controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating use of UTI-specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a two-year lag-time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared with no use (0-1 prescriptions), high-use (≥10 prescriptions) of UTI-specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6-17.2) and a clear dose-response pattern (ptrend

Laboratory studies suggest that inhibition of the cyclooxygenase (COX)-2 enzymes inhibits breast cancer development. We aimed to evaluate whether postdiagnosis use of COX-2 selective or other nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of contralateral breast cancer (CBC) among Danish breast cancer patients. From the clinical database of the Danish Breast Cancer Group, we identified 52,723 women diagnosed with breast cancer between 1996 and 2012. Data on nonaspirin NSAID use, CBC and potential confounding variables were obtained from nationwide registries. We defined postdiagnosis use (two or more prescriptions) as a time-varying covariate with a one-year lag. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with nonaspirin NSAID use. During a median follow-up of 4.8 years (interquartile range: 2.3-9 years), 1,444 patients were diagnosed with CBC. Overall, postdiagnosis use of nonaspirin NSAID was associated with an adjusted HR for CBC of 0.98 (95% CI: 0.87-1.11). The HRs did not vary substantially with duration or intensity of nonaspirin NSAID use. Moreover, similar associations were found for COX-2 selective (HR: 1.02; 95% CI: 0.85-1.23) and nonselective (HR: 0.96; 95% CI: 0.82-1.13) nonaspirin NSAIDs. In conclusion, our nationwide cohort study of breast cancer patients does not suggest a reduced risk of CBC with nonaspirin NSAID use regardless of the COX-2 selectivity.

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 (

Purpose: Preclinical studies have suggested that proton pump inhibitors (PPIs) may increase pancreatic cancer risk; however, epidemiological studies are few, with conflicting results. This spurred us to evaluate whether PPI use is associated with an increased risk of pancreatic cancer in a large population-based study. Methods: We conducted a nationwide case-control study using data from Danish demographic and health care registries. All patients with a first cancer diagnosis of pancreatic cancer between 2000 and 2015 were identified from the Danish Cancer Registry and age-matched, sex-matched, and calendar-matched 1:20 to population controls using risk set sampling. Conditional logistic regression was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer associated with PPI use, adjusting for potential confounders. Secondary analyses examined dose-response patterns and associations with individual PPIs as well as with histamine-2-receptor antagonists. Results: Ever use of PPIs occurred among 27.8% of 6921 pancreatic cancer cases and 25.4% of 34 695 matched controls, yielding a neutral adjusted OR of 1.04 (95% CI 0.97-1.11). Odds ratios were also close to unity in analyses of high use of PPIs (≥1000 DDDs; OR, 0.92 95% CI 0.80-1.07). There was no evidence of a dose-response relationship, with ORs close to unity across categories, including for those with the highest cumulative use (>2000 DDDs; OR, 1.03 95% CI 0.84-1.26). Analyses of subgroups as well as individual types of PPI and of histamine-2-receptor antagonists use also returned neutral associations. Conclusions: In this large nationwide case-control study, PPI use was not associated with an increased risk of pancreatic cancer.

In this MiniReview, we provide general considerations for the planning and conduct of pharmacoepidemiological studies of associations between drug use and cancer development. We address data sources, study design, assessment of drug exposure, ascertainment of cancer outcomes, confounder adjustment and future perspectives. Aspects of data sources include assessment of complete history of drug use and data on dose and duration of drug use, allowing estimates of cumulative exposure. Outcome data from formal cancer registries are preferable, but cancer data from other sources, for example, patient or pathology registries, medical records or claims are also suitable. The two principal designs for observational studies evaluating drug-cancer associations are the cohort and case-control designs. A key challenge in studies of drug-cancer associations is the exposure assessment due to the typically long period of cancer development. We present methods to examine early and late effects of drug use on cancer development and discuss the need for employing 'lag-time' in order to avoid reverse causation. We emphasize that a new-user study design should always be considered. We also underline the need for 'dose-response' analyses, as drug-cancer associations are likely to be dose-dependent. Generally, studies of drug-cancer associations should explore risk of site-specific cancer, rather than cancer overall. Additional differentiation may also be crucial for organ-specific cancer with various distinct histological subtypes (e.g., lung or ovary cancer). We also highlight the influence of confounding factors and discuss various methods to address confounding, while emphasizing that the choices of methods depend on the design and specific objectives of the individual study. In some studies, use of active comparator(s) may be preferable. Pharmacoepidemiological studies of drug-cancer associations are expected to evolve considerably in the coming years, due to the increasing availability of long-term data on drug exposures and cancer outcomes, the increasing conduct of multinational studies, allowing studies of rare cancers and subtypes of cancer, and methodological improvements specifically addressing cancer and other long-term outcomes.

SummaryIntroduction Previous studies have reported diverging results on the association between benzodiazepine use and cancer risk. Methods We investigated this association in a matched case–control study including incident cancer cases during 2002-2009 in the Danish Cancer Registry (n=94,923) and age and sex-matched (1:8) population controls (n=759,334). Long-term benzodiazepine use was defined as ≥500 defined daily doses 1-5 years prior to the index date. We implemented propensity score (PS) calibration using external information on confounders available from a survey of the Danish population. Two PSs were used: The error-prone PS using register-based confounders and the calibrated PS based on both register- and survey-based confounders, retrieved from the Health Interview Survey. Results Register-based data showed that cancer cases had more diagnoses, higher comorbidity score and more co-medication then population controls. Survey-based data showed lower self-rated health, more self-reported diseases, and more smokers as well as subjects with sedentary lifestyle among benzodiazepine users. By PS calibration, the odds ratio for cancer overall associated with benzodiazepine use decreased from 1.16 to 1.09 (1.00, 1.19) and for smoking-related cancers from 1.20 to 1.10 (1.00, 1.21). Conclusion We conclude that the increased risk observed in the solely register-based study could partly be attributed to unmeasured confounding.

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.

IntroductionLaboratory 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 methodsCases 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.ResultsThe 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.ConclusionsIn our nationwide case-control study, we found no association between statin use and risk of endometrial cancer.

AIM: Oral contraceptive use influences the risk for certain cancers. However few studies have examined any link with risk of central nervous system tumours. We investigated the association between hormonal contraceptive use and glioma risk among premenopausal women in a population-based setting. METHODS: Using national administrative and health registries in Denmark to conduct a nationwide case-control study we identified all women ages 15 to 49 years with a first time diagnosis of histologically verified glioma between 2000 and 2009. Each case was age-matched to eight population controls using risk set sampling. Based on prescription data exposure until 2 years prior to the index date was categorized according to hormonal contraceptive type i.e. combined oestrogen-progestagen or progestagen only and duration of use ( /=5 years). We used conditional logistic regression to compute odds ratios (ORs) with 95% confidence intervals (CIs) for glioma associated with hormonal contraceptive use adjusting for potential confounders. RESULTS: We identified 317 cases and 2126 controls. Ever use of hormonal contraceptive was associated with an OR of 1.5 (95% CI 1.2 2.0) and the OR increased with duration of use (long term >/=5 years: OR 1.9; 95% CI 1.2 2.9). The association between long term hormonal contraceptive use and glioma risk was most pronounced for progestagen only therapy (OR 2.4; 95% CI 1.1 5.1) especially when this regimen constituted the sole hormonal contraceptive therapy (OR 4.1; 95% CI 0.8 20.8). CONCLUSION: Long term hormonal contraceptive use may increase the risk of glioma. (c) 2014 The British Pharmacological Society.

Aim Studies of the carcinogenic potential of benzodiazepines and related drugs (BZRD) have been equivocal. A recent study reported a 35% excess cancer risk among users of hypnotics, including benzodiazepines.

Objective Several observational studies have investigated the association between nonsteroidal anti-inflammatory drug (NSAID) use and ovarian cancer risk, but with conflicting results. We performed a systematic review and meta-analysis of the association between NSAID use and ovarian cancer risk. Design Systematic review and meta-analysis of observational studies published until September 2012. Setting Studies were identified from the PubMed database. Population Fourteen case-control and seven cohort studies were included. Methods Pooled relative risks (RRs) with corresponding 95% confidence intervals (CI) for aspirin and non-aspirin NSAIDs, separately, were calculated. Both fixed and random effect models were applied, but only random effect pooled RRs are presented. Risk estimates for invasive and borderline ovarian tumors combined and for invasive ovarian tumors only were calculated. Furthermore, heterogeneity and publication bias were evaluated. Main outcome measures Ovarian cancer. Results In the combined analysis, a slight inverse association between use of aspirin (RR 0.93; 95% CI 0.84–1.02) and non-aspirin NSAIDs (RR 0.94; 95% CI 0.84–1.06) and ovarian cancer risk was found, although it was not statistically significant. However, the risk of invasive ovarian cancer was significantly reduced with use of aspirin (RR 0.88; 95% CI 0.79–0.98). A similar tendency was observed for non-aspirin NSAIDs, but the results were not significant. Conclusions This meta-analysis showed a slight inverse association between NSAIDs and risk of ovarian cancer. However, data suggest that a chemopreventive effect of NSAIDs may be restricted to invasive ovarian tumors. Further research on NSAIDs and ovarian cancer is needed before definite conclusions can be drawn.

Some evidence suggests that long-term use of vitamin K antagonists (VKAs) has a cancer chemopreventive effect. Such aneffect would have considerable implications in terms of understanding tumor biology. To evaluate if long-term VKA treatmentinfluences the risk of developing cancer, we performed a matched case–control analysis. We used data from four Danishnationwide registers. Cases were all Danish individuals with a first-time cancer diagnosis (except nonmelanoma skin cancer)between 2000 and 2009. For each case, eight controls, matched by birth year and gender, were selected from the sourcepopulation by risk-set sampling. Long-term VKA use was defined as exposure to VKA for a period of 3 or more years.Conditional logistic regression was used to compute odds ratios (ORs) for cancer associated with long-term VKA exposure,adjusting for potential confounders. Prespecified subanalyses were performed for selected cancer sites, subgroups andmeasures of exposure. A total of 238,196 cases and 1,713,176 controls were included. The adjusted OR for cancer associatedwith long-term VKA exposure was 0.99 (95% CI: 0.95–1.02). Long-term VKA use was associated with increased ORs foralcohol- or obesity-related cancer sites, whereas we observed a decreased risk of prostate cancer (OR: 0.86; 95% CI:0.78–0.95). Our study does not support a general chemopreventive effect of VKA drugs. However, in accordance with findingsfrom previous studies, we found an inverse association between use of VKA and prostate cancer.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • A recent meta-analysis has suggested an increased risk of cancer among users of angiotensin receptor blockers. WHAT THIS STUDY ADDS • Within the limitations of an observational study there is no difference in the cancer incidence between users of drugs affecting the renin-angiotensin system and users of other antihypertensives. • No consistent dose or duration dependency could be demonstrated for angiotensin reeptor blockers and angiotensin converting enzyme inhibitors. AIMS A recent meta-analysis of clinical trials has demonstrated a small excess of cancers in persons who had been allocated to angiotensin receptor blockers (ARBs). We undertook this observational study to look at dose–response and dose–duration effects and look for specificity with respect to outcome. Use of angiotensin converting enzyme inhibitors (ACEIs) was included in the main analysis since ACEIs share pharmacological properties with ARBs. METHODS We identified 149 417 incident cancer cases in Denmark during the period 2000–2005. Four controls, matched by age and gender, were selected for each case by a risk-set sampling. Data on medication were retrieved from the Danish National Prescription Registry. We defined long term exposure as at least 1000 defined daily doses redeemed within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS The odds ratio (OR) associating long term drug use with incident cancer was 1.12 (95% CI 1.06, 1.18), 1.17 (95% CI 1.14, 1.20), 1.23 (95% CI 1.20, 1.26), 1.18 (95% CI 1.14, 1.22), 1.25 (95% CI 1.22, 1.28), 1.37 (95% CI 1.21, 1.54), 1.29 (95% CI 1.22, 1.37) for ARBs, ACEIs, calcium channel blockers, β-adrenoceptor blockers, thiazide diuretics and α-adrenoceptor blockers. No consistent dose–duration or dose–response association could be demonstrated for ARBs or ACEIs. CONCLUSIONS The indication or possibly threshold for prescribing antihypertensives appears to be related to a small increase in cancer risk. The ARB-cancer association is probably too weak to be addressed in observational studies, given their limitations.

Objective—It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to development of Parkinson’s disease (PD). We used nationwide Danish registers to investigate this hypothesis. Research Design and Methods—We identified 4,484 patients with a first time PD diagnosis between 2001–2008 from the Danish National Patient Register (DNPR) and 22,416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. Results—Prescriptions for HP eradication drugs and proton pump inhibitors (PPI) five or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD.

It has been suggested that use of nonsteroidal anti-inflammatory drugs (NSAID) protects against Parkinson's disease, although the results are not consistent. We investigated the risk for Parkinson's disease in patients with osteoarthritis, who are typically intensive users of NSAID. By using the files of the National Danish Hospital Register for the period 1977-2006, we identified a cohort of 134,176 patients with osteoarthritis severe enough to have required subsequent hip or knee implant surgery. The number of first hospital contacts for Parkinson's disease among cohort members in 1986-2007 was compared with that expected from the age-, gender- and period-specific hospital contact rates of the general Danish population, and standardized incidence ratios (SIRs) and associated 95% confidence intervals (CIs) were derived. Cohort members were also linked to the Danish Cancer Register to estimate the SIRs for colorectal and lung cancer. We observed a slightly increased risk for Parkinson's disease among patients with osteoarthritis and subsequent implant surgery (SIR, 1.07; 95% CI, 0.99-1.16). Decreased SIRs were found for both colorectal cancer (0.92; 95% CI, 0.88-0.97), consistent with a high prevalence of NSAID use among cohort members, and lung cancer (0.77; 95% CI, 0.73-0.80), indicating a lower prevalence of smoking than usual. Our results do not support the hypothesis that patients with prolonged use of NSAID and other analgesics are at reduced risk for Parkinson's disease. A possible lower smoking prevalence among patients with osteoarthritis might explain the slightly increased risk for Parkinson's disease.

The objective of this study was to investigate whether statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use is associated with risk of Parkinson's disease (PD) in Denmark. We identified 1,931 patients with a first time diagnosis of PD reported in hospital or outpatient clinic records between 2001 and 2006. We density matched to these patients 9,651 population controls by birth year and sex relying on the Danish population register. For every participant, we identified pharmacy records of statin and anti-Parkinson drug prescriptions since 1995 and before index date from a prescription medication use database for all Danish residents. Whenever applicable, the index dates for cases and their corresponding controls were advanced to the date of first recorded prescription for anti-Parkinson drugs. In our primary analyses, we excluded all statin prescriptions 2-years before PD diagnosis. Employing logistic regression adjusting for age, sex, diagnosis of chronic obstructive pulmonary disease, and Charlson comorbidity, we observed none to slightly inverse associations between PD diagnosis and statin prescription drug use. Inverse associations with statin use were only observed for short-term (

No increased risks of specific types of cancer following breast implantation have been consistently reported, but data on risk beyond 15 years are limited. We have pooled the results of 2 nationwide cohort studies of 3,486 Swedish and 2,736 Danish women who underwent cosmetic breast implantation between 1965 and 1993. Cancer incidence through 2002 was ascertained through nationwide cancer registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to compare cancer incidence among women with implants with women in the general population. Mean duration of follow up was 16.6 years (range 0.1–37.8 years). Over 50% of women were followed for 15 years or more after breast implantation and 13.3% for at least 25 years. There was a reduced incidence of breast cancer (SIR 5 0.73; 95% CI 0.58–0.90), whereas lung cancer was above expectation (SIR 5 1.64; 95% CI 1.10–2.36). The increased risk of lung cancer is expected due to the high prevalence of smoking among the women with implants in our study. With respect to other site-specific cancers, no significantly increased or decreased SIR was observed. This study, which includes women followed for almost 4 decades, represents the longest follow up of women with cosmetic breast implants to date. The results provide no evidence of an association between breast implants and any type of cancer. ' 2008 Wiley-Liss, Inc.

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI = 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR = 1.35), colorectal (SIR = 1.22), lung (SIR = 1.24), soft tissue sarcoma (SIR = 2.25), melanoma (SIR = 1.29), non-melanoma skin (SIR = 1.58), endometrium (SIR = 1.52), ovary (SIR = 1.48), kidney (SIR = 1.27), thyroid gland (SIR = 1.62) and leukaemia (SIR = 1.52). The excess of cancer after a breast cancer diagnosis is likely to be explained by treatment for breast cancer and by shared genetic or environmental risk factors, although the general excess of cancer suggests that there may be additional explanations such as increased surveillance and general cancer susceptibility. © 2005 Wiley-Liss, Inc.

The available epidemiologic evidence does not support a carcinogenic effect of silicone breast implants on breast or other cancers. Data on cancer risk other than breast cancer are limited and few studies have assessed cancer risk beyond 10-15 years after breast implantation. We extended follow-up of our earlier cohort study of Danish women with cosmetic breast implants by 7 years, yielding 30 years of follow-up for women with longest implant duration. The study population consisted of women who underwent cosmetic breast implant surgery at private clinics of plastic surgery (n = 1,653) or public hospitals (n = 1,110), and a control group of women who attended private clinics for other plastic surgery (n = 1,736), between 1973-95. Cancer incidence through 2002 was ascertained using the Danish Cancer Registry. Risk evaluation was based on computation of standardized incidence ratios (SIR) and Cox proportional hazards models, adjusting for age, calendar period and reproductive history. We observed 163 cancers among women with breast implants compared to 136.7 expected based on general population rates (SIR = 1.2; 95% confidence interval [CI] = 1.0-1.4), during a mean follow-up period of 14.4 years (range = 0-30 years). Women with breast implants experienced a reduced risk of breast cancer (SIR = 0.7; 95% CI = 0.5-1.0), and an increased risk of non-melanoma skin cancer (SIR = 2.1; 95% CI = 1.5-2.7). Stratification by age at implantation, calendar year at implantation and time since implantation showed no clear trends, however, the statistical precision was limited in these analyses. When excluding non-melanoma skin cancer, the SIR for cancer overall was 1.0 (95% CI = 0.8-1.2). With respect to other site-specific cancers, no significantly increased or decreased SIR were observed. Similar results were found when directly comparing women who had implants at private clinics with women who attended private clinics for other plastic surgery, with rate ratios for cancer overall, breast cancer and non-melanoma skin cancer of 1.1 (95% CI = 0.8-1.6), 0.7 (95% CI = 0.4-1.3) and 1.5 (95% CI = 0.8-2.7), respectively. In conclusion, our study lends further support to the accumulating evidence that silicone breast implants are not carcinogenic. Reasons for the consistently reported deficit of breast cancer among women with breast implants remain unclear, whereas increased exposure to sunlight may explain the excess occurrence of non-melanoma skin cancer. We found no indication of delayed diagnosis of breast cancer due to the presence of breast implants.

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been linked with potential chemopreventive effects; however, the data are conflicting. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry for the period 1989-2002. In a study population of 334,754 county residents, we compared overall and site-specific cancer incidence among 12,251 statin users (> or =2 prescriptions) with cancer incidence among nonusers and users of other lipid-lowering drugs (n = 1,257). Statistical analyses were based on age-standardization and Poisson regression analysis, adjusting for age, gender, calendar period and use of NSAIDs, hormone replacement therapy and cardiovascular drugs. We identified 398 cancer cases among statin users during a mean follow-up period of 3.3 years (range 0-14 years). The age- and gender-standardized incidence rates of cancer overall were 596 per 100,000 person-years among statin users, 645 per 100,000 person-years among nonusers and 795 per 100,000 person-years among users of other lipid-lowering drugs. Adjusted rate ratios for cancer overall among statin users were 0.86 (95% CI, 0.78-0.95) compared to nonusers and 0.73 (95% CI, 0.55-0.98) compared to users of other lipid-lowering drugs. No significantly increased or decreased rate ratios were observed for any of the studied site-specific cancers (liver, colorectum, lung, breast, prostate, female genital organs and lymphatic and haematopoietic tissue), but most estimates tended to be less than 1.0. Stratification by duration of follow-up or number of prescriptions revealed no clear trends. In summary, individuals prescribed statins experienced a slightly reduced cancer incidence compared to population controls of nonusers and users of other lipid-lowering drugs. Larger and longer-term studies are needed to determine the potentially protective effect of statin use on cancer development.

Summary Background : Clinical trials have suggested that cyclo-oxygenase-2-selective inhibitors are associated with a lower risk of upper gastrointestinal bleeding than are non-selective, non-aspirin, non-steroidal anti-inflammatory drugs. This has not yet been confirmed in studies of patients with an increased susceptibility to upper gastrointestinal bleeding. Aim : To examine the risk of upper gastrointestinal bleeding in high-risk patients who filled prescriptions for cyclo-oxygenase-2 inhibitors or other non-steroidal anti-inflammatory drugs. Methods : A population-based case–control study was performed in the Danish county of North Jutland from 1 January 2000 to 31 December 2002. From the County Hospital Discharge Registry and the Civil Registration System, we identified incident cases with upper gastrointestinal bleeding (n = 780) and randomly selected controls (n = 2906), respectively. All cases and controls had previous gastrointestinal diseases. Data on drug exposure were obtained from the countywide Prescription Database. Results : Thirty-five cases (4.5%) filled prescriptionss for cyclo-oxygenase-2 inhibitors within 30 days of the date of upper gastrointestinal bleeding, compared with 79 controls (2.7%). Adjusted odds ratios for upper gastrointestinal bleeding according to prescription for celecoxib, rofecoxib and non-steroidal anti-inflammatory drugs were 1.3 [95% confidence interval (CI), 0.7–2.8], 2.1 (95% CI, 1.2–3.5) and 3.3 (95% CI, 2.4–4.4), respectively. Conclusions : In patients with increased susceptibility to gastrointestinal adverse events, a lower risk of upper gastrointestinal bleeding was observed in users of cyclo-oxygenase-2 inhibitors compared with users of other non-aspirin, non-steroidal anti-inflammatory drugs.

The use of paracetamol has been associated with increased risks for urinary tract cancers and decreased risk for ovarian cancer, although results have been inconsistent. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry. Cancer incidence among 39,946 individuals receiving prescriptions for paracetamol was compared with expected incidence based on the North Jutland population who did not receive paracetamol prescriptions, during a 9-year follow-up period. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. Overall, 2,173 cancers were observed with 1,973 expected, yielding a SIR of 1.10 (95% CI, 1.06-1.15). Significantly elevated SIRs were found for cancers of the esophagus (1.9; 95% CI, 1.3-2.8) and lung (1.6; 95% CI, 1.4-1.7). Nonsignificantly increased SIRs were observed for cancers of the liver (1.5; 95% CI, 0.96-2.2), renal parenchyma (1.3; 95% CI, 0.9-1.7) and renal pelvis/ureter (1.6; 95% CI, 0.96-2.6), whereas the SIR for cancer of the urinary bladder was close to unity (1.1; 95% CI, 0.9-1.4). For ovarian cancer, the SIR was close to expectation (0.9; 95% CI, 0.6-1.2) with no evidence of trends with duration of follow-up or number of prescriptions. A similar risk pattern was observed after exclusion of person-time experience following prescription for aspirin or other nonsteroidal antiinflammatory drugs in the study cohort and reference population. Our results do not support a major role for paracetamol in the development of cancers of the urinary tract, and we found little evidence of a protective effect of paracetamol against ovarian cancer. The elevated risks for cancers of the esophagus, lung and liver are most likely a result of confounding variables, but may warrant further investigation.

BACKGROUND A recent observational study suggested that the use of angiotensin-converting enzyme (ACE) inhibitors protects against cancer in general and against breast and female reproductive tract cancers in particular. To explore these hypotheses, the authors examined cancer risk among users of ACE inhibitors in North Jutland County, Denmark. METHODS Using data from the population-based Prescription Database of North Jutland County and the Danish Cancer Registry, cancer incidence among 17,897 individuals prescribed ACE inhibitors was compared with expected incidence based on county specific cancer rates during an 8-year study period with a mean follow-up of 3.7 years. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. In addition, the authors performed a direct comparison of users of ACE inhibitors with users of β-blockers or calcium channel blockers (n = 47,579 individuals) by means of a Cox proportional hazards model. RESULTS Overall, 909 cancer cases were observed among users of ACE inhibitors, with 846 expected based on general population rates, yielding an SIR of 1.07 (95% CI, 1.01–1.15). No risk reductions were observed for cancers of the breast and female reproductive tract, whereas nonsignificantly decreased SIRs were observed for cancers of the esophagus, stomach, and liver. Cancer of the kidney was found in significant excess (SIR, 1.6; 95% CI, 1.1–2.2). Stratification by duration of follow-up or number of prescriptions revealed no apparent trends, except for a tendency toward decreasing risk with increasing length of follow-up for smoking-related cancers. The direct comparison of users of ACE inhibitors with users of β-blockers or calcium channel blockers yielded results comparable to those derived from the comparison with the general population, with a hazard ratio for cancer overall of 1.01 (95% CI, 0.93–1.09). CONCLUSIONS This large, population-based cohort study did not confirm a protective effect of ACE inhibitors on the development of cancer. The excess of kidney cancer observed likely reflects a correlation between hypertension and kidney cancer. Further investigation is needed to evaluate the long-term effects of ACE inhibitors beyond the observation period of this and previous studies. Also, the suggestive evidence of decreased risks for upper digestive system cancers and for smoking-related cancers over time may warrant additional investigation. Cancer 2001;92:2462–70. © 2001 American Cancer Society.

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973–1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17–2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76–1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78–1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5–2.2) among private clinic patients and 0.9 (95% CI = 0.4–1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted. Int. J. Cancer 88:301–306, 2000. © 2000 Wiley-Liss, Inc.

In our reply to the letter by Kripke & Langer [1], we have focused on what we believe to be the two most important points of discussion: (i) how to interpret an outcome measure that is very close to unity, yet still statistically significant; and (ii) our critique of the control cohort selection in the original study by Kripke et al. [2]. We respectfully disagree with Kripke & Langer's assertion that a statistically significant odds ratio (OR) of 1.09 supports the notion of a carcinogenic effect of benzodiazepines or benzodiazepine-related drugs (BZRD). This is a very weak association that is likely to be explained by the known confounders in this relationship. The only reason this weak association becomes statistically significant is because we were allowed to tap into a database that covered the cumulative BZRD use in a population of 5.6 million persons over a 15 year period. The same argument applies to the ‘dose–response effect’, which comfortably could (and should) be interpreted as residual confounding and only becomes statistically significant as a result of the vast amount of data. We agree with Kripke & Langer that it is a weakness that we could not account for smoking; a fact we also acknowledged in our paper. However, the direction of this bias is given, because users of BZRD smoke more than other individuals [3,4]. Thereby, some of the ‘elevated’ risk of 1.09 that Kripke & Langer attribute to BZRD use is most probably due to the smoking behaviour among BZRD users. This is also supported by our finding of an OR of 1.01 for nontobacco-related cancers. Had we been able to account for smoking, our OR estimates for all cancers would have been even lower than 1.09. Our main concern with the analysis performed by Kripke et al. [2] relates to the selection of unexposed subjects, i.e. control subjects, as described in our previous letter [5]. In the study by Kripke et al., ‘non-use’ was defined as ‘no BZRD use at any time during the study period’ [2]. Basically, this implies that the eligibility of a given individual in, for example, 2002, is dependent on the same individual's drug exposure in, for example, 2005. Such classification of exposure dependent on future events violates one of the fundamentals of epidemiological study conduct. Consider this example. A man who has never used any BZRD in his life is diagnosed with cancer at age 70 years. A week later, the general practitioner for the patient prescribes him a BZRD to help him sleep. Although this use of BZRD could obviously not have influenced the occurrence of the cancer disease (as this occurred before the BZRD use), this patient would not be eligible to enter the unexposed cohort in the study by Kripke et al. as he would no longer be classified as a ‘BZRD never-user’, and thus be excluded from the study. Exclusion of patients in cancer risk analyses due to drug exposure after the cancer diagnosis is clearly wrong. In the above example, the problem is accentuated by the fact that the erroneous exclusion criterion is applied only for non-users of BZRD prior to the cancer diagnosis, i.e. if the same patient had used BZRD prior to the cancer diagnosis, he would have been eligible to enter the exposed cohort. Furthermore, it is well known that a recent cancer diagnosis is associated with increased use of BZRD and other psychotropics [6]. In the study by Kripke et al., valid non-users of BZRD were not only excluded selectively from the non-exposed cohort, but the erroneous exclusion was also performed with a preference for study subjects who experienced the outcome of interest, i.e. cancer. In other words, the sampling strategy defining non-use as ‘no BZRD use at any time during the study period’ conferred a spurious protective effect against cancer that selectively applied to BZRD non-users. As highlighted by Kripke & Langer [1], subsequent studies by Kao et al. [7,8] have replicated their findings of an increased cancer risk associated with use of BZRD. However, the selection procedure applied in these studies seems to suffer from the same flaw as explained above [7,8]. In our study [9], we included a supplementary analysis that mimicked the erroneous control selection in the study by Kripke et al. [2,5]. This analysis yielded a result strikingly similar to the result in the study by Kripke et al. However, we strongly disagree with the interpretation offered by Kripke & Langer [1] that this supplementary analysis should be a confirmation of their results. The selection bias illustrated above bears close resemblance to ‘immortal time bias’ described by Suissa [10]. We encourage readers with an interest in epidemiology to read this excellent paper, illustrating the reasons why future events should have no influence on the selection criteria in epidemiological studies. In conclusion, we maintain that the weak association seen in our study should not be interpreted as evidence of a causal association. Furthermore, we claim that the associations seen in the study by Kripke et al. [2] are heavily influenced by erroneous selection of the unexposed control cohorts. Lastly, we do agree with Kripke & Langer on one important aspect, which is that use of BZRD should generally be avoided for several reasons [11] or at least reserved for short-term use in select patient groups.

Objective This study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood–brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk. Methods We identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blocker prescriptions 2 years before index date/PD diagnosis. Results Employing logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity score, we found that subjects prescribed dihydropyridines (excludes amlodipine) between 1995 and 2 years prior to the index date were less likely to develop PD (odds ratio, 0.73; 95% confidence interval, 0.54–0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications. Interpretation Our data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-type channel blockers. ANN NEUROL 2010;67:600–606

Although millions of women worldwide have received breast implants for cosmetic or medical reasons, possible late effects (in particular cancer) have not been well studied. To provide quantitative information on cancer occurrence among women undergoing breast implant surgery, 1,135 women treated for cosmetic reasons in Denmark were evaluated. Patients were identified using the nationwide Hospital Discharge Registry with linkage to the nationwide Danish Cancer Registry to determine subsequent cancer incidence. The average age of the women at implant surgery was 31 years, and the average follow-up was 8.4 years, up to a maximum of 17 years. Overall, 27 cancers developed after implant surgery compared with 24.7 expected based on incidence rates from the general population (standardized incidence ratio [SIR] = 1.1; 95% CI: 0.7-1.6). Eight breast cancers were observed vs. 7.8 expected (SIR = 1.0; 95% CI: 0.4-2.0). No evidence was found to link breast implants with increased cancer risk in the decade after surgery. While the results are encouraging, longer follow-up into later life will be necessary to assess fully any possible adverse effects.

Dear Sir, We did not report results for melanoma in our study because of limited statistical precision. Prompted by the letter by Kirsner et al., we calculated relative risk estimates for melanoma among the 12,251 statin users ( 2 prescriptions) in North Jutland County, Denmark, during the study period 1989–2002. The adjusted rate ratio for malignant melanoma among statin users was 0.78 (95% CI 5 0.42– 1.47) compared with nonusers (based on 10 cases among statin users), which is consistent with a 20% lower incidence of melanoma among statin users. As with other sitespecific cancers in our study, stratification by duration of follow-up or number of prescriptions revealed no clear trends. The small number of users of nonstatin lipid-lowering drugs (n 5 1,257) did not allow analysis of melanoma risk. Larger and longer-term studies are needed to evaluate the potential chemopreventive effects of statins against melanoma and other cancers. Yours sincerely, Soren FRIIS