Screening of substance use in pregnancy: A Danish cross-sectional study.

INTRODUCTION: There is a paucity of objectively verified data on substance use among Danish pregnant women. We estimated the prevalence of substance use including alcohol and nicotine among the general population of Danish pregnant women. MATERIAL AND METHODS: In this anonymous, national, cross-sectional, descriptive study, pregnant women were invited when attending an ultrasound scan between November 2019 and December 2020 at nine Danish hospitals. Women submitted a urine sample and filled out a questionnaire. Urine samples were screened on-site with a qualitative urine dipstick for 15 substances including alcohol, nicotine, opioids, amphetamines, cannabis, and benzodiazepines. All screen-positive urine samples underwent secondary quantitative analyses with gold standard, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results were compared to questionnaire information to analyze the validity of self-reporting and to examine possible cross-reactions. RESULTS: A total of 1903 of 2154 invited pregnant women participated (88.3%). The prevalence of dipstick-positive urine samples was 25.0%. 44.0% of these were confirmed positive, resulting in a total confirmed prevalence of 10.8%. The prevalence of nicotine use was 10.1%-and for all other substances, <0.5%. Nicotine use was more prevalent among younger pregnant women, while other substance use appeared evenly distributed over age groups. Self-reporting of use of nicotine products was high (71.1%), but low for cannabis and alcohol intake (0% and 33.3%, respectively). Prescription medication explained almost all cases of oxycodone, methylphenidate, and benzodiazepine use. CONCLUSIONS: Substance use among pregnant women consisted mainly of nicotine. Dipstick screening involved risks of false negatives and false positives. Except for alcohol intake and cannabis use, dipstick analyses did not seem to provide further information than self-reporting. LC-MS/MS analyses remain gold standard, and future role of dipstick screenings should be discussed.

Treatment patterns of antidepressants in children and adolescents in Scandinavia.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.

A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy.

In March 2022, the Summary of Product Characteristics for the Lyrica brand of pregabalin was updated with warnings regarding malformation risks. This literature review and critical appraisal aims to explore whether these Summary of Product Characteristics updates are justified and provide clarity on the risk-benefit balance for pregabalin use in early pregnancy. A literature review was conducted in May 2022 to identify English language comparative studies of any design providing data about first trimester maternal pregabalin use and malformation risk. Five observational comparative cohort studies using data from 9 distinct datasets were located. Collectively these studies described at least 5300 unique pregabalin exposed pregnancies, with 4900 exposed in at least the first trimester. Three studies investigated overall major malformation risks, and 4 investigated specific malformation risks. The available evidence was found to be conflicting and generally of low quality, probably influenced by bias and data confounding, with no clear pattern of specific malformations observed. Findings from the largest study suggested absolute risks of major malformation of 4.8-5.6%, relative to a background risk of approximately 4%. Due to study methodology limitations, the available data were judged to only provide low quality evidence suggestive of a possible and unconfirmed small increased risk that cannot be solely attributed to foetal pregabalin exposure. This literature review and critical appraisal indicates that the Lyrica product literature updates are insufficiently substantiated and could result in confusion and misinformed clinical risk-benefit decision making.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark.

PURPOSE: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98). CONCLUSION: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake.

AIMS: The Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake and characteristics of COVID-19 vaccine recipients in Denmark. METHODS: Using nationwide healthcare registries, we identified all Danish residents ⩾5 years of age who received at least one dose of a COVID-19 vaccine from 27 December 2020-29 January 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups and vaccination priority groups, and described characteristics of vaccine recipients during two-month-intervals and in vaccination priority groups. RESULTS: By 29 January 2022, 88%, 86% and 64% of Danish residents ⩾5 years (n=5,562,008) had received a first, second and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84%). Uptake ranged from 48% in 5-11-year-olds to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs 3.7-4.6% in later periods) and diabetes (9.3-12% vs 0.91-2.4% in later periods). CONCLUSIONS: We document substantial changes over time in, for example, age, sex and medical history of COVID-19 vaccine recipients. Though these results are related to the differential vaccine rollout in Denmark, similar findings are probable in other countries and should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Hypoxia-inducible factor-1α expression and breast cancer recurrence in a Danish population-based case control study.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence. METHODS: In this population-based case-control study, we included women diagnosed with stage I-III breast cancer between 1985 and 2001, aged 35-69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER-/TAM-). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence. RESULTS: HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER-/TAM- stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER-/TAM- OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER-/TAM- stratum. CONCLUSION: In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER- breast cancer.

Socioeconomic position and prognosis in premenopausal breast cancer: a population-based cohort study in Denmark.

BACKGROUND: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality. METHODS: We conducted a cohort study nested in the ProBeCaRe (Predictors of Breast Cancer Recurrence) cohort (n = 5959). We identified all premenopausal women aged 18-55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007-2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate, or high), income (low, medium, or high), and employment status (employed, unemployed, or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs), and used Poisson regression to compute incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of recurrence and death. We stratified on estrogen receptor (ER) status/tamoxifen to evaluate interaction. RESULTS: Our study cohort included 2616 women; 286 (CIP 13%) experienced recurrence and 223 (CIP 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased 5-year risks of recurrence (IRR 1.45, 95% CI 1.11-1.89) and mortality (IRR 1.83, 95% CI 1.32-2.52). Furthermore, we observed increased 5-year mortality in women with low education (IRR 1.49, 95% CI 0.95-2.33), low income (IRR 1.37, 95% CI 0.83-2.28), unemployment (IRR 1.61, 95% CI 0.83-3.13), or health-related work absenteeism (IRR 1.80, 95% CI 1.14-2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen. Overall analyses (follow-up max. 10 years) provided similar results. CONCLUSIONS: Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence.

Use of hypnotic drugs among children, adolescents, and young adults in Scandinavia.

BACKGROUND: Hypnotic use in children and adolescents is controversial. OBJECTIVE: To describe the use of hypnotic drugs (melatonin, z-drugs, and sedating antihistamines) among 5- to 24-year-old Scandinavians during 2012 to 2018. METHODS: Aggregate-level data were obtained from public data sources in Sweden, Norway, and Denmark. We calculated annual prevalence (users/1000 inhabitants) stratified by age group, sex, and country. Quantity of use (Defined Daily Dose (DDD)/user/day) was estimated for Norway and Denmark. RESULTS: Melatonin was the most commonly used hypnotic, and its use increased markedly from 2012 to 2018, particularly among females and 15- to 24-year-old individuals. Sweden had the highest increase in use (6.5 to 25/1000) compared with Norway (10-20/1000) and Denmark (5.7-12/1000). The annual prevalence of sedating antihistamine use was also highest in Sweden, reaching 13/1000 in 2018 in comparison to 7.5/1000 in Norway and 2.5/1000 in Denmark. Z-drug use decreased in all countries toward 2018, dropping to 3.5/1000 in Sweden, 4.4/1000 in Norway, and 1.7/1000 in Denmark. The quantity of hypnotic use in Norway and Denmark was 0.8-1.0 DDD/user/day for melatonin in 2018, as compared to 0.1-0.3 for z-drugs and antihistamines. CONCLUSION: The use of melatonin and sedating antihistamines increased among young Scandinavians during 2012-2018, and the increase was twice as high in Sweden compared with Norway and Denmark. In addition, Sweden had the highest use of sedating antihistamines. The Scandinavian variation of hypnotic use could reflect differences in frequency of sleep problems between populations or variation of healthcare access or clinical practice between countries.

Use of sildenafil and other phosphodiesterase type 5 inhibitors among pregnant women in Scandinavia.

INTRODUCTION: For phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, the only approved indication in women is for pulmonary arterial hypertension. These drugs are increasingly being proposed and tested for treatment of female infertility and complications in pregnancy. However, the extent of use of PDE5 inhibitors in the general pregnant population over the last decades is unknown. Therefore, we conducted a descriptive cohort study using data from the population health registers in the Scandinavian countries. MATERIAL AND METHODS: By linking the Medical Birth Registers and the Prescribed Drug Registers in Denmark (1997-2017), Norway (2004-2017), and Sweden (2006-2016), women with filled prescriptions of PDE5 inhibitors in outpatient settings in the 90 days before the date of last menstrual period and/or during pregnancies were identified. With additional linkage to the National Patient Registers, information on maternal, pregnancy, and infant characteristics, co-morbidities, and co-medication was collected and described. RESULTS: Among over 3 million singleton pregnancies, only 77 were pregnancies in women who had at least one filled prescription of a PDE5 inhibitor within the 90 days before the start of pregnancy to delivery. Prescription fills most often occurred before the last menstrual period and in the first trimester, with very few occurring later in pregnancy. Sildenafil was the most used PDE5 inhibitor. Among pregnant women using PDE5 inhibitors, 44% were 35 years of age or older, eight had a cardiovascular diagnosis, and three specifically had a diagnosis of pulmonary arterial hypertension. Among the infants born to mothers using PDE5 inhibitors, nine were born preterm, six were small-for-gestational age, five had an Apgar score at 5 minutes below 8, 18 were admitted to the Neonatal Intensive Care Unit, and eight had respiratory and cardiovascular conditions. CONCLUSIONS: Few women used PDE5 inhibitors in outpatient settings before or during pregnancy in the Scandinavian countries in the last decades. Only a small proportion had a diagnosis for pulmonary arterial hypertension, suggesting off-label use in the remaining users. Use was predominantly in mothers over age 35 years. The safety of fetal exposure to sildenafil and other PDE5 inhibitors in pregnancy has not been established. As maternal age continues to increase and additional uses of PDE5 inhibitors are investigated, the safety of these drugs in pregnancy should be thoroughly evaluated.

Bayesian Pathway Analysis for Complex Interactions.

Modern epidemiologic studies permit investigation of the complex pathways that mediate effects of social, behavioral, and molecular factors on health outcomes. Conventional analytical approaches struggle with high-dimensional data, leading to high likelihoods of both false-positive and false-negative inferences. Herein, we describe a novel Bayesian pathway analysis approach, the algorithm for learning pathway structure (ALPS), which addresses key limitations in existing approaches to complex data analysis. ALPS uses prior information about pathways in concert with empirical data to identify and quantify complex interactions within networks of factors that mediate an association between an exposure and an outcome. We illustrate ALPS through application to a complex gene-drug interaction analysis in the Predictors of Breast Cancer Recurrence (ProBe CaRe) Study, a Danish cohort study of premenopausal breast cancer patients (2002-2011), for which conventional analyses severely limit the quality of inference.

Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin.

Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancer patients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancer patients.Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004-2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models.Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5).Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged.

Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial's duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial's duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan-Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9-19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1-18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0-16.3), 17.4 days (PI, 6.0-28.8), and 8.5 days (PI, 1.9-15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507] .

In utero exposure to antibiotics and risk of congenital malformations: a population-based study.

BACKGROUND: Antibiotics are commonly prescribed during pregnancy. Although the safety of most penicillins is well established, some controversy and uncertainty are associated with the use of other commonly prescribed antibiotics. OBJECTIVE: To determine the risk of congenital malformations following first-trimester in utero exposure to 10 commonly prescribed antibiotics in Denmark. MATERIALS AND METHODS: This was a cohort study comprising all singleton liveborn children in Denmark between 2000 and 2015. Data on malformations were collected through 2016. Merging validated and comprehensive populationwide Danish healthcare and civic registries, we merged data on pregnancy, prescription drugs purchases during first trimester and congenital malformations. Using logistic regression, we calculated the odds ratio for congenital malformations (any), major congenital malformations, and cardiac congenital malformations for the 10 most commonly prescribed antibiotics (excluding 4 penicillins that served as control). In the primary analysis, the exposed cohort was compared to a cohort exposed to any of 4 penicillins considered safe during pregnancy (ampicillin, pivampicillin, benzylpenicillin, and phenoxymethylpenicillin). In sensitivity analysis, the exposed cohort was compared to an unexposed cohort. Covariate adjustments were made for maternal age at delivery, year of delivery, parity, pre-pregnancy body mass index, smoking, educational status, employment status, and annual personal income. RESULTS: We found no increased risk of congenital malformations to be related to first-trimester in utero exposure to the 10 most commonly prescribed antibiotics in Denmark compared to a cohort of pregnant women exposed to penicillins that are considered safe during pregnancy. Compared to unexposed pregnancies, small increased risks for major malformations and cardiac malformations were apparent for pivmecillinam (odds ratio, 1.13; confidence interval, 1.06-1.19; and odds ratio, 1.15; confidence interval, 1.04-1.28, respectively), sulfamethizole (odds ratio, 1.15; confidence interval, 1.07-1.24; and odds ratio, 1.22; confidence interval, 1.07-1.39, respectively), and azithromycin (odds ratio, 1.19, confidence interval, 1.03-1.38; and odds ratio, 1.29, confidence interval, 0.99-1.67, respectively). CONCLUSION: In this large populationwide cohort study, we found, with a high degree of precision, no increased risk of congenital malformations following first-trimester exposure to 10 commonly prescribed systemic antibiotics.

Use of phthalate-containing prescription drugs and the risk of gastric cancer: a Danish nationwide case-control study.

Background: Phthalates are used as excipients in some drug products, and up to a 50-fold increased urinary excretion of phthalate metabolites compared to non-users has been demonstrated in users of such products. In vitro studies have demonstrated that phthalates stimulate mechanisms involved in gastric cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and the risk of gastric adenocarcinomas. Methods: Using the Danish Cancer Registry, we identified all patients with incident gastric adenocarcinoma from 2008 to 2015 (n = 1525). Cancer cases were matched to 10 controls. Linking information retrieved from nationwide Danish registries, we determined individual cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP) and enteric phthalate polymers from prescription drugs. The association between cumulative phthalate exposure and gastric adenocarcinoma was estimated using conditional logistic regression, adjusting for socioeconomical status and drugs or comorbidities known or suspected to modify the risk of gastric adenocarcinoma. Results: No association was seen for the risk of gastric adenocarcinomas among individuals with high cumulative exposure to ortho-phthalates (exceeding 500 mg) (ORadj 1.22, 95% CI: 0.84-1.77). Likewise, no associations were observed individually for DEP (ORadj 1.06 95% CI: 0.63-1.76) or DBP (ORadj 1.32 95% CI: 0.78-2.23). Cumulative exposure to enteric phthalate polymers exceeding 10,000 mg, did not reveal an association with gastric adenocarcinoma (ORadj 0.79, 95% CI: 0.54-1.16) and no association was seen for individual compounds. Additionally, no dose-response pattern was observed across exposure strata (p = .39, test for trend). Conclusion: We did not find an increased risk of gastric adenocarcinoma among Danish users of phthalate-containing drug products. Our study is limited by a low number of cases exposed to high cumulative doses of phthalates.

Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case-control study.

BACKGROUND: Adjuvant tamoxifen therapy approximately halves the risk of recurrence in estrogen receptor-positive (ER+) breast cancer patients, but many women respond insufficiently to therapy. Expression of multi-drug resistance protein 2 (MRP2) in breast cancer may potentiate tamoxifen resistance. Thus, we investigated the expression of MRP2 in breast cancer as a predictor of tamoxifen therapy effectiveness. MATERIAL AND METHODS: We conducted a case-control study nested in the Danish Breast Cancer Group clinical database. The study included women aged 35-69 years diagnosed with stage l-lll breast cancer during 1985-2001, in Jutland, Denmark. We identified 541 recurrent breast cancers (cases) among women with estrogen receptor positive (ER+) disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases among women with estrogen receptor-negative (ER-) disease, never treated with tamoxifen (ER-/TAM-). We matched one recurrence-free control to each recurrent case. We retrieved paraffin-embedded primary tumor tissue for all patients, and all available recurrent tumor tissue from pathology archives. MRP2 expression was evaluated using immunohistochemistry. We computed odds ratios (ORs) and 95% confidence intervals (95% CIs) associating MRP2 expression (positive vs. none) with breast cancer recurrence in conditional logistic regression models. We compared MRP2 expression in paired primary- and recurrent tumors. RESULTS: MRP2 expression was more prevalent in the ER+/TAM + group, than in the ER-/TAM - group. No predictive utility of MRP2 for breast cancer recurrence was found in the ER+/TAM + group (ORadj = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER-/TAM - group (ORadj = 0.81, 95% CI 0.53, 1.23). MRP2 expression was not increased in recurrent versus primary tumors. CONCLUSIONS: MRP2 expression is neither a predictive marker of tamoxifen effectiveness nor a prognostic marker in breast cancer.

Expression of survivin does not appear to influence breast cancer recurrence risk.

BACKGROUND: Survivin is an inhibitor of apoptosis, and its expression associates with poor outcomes in multiple cancers. It may be a therapeutic target due to its unique expression in cancer cells. METHODS: We estimated the association between nuclear and cytoplasmic survivin expression in primary tumors and breast cancer recurrence. In this case-control study, we included women age 35-69, diagnosed with stage I-III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Group. We identified 541 patients with breast cancer recurrence with estrogen receptor-positive disease who were treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 with estrogen receptor-negative carcinomas, not treated with tamoxifen, and who survived at least 1 year (ER-/TAM-). Controls were matched to cases on ER/TAM status, date of surgery, menopausal status, stage and county. Survivin expression was estimated by immunohistochemistry on tissue microarrays. We fit logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associating nuclear and cytoplasmic survivin expression with recurrence. RESULTS: Associations between nuclear and cytoplasmic survivin expression and breast cancer recurrence were near-null in both ER+/TAM + and ER-/TAM - strata. For the cytoplasmic to nuclear ratio (CNR) of survivin expression, we found a null association in the ER+/TAM + group comparing CNR ≥5 with CNR <5, but an association (OR =2.48, 95% CI: 1.15, 5.31) in the ER-/TAM - group. CONCLUSIONS: Survivin expression was not associated with breast cancer recurrence in this study. The CNR ratio may warrant further investigation especially among ER - tumors.

Exposure to phthalate-containing prescription drugs and the risk of colorectal adenocarcinoma: A Danish nationwide case-control study.

PURPOSE: Some drug products contain phthalates as excipients, and in vitro studies have demonstrated that phthalates interfere with cellular mechanisms involved in colorectal cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and risk of colorectal adenocarcinomas. METHODS: We used the Danish Cancer Registry to identify all patients with incident colorectal adenocarcinoma from 2008 to 2015 (n = 25 814). Each cancer case was matched to ten population controls. Linking information from Danish registers, we quantified cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP) and dibutyl phthalate (DBP) as well as enteric phthalate polymers from orally administered drugs. The association between cumulative phthalate exposure and colorectal cancer was estimated using conditional logistic regression. RESULTS: Cumulative exposure to ortho-phthalates exceeding 500 mg was associated with lower odds of colorectal cancer diagnosis (ORadj  = 0.89; 95% CI, 0.81-0.96). Similar associations were observed for all DEP exposure exceeding 500 mg. Subgroup analysis excluding NSAID users, demonstrated that ortho-phthalate exposure was positively associated with colorectal cancer (ORadj  = 1.26; 95% CI, 1.05-1.51). CONCLUSION: We found an apparent overall protective effect of cumulative phthalate exposure from drug excipients for colorectal adenocarcinoma. Omitting NSAID users reversed the signal and suggested a slightly increased risk associated with high cumulative ortho-phthalate exposure.

Patterns and predictors for prescription of psychotropics and mood-stabilizing antiepileptics during pregnancy in Denmark 2000-2016.

AIMS: To analyse prescribing patterns during pregnancy for antipsychotics (APs), antidepressants (ADs) and mood-stabilizing antiepileptics (AEDs) in Denmark from 2000 to 2016. METHODS: Data were obtained from the Danish Medical Birth Register, the Register for Legally Induced Abortions, the Danish National Patient Register and the Register of Medicinal Product Statistics. Data were linked through a unique personal identifier by Statistics Denmark. RESULTS: The use of APs increased 2.5-fold from a prevalence of 1.5 per 1000 pregnancies to 3.8 for pregnancies ending in a delivery. Use of mood-stabilizing AEDs increased from a prevalence of 0.1 to 2.1 during the study period. The prevalence for APs and mood-stabilizing AEDs was nearly twice as high for pregnancies ending in miscarriage or termination compared to pregnancies ending in delivery. A marked increase in the prevalence of ADs use during pregnancy was seen from 2000-2011 (from 6 to 41 per 1000 pregnancies ending in a delivery) but appears slightly in decline. Age, smoking, obesity and social status were generally associated with increased use of psychotropic drugs. CONCLUSIONS: The use of APs, ADs and mood-stabilizing AEDs during pregnancy has increased substantially in Denmark from 2000-2016. The use of ADs appears to be slightly in decline since 2011.

Use of antipsychotics and risk of breast cancer: a Danish nationwide case-control study.

AIMS: Some antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Existing evidence is conflicting and based on sparse data, especially for the increasingly used second-generation antipsychotics. We conducted a nationwide case-control study of the association between antipsychotic use and incident breast cancer. METHODS: From the Danish Cancer Registry, we identified women with a first-time diagnosis of breast cancer 2000-2015 (n = 60 360). For each case, we age-matched 10 female population controls. Using conditional logistic regression, we calculated odds ratios (ORs) for breast cancer associated with use of antipsychotics. We stratified antipsychotics by first- and second-generation status and by ability to induce elevation of prolactin. RESULTS: In total, 4951 cases (8.1%) and 47 643 controls (7.9%) had ever used antipsychotics. Long-term use (≥10 000 mg olanzapine equivalents) was associated with breast cancer, with an adjusted OR of 1.18 [95% confidence interval (CI), 1.06, 1.32]. A weak dose-response pattern was seen, with ORs increasing to 1.27 (95% CI 1.01, 1.59) for ≥50 000 mg olanzapine equivalents. Associations were similar for first- and second-generation antipsychotics (ORs 1.17 vs. 1.11), but also for nonprolactin inducing-antipsychotics (OR 1.17). Stratifying by oestrogen receptor status, positive associations were seen for oestrogen receptor-positive cancers (long-term use: OR 1.29; 95% CI 1.13, 1.47) while no associations were observed for oestrogen receptor-negative cancers. CONCLUSIONS: Overall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. The importance of drug-induced prolactin elevation is unclear but may lead to a slightly increased risk of oestrogen receptor-positive breast cancer.