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The stage at diagnosis is one of the most important predictors for cancer survival. TNM stage is constructed from T (tumor size), N (nodal spread), and M (distant metastasis) components. In many notifications to cancer registries, TNM information is incomplete with unknown N and/or M. We aimed to evaluate the influence of various assumptions for recoding missing N (NX) and M (MX) as N0 and M0 on the proportion with available TNM stage, stage-distribution, and stage-specific relative survival. We identified 140,201 patients diagnosed with incident cancer of the colon, rectum, lung, breast, or kidney during 2014–2016 in Denmark, Norway, Sweden, or Iceland. Information on TNM were obtained from cancer registry records used for an update of the Nordic cancer statistics database NORDCAN. Patients were followed for death or emigration through 2017. We calculated proportions of available TNM stage, stage distribution, and stage-specific relative survival under different approaches for each cancer site and country. Application of the assumptions yielded higher numbers of cases with available TNM stage for stages 0–I, II, and III. We observed only minor differences in stage-specific one-year relative survival when applying N0M0 for missing N and M, especially for high completeness of TNM registrations, whereas relative survival for remaining cases with missing TNM stage declined substantially. We found no major changes in stage-specific one-year relative survival applying N0M0 for NXMX. We conclude that complete TNM information is preferable to making assumptions, but it seems reasonable to consider assuming N0M0 for missing N and M in future studies based on the Nordic cancer registries. An automatic algorithm, though, is not recommended without considering potential area-specific reasons for frequent use of NX and MX. Clinicians should be urged to report complete TNM information to improve surveillance of the TNM stage.

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.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.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.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.

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case–control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug–cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug–cancer pairs where an association with high use and a cumulative dose–response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies.Significance:This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.

Online Supplementary Material for publication containing additional information on covariate definitions (table S1 - S2) and statistical methods (methods S3) as well as the number of cases and examined drugs for each cancer under examination (table S4).

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.

Natascha Gaster,1 Jesper Hallas,2 Anton Pottegård,2 Søren Friis,3 Morten Schmidt1,4 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; 4Department of Cardiology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Natascha GasterDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N, DK-8200, DenmarkTel +45 87168063Fax +45 87167215Email ng@clin.au.dkPurpose: To evaluate the potential of Danish prescription registries to capture aspirin and non-aspirin non-steroidal anti-inflammatory drug (NSAID) use and to quantitatively evaluate the magnitude of bias from misclassification of true NSAID and aspirin use as apparent non-use in drug outcome studies.Patients and Methods: In a population-based cohort study, we retrieved sales statistics for NSAIDs and aspirins based on nationwide data from the Danish Health Data Authority and the Danish National Prescription Registry. We estimated prevalence of recorded and non-recorded NSAID use in the prescription registry and resulting proportions of true NSAID and aspirin use misclassified as apparent non-use from 1999 to 2019 at population and patient levels.Results: The prevalence of true use misclassified as non-use (mainly due to over-the-counter use) peaked at 4.7% in 2012 for NSAIDs overall, 5.5% in 2012 for ibuprofen, and at 5.9% in 2002 for high-dose aspirin. Misclassification of other individual NSAIDs was near null. Misclassification of true low-dose aspirin use as non-use declined during the study period but remained around 1% since 2005. In subgroups of cardiac patients, the highest prevalence of true NSAID use misclassified as non-use was 5.0% in 2002 and 4.3% in 2017. Quantitative bias analyses showed how such misclassification of true NSAID and aspirin use as non-use remained minimal both at population and patient levels. In hypothetical examples simulating real study populations with differing exposure prevalence and prevalence of true NSAID and aspirin use misclassified as apparent non-use, the approximate percentage change due to misclassification of use as non-use did not exceed 5% and in most scenarios stayed around 1%.Conclusion: The Danish prescription registries are valid data sources for assessing the effects of aspirin and NSAID use. The influence of non-recorded NSAID and aspirin use on estimates of association is virtually negligible.Keywords: registries, over-the-counter, bias epidemiology

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case–control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug–cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug–cancer pairs where an association with high use and a cumulative dose–response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies. Significance: This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.

Background Low-dose aspirin irreversibly inhibits the cyclooxygenase enzymes COX-1 and COX-2, which catalyze the formation of prostaglandins and thromboxanes, inhibiting platelet aggregation. Platelets are thought to play a role in tumorigenesis. As such, aspirin may have a beneficial effect on breast cancer prognosis, but results to date are conflicting. Objectives To evaluate the association between aspirin use and breast cancer recurrence up to 23 years after primary diagnosis. Methods We included all women diagnosed with non-metastatic breast cancer during 1996-2004 registered in the Danish Breast Cancer Group (DBCG) clinical database. We obtained information on aspirin prescriptions (>= 2 prescriptions filled between cancer diagnosis and the landmark) from the Danish National Prescription Registry. Information on early and late (>10 years after primary diagnosis) recurrence was obtained using the DBCG database (for recurrence within the first 10 years after diagnosis) and for late recurrence via a previously described and validated algorithm, drawing on data from the Danish National Patient Registry, the Danish Pathology Registry, the Danish Cancer Registry and a contralateral breast cancer database. We used Cox regression to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CI) employing landmark analyses starting follow-up at years 5, 10, 15, and 20 after primary diagnosis. We adjusted for potential confounders including calendar year of diagnosis, menopausal status, comorbidities, estrogen receptor status, clinical stage, grade, surgery type, chemo- and endocrine therapy, diagnostic codes for alcoholism and obesity, as well as co-medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, bisphosphonates, metformin, digoxin, hormone replacement therapy, non-steroidal anti-inflammatory drugs, and vitamin K antagonists). We followed patients until recurrence, death, second cancer, loss to follow-up, or 31 December 2018. Results Among 21,684 women with non-metastatic breast cancer, 4,902 experienced recurrence during 242,427 person-years of follow-up. Our landmark analyses showed a reduced hazard of recurrence in the 5-, 10-, and 15-year landmark cohorts (5-year landmark adjusted HR = 0.80, 95% CI = 0.68, 0.94; 10-year landmark adjusted HR = 0.84, 95% CI = 0.71, 1.00, 15-year landmark adjusted HR = 0.83, 95% CI = 0.61, 1.14). The 20-year landmark analysis revealed an adjusted HR of 1.09 (95% CI = 0.49, 2.46). Conclusions The potential anti-cancer effect of aspirin appears most pronounced in the first 15 years after breast cancer diagnosis. Funding Elisabeth Solmunde is funded by the Danish Cancer Society (R320-A18464-B5768) and the Independent Research Fund Denmark (1149-00013B). This work was supported by grants to Deirdre Cronin-Fenton from the Danish Cancer Society (“Knæk Cancer” R147-A10100). Citation Format: Elisabeth Solmunde, Rikke N Pedersen, Mette Nørgaard, Lene Mellemkjær, Søren Friis, Bent Ejlertsen, Thomas P. Ahern, Deirdre Cronin-Fenton. Low-dose aspirin prescriptions and breast cancer recurrence: a Danish nationwide cohort study with up to 23 years of follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-02.

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.

Purpose About 70% of women with breast cancer survive at least 10 years after diagnosis. We constructed an algorithm to ascertain late breast cancer recurrence-which we define as breast cancer that recurs 10 years or more after primary diagnosis (excluding contralateral breast cancers)-using Danish nationwide medical registries. We used clinical information recorded in medical records as a reference standard. Methods Using the Danish Breast Cancer Group clinical database, we ascertained data on 21,134 women who survived recurrence-free 10 years or more after incident stage I-III breast cancer diagnosed in 1987-2004. We used a combination of Danish registries to construct the algorithm-the Danish National Patient Registry for information on diagnostic, therapeutic and procedural codes; and cancer diagnoses from the Danish Pathology Registry, the Danish Cancer Registry and the Contralateral Breast Cancer database. To estimate the positive predictive value (PPV), we selected 105 patients who, according to our algorithm, had late recurrence diagnosed at Aarhus University Hospital. To estimate the sensitivity, specificity and negative predictive value (NPV), we selected 114 patients diagnosed with primary breast cancer at Aalborg University Hospital. We abstracted clinical information on late recurrence for patients with medical record-confirmed late recurrence at Aarhus University Hospital. Results Our algorithm had a PPV of late recurrence of 85.7% (95% CI: 77.5-91.3%), a sensitivity of 100.0% (95% CI, 39.8-100.0%), a specificity of 97.3 (95% CI, 92.2-99.4) and a NPV of 100% (95% CI, 96.6-100.0%). Conclusion Our algorithm for late recurrence showed a moderate to high PPV and high sensitivity, specificity and negative predictive value. The algorithm could be an important tool for future studies of late breast cancer recurrence.

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

Background Accumulating evidence suggests that aspirin use may improve survival in cancer patients, however, for endometrial cancer, epidemiological evidence is limited and results are equivocal. In a nationwide cohort study, we examined the association between post-diagnostic low-dose aspirin use and endometrial cancer mortality. Methods From the Danish Cancer Registry, we identified all women with a primary diagnosis of endometrial cancer. Women diagnosed between 2000 and 2012, aged 30–84 years, who had no history of cancer (except non-melanoma skin cancer) and were alive 1 year after the cancer diagnosis were eligible. We obtained information on pre- and post-diagnostic use (≥1 prescription) of low-dose aspirin, mortality and potential confounding factors from nationwide registries. Using Cox regression models, we estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic low-dose aspirin use and endometrial cancer mortality. The exposure was modelled as both time-varying as well as time-fixed within exposure windows of 1 and 5 years. Results We identified 6694 endometrial cancer patients with a maximum follow-up of 13 years. In the time-varying analysis, post-diagnostic low-dose aspirin use was associated with a HR of 1.10 (95% CI 0.90–1.33) for endometrial cancer mortality. We found no indication of a dose–response association according to increasing tablet strength, cumulative amount or duration of use, and the HRs were similar for pre-diagnostic and post-diagnostic low-dose aspirin use compared with non-use. Conclusions We found no indication that post-diagnostic low-dose aspirin use was associated with reduced mortality for endometrial cancer; rather our findings suggested a concern for increased mortality.

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.

Although automated patch clamp (APC) devices have been around for many years and have become an integral part of many aspects of drug discovery, high throughput instruments with gigaohm seal data quality are relatively new. Experiments where a large number of compounds are screened against ion channels are ideally suited to high throughput APC, particularly when the amount of compound available is low. Here we evaluate different APC approaches using a variety of ion channels and screening settings. We have performed a screen of 1920 compounds on GluN1/GluN2A NMDA receptors for negative allosteric modulation using both the SyncroPatch 384 and FLIPR. Additionally, we tested the effect of 36 arthropod venoms on NaV1.9 using a single 384-well plate on the SyncroPatch 384. As an example for mutant screening, a range of acid-sensing ion channel variants were tested and the success rate increased through fluorescence-activated cell sorting (FACS) prior to APC experiments. Gigaohm seal data quality makes the 384-format accessible to recording of primary and stem cell-derived cells on the SyncroPatch 384. We show recordings in voltage and current clamp modes of stem cell-derived cardiomyocytes. In addition, the option of intracellular solution exchange enabled investigations into the effects of intracellular Ca2+ and cAMP on TRPC5 and HCN2 currents, respectively. Together, these data highlight the broad applicability and versatility of APC platforms and also outlines some limitations of the approach. Key points: High throughput automated patch clamp (APC) can be used for a variety of applications involving ion channels. Lower false positive rates were achieved using automated patch clamp versus a fluorometric imaging plate reader (FLIPR) in a high throughput compound screen against NMDA receptors. Genetic variants and mutations can be screened on a single 384-well plate to reduce variability of experimental parameters. Intracellular solution can be perfused to investigate effects of ions and second messenger systems without the need for excised patches. Primary cells and stem cell-derived cells can be used on high throughput APC with reasonable success rates for cell capture, voltage clamp measurements and action potential recordings in current clamp mode.

Introduction: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. Methods: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. Results: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. Conclusion: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

Background The voltage-gated K+-channel Kv11.1 has a central role in cardiac repolarization. Blockage of Kv11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). Kv11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of Kv11.1. This suggests that equine Kv11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. Aim To screen a series of commonly used drugs in equine medicine for interaction with Kv11.1. Methods High-throughput screening of selected compounds on human Kv11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine Kv11.1 expressed in CHO-K1 cells by manual patch clamp. Results Acepromazine maleat (IC50 = 0.5 μM) trimethoprim (IC50 = 100 μM), diphenhydramine hydrochloride (IC50 = 2 μM) and cyproheptadine hydrochloride (IC50 = 1.84 μM) inhibited equine Kv11.1 current at clinically relevant drug concentrations. Conclusion The results suggest that drug interaction with Kv11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.

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.

Purpose Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma. Design Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries. Participants All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016. Methods For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks. Main Outcome Measures All-cause and melanoma-specific mortality. Results Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size ( P 0.001) and younger age ( P 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89–1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89–1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients. Conclusions All-cause and melanoma-specific mortality after primary treatment were similar among biopsied and nonbiopsied patients with posterior uveal melanoma. Our findings do not support an increased metastatic risk after intraocular tumor biopsy.

The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium around 10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). The most obvious explanation for this discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we use conventional and non-canonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that they contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work supports the notion that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. The results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.

BackgroundPreclinical 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).MethodsFrom 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.ResultsThe 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).ConclusionsUse 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.

Incorporation of noncanonical amino acids (ncAAs) can endow proteins with novel functionalities, such as crosslinking or fluorescence. In ion channels, the function of these variants can be studied with great precision using standard electrophysiology, but this approach is typically labor intensive and low throughput. Here, we establish a high-throughput protocol to conduct functional and pharmacological investigations of ncAA-containing human acid-sensing ion channel 1a (hASIC1a) variants in transiently transfected mammalian cells. We introduce 3 different photocrosslinking ncAAs into 103 positions and assess the function of the resulting 309 variants with automated patch clamp (APC). We demonstrate that the approach is efficient and versatile, as it is amenable to assessing even complex pharmacological modulation by peptides. The data show that the acidic pocket is a major determinant for current decay, and live-cell crosslinking provides insight into the hASIC1a–psalmotoxin 1 (PcTx1) interaction. Further, we provide evidence that the protocol can be applied to other ion channels, such as P2X2 and GluA2 receptors. We therefore anticipate the approach to enable future APC-based studies of ncAA-containing ion channels in mammalian cells., This study describes a method to rapidly screen hundreds of ion channel variants containing non-canonical amino acids. A proof-of-principle introducing photocrosslinking non-canonical amino acids into the human ion channel hASIC1a shows how this approach can provide insights into function and pharmacology.

Evidence suggests that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have antineoplastic properties of potential importance for survival of head and neck cancer.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.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.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.

Background: We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC. Methods: Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000–2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs). Results: The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63–1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs. Conclusions: In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs.

Antihistamines with cationic amphiphilic drug (CAD) characteristics induce cancer-specific cell death in experimental studies. Epidemiologic evidence is, however, limited. In a Danish nationwide cohort of ovarian cancer patients diagnosed during 2000–2015 (n = 5075), we evaluated the association between filled antihistamine prescriptions and cancer mortality. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer mortality. In an in vitro cell viability assay, we evaluated cell death in three ovarian cancer cell lines after treatment with clinically relevant doses of eight antihistamines. In our cohort study, CAD antihistamine use (≥1 prescription; n = 133) was associated with a hazard ratio of 0.63 (95% CI = 0.40 to 0.99) compared to use of non-CAD antihistamines (n = 304), and we found a tendency toward a dose-response association. In our cell viability assay, we found consistent and dose-dependent cytotoxicity for all CAD but not non-CAD antihistamines. In this nationwide cohort study, use of antihistamines with CAD characteristics is associated with a prognostic benefit in ovarian cancer patients.

Patch-clamp electrophysiology remains an important technique in studying ion channels; indeed, it is still considered the gold standard since it was first described by Neher and Sakmann in the 1970...

Following the first case of acute respiratory syndrome coronavirus 2 (SARS-CoV-2, known as COVID-19) in Denmark at the end of February 2020, wide-spread social distancing was implemented and societ...

Introduction hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. Methods A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. Results A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. Discussion This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment., Highlights • hERG potency/safety margin is a widely used nonclinical cardiac safety strategy. • A new regulatory paradigm promotes the integration of nonclinical and clinical data. • Lack of uncertainty quantification hindered using hERG potency in the new paradigm. • A systematic method was established to address this limitation. • Analysis supports using different safety margin thresholds in different context.

Background Preclinical studies have shown both pro- and antineoplastic effects of antihistamines. Here, we evaluated the effect of H1 antihistamines on contralateral breast cancer (CBC) risk, and whether cationic amphiphilic (CAD) antihistamines could increase the sensitivity to chemotherapy. Methods From the Danish Breast Cancer Group clinical database, we identified all women aged ≥20 years with a first-time diagnosis of breast cancer during 1996–2012. Information on drug use, CBC and potential confounding factors was retrieved from nationwide registries. Using Cox proportional hazard regression models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with H1-antihistamine use. Results We identified 52,723 patients with breast cancer with a total of 310,583 person-years of follow-up. Among them, 1444 patients developed a new primary tumour in the contralateral breast. Post-diagnosis use of H1 antihistamines (≥2 prescriptions) was not strongly associated with CBC risk (HR 1.08, 95% CI: 0.90–1.31) compared with non-use ( Conclusions Taken together, our findings do not suggest any association of H1-antihistamine use with CBC development.

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 (

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

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

Background: Breast cancer patients have a lifelong 2–4-fold increased risk of developing a second primary tumor in the contralateral breast compared with the risk for a first primary breast cancer in the general female population. Prevention of contralateral breast cancer (CBC) has received increased attention during recent decades. Here, we summarize and discuss the available literature on drug preventive therapy and CBC. Results: The endocrine-targetting drugs, tamoxifen and aromatase inhibitors are used as standard adjuvant treatment for estrogen receptor (ER)-positive breast cancer. Both are associated with relative risk reductions of CBC of up to 50%, but incur serious side effects. Several prescription drugs originally developed for other purposes, including bisphosphonates, statins, non-steroidal anti-inflammatory drugs, metformin, anti-hypertensives and retinoids, have shown anti-cancer activity in preclinical models. However, results of observational studies on CBC are sparse and inconsistent, with only statins demonstrating promise as preventive agents and a potential treatment option for ER-negative breast cancer patients. Conclusion: Future studies are needed to assess the effect of statins in risk reduction and to identify other drugs with chemopreventive potential against CBC. Eventually, efforts must be directed towards identifying those breast cancer patients likely to benefit most from specific preventive therapies.