Background Extended, more effective breast cancer (BC) treatments have increased the prevalence of long term survivors. We investigated the risk of late breast cancer recurrence (BCR), 10 years or more after primary diagnosis, and associations between patient and tumor characteristics at primary diagnosis and late BCR up to 32 years after primary BC diagnosis. Methods Using the Danish Breast Cancer Group clinical database, we identified all women with an incident early BC diagnosed during 1987–2004. We restricted to women who survived 10 years without a recurrence or second cancer (10-year disease-free survivors) and followed them from 10 years after BC diagnosis date until late recurrence, death, emigration, second cancer or December 31, 2018. We calculated incidence rates per 1,000 person-years and cumulative incidences for late BCR, stratifying by patient- and tumor characteristics. Using Cox regression, we calculated adjusted hazard ratios for late BCR accounting for competing risks. Results Among 36,924 women with BC, 20,315 became 10-year disease-free survivors. Of these, 2,595 developed late BCR (incidence rate = 15.53 per 1,000 person-years, 95% confidence interval = 14.94–16.14; cumulative incidence = 16.6%, 95% confidence interval = 15.8%–17.5%) from year 10 to 32 after primary diagnosis. Tumor size larger than 20 mm, lymph node positive disease, and estrogen receptor-positive tumors were associated with increased cumulative incidences and hazards for late BCR. Conclusion Recurrences continued to occur up to 32 years after primary diagnosis. Women with high lymph node burden, large tumor size and ER-positive tumors had increased risk of late recurrence. Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches.

Background Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. Methods Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996–2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. Results We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7–1.9) and 1.6% (95%CI = 1.5–1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25–4.67) and 3.81 (95%CI = 3.73–3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11–1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50–2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14–1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45–2.01 and HR = 1.36, 95%CI = 1.17–1.58, respectively]. Conclusions BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

Background The mortality of older patients after early discharge from hospitals is sparsely described. Information on factors associated with mortality can help identify high-risk patients who may benefit from preventive interventions. The aim of this study was to examine whether demographic factors, comorbidity and admission diagnoses are predictors of 30-day mortality among acutely admitted older patients discharged within 24 h after admission. Methods All medical patients aged ≥65 years admitted acutely to Danish hospitals between 1 January 2013 and 30 June 2014 surviving a hospital stay of ≤24 h were included. Demographic factors, comorbidity, discharge diagnoses and mortality within 30 days were described using data from the Danish National Patient Registry and the Civil Registration System. Cox regression was used to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for all-cause mortality. Results A total of 93,295 patients (49.4% men) with a median age of 75 years (interquartile range: 69–82 years), were included. Out of these, 2775 patients (3.0%; 95% CI 2.9–3.1%) died within 30 days after discharge. The 30-day mortality was increased in patients with age 76–85 years (aHR 1.59; 1.45–1.75) and 86+ years (aHR 3.35; 3.04–3.70), male gender (aHR 1.22; 1.11–1.33), a Charlson Comorbidity Index of 1–2 (aHR 2.15; 1.92–2.40) and 3+ (aHR 4.07; 3.65–4.54), and unmarried status (aHR 1.17; 1.08–1.27). Discharge diagnoses associated with 30-day mortality were heart failure (aHR 1.52; 1.17–1.95), respiratory failure (aHR 3.18; 2.46–4.11), dehydration (aHR 2.87; 2.51–3.29), constipation (aHR 1.31; 1.02–1.67), anemia (aHR 1.45; 1.27–1.66), pneumonia (aHR 2.24; 1.94–2.59), urinary tract infection (aHR 1.33; 1.14–1.55), dyspnea (aHR 1.57; 1.32–1.87) and suspicion of malignancy (aHR 2.06; 1.64–2.59). Conclusions Three percent had died within 30 days. High age, male gender, the comorbidity burden, unmarried status and several primary discharge diagnoses were identified as independent prognostic factors of 30-day all-cause mortality.

Background: Uncontrolled confounding from maternal depression and genetic and environmental factors is expected in studies investigating the effect of prenatal antidepressant exposure on the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood and may explain inconsistencies in the existing evidence. We aimed to assess this effect using triangulation. Methods: Using population-based health registries, we conducted a nationwide cohort study of all children born in Denmark between 1997 and 2017 and followed through 2018 for ADHD. We assessed the effect of prenatal antidepressant exposure on the risk of ADHD in childhood by comparing children with and without prenatal antidepressant exposure in terms of adjusted incidence rate ratios (IRRs), adjusted incidence rate differences (IRDs), and adjusted risk differences (RDs) and the associated 95% confidence intervals (CIs). We triangulated results from four different analytic approaches: an overall analysis, a negative control analysis, a sibling analysis, and a former-user analysis. Results: The overall study cohort consisted of 1,253,362 children, among whom 28,910 (2.3%) had prenatal antidepressant exposure. ADHD during follow-up was diagnosed among 1,411 (4.9%) of the exposed and in 37,196 (3.0%) of the unexposed children. Triangulation suggested an IRR of 1.09-1.15; an IRD less than 1 case/1,000 personyears, and an RD of 0.9%-2.2% over an up to 18-year period. Conclusions: Based on triangulation, we estimated a modest effect of prenatal antidepressant exposure on the risk of ADHD in childhood. However, considering the limitations of our approaches, this observed association may be partially due to residual biases. See video abstract at, http://links.lww.com/EDE/B935.

Background Human phthalate exposure is widespread through contact with myriad consumer products. Exposure is particularly high through medications formulated with phthalates. Phthalates disrupt normal endocrine signaling and are associated with reproductive outcomes and incidence of some cancers. We measured associations between gestational and childhood medication-associated phthalate exposures and the incidence of childhood cancers. Methods We identified all live births in Denmark between 1997–2017, including both children and birth mothers. Using drug ingredient data merged with the Danish National Prescription Registry, we measured phthalate exposure through filled prescriptions for mothers during pregnancy (gestational exposure) and for children from birth until age 19 years (childhood exposure). Incident childhood cancers were ascertained from the Danish Cancer Registry, and associations were estimated with Cox regression models. Results Among 1,278,685 children, there were 2,027 childhood cancer cases diagnosed over 13.1 million person-years of follow-up. Childhood phthalate exposure was strongly associated with incidence of osteosarcoma (HR = 2.78, 95% CI: 1.63, 4.75). We also observed a positive association with incidence of lymphoma (HR = 2.07, 95% CI: 1.36, 3.14), driven by associations with Hodgkin and non-Hodgkin lymphoma, but not Burkitt lymphoma. Associations were apparent only for exposure to low-molecular phthalates, which have purportedly greater biological activity. Conclusions Childhood phthalate exposure was associated with incidence of osteosarcoma and lymphoma before age 19 years. Lingering questions include which specific phthalate(s) are responsible for these associations, by what mechanisms they occur, and to what extent childhood cancer cases could be avoided by reducing or eliminating the phthalate content of medications and other consumer products.