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Diana H Christensen,1 Katalin Veres,1 Anne G Ording,1 Jens Otto L Jørgensen,2 Suzanne C Cannegieter,3 Reimar W Thomsen,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands Objective: Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. Design: Nationwide population-based cohort study based on Danish medical registry data. Methods: We identified all patients diagnosed with VTE during 1978–2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. Results: During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42–2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07–3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97–1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08–1.46]). Conclusion: VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism. Keywords: hyperthyroidism, hypothyroidism, venous thromboembolism, cancer, cohort study

Anne Gulbech Ording,1 Deirdre Cronin-Fenton,1 Vera Ehrenstein,1 Timothy L Lash,1,2 John Acquavella,1 Mikael Rørth,1 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA Abstract: Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. Keywords: endpoint determination, medical oncology, treatment outcome, neoplasms, research design

Anne Gulbech Ording,1 Deirdre P Cronin-Fenton,1 Jacob Bonde Jacobsen,1 Mette Nørgaard,1 Reimar Wernich Thomsen,1 Peer Christiansen,2 Mette Søgaard1 1Department of Clinical Epidemiology, 2Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark Objective: Previous studies have suggested that breast cancer survival in Denmark has improved, primarily in cancer patients without comorbidity. We therefore conducted a population-based cohort study to examine recent temporal changes in survival and mortality among breast cancer patients with different extents of comorbidity. Methods: We used population-based medical and administrative registries to identify breast cancer patients diagnosed between 2000 and 2011 in the Central Denmark Region. We defined comorbid diseases according to the Charlson Comorbidity Index (CCI), including a history of hospitalization for comorbid disease up to 10 years before breast cancer diagnosis. We studied the impact of comorbidities on overall 1- and 5-year survival in different calendar time periods, using a hybrid analysis for survival prediction in the most recent calendar periods. Results: We included 9,329 breast cancer patients. The proportion of patients within different comorbidity categories remained stable from 2000 to 2011. One-year survival improved from 91% in 2000–2002 to 95% in 2009–2011, while 5-year survival improved from 72% to a predicted 78%. During the entire study period, comorbidity was a strong predictor of the survival of breast cancer patients. However, we observed improvements over time in 1- and 5-year survival for all comorbidity groups. During the 12-year study period, the estimated 5-year survival for patients with a high comorbidity disease burden (CCI score ≥3) increased from 25% to a predicted 50%, and their 5-year age-adjusted mortality hazard ratio (HR) fell from 4.0 (95% confidence interval [CI]: 3.0, 5.4) to 2.7 (95% CI: 2.0, 3.6), respectively, compared with patients with no comorbid disease. Conclusion: Survival of breast cancer patients diagnosed in the Central Denmark Region improved from 2000 to 2011, regardless of the extent of comorbid disease. Keywords: breast neoplasm, survival, mortality, comorbidity, prognosis

Anne Gulbech Ording, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital, Denmark Abstract: The proportion of older people in the world population is expected to increase rapidly during the upcoming decades. Consequently, the number of patients with multimorbidity will increase dramatically. In epidemiologic research, the concepts of multimorbidity, comorbidity, and complications have been confusing, and some of these concepts are used interchangeably. In this commentary, the authors propose a clear terminology for clinical concepts describing different aspects of multimorbidity and elucidate the relationship between these clinical concepts and their epidemiologic analogs. Depending on whether a study uses causal or predictive models, a proper distinction between concepts of multimorbidity is important. It can be very difficult to separate complications of the index disease under study from comorbidity. In this context, use of comorbidity indices as confounding scores should be done with caution. Other methodologic issues are type, duration, severity, and number of comorbidities included in the ascertainment methods, as well as sources included in the research. Studies that recognize these challenges have the potential to yield valid estimates of the comorbidity burden and results that can be compared with other studies. Keywords: epidemiology, epidemiologic methods, comorbidity, complications, diagnosis-related groups, risk adjustment

Lone Winther Lietzen1, Gitte Vrelits Sørensen1, Anne Gulbech Ording1, Jens Peter Garne2, Peer Christiansen3, Mette Nørgaard1, Jacob Jacobsen11Department of Clinical Epidemiology, 2Department of Breast Surgery, Aalborg Hospital, 3Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, DenmarkObjective: Breast cancer is the most common cancer among women worldwide. The Nordic countries have relatively high survival, but Denmark has a lower survival than neighboring countries. A breast cancer screening program was introduced in 2007 and 2008 in the northern and central regions of Denmark respectively. We aimed to examine possible changes in survival of Danish breast cancer patients in central and northern Denmark in the period 1998–2009.Materials and methods: From the northern and central Denmark regions, we included all women (n = 13,756) with an incident diagnosis of breast cancer, as recorded in the Danish National Registry of Patients during the period January 1, 1998 through December 31, 2009. We calculated age-stratified survival and used Cox proportional hazard regression to estimate mortality rate ratios (MRRs) for all breast cancer patients.Results: Median age was 62 years (21–102 years). The overall 1-year survival improved steadily over the period from 90.9% in 1998–2000 to 94.4% in 2007–2009, corresponding to a 1-year age adjusted MRR of 0.68 in 2007–2009 compared with the reference period 1998–2000. We estimated the 5-year survival to improve from 70.0% in 1998–2000 to 74.7% in 2007–2009, corresponding to a 5-year age adjusted MRR of 0.82 in 2007–2009 compared with the reference period 1998–2000. For middle-aged women (50–74 years) 1-year survival increased from 92.8% in 1998–2000 to 96.6% in 2008–2009, and 5-year survival was expected to increase from 73.9% in 1998–2000 to 80.2% in 2007–2009. Among younger women (15–49 years) and elderly women (>75 years), 1-year survival and 5-year predicted survival did not change over the two time periods.Conclusion: Survival of breast cancer patients has improved in Denmark over the period 1998–2009, and this change was most distinct in women aged 50–74 years. Survival improved even before the implementation of a formal breast cancer screening program.Keywords: breast neoplasm, mortality, epidemiology, population-based

Introduction: Implementation science focuses on improving the dissemination, uptake and adoption of evidence into practice. Over the last decade, implementation science research has proliferated, particularly in healthcare and social science. The key synthesis of implementation frameworks conducted by Meyers and colleagues in 2012, and the resulting Quality Implementation Framework, has yet to be updated to incorporate this research. This protocol proposes an umbrella review of reviews (RORs) to synthesise the literature since 2012 on implementation science in the fields of healthcare and social science and provides recommendations for an updated Quality Implementation Framework., Methods and Analysis: This ROR will be conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four academic databases (PubMed, Scopus, PsycINFO and Web of Science) will be used to identify peer-reviewed meta-analyses, systematic reviews and scoping reviews published in the English language since January 2012 and report on the development, application or update of one or more implementation frameworks in healthcare or social science contexts. Multiple reviewers will be involved in the screening of articles and extraction of data, and the quality of reviews will be assessed using the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) 2. The outcome of interest is the content of implementation science frameworks reported in the included reviews. The content of these frameworks will be synthesised, aggregated and mapped to the four phases and 14 steps outlined in the original Quality Implementation Framework using both deductive and inductive analysis., Ethics and Dissemination: Ethics approval is not required as this ROR protocol and the resulting ROR do not involve primary data collection. The protocol as well as the ROR will be disseminated in peer-reviewed journals., Prospero Registration Number: CRD42023475994., Competing Interests: Competing interests: KH, AGO, MJ, JM, LAE, SS, LP, GF and SPJ declare no conflict of interest. JB is a member of the Editorial Advisory Board at BMJ Open. This association played no role in the decision to submit the protocol for publication in BMJ Open and presents no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite uncertain benefit-risk profile near the end of life, antithrombotic therapy (ATT) is prevalent in patients with terminal cancer., Objectives: To examine adherence and persistence with ATT in terminally ill cancer patients and investigate risks of major and clinically relevant bleeding, venous thromboembolism (VTE), and arterial thromboembolism (ATE) by ATT exposure., Methods: Using a Danish nationwide cohort of terminal cancer patients, ATT adherence in the year following terminal illness declaration was measured by the proportion of days covered (PDC) by prescription. Discontinuation was defined as a treatment gap of ≥30 days between prescription renewals. One-year cumulative incidences of bleeding complications, VTE, and ATE were calculated, considering the competing risk of death., Results: During 2013-2022, 86 732 terminally ill cancer patients were identified (median age, 75 years; 47% female; median survival, 57 days). At terminal illness declaration, 37.5% were receiving ATT (66.6% platelet inhibitors, 23.0% direct oral anticoagulants, and 10.4% vitamin K antagonists [VKAs]). The mean PDC with ATT was 88% (SD, 30%), highest among platelet inhibitor users (mean PDC, 89%) and lowest among VKA users (73%). One-year ATT discontinuation incidence was 7.9% (95% CI, 7.7%-8.1%). Most patients continued ATT until death (74.8% platelet inhibitors, 58.8% direct oral anticoagulants, and 61.6% VKAs). Patients receiving ATT had a lower 1-year VTE risk but higher risks of ATE and major bleeding., Conclusion: Despite uncertain benefit-risk profile, most terminally ill cancer patients continue ATT until the end of life. These findings provide insights into current ATT utilization and discontinuation dynamics in the challenging context of terminal illness., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) is a common complication in patients starting cancer therapies for non-small-cell lung cancer (NSCLC). We examined the risk and timing of VTE in patients with stage IIIA, IIIB to C, and stage IV NSCLC according to received cancer treatments., Materials and Methods: A nationwide registry-based cohort study of patients recorded in the Danish Lung Cancer Registry (2010-2021) followed for 1 year after entry into the registry to assess the incidence of VTE. The Aalen-Johansen estimator was used to calculate the risk of VTE after treatment commencement with chemotherapy, radiotherapy, chemoradiation, immunotherapy, and targeted therapy., Results: Among the 3475 patients with stage IIIA, 4047 with stage IIIB to C, and 18,082 patients with stage IV cancer, the 1-year risk of VTE was highest in the first 6 months and varied markedly by cancer stage and cancer treatment. In stage IIIA, VTE risk was highest with chemotherapy (3.9%) and chemoradiation (4.1%). In stage IIIB to C, risks increased with chemotherapy (5.2%), immunotherapy (9.4%), and targeted therapy (6.0%). Stage IV NSCLC showed high risk with targeted therapy (12.5%) and immunotherapy (12.2%). The risk was consistently higher for pulmonary embolism than deep vein thrombosis., Conclusion: VTE risks vary substantially according to cancer treatments and cancer stages. The highest risk was observed in the initial 6 months of therapy initiation. These insights emphasize the need for tailored risk assessment and vigilance in managing VTE complications in patients with NSCLC. Further research is needed to optimize individual thromboprophylaxis strategies for patients with unresectable and metastatic NSCLC., Competing Interests: Disclosure Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer–Ingelheim, Pfizer, Roche Diagnostics, Takeda, Merck Sharp & Dohme (MSD) and Bristol–Myers Squibb (BMS) and on Advisory Board for Bayer, Merck MSD, AstraZeneca, and Sanofi. René Horsleben Petersen has received a speaker's fee from Medtronic, AMBU, Medela, and AstraZeneca and on the advisory board for AstraZeneca, Roche, MSD, and BMS. Torben Bjerregaard Larsen reports a relationship with Bayer, Pfizer, Janssen Pharmaceuticals, Roche Diagnostics, and Bristol Meyers Squibb that includes: consulting or advisory. Peter Meldgaard has received research support from Astra Zeneca, MSD, Novartis, Roche, and Takeda; and on advisory board for MSD, Roche, Astra Zeneca, BMS, Takeda, Novartis, and Amgen. Flemming Skjøth has received consultancy fees from Bayer. Simon Noble had received research support and been on speakers bureau from Leo Pharma. Anette Arbjerg Højen has received research grants from the Danish Heart Foundation and The Novo Nordisk Foundation, been on the speaker bureaus for Bayer, Pfizer, MSD, Leo Pharma, and BMS; and on Advisory Board for Bayer and BMS. Other authors: None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Venous thromboembolic event (VTE) is a severe complication in patients with lung cancer undergoing thoracic surgery. Nevertheless, because of insufficient evidence, there are no clear guidelines, and VTE prophylaxis practices vary widely. This nationwide cohort study was a comparative study investigating VTE risk in surgical departments that routinely administered in-hospital thromboprophylaxis with low-molecular-weight heparin compared to those that did not., Methods: We identified all patients with non-small-cell lung cancer (NSCLC) who underwent surgery in Denmark during 2010-2021. Thoracic surgery was exclusively performed in the 4 university hospitals. Three hospitals implemented in-hospital thromboprophylaxis as standard care since 2000, while the fourth adopted this practice in September 2016. VTE events were assessed at 6-month follow-up according to hospital and study period, using an inverse probability of treatment weighting approach., Results: We identified 9615 patients. During 6-month follow-up, a total of 190 VTE events were observed, resulting in a weighted rate of 4.5 events per 100 person-years and an absolute risk of 2.2%. There was no clear trend according to hospital site or use of in-hospital thromboprophylaxis with a 2.2% risk in the hospital not using thromboprophylaxis compared to 1.7-3.1% in those that did., Conclusions: Use of in-hospital thromboprophylaxis did not affect the risk of VTE after surgery for NSCLC, suggesting that relying solely on in-hospital thromboprophylaxis may be insufficient to mitigate VTE risk in these patients. Further research is warranted to investigate the potential benefits of extended thromboprophylaxis in reducing VTE risk in selected NSCLC surgical patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Aims: Although frail patients with atrial fibrillation (AF) carry a high risk of stroke and treatment-related bleeding complications, evidence for the safety and effectiveness of anticoagulation remains sparse. This study investigated the effectiveness and safety of direct oral anticoagulant (DOAC) vs. warfarin in frail AF patients., Methods and Results: Nationwide registry-based cohort study including 32 048 anticoagulation naïve frail patients (median age 80 years, 53% female) with incident AF during 2012-20. Frailty was assessed using the hospital frailty risk score. To address baseline confounding, we applied inverse probability of treatment weighting (IPTW) and marginal structural models with weighted pooled regression to compute weighted hazard ratios (wHRs) and risk differences for thromboembolism and major bleeding comparing specific DOAC doses with warfarin. After AF diagnosis, 6747 (21.1%) initiated warfarin, 17 076 (50.3%) initiated standard-dose DOAC, and 9179 (28.6%) initiated reduced-dose DOAC. Comparative effectiveness analyses in the IPTW pseudo-populations revealed similar thromboembolism risk between standard-dose DOAC and warfarin [wHR 0.95, 95% confidence interval (CI) 0.80-1.13] and between reduced-dose DOAC and warfarin (wHR 0.97, 95% CI 0.77-1.23). The 1-year thromboembolic event-free survival difference was -0.2% for DOAC, regardless of dosing, vs. warfarin. Major bleeding risk was significantly lower with standard-dose DOAC (wHR 0.69, 95% CI 0.59-0.87) and reduced-dose DOAC (wHR 0.67, 95% CI 0.55-0.81) vs. warfarin. The 1-year bleeding risk difference with DOAC ranged from -1.3% to -3.0%., Conclusion: Our findings indicate comparable thromboembolism risk and significantly lower bleeding risk with both standard and reduced DOAC regimens compared with warfarin in frail AF patients in routine care., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Frail people with atrial fibrillation are often undertreated with oral anticoagulants (OACs), and evidence for the net clinical benefit (NCB) of OAC is sparse. We, therefore, examined the risk of thromboembolic events, major bleeding, and NCB of anticoagulation treatment., Methods: This was a nationwide cohort study including frail patients aged with incident atrial fibrillation between 2013 and 2018. Patients were categorized according to OAC treatment exposure. One-year risks of thromboembolic events and major bleeding were ascertained where death was treated as a competing risk. The NCB of anticoagulation was assessed by a bivariate trade-off between thromboembolism and bleeding., Results: We identified 36 223 frail patients with atrial fibrillation (median age, 79 years; 50.5% female), of whom 61.8% started OAC therapy, while 38.2% were untreated despite indication for stroke prevention. At 1 year, the risk of thromboembolic events was 2.1% (95% CI, 1.8%-2.3%) among patients not receiving OAC versus 1.5% (95% CI, 1.4%-1.7%) in patients with OAC. The bleeding risk was 3.2% (95% CI, 2.9%-3.5%) among patients without OAC versus 3.5% (95% CI, 3.2%-3.8%) among anticoagulated patients. The NCB was 0.70% (95% CI, 0.32%-1.08%), suggesting a benefit of OAC treatment; however, the NCB declined with age and increasing frailty and was lowest among patients >75 years of age or with high frailty level., Conclusions: Frail patients with atrial fibrillation are often untreated with OAC in routine clinical care despite an indication for stroke prevention. The NCB balancing thromboembolic events and major bleeding was in favor of anticoagulation but decreased with advancing age and increasing frailty., Competing Interests: Disclosures Dr Søgaard has received speaker fees from Bayer. Dr Højen reports compensation from Bayer for consultant services and other services; compensation from LEO Pharma AS for other services; compensation from Bristol Myers Squibb (BMS) for consultant services; compensation from Pfizer for other services; and grants from Novo Nordisk Fonden. Dr Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. No fees are received personally. Dr Larsen is an investigator for Janssen Scientific Affairs, LLC, Bayer AG, and Boehringer Ingelheim and reports speaker honorarium from Bayer, BMS, Pfizer, and Merck, Sharp & Dome. Dr Nielsen reports consultant fees from Boehringer Ingelheim, grants and consultant fees from Daiichi Sankyo, grants from BMS/Pfizer, and grants and consultant fees from Bayer outside the submitted work. The other authors report no conflicts.

Background: Venous thromboembolism (VTE) is a potentially preventable serious complication in patients with lung cancer undergoing thoracic operation. We examined the risk and timing of VTE after surgery for primary non-small cell lung cancer (NSCLC)., Methods: All patients undergoing operation for NSCLC in Denmark between 2003 and 2021 were identified in the Danish Lung Cancer Registry. VTE events in the year after operation were assessed by stage, patient characteristics, and surgical procedure., Results: We identified 13,197 patients who underwent operation for NSCLC in 2003 to 2021 (mean age, 67.6 years; 50% female); 10,524 (79.7%) had stage I-II NSCLC, and 2673 (20.3%) had stage III-IV. During 1-year follow-up, there were 335 VTE events, yielding a rate of 2.87 events/100 person-years and an absolute risk of 3.3% (95% CI, 2.3-4.0). VTE risk increased with advancing cancer stage (1.8% for stage I vs 3.9% for stage IV) but varied little by pathologic type, sex, and comorbidity level. Bilobectomy was associated with highest VTE risk (4.8%; 95% CI, 3.2-6.9), followed by pneumonectomy (3.5%; 95% CI, 2.3-5.0). The hazard of VTE was highest during the first 3 months after operation, after which it declined. For stage IV cancer, hazards increased again after 6 months. At 1 year, all-cause death was 12.6% (95% CI, 12.0%-13.1%)., Conclusions: VTE developed in 3.3% of patients undergoing operation for NSCLC, most commonly within 3 months postoperatively. Prolonged thromboprophylaxis could be considered, particularly in those with advanced cancer stage and undergoing extended resections., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Individuals with major birth defects are at increased risk of developing cancer, indicating a common aetiology. However, whether the siblings of individuals with birth defects are also at an increased risk of cancer is unclear., Methods: We used nationwide health registries in four Nordic countries and conducted a nested case-control study. We included 40 538 cancer cases (aged 0-46 years) and 481 945 population controls (matched by birth year and country), born between 1967 and 2014. The relative risk of cancer among individuals whose siblings had birth defects was computed with odds ratios (OR) and 95% confidence intervals (CIs), using logistic regression models., Results: In the total study population (aged 0-46 years), we observed no overall difference in cancer risk between individuals whose siblings had birth defects and those who had unaffected siblings (OR 1.02; 95% CI 0.97-1.08); however, the risk of lymphoid and haematopoietic malignancies was elevated (1.16; 1.05-1.28). The overall risk of childhood cancer (0-19 years) was increased for siblings of individuals who had birth defects (1.09; 1.00-1.19), which was mainly driven by lymphoma (1.35; 1.09-1.66), neuroblastoma (1.51; 1.11-2.05) and renal carcinoma (5.03; 1.73-14.6). The risk of cancer also increased with the number of siblings with birth defects (Ptrend = 0.008)., Conclusion: Overall risk of cancer among individuals (aged 0-46 years) whose siblings had birth defects was not elevated, but the risk of childhood cancer (ages 0-19 years) was increased. Our novel findings are consistent with the common aetiologies of birth defects and cancer, such as shared genetic predisposition and environmental factors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Predictive factors for recurrent cancer-associated venous thromboembolism have been inconsistent across previous studies. To provide data for improved risk stratification, we described the risk of recurrent venous thromboembolism overall and across age, sex, calendar period, cancer type, Ottawa risk score, cancer stage, and cancer treatment in a nationwide cohort of patients with active cancer., Methods: Using Danish administrative registries, we identified a cohort of all adult patients with active cancer and a first-time diagnosis of venous thromboembolism during 2003-2018. We accounted for the competing risk of death and calculated absolute risks of recurrent venous thromboembolism at six months., Results: The population included 34,072 patients with active cancer and venous thromboembolism. Recurrence risks at six months were higher for patients with genitourinary cancer (6.5%), lung cancer (6.1%), gastrointestinal cancer (5.6%), brain cancer (5.2%), and hematological cancer (5.1%) than for patients with gynecological cancer (4.7%), breast cancer (4.1%), and other cancer types (4.8%). Recurrence risks were similar for men (5.2%) and women (4.9%), with and without chemotherapy (5.1%), across Ottawa risk score group (low: 5.0%; high: 5.1%) and across calendar periods but increased with increasing cancer stage. The overall six-month all-cause mortality risk was 26%, and highest for patients with lung cancer (49%) and lowest among breast cancer patients (4.1%)., Conclusions: Six-month recurrence risk after first-time cancer-associated venous thromboembolism was high and varied by cancer type and patient characteristics. Refining risk stratification for recurrence may improve decision-making regarding treatment duration after cancer-associated thromboembolism., Competing Interests: Declaration of Competing Interest Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche Diagnostics, Takeda, Merck, Sharp & Dohme (MSD) and Bristol-Myers Squibb and has been in an Advisory Board for Bayer, Merck Sharp & Dohme (MSD) and AstraZeneca. Torben Bjerregaard Larsen has been a speaker for Bayer, BMS/Pfizer, Janssen Pharmaceuticals, and Roche Diagnostics, and on an advisory board for Bayer, Bristol Meyers Squibb and Roche Diagnostics. Mette Søgaard has received consulting and speaker fees from Bayer. The other authors have nothing to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs., Methods: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe., Results: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life., Conclusions: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers., Competing Interests: Declaration of competing interest AAH reports grants, speaking, or consulting fees from Bayer, MSD, LEO-Pharma and Bristol-Myers Squibb/Pfizer. MS reports grants and consulting fees from Bayer. JJB is a speaker for Abbott and Edwards Lifesciences. GJG is vice-chair of the Dutch Federation of Thrombosis services, and reports grants from Bayer, BMS, Pfizer and Daiichi-Sankyo, The Dutch Research Council, The Netherlands Organisation for Health Research and Development, and the Dutch Heart Foundation, all unrelated to this work and paid to his institution. MVH reports grants from Dutch Heart Foundation, ZonMw, Bayer Health Care, Pfizer-BMS, and Leo Pharma, all unrelated to this work. FAK reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Varm-X, The Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all unrelated to this work and paid to his institution. AM reports advisory board honoraria from Bayer, BMS Sanofi and Pfizer, speaker's bureau for BMS and Bayer and an educational grant from Bayer. DM reports contracts from BMS, Leo Pharma, Pfizer and Sanofi. MJHAK reports grants from Sobi, The Netherlands Organisation for Health Research and Development and the Dutch Thrombosis Association and speakers fee from Roche, Sobi and BMS, all unrelated to this work and paid to his institution. FEMM reports grants from Yorkshire Cancer Research, Marie Curie Cancer Care, the UK National Institute of Health and Care Research, and Hull Clinical Commissioning Group, all unrelated to this work. LV reports a grant from the Dutch Cancer Society, the Netherlands Organization for Health Service Research and Development, and the Dutch Research Council, all unrelated to this work. All others report no conflicts of interest related to this project., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear., Methods: We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0-19 years) and 218 980 matched population controls, born 1967-2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects., Results: Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6-12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8-2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6-3.1) than males (OR = 2.1, 95% CI = 1.9-2.2, Pinteraction <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, PNIE <0.001), although more at younger ages (10% below years and 28% below 1 year)., Conclusions: The birth defect-cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Thrombosis is common among patients with cancer. Primary thromboprophylaxis guided by the Khorana score is endorsed by guidelines but recommendations rely mainly on data from patients treated with chemotherapy., Objectives: To explore if the Khorana score could risk stratify patients with cancer treated with immune checkpoint inhibitors according to risk of venous and arterial thrombosis., Patients/methods: The study population and Khorana score were defined using administrative Danish health registries. The primary outcome was 6-month risk of venous thromboembolism after initiation of checkpoint inhibitor treatment. Secondary outcomes were arterial thrombosis and any thromboembolic event. Death was considered a competing risk event., Results: Among 3946 patients with cancer initiating checkpoint inhibitor treatment without other indications for anticoagulation, the overall 6-month incidence of venous thromboembolism was 2.6% (95% confidence interval [CI]: 2.1-3.1). Risks were 2.1% (95% CI: 1.5-3.0), 2.6% (95% CI: 2.0-3.4), and 3.7% (95% CI: 2.1-5.9) in low (score 0), intermediate (score 1-2), and high risk (score ≥3) Khorana categories, respectively. Among patients eligible for primary thromboprophylaxis according to guidelines (Khorana score ≥2), risk of venous thromboembolism was 4.1% (95% CI: 3.1-5.4). Higher Khorana risk category was also associated with higher 6-month risk of both arterial thrombosis and any thromboembolic events., Conclusions: The Khorana score was able to risk stratify patients with cancer treated with immune checkpoint inhibitors according to 6-month risk of thromboembolic events. Risks of venous thromboembolism were lower than in randomized thromboprophylaxis trials, thus questioning the absolute benefit of routine primary thromboprophylaxis in an unselected population of patients treated with immune checkpoint inhibitors., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

The concept of pulmonary embolism is evolving. Recent and emerging evidence on the treatment of specific patient populations, its secondary prevention, long-term complications, and the unmet need for rehabilitation has the potential to change clinical practice for the benefit of the patients. This review discusses the recent evidence from clinical trials, observational studies, and guidelines focusing on anticoagulation treatment, rehabilitation, emotional stress, quality of life, and the associated outcomes for patients with pulmonary embolism. Guidelines suggest that the type and duration of treatment with anticoagulation should be based on prevalent risk factors. Recent studies demonstrate that an anticoagulant treatment that is longer than two years may be effective and safe for some patients. The evidence for extended treatment in cancer patients is limited. Careful consideration is particularly necessary for pulmonary embolisms in pregnancy, cancer, and at the end of life. The rehabilitation and prevention of unnecessary deconditioning, emotional distress, and a reduced quality of life is an important, but currently they are unmet priorities for many patients with a pulmonary embolism. Future research could demonstrate optimal anticoagulant therapy durations, follow-ups, and rehabilitation, and effective patient-centered decision making at the end of life. A patient preferences and shared decision making should be incorporated in their routine care when weighing the benefits and risks with primary treatment and secondary prevention.

Background:  Cerebral venous thrombosis (CVT) is a rare manifestation of stroke and venous thromboembolism (VTE), compared with deep vein thrombosis (DVT) and pulmonary embolism (PE). We examined whether CVT was associated with adverse cardiovascular events., Methods:  A Danish cohort study with adult patients diagnosed with CVT ( N  = 1,015) between 1997 and 2017. We matched 10 patients with VTE (DVT and PE) to each patient with CVT for age, sex, and diagnosis year. We also matched 10 individuals from the general population to each patient with CVT. We computed cumulative incidence and estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs) at 5 years for major bleeding, intracranial bleeding, ischemic stroke, and cardiovascular events. Death was examined separately., Results:  Major bleeding risks were 1.2% for CVT and 0.7% for VTE at 6 months; these risks increased to 2.7% and 2.6%, respectively, at 5 years. Although rare, intracranial bleeding risks were markedly higher for CVT (2.9%) than for VTE (0.4%) at 5 years (HR = 8.9, 95% CI: 5.3-15.1). Incidences of ischemic stroke were 5.9% for CVT and 0.3% for VTE, at 6 months; and 10.0% and 1.4%, respectively, at 5 years (HR = 9.5, 95% CI: 7.1-12.7). In contrast, incidence of cardiac events was lower for CVT that VTE (1.7% vs. 3.6% at 5 years). Mortality risk was higher after CVT compared with VTE, at 6 months (6.6% vs. 3.8%), but the risks differed little at 5 years (14.3% vs. 14.1%)., Conclusion:  Intracranial bleeding, ischemic stroke, and mortality risks were higher for patients with CVT than matched patients with VTE and the general population, particularly within 6 months after diagnosis., Competing Interests: T.B.L. reports personal fees from Boehringer Ingelheim, Bayer, MSD, and BMS/Pfizer, outside the submitted work. The other authors declare no conflicts of interest., (Thieme. All rights reserved.)

Background and Purpose: The effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation have not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice., Methods: We used Danish nationwide registries to identify patients with atrial fibrillation during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios with 95% confidence intervals comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons., Results: We identified 6451 atrial fibrillation patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA 2 DS 2 -VASc score was similar between warfarin and edoxaban 60 mg with a score of 3 (interquartile range (IQR) 2-4). In the inverse probability of treatment-weighted pseudo-population, the thromboembolic event rate for edoxaban 60 mg was 0.95 and 1.0 for warfarin, corresponding weighted hazard ratio of 1.00 (95% confidence intervals (CI) 0.59, 1.71). Edoxaban 60 mg users were associated with lower rates of all-cause mortality (3.93) compared to warfarin (6.04), with a hazard ratio of 0.64 (95% CI 0.47 to 0.88). The event rates for bleeding were 3.36 and 3.14, respectively; hazard ratio 1.09 (95% CI 0.77, 1.57)., Conclusion: Edoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for Danish (mainly Caucasian) patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality.

The Khorana score is recommended for guiding primary venous thromboembolism (VTE) prophylaxis in cancer patients, but its clinical utility overall and across cancer types remains debatable. Also, some previous validation studies have ignored the competing risk of death, hereby potentially overestimating VTE risk. We identified ambulatory cancer patients initiating chemotherapy without other indications for anticoagulation using Danish health registries and estimated 6-month cumulative incidence of VTE stratified by Khorana levels. Analyses were conducted with and without considering death as a competing risk using the Kaplan-Meier method vs the cumulative incidence function. Analyses were performed overall and stratified by cancer types. Of 40 218 patients, 35.4% were categorized by Khorana as low risk (score 0), 53.6% as intermediate risk (score 1 to 2), and 10.9% as high risk (score ≥3). Considering competing risk of death, the corresponding 6-month risks of VTE were 1.5% (95% confidence interval [CI], 1.3-1.7), 2.8% (95% CI, 2.6-3.1), and 4.1% (95% CI, 3.5-4.7), respectively. Among patients recommended anticoagulation by guidelines (Khorana score ≥2), the 6-month risk was 3.6% (95% CI, 3.3-3.9). Kaplan-Meier analysis overestimated incidence up to 23% compared with competing risk analyses. Using the guideline-recommended threshold of ≥2, the Khorana score did not risk-stratify patients with hepatobiliary or pancreatic cancer, lung cancer, and gynecologic cancer. In conclusion, the Khorana score was able to stratify ambulatory cancer patients according to the risk of VTE, but not for all cancer types. Absolute risks varied by methodology but were lower than in key randomized trials. Thus, although certain limitations with outcome identification using administrative registries apply, the absolute benefit of implementing routine primary thromboprophylaxis in an unselected cancer population may be smaller than seen in randomized trials., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Data on the use of oral anti-coagulants (OAC) for stroke prevention in cancer patients with atrial fibrillation (AF) are sparse. Nationwide cohort study of patients with AF (2012-2018) and an indication for OAC who were diagnosed with cancer at least one year later (N = 12 756). We identified treatment with OAC at cancer diagnosis and the following year and described the incidence of discontinuing or switching between warfarin and direct oral anti-coagulants (DOACs). We also described baseline characteristics associated with OAC non-persistence. One third of the cancer patients received no OAC therapy, whereas 42% received warfarin and 24% received DOAC treatment. Switching incidence between OACs was higher for those receiving warfarin treatment (8.6%) than DOAC treatment (1.7%) within one year. Treatment discontinuation was 61% for warfarin and 26% for DOAC. Females were less likely to discontinue DOAC than males (ratio 0.77, 95% confidence interval: 0.66, 0.90). Increasing cancer stage was associated with discontinuation of DOAC, but not warfarin. OAC for stroke prevention in AF was used by two thirds of patients with newly diagnosed cancer. Switching between OACs and discontinuation was more common for warfarin than DOAC, and females had higher persistence with DOACs., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Based on their renal excretion, direct oral anticoagulants (DOACs) may increase the risk of hematuria in patients with atrial fibrillation (AF) and urologic cancer compared with vitamin K antagonists., Objectives: To examine the risk of bleeding associated with DOAC versus warfarin in patients with AF and urologic cancer., Methods: We conducted a Danish nationwide cohort study with individually linked registry data on patients with AF and active or a history of urologic cancer. We calculated crude rates per 100 person-years of hospital episodes of major bleeding and hematuria. We then compared rates of hematuria during the year after initial oral anticoagulation filled prescription by treatment regimen using inverse probability of treatment weighting and Cox regression., Results: The study population included 2615 patients with AF and urologic cancer (6.1% women; median age, 76 years) initiating a DOAC or warfarin. One-year risk of hematuria was 4.8% in the DOAC group and 4.7% in the warfarin group with a corresponding weighted hazard ratio (HR) of 1.21 (95% confidence interval [CI], 0.81-1.81). HRs for hematuria were generally similar in analyses restricted to patients treated with standard-dose DOAC and patients with active cancer. For those with cancer of the kidney, renal pelvis, ureter, and bladder, the HR was 0.82 (95% CI, 0.44-1.54). Results were mirrored for other bleeding events, whereas the risk for intracranial bleeding was lower with DOACs., Conclusion: In patients with AF and urologic cancer, there was a similar risk of hematuria associated with DOAC and warfarin treatment., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Purpose: To describe use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark., Methods: Using data from the Danish National Multiple Myeloma Registry, we conducted a population-based cohort study. Among patients newly diagnosed with multiple myeloma from 2005 to 2015, we examined use of bisphosphonates at first- and at progression/second-line anti-myeloma treatment overall, by patient characteristics, and myeloma complications., Results: Of 2947 patients starting first-line anti-myeloma treatment, 2207 patients (74.9%) received bisphosphonates. During a median follow-up of 27.6 (quartiles, 10.6-52.5) months, disease progression post-first-line treatment was recorded in 1546 patients, of whom 1065 (68.9%) were treated with bisphosphonates. Altogether, 80.9% of patients with and 37.6% of patients without myeloma bone disease were treated with bisphosphonates at first line and 73.0% and 42.7%, respectively, at progression/second line. Moreover, the proportion of patients treated with bisphosphonates decreased with increasing severity of renal impairment at first and at progression/second-line treatment., Conclusion: The proportion of patients treated with bisphosphonates as part of first- and second-line anti-myeloma treatment increased with presence of myeloma bone disease and decreased by presence and severity of renal impairment. Overall, 25% of newly diagnosed multiple myeloma patients had no record of bisphosphonate treatment, potentially indicating an unmet need.

Purpose: The incidence of cancer-associated venous thromboembolism has increased, but whether short-term mortality after cancer-associated venous thromboembolism has changed remains uncertain. We investigated whether the increasing incidence of venous thromboembolism in cancer patients is associated with a change in mortality., Methods: We used administrative medical registries to identify a cohort of all Danish patients diagnosed with a first primary cancer from 2006 to 2017. We examined temporal changes in 1-year risks of venous thromboembolism and in mortality risks at 30 days and 1 year after venous thromboembolism. Cox regression was used to assess changes in mortality rate ratios over time., Results: We included 350,272 cancer patients (median age 68 years, 49.1% female), of whom 8167 developed venous thromboembolism within 1 year after cancer diagnosis. The cumulative 1-year risk of venous thromboembolism was 1.8% in 2006-2008, increasing to 2.8% for patients diagnosed in 2015-2017. The 30-day mortality after venous thromboembolism decreased from 15.1% in 2006-2008 to 12.7% in 2015-2017, and the 1-year mortality decreased from 52.4% to 45.8%, equivalent to a hazard ratio (HR) of 0.83 (95% confidence interval [CI], 0.75-0.90). This pattern of declining 1-year mortality was consistent for patients with pulmonary embolism, HR 0.79 (95% CI, 0.69-0.90), and deep venous thrombosis, HR 0.76 (95% CI, 0.67-0.87). Lower mortality over time was evident across all strata of cancer stage, cancer type, and cancer treatment., Conclusions: The 1-year risk of venous thromboembolism after a first primary cancer diagnosis in Denmark increased during 2006-2017. This increase was accompanied by declining mortality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) may increase the risk of gastrointestinal (GI) bleeding in patients with atrial fibrillation (AF) and GI cancer compared with vitamin K antagonists (VKA)., Methods: We conducted a Danish nationwide cohort study comparing the bleeding risk associated with DOAC versus VKA in patients with AF and GI cancer. We calculated crude bleeding rates per 100 person-years (PYs) for GI and major bleeding. We then compared rates of bleeding at 1 year after initial oral anticoagulation filled prescription by treatment regimen using inverse probability of treatment weighting and Cox regression., Results: The unweighted study population included 1476 AF patients with GI cancer (41.6% women, median age 78 years) initiating a DOAC and 652 initiating a VKA. One-year risk of GI bleeding was 5.0% in the DOAC group and 4.7% in the VKA group with a corresponding weighted hazard ratio (HR) of 0.95 (95% confidence interval [CI]: 0.63, 1.45). For patients with active cancer, weighted GI bleeding rates were slightly higher in both the VKA and DOAC group, and the weighted HR was 1.00 (95% CI: 0.53, 1.88). The HR was 1.12 (95% CI: 0.71, 1.76) for all bleedings. Hazard ratios for GI bleeding were 0.61 (95% CI: 0.25, 1.52) for patients with upper GI cancer, and 0.92 (95% CI: 0.58, 1.46) in patients with colorectal cancer., Conclusion: Evidence from this nationwide cohort study suggests a comparable 1-year risk of bleeding associated with DOAC compared with VKA among patients with AF and GI cancer., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Aspirin inhibits platelet function and may therefore accelerate early lower gastrointestinal bleeding (LGIB) from colorectal cancer (CRC) precursor polyps. The bleeding may increase endoscopic polyp detection., Study Question: To estimate the prevalence of polyps and CRC comparing new users of low-dose aspirin with nonusers who all received a diagnosis of LGIB and to investigate the mortality among these patients., Study Design: Using Danish nationwide health registries, we conducted a cohort study (2006-2013) of all new aspirin users who also received a diagnosis of LGIB (n = 40,578). Each new user was matched with 5 nonusers with LGIB by gender and age at the LGIB diagnosis date., Measures and Outcomes: We computed the prevalence and prevalence ratios (PRs) of colorectal polyps and CRCs, and the mortality ratios within 6 months after the LGIB, comparing new users with nonusers., Results: We identified 1038 new aspirin users and 5190 nonusers with LGIB. We observed 220 new users and 950 nonusers recorded with endoscopically detected polyps. New aspirin users had a higher prevalence of conventional {PR = 1.28 [95% confidence interval (CI): 1.06-1.55]} and serrated [PR = 1.31 (95% CI: 0.95-1.80)] polyps. New users and nonusers had a similar prevalence of CRC [PR = 1.04 (95% CI: 0.77-1.39)]. However, after stratifying by location of CRC, the prevalence of proximal tumors was lower [PR = 0.71 (95% CI: 0.35-1.43)] in new users than in nonusers. No difference in mortality was observed., Conclusions: These findings indicate that new use of low-dose aspirin is associated with an increased detection of colorectal polyps compared with nonuse., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia., Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes)., Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia., Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia., Conclusion: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

Introduction: Cancer-associated venous thromboembolism remains an important but challenging aspect in the treatment of patients with cancer. Recently, alternatives to injection of low-molecular-weight heparin (LMWH) have been introduced, the non-vitamin K antagonist oral anticoagulants (NOACs), which could potentially alleviate patients from burdensome daily injections., Areas Covered: This review discusses the available evidence exploring the role of NOACs in the treatment and secondary prevention of cancer-associated venous thromboembolism, from randomized trials, observational data, contemporary guideline recommendations, and patient perspectives., Expert Opinion: Edoxaban, rivaroxaban, and apixaban have proven attractive alternatives to LMWH for the treatment of cancer-associated venous thromboembolism. Contemporary guidelines have promptly endorsed the use of NOACs in patients with most cancer types. Nonetheless, issues remain regarding bleeding risk, interactions with medical cancer treatment, and the effectiveness and safety for extended treatment periods. There are head-to-head comparisons of the NOACs, and therefore no data favoring the use of one NOAC over the others. Patient's preferences are highly diverse and should be part of routine considerations when weighing risks and benefits associated with various available anticoagulant drugs.

Objectives: To examine the long-term outcomes for patients hospitalised with chronic diseases at age 30, 40 or 50 years., Design: Nationwide, population-based cohort study., Setting: All Danish hospitals, 1979-1989, with follow-up through 2014., Participants: Patients hospitalised during the study period with one, two or three or more chronic diseases and age-matched and sex-matched persons from the general population without chronic disease leading to hospitalisation: age-30 group: 13 857 patients and 69 285 comparators; age-40 group: 24 129 patients and 120 645 comparators; and age-50 group, 37 807 patients and 189 035 comparators., Main Outcome Measures: Twenty-five-year mortality risks based on Kaplan-Meier estimates, years-of-life-lost (YLLs) and mortality rate ratios based on Cox regression analysis. YLLs were computed for each morbidity level, as well as in strata of income, employment, education and psychiatric conditions., Results: Twenty-five-year mortality risks and YLLs increased steadily with increasing number of morbidities leading to hospitalisation and age, but the risk difference with general population comparators remained approximately constant across age cohorts. In the age-30 cohort, the risk differences for patients compared with comparators were 35.0% (95% CI 32.5 to 37.5) with two diseases and 62.5% (54.3% to 70.3%) with three or more diseases. In the age-50 cohort, these differences were, respectively, 48.4% (47.4 to 49.3) and 61.7% (60.1% to 63.0%). Increasing morbidity burden augmented YLLs resulting from low income, unemployment, low education level and psychiatric conditions. In the age-30 cohort, YYLs attributable to low income were 2.4 for patients with one disease, 6.2 for patients with two diseases and 11.5 for patients with three or more diseases., Conclusions: Among patients with multiple chronic diseases, the risk of death increases steadily with the number of chronic diseases and with age. Multimorbidity augments the already increased mortality among patients with low socioeconomic status., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Brain metastases (BMs) are an uncommon presentation of metastatic colorectal cancer (mCRC) with reported incidence of about 2-4%. Today, there is an increased awareness towards a metastasis directed treatment approach with either surgical resection, stereotactic radiotherapy (SRT) or both. We examined patient characteristics and survival for patients treated with a localized modality for BM from CRC in a nationwide population-based study. Methods: A registry-based cohort study of all patients with a resected primary colorectal cancer and localized treatment of BM during 2000-2013. We computed descriptive statistics and analysed overall survival by the Kaplan-Meier method and Cox regression. Results: A total of 38131 patients had surgery for a primary CRC and 235 patients were recorded with a metastasis directed treatment for BM, comprising resection alone ( n  = 158), SRT alone ( n  = 51) and combined resection and SRT ( n  = 26). Rectal primary tumor (48.9% vs. 36.2%, p  < .001) and lung metastasectomy (11.9 vs 2.8%, p  < .001) were more frequent in the BM group. The median survival of patients receiving localized treatment for BM was 9.6 months (95% confidence interval (CI) 7.2-10.8). The 1- and 5-year overall survival were 41.7% (95% CI 35-48%) and 11.2% (95% CI 6.9-16.3%). In multivariate analysis, nodal stage was associated with increased mortality with a hazard ratio of 1.63 (95% CI 1.07-2.60, p  = .03) for N2 stage with reference to N0. Conclusion: We report a median overall survival of 9.6 months for patients receiving localized treatment for BM from CRC. Lung metastases and rectal primary tumor are more common in the population treated for BM.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia. Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia. Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8). Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Introduction: Small observational studies with short-term follow-up suggest that cancer patients are at reduced risk of Alzheimer's disease (AD) compared to the general population., Methods: A nationwide cohort study using Danish population-based health registries (1980-2013) with cancer patients (n = 949,309) to identify incident diagnoses of AD. We computed absolute reductions in risk attributed to cancer and standardized incidence rate ratios (SIRs) accounting for survival time, comparing the observed to expected number of AD cases., Results: During up to 34 years of follow-up of cancer survivors, the attributable risk reduction was 1.3 per 10,000 person-years, SIR = 0.94 (95% confidence interval 0.92-0.96). SIRs were similar after stratification by sex, age, and cancer stage, and approached that of the general population for those surviving >10 years., Discussion: Inverse associations between cancer and AD were small and diminished over time. Incidence rates in cancer survivors approached those of the general population, suggesting limited association between cancer and AD risk., (© 2020 the Alzheimer's Association.)

Background: Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear., Methods: Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970-2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases' birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs., Results: The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus <25 years: OR 0.48 (95% CI 0.23-0.98)]. The risk of SCSTs (but not GCTs) also decreased with shorter time since last birth. Number of births, preterm birth, preeclampsia, and offspring size were not associated with risk of SCSTs or GCTs., Conclusions: We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman's reproductive history.

Background: Whether the prognostic impact of comorbidity on myocardial infarction (MI) mortality is due to comorbidity alone or/and its interaction effect is unknown., Methods: We used Danish medical registries to conduct a nationwide cohort study of all first-time MIs during 1995-2016 (n = 179,515) and a comparison cohort matched on age, sex, and individual comorbidities (n = 880,347). We calculated age-standardized 5-year all-cause mortality rates. Interaction was examined on an additive scale by calculating interaction contrasts (difference in rate differences)., Results: Among individuals without comorbidity, the 30-day mortality rate per 1000 person-years was 1851 (95% CI: 1818-1884) for MI patients and 22 (21-24) for comparison cohort members (rate difference = 1829). For individuals with low comorbidity, corresponding baseline mortality rates were 2498 (2436-2560) in the MI and 54 (50-57) in the comparison cohort (rate difference = 2444). The interaction contrast (616) indicated that the interaction accounted for 25% (616/2498) of the total 30-day mortality rate in MI patients with low comorbidity. This percentage increased further for moderate (35%) and severe (45%) comorbidity levels. Absolute and relative interaction effects were largest within the first 30 days and younger individuals. Dose-response patterns were also observed during 31-365 days and 1-5 years of follow-up (p-values for trends<0.002). The interaction differed substantially between individual types of cardiac and non-cardiac comorbidities., Conclusion: Cardiac and non-cardiac comorbidities interact with MI to increase short- and long-term mortality beyond that explained by their additive effects. The interaction had a dose-response relation with comorbidity burden and a magnitude of clinical importance., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work. None of the authors has received any fees, honoraria, grants or consultancies that would constitute a conflict of interest with the current study. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of those studies has any relation to the present study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Obesity is associated with metabolic abnormalities that predispose patients to increased cancer risk. Contemporary data on the long-term risk of specific cancers are sparse among patients with hospital-diagnosed overweight and obesity., Objectives: To examine the overall cancer incidence and specific site-related cancer incidences among patients with overweight and obesity, compared to the general Danish population., Methods: For this 40-year (1977-2016), nationwide, Danish cohort study, we reviewed medical databases to identify individuals with hospital-based overweight and obesity diagnoses. We computed age- and gender-standardized incidence ratios (SIRs) for subsequent cancer compared to the general population., Results: We observed 20 706 cancers among 313 321 patients diagnosed with overweight and obesity (median age 43 years; median follow-up 6.7 years, range 1-40 years) compared to the 18 480 cancers expected; thus, the SIR was 1.12 [95% confidence interval (95% CI): 1.11-1.14]. The SIR associated with overweight and obesity was increased with concomitant comorbidities, like type 2 diabetes (SIR: 1.18; 95% CI: 1.13-1.23) and alcoholism-related diseases (SIR: 1.62; 95% CI: 1.45-1.82). The SIR was 1.31 (95% CI: 1.28-1.34) for cancers previously identified as obesity-related, including pancreatic (SIR: 1.38; 95% CI; 1.27-1.49) and postmenopausal breast cancer (SIR: 1.14; 95% CI: 1.09-1.19). Obesity/overweight status also elevated the SIRs for haematological (SIR: 1.24; 95% CI: 1.18-1.29) and neurological cancers (SIR: 1.19; 95% CI: 1.11-1.27]. In contrast, SIRs were 1.01 (95% CI: 0.97-1.05) for immune-related cancers, 0.88 (95% CI: 0.82-0.95) for malignant melanoma, and 0.88 (95% CI: 0.85-0.92) for hormone-related cancers, other than postmenopausal breast cancer., Conclusion: In this large cohort study, overweight and obesity was associated with increased risk of several common cancers., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Objectives: We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods., Study Design: We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18-49 years., Results: In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence., Conclusion: All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE., Implications: Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2020 The Authors.)

Objectives: To describe routine treatment and clinical characteristics of patients with chronic ITP (cITP). Methods: We used data from Danish nationwide registers and medical records to examine routine clinical care, including splenectomy and medical treatment, of Danish patients with chronic immune thrombocytopenia (cITP, defined as two or more ITP diagnoses at least 6 months apart), i.e. treatment initiation before cITP diagnosis and treatment initiation within one year post-diagnosis for treatment-naïve patients. Results: Nearly half of all 964 cITP patients diagnosed during 2009-2015 initiated treatment between initial ITP diagnosis and chronic onset; 43% received glucocorticoids, 12% received IVIG and 18% received rituximab. Within one year post-diagnosis, 9.2% of previously untreated patients commenced therapy, most often corticosteroids and rituximab. Discussion: Our results are in line with findings of recent studies from other countries. Conclusion: We found that corticosteroids, IVIG, and rituximab are common first- choice of ITP drugs. Bleeding events occurred in nearly one third of treated patients in the year before cITP diagnosis and in 5% of the treatment-naïve patients. A substantial number of patients do not need treatment during the first 6-12 months. However, some of these patients will subsequently need treatment as the disease may worsen, indicating the need for continuous follow-up of these patients.

The CHA 2 DS 2 -VASc score is used to predict stroke risk among patients with atrial fibrillation (AF). We examined whether a CHA 2 DS 2 -VASc score predicts stroke risk among individuals without hospital-diagnosed AF and quantified the magnitude of the association in comparison to AF patients. We used data from population-based medical registries (1995 to 2005) covering all Danish hospitals to identify patients diagnosed with AF (n = 122,980). We matched ≤5 non-AF individuals (n = 612,723) to each AF patient on the individual risk factors included in the CHA 2 DS 2 -VASc score. We calculated 10-year absolute risk of ischemic and all-cause stroke in AF and non-AF individuals and compared the stroke risk between cohorts within strata of CHA 2 DS 2 -VASc scores using Cox regression. The 10-year risk of ischemic/all-cause stroke was 4.4%/8.8% among non-AF individuals and 6.2%/12% in AF patients, corresponding to a risk difference of 1.8% for ischemic stroke and 3.3% for all-cause stroke. In both cohorts, the stroke risk correlated with increasing CHA 2 DS 2 -VASc scores. However, in individuals with CHA 2 DS 2 -VASc scores ≥5 who were <75 years or male, the absolute risk of ischemic stroke in individuals without AF exceeded the risk in AF patients. In the same subgroups, the hazard ratio approached unity. Similar results were observed for all-cause stroke. The CHA 2 DS 2 -VASc score was associated with 10-year stroke risk also among individuals without hospital-diagnosed AF. In conclusion, primary prophylactic anticoagulation therapy may be relevant in male and younger non-AF individuals with CHA 2 DS 2 -VASc scores ≥5. These findings should be confirmed in clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980-2012). The study included patients with dementia (n = 173,434) and with Parkinson's disease (n = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson's disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer's disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson's disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer's disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson's disease and cancer.

About 10-20% of patients with metastatic colorectal cancer (mCRC) are candidates for metastasis directed therapies such as surgical resection, ablation and stereotactic radiotherapy. We examined the temporal changes in use of metastasis directed therapies and established prognostic factors for survival in a nationwide cohort study. The Danish nationwide medical registries were used to retrieve data on treatment for liver and/or lung metastasis in patients with metastatic colorectal cancer in the period 2000-2013. Overall survival through 2014 was calculated from the time of treatment of metastases by Kaplan-Meier method and mortality between groups was assessed using Cox regression. We report 2,912 patients undergoing a total of 3,602 procedures with an increased use of all modalities during 14 calendar years. Median survival was 3.7 years (interquartile range (IQR) 2.0-9.7 years). In the multivariate analysis, the nodal stage of the primary tumor had the most pronounced association with survival with a hazard ratio for mortality of 1.56 (95% CI: 1.33-1.83) for N2 stage with reference to N0. Furthermore, female gender, age, comorbidity, surgical treatment, administration of chemotherapy, and left-sided primary tumors were associated with improved prognosis in the multivariate analysis., (© 2018 UICC.)

Importance: Data on the long-term risk of urologic and nonurologic cancer after hematuria diagnosis are sparse. Such data can improve understanding of hematuria and cancer and can provide insight into the clinical course of patients with hematuria., Objective: To assess the risk of urologic or nonurologic cancer after a hospital-based diagnosis of hematuria., Design, Setting, and Participants: This cohort study used population-based, nationwide health care databases covering all hospitals in Denmark. The data set included records of all adults (n = 134 173) with an inpatient, outpatient, or emergency department diagnosis of hematuria. The study was conducted from January 1, 1995, to December 31, 2013. Follow-up ended on December 31, 2013. Data analysis was performed from January 16, 2017, to September 18, 2018., Main Outcomes and Measures: Cumulative risk of cancer was computed, and observed cancer incidence was compared with incidence expected in the general population, using standardized incidence ratios., Results: Of the 134 173 patients included, 52 367 (39.0%) were women, 81 806 (61.0%) were men, and the median (interquartile range) age was 59 (44-72) years. Within 3 months after hematuria diagnosis, 2647 patients (1.9%) received an invasive bladder cancer diagnosis, 1077 (0.8%) a noninvasive bladder cancer diagnosis, 569 (0.4%) a kidney cancer diagnosis, and 908 (1.1%) a prostate cancer diagnosis. The 3-month cumulative incidence (or absolute risk) of any cancer diagnosis was 4.81% (95% CI, 4.70%-4.93%), the 1-year risk was 6.65% (95% CI, 6.51%-6.78%), and the 5-year risk was 12.34% (95% CI, 12.15%-12.53%). The cumulative incidence of bladder cancer only increased from 1.20% (95% CI, 1.11%-1.30%) after 1 year to 1.36% (95% CI, 1.26%-1.46%) after 5 years of follow-up in women and from 2.93% (95% CI, 2.82%-3.05%) to 3.31% (95% CI, 3.19%-3.44%) in men. For noninvasive bladder cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 5.39 (95% CI, 4.58-6.30) in patients without initial cystoscopy and was 0.16 (95% CI, 0.04-0.42) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. For kidney cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 2.63 (95% CI, 2.15-3.18) in patients without cystoscopy and 1.20 (95% CI, 0.87-1.61) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. After 1 year, the risk of gynecologic and colorectal cancers was as expected or even lower, whereas the risk of hematologic malignant neoplasms remained slightly elevated., Conclusions and Relevance: Increased risk of bladder and kidney cancers even more than 1 year after hospital-based hematuria diagnosis, as well as the slightly elevated risk of invasive bladder cancer after 5 years, may indicate that it is a marker of greater cancer risk; these findings could inform follow-up recommendations for hematuria.

Background: Substantial but inconclusive evidence suggests in utero exposure to influenza infection may be linked with Alzheimer's disease., Objectives: We examined whether individuals exposed in utero to the 1918 influenza pandemic are at increased risk of dementia., Patients/methods: In this cohort study, surveillance data were used to identify months when influenza activity was at its peak during the pandemic. Using birth dates, exposed and unexposed individuals were identified based on whether they were in utero during ≥1 of the peak months. The outcome, any type of dementia, was identified in population-based medical registries. Time and age at risk were restricted so exposed and unexposed had equal time at risk; diagnoses for dementia were assessed between ages 62 and 92, with a maximum of 30 years at risk. Poisson regression was used to estimate sex-adjusted incidence rate ratios (IRRs)., Results: We identified 106 479 exposed and 177 918 unexposed persons. Using the cumulative risk function, there were similar proportions of exposed and unexposed with a dementia diagnosis at 11.9% and 11.7%, respectively. Across all ages, the IRR for the association between in utero influenza exposure and any dementia was 1.01 (95% CI 0.99-1.04); for Alzheimer's disease, it was 0.97 (0.93-1.01). When stratified by age and sex, and when dementia type was examined, estimates of association were also null or close to null., Conclusions: Our study suggests there is likely not an association between in utero exposure to the 1918 influenza pandemic and dementia among those 62 and older., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence foetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial and possibly pancreatic cancer, whilst the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer, and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal aetiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, is expected to affect the incidence of pregnancy-associated cancer., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

This corrects the article DOI: 10.1038/bjc.2017.85.

Essentials Comorbidity is prevalent in the stroke population and affects post-stroke survival. A stroke patient cohort (n = 201 691) and a general population cohort were followed for survival. Cancer and advanced renal/liver disease substantially increased one-year stroke mortality. Tailoring stroke interventions according to comorbidity may reduce excess mortality., Summary: Background Comorbidity is prevalent among stroke patients, affecting post-stroke survival. It remains unknown whether comorbidity impacts post-stroke mortality beyond the combined individual effects of stroke and comorbidity. Methods Using nationwide Danish databases, we performed a cohort study of 201 691 patients ≥ 18 years old with incident ischemic stroke, intracerebral or subarachnoid hemorrhage, or unspecified stroke during 1995-2012, and 992 942 adults from the general population, matched to stroke patients by birth year, sex and individual comorbidities in the Charlson Comorbidity Index. During up to 5 years of follow-up, we computed standardized mortality rates (SMRs) to assess interaction contrasts as a measure of excess mortality not explained by the additive effects of stroke and comorbidity acting alone. Results Five-year post-stroke mortality was 48%, corresponding to an SMR of 187 deaths per 1000 person-years. During the 30-day peak post-stroke mortality (SMR, 180 per 1000 person-months), interaction with comorbidity represented 23%, 34% and 51% of post-stroke mortality rates among patients with low (score = 1), moderate (score = 2-3) and high (score = 4+) comorbidity based on Charlson Comorbidity Index scores. The interaction accounted for 5% to 32% of subsequent 31-365-day post-stroke mortality rates, depending on comorbidity level. The interaction contrasts were most notable among comorbid patients with cancer, particularly with hematological or metastatic disease, followed by patients with moderate-to-severe liver or renal disease. Conclusion Comorbidity, notably cancer and advanced renal or liver disease, increased 1-year mortality after stroke beyond the combined effects expected from either disease acting alone., (© 2017 International Society on Thrombosis and Haemostasis.)

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA 2 DS 2 VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Apolipoprotein D (ApoD) has been proposed as a predictor of breast cancer recurrence among estrogen receptor-positive (ER+), tamoxifen-treated patients., Methods: We conducted a population-based case-control study nested in a population of 11,251 women aged 35-69 years at diagnosis with Stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers cases among women with ER+ disease treated with tamoxifen for at least 1 year and 300 cases in women with ER- disease never treated with tamoxifen. We matched one control subject per case and assessed ApoD expression in the tumor cell nucleus and cytoplasm using tissue microarray immunohistochemistry. We computed the odds ratio (OR) associating ApoD expression with recurrence and adjusted for potential confounding using logistic regression., Results: Cytoplasmic ApoD expression was seen in 68% of ER+ tumors, in 66% of ER- tumors, and in 66% of controls across both groups. In women with ER+ tumors, the associations of cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% CI = 0.7 to 1.4) and increasing cytoplasmic expression with recurrence (OR = 1.0; 95% CI = 0.996 to 1.003) were null, as were those for women with ER- tumors. Associations for nuclear ApoD expression and combined nuclear and cytoplasmic expression were similarly near-null., Conclusion: ApoD expression is likely not a predictor of recurrence in tamoxifen-treated patients., Impact: This study eliminates the previously suggested marker ApoD as a predictor of recurrence among tamoxifen-treated women.