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Shahid Akhtar,1 Birgitte Berg,2 Johan Medina,3 Maya Nicole Gonczi,4 Sophie Hamilton,5 Emily Hildebrand,4 Nicky Kelepouris,6 Jesper Skov Neergaard,7 Claus Sværke,8 Gitte Ter-Borch,2 Niklas Kahr Rasmussen3 1Devices & Digital Health, Novo Nordisk A/S, Søborg, Denmark; 2Clinical Operations, Obesity, Liver Diseases & Devices, Novo Nordisk A/S, Søborg, Denmark; 3Medical & Science, Devices & Digital Health, Novo Nordisk A/S, Søborg, Denmark; 4Human Factors, Research Collective, Tempe, AZ, USA; 5Rare Endocrine Rare Renal Diseases, Novo Nordisk Inc, Plainsboro, NJ, USA; 6Rare Endocrine Disorders, Novo Nordisk Inc, Plainsboro, NJ, USA; 7Safety Surveillance, Cardiovascular Disease, Novo Nordisk A/S, Søborg, Denmark; 8Global Development, Novo Nordisk A/S, Søborg, DenmarkCorrespondence: Shahid Akhtar, Medical & Science, Devices & Digital Health, Novo Nordisk A/S, Vandtårnsvej 108– 110, Søborg, DK-2860, Denmark, Email SAHT@novonordisk.comPurpose: Adherence to growth hormone treatment is known to affect growth outcomes. Both device preference and ease of use have been shown to affect treatment adherence. In this study, we assessed device preference and ease of use with two long-acting growth hormones, somapacitan (Sogroya®, Novo Nordisk A/S) and somatrogon (Ngenla®, Pfizer).Patients and Methods: In a randomized, crossover study conducted between September 20 and November 2, 2023, we recruited 33 adolescents with a growth-related disorder, and 37 caregivers, at six locations in the United States. Each participant was trained in the use of both devices and asked to perform a simulated injection. Device training time, preparation and injection time, and injection completeness were recorded. Participants also completed the Device Handling and Preference Questionnaire (DHPAQ) to indicate their device preference and ease of use opinions. Following conclusion of the “standard” visit, 10 adolescents and 10 caregivers were randomly selected to participate in a sub-study to validate the relevance, comprehensiveness, and comprehension of the DHPAQ.Results: The majority of participants (84.3%; 95% confidence interval [CI]: 74;92) preferred the somapacitan device to the somatrogon device (p

Karoline Skov Dalgaard,1 Henrik Gammelager,1 Claus Sværke,1 Tamás Kurics,1 Karynsa Cetin,2 Christian Fynbo Christiansen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA Objective: Skeletal-related events (SREs) among patients with bone metastases from lung cancer may be associated with considerable use of health care resources. We analyzed in- and outpatient hospital contacts in relation to SREs among all Danish lung cancer patients with bone metastases. Methods: For this cohort study, we used the Danish Cancer Registry and the Danish National Registry of Patients to identify all persons diagnosed with first-time lung cancer and bone metastases from 2003 through 2009 in Denmark. We followed these patients until December 31, 2010, for the development of SREs (spinal cord compression; pathological or osteoporotic fracture, surgery to bone; or conventional external radiation therapy). We examined the number of inpatient hospitalizations, inpatient bed-days, hospital outpatient clinic visits, and emergency room visits within three time periods: a pre-SRE period (90-day period prior to the diagnostic period), a SRE diagnostic period (14-day period prior to the SRE), and a post-SRE period (90-day period after the SRE). Results: We identified 1,146 patients with lung cancer, bone metastases, and ≥1 subsequent SRE among 28,443 patients with incident lung cancer. Over 75% of patients with SREs (n=852) had more than one SRE. The number of hospital bed-days was high in the post-SRE period compared to the pre-SRE period, as illustrated by patients with multiple SREs who had 10.7 (95% confidence interval, 10.4–10.9) hospital bed-days per 100 person-days in the pre-SRE period and 28.2 (95% confidence interval, 27.8–28.6) bed-days per 100 person-days in the post-SRE period. Conclusion: SREs secondary to bone metastases in lung cancer patients are associated with a substantial number of hospital contacts and hospital bed-days. Keywords: hospital services, lung neoplasm, utilization

Henrik Gammelager,1 Claus Sværke,1 Sven Erik Noerholt,2 Bjarne Neumann-Jensen,3 Fei Xue,4 Cathy Critchlow,4 Johan Bergdahl,5 Ylva Trolle Lagerros,5 Helle Kieler,5 Grethe S Tell,6 Vera Ehrenstein11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark; 3Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Aalborg, Denmark; 4Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA; 5Center for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 6Department of Global Public Health and Primary Care, University of Bergen, Bergen, NorwayBackground: Osteonecrosis of the jaw (ONJ) is an adverse effect of drugs that suppress bone turnover – for example, drugs used for the treatment of postmenopausal osteoporosis. The Danish National Registry of Patients (DNRP) is potentially valuable for monitoring ONJ and its prognosis; however, no specific code for ONJ exists in the International Classification of Diseases 10th revision (ICD-10), which is currently used in Denmark. Our aim was to estimate the positive predictive value (PPV) of an algorithm to capture ONJ cases in the DNRP among women with postmenopausal osteoporosis.Methods: We conducted this cross-sectional validation study in the Central and North Denmark Regions, with approximately 1.8 million inhabitants. In total, 54,956 women with postmenopausal osteoporosis were identified from June 1, 2005 through May 31, 2010. To identify women potentially suffering from ONJ, we applied an algorithm based on ICD-10 codes in the DNRP originating from hospital-based departments of oral and maxillofacial surgery (DOMS). ONJ was adjudicated by chart review and defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of recorded history of craniofacial radiation therapy. We estimated the PPV for the overall algorithm and for each separate ICD-10 code used in the algorithm.Results: Charts were obtained and reviewed for all 60 women with an ICD-10 code potentially representing ONJ. Nineteen potential ONJ cases were confirmed, corresponding to an overall PPV of 32% (95% confidence interval: 20%–45%).Conclusion: Among women with postmenopausal osteoporosis, only about one-third of the potential ONJ cases identified by our ICD-10 based algorithm were confirmed by medical chart review, despite the restriction to patients treated at DOMS. To capture true ONJ cases among women with postmenopausal osteoporosis, alternative approaches are needed.Keywords: bisphosphonate-associated osteonecrosis of the jaw, International Classification of Diseases, osteonecrosis of the jaw, osteoporosis, registries, validity

Marie Louise Svendsen,1 Henrik Gammelager,1 Claus Sværke,1 Mellissa Yong,2 Victoria M Chia,2 Christian F Christiansen,1 Jon P Fryzek1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research, Amgen, Thousand Oaks, CA, USA Objective: Skeletal-related events (SREs) among women with breast cancer may be associated with considerable use of health-care resources. We characterized inpatient and outpatient hospital visits in a national population-based cohort of Danish women with SREs secondary to breast cancer and bone metastases. Methods: We identified first-time breast cancer patients with bone metastases from 2003 through 2009 who had a subsequent SRE (defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone). Hospital visits included the number of inpatient hospitalizations, length of stay, number of hospital outpatient clinic visits, and emergency room visits. The number of hospital visits was assessed for a pre-SRE period (90 days prior to the diagnostic period), a diagnostic period (14 days prior to the SRE), and a post-SRE period (90 days after the SRE). Patients who experienced more than one SRE during the 90-day post-SRE period were defined as having multiple SREs and were followed until 90 days after the last SRE. Results: We identified 569 women with SREs secondary to breast cancer with bone metastases. The majority of women had multiple SREs (73.1%). A total of 20.9% and 33.4% of women with single and multiple SREs died in the post-SRE period, respectively. SREs were associated with a large number of hospital visits in the diagnostic period, irrespective of the number and type of SREs. Women with multiple SREs generally had a higher number of visits compared to those with a single SRE in the post-SRE period, eg, median length of hospitalization was 5 days (interquartile range 0–15) for women with a single SRE and 13 days (interquartile range 4–30) for women with multiple SREs. Conclusion: SREs secondary to breast cancer and bone metastases were associated with substantial use of hospital resources. Keywords: breast neoplasms, bone metastases, skeletal-related events, hospital services, utilization

Study Design and Objective: Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses., Methods: Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18-45 years and body mass index 18.5-24.9 kg/m 2 . Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC 0-t ), maximum serum concentration (C max ), time to C max and terminal half-life of somapacitan and safety were assessed., Results: In total, 33 participants were randomised. For AUC 0-t , estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90% CIs were within the acceptance range (0.80-1.25). For C max , ETR was 0.77 (90% CI 0.68-0.89). Point estimate and 90% CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified., Conclusions: Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC 0-t but not for C max . The two strengths had equivalent IGF-I responses., Trial Registration: ClinicalTrials.gov, NCT03905850 (3 April 2019)., (© 2024. The Author(s).)

Purpose: The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD., Methods: In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan)., Results: No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-β did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters., Conclusions: Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017)., (© 2022. The Author(s).)

Context: Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD)., Objective: To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD., Design: Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851)., Setting: Clinics in 17 countries., Patients: Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial., Interventions: Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH., Main Outcome Measures: Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate., Results: At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: -1.53% [-2.68; -0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH., Conclusions: In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1)., (© Endocrine Society 2020.)

Background: An elevated erythrocyte sedimentation rate (ESR) may be a marker of occult cancer., Methods: We linked Danish medical databases to examine cancer incidence in patients with a first-time hospital contact for elevated ESR during 1980 to 2013. We calculated standardized incidence ratios (SIR) of cancer compared with the general population, and comorbidity-adjusted HRs (aHR) versus matched population comparisons without elevated ESR. We also compared survival among patients with cancer with elevated ESR with that among patients with cancer without elevated ESR., Results: During median follow-up of 4.9 years, we observed 3,926 cancers among 18,540 patients with a first-time hospital contact for elevated ESR. The risk for any cancer diagnosed during the first year following the contact for elevated ESR was 8.5% [95% confidence interval (CI), 8.1%-8.9%]. The overall 1-year cancer incidence was markedly elevated [SIR 5.3 (95% CI, 5.1-5.6); aHR 5.8 (95% CI, 5.4-6.3)] and was more than 3-fold elevated for most hematologic cancers and for cancers of the peritoneum and connective tissue in the abdominal wall, kidney, and adrenal glands. After the first year, patients were at increased risk of developing especially hematologic cancers. Patients diagnosed with cancer within 1 year after a contact for elevated ESR had poorer survival compared with matched cancer comparisons [adjusted mortality rate ratio 1.2 (95% CI, 1.1-1.3)]., Conclusions: Elevated ESR is a strong marker of undiagnosed cancer and is associated with poorer survival., Impact: Our findings may help clinicians in assessing absolute risk, common sites, and prognosis of cancers discovered after hospital contact with elevated ERS., (©2018 American Association for Cancer Research.)

Background: Deficits in information processing may be a core deficit after fetal alcohol exposure. This study was designed to investigate the possible effects of weekly low to moderate maternal alcohol consumption and binge drinking episodes in early pregnancy on choice reaction time (CRT) and information processing time (IPT) in young children., Method: Participants were sampled based on maternal alcohol consumption during pregnancy. At the age of 60-64 months, 1,333 children were administered a modified version of the Sternberg paradigm to assess CRT and IPT. In addition, a test of general intelligence (WPPSI-R) was administered., Results: Adjusted for a wide range of potential confounders, this study showed no significant effects of average weekly maternal alcohol consumption during pregnancy on CRT or IPT. There was, however, an indication of slower CRT associated with binge drinking episodes in gestational weeks 1-4., Conclusion: This study observed no significant effects of average weekly maternal alcohol consumption during pregnancy on CRT or IPT as assessed by the Sternberg paradigm. However, there were some indications of CRT being associated with binge drinking during very early pregnancy. Further large-scale studies are needed to investigate effects of different patterns of maternal alcohol consumption on basic cognitive processes in offspring.

Purpose: This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients., Methods: We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011., Results: We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%])., Conclusions: The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Nephrotic syndrome may be a marker of occult cancer, but population-based studies of this association are lacking. Therefore, we examined the risk and prognosis of cancer in patients with nephrotic syndrome., Methods: We conducted this population-based cohort study in Denmark, including all individuals diagnosed with nephrotic syndrome between 1980 and 2010 without a preceding cancer history. We computed the 5-year risk of cancer accounting for competing risk by death and standardized incidence ratios (SIRs) of cancer in patients with nephrotic syndrome relative to the general population. We compared the 5-year mortality for patients with cancer after nephrotic syndrome with that for a cancer cohort without a history of nephrotic syndrome using Cox regression adjusted for age, gender, and comorbidity., Results: Of 4293 individuals with nephrotic syndrome, 338 developed an incident cancer during a median follow-up of 5.7 years. The 5-year risk of any cancer was 4.7% in patients with nephrotic syndrome, a 73% increased risk (SIR, 1.73; 95% confidence interval [CI], 1.55-1.92). The association was most pronounced for lung cancer, kidney cancer, lymphoma, and multiple myeloma. It was highest within 1 year of nephrotic syndrome diagnosis (SIR, 4.49; 95% CI, 3.68-5.42), but remained increased beyond 1 year (SIR, 1.34; 95% CI, 1.17-1.53). The 5-year mortality after cancer was 68.5% in patients with cancer with nephrotic syndrome and 63.4% in the cancer comparison cohort (adjusted hazard ratio, 1.20; 95% CI, 1.02-1.42)., Conclusions: Nephrotic syndrome is a marker of occult solid tumors and hematologic malignancies and is associated with a worsened cancer prognosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Pharmacovigilance studies of cancer treatment frequently monitor infections. Predictive values of algorithms identifying disease depend on prevalence of the disease in the population under study. We therefore estimated the positive predictive value (PPV) of primary inpatient diagnosis of infection among cancer patients in the Danish National Registry of Patients (DNRP)., Methods: The algorithm to identify infections in the DNPR was based on International Classification of Diseases, 10th revision (ICD-10) codes. A physician blinded to the type of sampled infection reviewed the medical charts and assessed the presence and type of infection. Using the physician global assessment as gold standard, we computed PPVs with and without requiring agreement on infection type., Results: We retrieved 266 of 272 medical charts (98%). Presence of infection was confirmed in 261 patients, resulting in an overall PPV of 98% (95% confidence interval, 96%-99%). When requiring agreement on infection type, overall PPV was 77%. For skin infections, pneumonia, and sepsis, PPVs were 79%, 93% and 84%, respectively. For these infections, we additionally calculated PPVs using evidence-based criteria as the gold standard. PPV was similar for pneumonia, but lower for skin infections and sepsis., Conclusions: The Danish National Registry of Patients is suitable for monitoring infections requiring hospitalization among cancer patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Chronic obstructive pulmonary disease (COPD) may increase the risk of postoperative complications and thus mortality after colorectal cancer (CRC) surgery, but the evidence is sparse., Methods: We conducted this nationwide population-based cohort study in Denmark, including all patients undergoing CRC surgery in the period 2005-2011, identified through medical databases. We categorised the patients according to the history of COPD. We assessed the rate of complications within 30 days. We computed 30-day mortality among patients with/without COPD using the Kaplan-Meier method. We used Cox regression to compute HRs for death, controlling for age, gender, type of admission, cancer stage, hospital volume, alcohol-related diseases, obesity and Charlson comorbidity score., Results: We identified 18 302 CRC surgery patients. Of these, 7.9% had a prior diagnosis of COPD. Among patients with COPD, 16.1% were admitted postoperatively to the intensive care unit, 1.9% were treated with mechanical ventilation, and 3.6% were treated with non-invasive ventilation. In patients without COPD, the corresponding proportions were 9.7%, 1.1% and 1.1%. The reoperation rate was 10.6% among patients with COPD and 8% among patients with cancer without COPD. 30-day mortality was 13% (95% CI 11.4% to 14.9%) among patients with COPD and 5.3% (95% CI 5.0% to 5.7%) among patients without COPD, corresponding to an adjusted HR of 1.7 (95% CI 1.5 to 2.0)., Conclusions: COPD is a strong predictor for intensive care unit admission and mortality after CRC surgery.

Objective: We aimed to assess cancer risk in congenital heart defect patients, with and without Down's syndrome, compared with the general population., Methods: We identified all patients born and diagnosed with congenital heart defects from 1977 to 2008 using the Danish National Registry of Patients, covering all Danish hospitals. We compared cancer incidence in the congenital heart defect cohort with that expected in the general population (∼5.5 million) using the Danish Cancer Registry, and computed age- and gender-standardised incidence ratios., Results: We identified 15,905 congenital heart defect patients, contributing a total of 151,172 person-years at risk; the maximum length of follow-up was 31 years (median 8 years). In all, 53 patients were diagnosed with cancer, including 30 female and 23 male patients (standardised incidence ratio = 1.63; 95% confidence interval: 1.22-2.13). Risks were increased for leukaemia, brain tumours, and basal cell carcinoma. After excluding 801 patients with Down's syndrome, the standardised incidence ratio was 1.19 (95% confidence interval: 0.84-1.64). In the subgroup of 5660 non-Down's syndrome patients undergoing cardiac surgery or catheter-based interventions, the standardised incidence ratio was 1.45 (95% confidence interval: 0.86-2.29)., Conclusion: The overall risk of cancer among congenital heart defect patients without Down's syndrome was not statistically significantly elevated. Cancer risk in the congenital heart defect cohort as a whole, including patients with Down's syndrome, was increased compared with the general population, although the absolute risk was low. Studies with longer follow-up and more information on radiation doses are needed to further examine a potential cancer risk associated with diagnostic radiation exposure.

Background: An association between colorectal cancer and acute myocardial infarction (AMI) and stroke has been suggested, but evidence is conflicting., Method: We conducted a population-based cohort study (1978-2010) of the association between AMI/stroke and colorectal cancer by linking nationwide Danish registries. We calculated standardized incidence ratios (SIR) of colorectal cancer after AMI/stroke as the ratios of observed to expected incidence., Results: A total of 297,523 patients with AMI (median age, 69.4 years; 64% men) were followed for a median of 3.1 years (range, 0-33 years) and 4,387 developed colorectal cancer [SIR, 1.08; 95% confidence interval (CI), 1.05-1.11; P < 0.001]. In the first year of follow-up, the SIR was 1.85 (95% CI, 1.73-1.98; P < 0.001), whereas it was 0.98 (95% CI, 0.95-1.02; P = 0.318) in the second and subsequent years. We followed 246,998 patients with stroke (median age, 72.4 years; 52% men) for a median of 2.9 years (range, 0-33 years) and 3,035 developed colorectal cancer (SIR, 1.04; 95% CI, 1.00-1.07; P = 0.053). In the first year of follow-up, the SIR was 1.42 (95% CI, 1.31-1.53; P < 0.001), whereas it was 0.96 (95% CI, 0.93-1.00; P = 0.072) thereafter. We found no difference between the SIRs for ischemic and hemorrhagic stroke. The increased one-year relative risks for AMI and stroke corresponded to a 0.3% absolute risk., Conclusions: Our findings reflect detection of occult cancer at the time of the vascular event. The lack of increased risk after one year suggests that an association based on shared risk factors or chronic inflammation is unlikely., Impact: In patients with AMI/stroke, the diagnostic workup including screening for colorectal cancer should follow that of the general population., (©2013 AACR.)

Enlarged lymph nodes may be a marker of occult cancer, but accurate data on cancer risk are limited. We used population-based Danish medical registries to assess cancer risk in a cohort of patients with a first-time inpatient or outpatient hospital contact for enlarged lymph nodes during 1994-2008. Observed cancer incidences were compared with that expected in the general population. We observed 1750 cancers among 11284 patients with enlarged lymph nodes during median follow up of 4.7 years. Only 389 cases were expected. Cancer risk was 11.5% [95% confidence interval (CI): 10.9-12.1%] during the first year of follow up, corresponding to an age- and sex-standardized incidence ratio (SIR) of 21.1 (95% CI: 20.0-22.3). One-year SIRs were more than 100 times increased for head and neck cancer and lymphomas. Beyond one year of follow up, overall cancer risk remained 1.4-fold (95% CI: 1.3-1.5-fold) higher than expected, while risk of lymphoma remained six to 10 times higher. Cancer risk was also elevated among patients with other conditions known to be associated with enlarged lymph nodes, such as infections and rheumatic disorders. We conclude that enlarged lymph nodes are a marker of occult cancer and long-term risk of cancer., (© 2012 Blackwell Publishing Ltd.)

Background: Endocarditis may be a marker for bacteremia-associated occult cancer. Intensive antibiotic treatment in endocarditis is suggested to reduce long-term cancer risk. We examined these hypotheses in a nationwide cohort study., Methods: Endocarditis patients and cancer cases were identified from the Danish National Registry of Patients and the Danish Cancer Registry during 1978-2008. We compared the incidences of various cancers among study subjects to expected incidences based on national age-, sex-, and site-specific rates., Results: We observed 997 cancers among 8445 endocarditis patients (median follow-up of 3.5 years), reflecting an increased standardized incidence rate (SIR) of 1.61 (95% confidence interval [CI], 1.51-1.71). Cancer risk was highly elevated during the first 3 months of follow-up (SIR=8.03; 95% CI, 6.92-9.26), partly due to a 15- to 30-fold increased risk of hematological or liver cancers. Between 3-month and 5-year follow-ups, cancer incidence remained 1.5-fold higher than expected, including 2- and 4-fold increased SIRs for colorectal and liver cancers, respectively. Beyond 5 years of observation, the overall cancer SIR was 1.21 (95% CI, 1.10-1.34). Long-term associations were weak for several cancers hypothesized to be associated with antibiotic use, including prostate, gastric, and breast cancer., Conclusion: Endocarditis is a substantial clinical marker for presence of occult cancer. We found no evidence of decreased long-term cancer risk after antibiotic treatment for endocarditis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) may be a harbinger of cancer. Inflammatory bowel disease (IBD) is known to increase the risk of VTE, but it is unclear whether VTE in IBD patients is also a marker for occult cancer. We assessed the risk of cancer after VTE in IBD patients., Methods: We conducted a population-based cohort study by linking Danish medical registries during 1978-2008. We calculated standardized incidence ratios (SIRs) by comparing observed cancer incidence after VTE in IBD patients with that expected based on national cancer incidence in the Danish population., Results: A total of 895 IBD patients with VTE were followed for a total of 5290 person-years. During the first year of follow-up, 28 (3.1%) patients were diagnosed with cancer, corresponding to an SIR of 3.2 (95% confidence interval [CI]: 2.2, 4.7). Patients with ulcerative colitis or Crohn's disease had similar relative risks (SIR = 3.1 [95% CI: 1.9, 4.9] and SIR = 3.5 [95% CI: 1.7, 6.3], respectively). In IBD patients <55 years the SIR was 5.7 (95% CI: 2.3, 11.8) and in patients ≥55 years the SIR was 2.8 (95% CI: 1.8, 4.3). During the second and subsequent years of follow-up 61 cancers were diagnosed (SIR = 1.2 [95% CI: 0.92, 1.6])., Conclusions: In patients with IBD a VTE event is not only a consequence of their disease, but might also be a marker of occult cancer. We suggest that IBD patients with VTE should follow the same diagnostic work-up guidelines as non-IBD VTE patients., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Objective: The aim was to examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on children's attention at 5 years of age., Design: Prospective follow-up study., Setting: Neuropsychological testing in four Danish cities 2003-2008., Population: A cohort of 1628 women and their children sampled from the Danish National Birth Cohort., Methods: Participants were sampled based on maternal alcohol consumption during pregnancy. At 5 years of age, the children were tested with the recently developed Test of Everyday Attention for Children at Five (TEACh-5). Parental education, maternal IQ, maternal smoking in pregnancy, the child's age at testing, gender, and tester were considered core confounding factors, whereas the full model also controlled the following potential confounding factors: maternal binge drinking or low to moderate alcohol consumption, age, body mass index (BMI), parity, home environment, postnatal smoking in the home, child's health status, and indicators for hearing and vision impairments., Main Outcome Measures: TEACh-5 attention scores., Results: There were no significant effects on test performance in children of mothers drinking up to 8 drinks per week compared with children of mothers who abstained, but there was a significant association between maternal consumption of 9 or more drinks per week and risk of a low overall attention score (OR 3.50, 95% CI 1.15-10.68). No consistent or significant associations were observed between binge drinking and attention test scores., Conclusions: The findings suggest an effect of maternal consumption of 9 or more drinks per week on attention functions in children, but the study detected no effects of lower levels of maternal consumption and no consistent effects of maternal binge drinking., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Introduction: Little is known about the risk of cancer in patients with chronic obstructive pulmonary disease (COPD), including which cancer sites are most affected. We examined the short- and long-term risk of lung and extrapulmonary cancer in a nationwide cohort of COPD patients., Methods: We linked the Danish National Registry of Patients and the nationwide cancer registry, and examined the incidence of various cancers in 236,494 individuals with a first incident hospital contact with COPD during 1980-2008. The observed cancer incidence in this cohort was compared with the expected incidence in the general population on the basis of national age-, sex-, and site-specific incidence rates., Results: Median follow-up was 3.5 years. During the first year of follow-up, 9434 cancers were diagnosed in COPD patients [standardized incidence ratio (SIR) = 3.1; 95% CI 3.0 to 3.2]. The 1-year SIR was 8.5 (8.2-8.9) for lung cancer, 5.1 (5.0-5.2) for all tobacco-related cancers, and 1.9 (1.9-2.0) for other cancers. In the following years, cancer incidence was increased 1.4-fold (1.4-1.5) in COPD patients. These patients had an increased risk of developing tobacco-related cancers (SIR = 2.1; 95% CI 2.0-2.1), including cancers of the lung, larynx, tongue, oral cavity, pharynx, esophagus, stomach, liver, pancreas, cervix uteri, and urinary tract (with SIRs ranging between 1.3 and 2.8)., Conclusions: Patients with first-time hospital-diagnosed COPD are at considerably increased risk of developing both lung cancer and extrapulmonary cancers. Physicians should be aware of cancer in COPD patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this investigation was to assess 30-day mortality among Danish inflammatory bowel diseases (IBD) patients and to examine the prognostic impact of hospital total colectomy volume, age, gender and comorbidity., Design: Cohort study., Setting: The authors compared 30-day survival over the period 1996-2010 among 2889 IBD patients with total colectomy identified in the Danish National Registry of Patients. This registry covers all hospitals in Denmark. Postoperative survival patterns for patients with ulcerative colitis and Crohn's disease were compared, using proportional hazard regression. The regression model accounted for the timing of surgery, hospital total colectomy volume, age, gender and comorbidity., Participants: Patients were enrolled in the study if they had a hospital registry diagnosis of IBD, with accompanying procedure codes for total colectomy (see codes in online appendix table 1). Hospitalisations were described as elective or emergency, and patients were categorised as having Crohn's disease, ulcerative colitis or as a mixed group., Outcome Measures: Primary outcome measure was 30-day mortality., Results: Among 2889 IBD patients with total colectomy, 1439 (50%) underwent surgery during an emergency hospitalisation. Thirty-day mortality was 5.3% (76/1439) among emergency cases compared with 1% (14/1450) among elective cases. The highest mortality (8.1%; 11 of 136) was observed among Crohn's patients undergoing emergency surgery. The mortality of patients with ulcerative colitis undergoing emergency surgery was 5.2% (55/1056). After elective surgery, the 30-day mortality was 0.9% (8/938) among patients with ulcerative colitis and 1.5% (3/201) among Crohn's disease patients. Low hospital total colectomy volume, comorbidity and high age were associated with increased 30-day mortality in ulcerative colitis patients undergoing emergency surgery., Conclusion: Emergency total colectomy among patients with ulcerative colitis and particularly Crohn's disease is associated with substantial 30-day mortality.

Background: In contrast to deep venous thrombosis and pulmonary embolism, superficial venous thrombosis has not been considered to be a marker of occult cancer. However, actual data regarding the association are very limited., Methods: We identified all patients in Denmark from 1994 to 2009 with a diagnosis of superficial venous thrombosis, deep venous thrombosis in the legs or pulmonary embolism using population-based health registries. The occurrence of cancer in the three venous thromboembolism cohorts was compared with the expected numbers of cases estimated using national incidence rates to compute standardised incidence ratios (SIRs)., Findings: We identified a total of 7663 patients with superficial venous thrombosis, 45,252 with deep venous thrombosis and 24,332 with pulmonary embolism. In the first year of follow-up, very similar proportions of patients in the three cohorts were diagnosed with cancer. The SIR was 2.46 (95% CI, 2.10-2.86) for superficial venous thrombosis, 2.75 (95% CI, 2.60-2.90) for deep venous thrombosis, and 3.27 (95% CI, 3.03-3.52) for pulmonary embolism. After one year, the SIRs declined to 1.05 (95% CI, 0.96-1.16), 1.11 (95% CI 1.07-1.16) and 1.15 (95% CI, 1.09-1.22), respectively. For all three patient cohorts, particularly strong associations were found for cancers of the liver, lung, ovaries and pancreas as well as for non-Hodgkin's lymphoma., Interpretation: Venous thrombosis, whenever it is seen in the lower limbs, is a preclinical marker of prevalent cancer, particularly during the first year after diagnosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Recent data suggest a reduced risk of malignant melanoma (MM) among atopic dermatitis (AD) patients, but an increased risk of other skin cancers (including basal cell carcinoma [BCC] and squamous cell carcinoma [SCC])., Objective: We examined the association between AD and skin cancers in a large cohort study in Denmark from 1977 through 2006., Methods: Our cohort consisted of 31 330 AD patients recorded in the Danish National Patient Registry, including AD patients admitted to hospitals and specialized outpatient clinics. Linkage to the Danish Cancer Registry allowed ascertainment of skin cancers. We calculated standardized incidence ratios (SIRs) and associated 95% confidence intervals (CIs) by comparing the incidence rate of skin cancers among AD patients with that among the general Danish population., Results: The overall observed number of MM cases among AD patients was 12, with 21 expected, yielding a SIR of 0.59 (95% CI 0.30, 1.02), with the most pronounced protective effect among AD patients with more than 5 years of follow-up (SIR = 0.46; 95% CI 0.19, 0.95). The corresponding SIRs for BCC and SCC were increased among AD patients (1.41 [95% CI 1.07, 1.83] and 2.48 [95% CI 1.00, 5.11], respectively)., Conclusions: Our findings support an inverse association between AD and MM, but an increased risk of BCC and SCC among AD patients.

Objective: To investigate fetal or neonatal inflammatory patterns based on 25 inflammatory markers in neonatal dried blood spots samples from infants born preterm and term, collected several days after birth., Methods: Dried blood spots samples from 160 neonates were analyzed for 25 inflammatory markers using multiplex technology: 26 neonates born very preterm (before 32 weeks of gestation), drawn at a mean 6 days (95% confidence interval [CI], 5-7 days) after birth; 52 born preterm (32-36 weeks of gestation), drawn at mean 5 days (95% CI, 5-6 days) after birth; and 82 born at term (at or after 37 weeks of gestation), drawn at mean 5 days (95% CI, 5-5 days) after birth. Markers statistically significantly associated with preterm birth were analyzed in a multivariable model together with maternal and neonatal risk factors for preterm birth., Results: Elevated levels of interleukin (IL)-1beta, IL-6, soluble IL-6ralpha, IL-8, matrix metalloproteinase-9, and transforming growth factor-beta1 and decreased levels of IL-18, brain-derived neurotrophic factor, and C-reactive protein were associated with preterm birth. Maternal risk factors could explain only an increase of IL-1beta, whereas neonatal factors could explain several of the elevated and decreased inflammatory markers in the dried blood spots samples from the infants born preterm compared with the infants born at term., Conclusion: The differences in levels of inflammatory markers in dried blood spots samples from infants born preterm compared with infants born at term supports the hypothesis that inflammation of fetal origin might be a cause of preterm birth., Level of Evidence: II.