Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02607865.

Pharmacokinetic and Pharmacodynamic Properties of Faster-Acting Insulin Aspart versus Insulin Aspart Across a Clinically Relevant Dose Range in Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: Absorption of current rapid-acting insulins is too slow for patients with diabetes mellitus to achieve optimal postprandial glucose control. Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with faster early absorption. We compared the pharmacokinetic/pharmacodynamic properties of faster aspart and insulin aspart across a clinically relevant dose range. METHODS: In this randomised, double-blind, crossover trial, 46 subjects with type 1 diabetes mellitus received single subcutaneous doses of faster aspart and insulin aspart at 0.1, 0.2 (repeated three times to estimate within-subject variability) and 0.4 U/kg in a euglycaemic clamp setting (target 5.5 mmol/L). RESULTS: Consistently for the three doses, faster aspart demonstrated faster onset and greater early absorption and glucose-lowering effect versus insulin aspart. Across all three doses, onset of appearance occurred approximately twice as fast (approximately 5 min earlier) and early insulin exposure (AUCIAsp,0-30min) was approximately 1.5- to 2-fold greater for faster aspart versus insulin aspart. Likewise, onset of action occurred approximately 5 min faster and early glucose-lowering effect (AUCGIR,0-30min) was approximately 1.5- to 2-fold larger for faster aspart versus insulin aspart. Relative bioavailability was approximately 100% and total glucose-lowering effect was similar for faster aspart versus insulin aspart. Dose-concentration and dose-response relationships were comparable between faster aspart and insulin aspart. Within-subject variability in glucose-lowering effect was low for faster aspart (coefficient of variation approximately 20%) and not significantly different from insulin aspart. CONCLUSION: The faster onset and greater early insulin exposure and glucose-lowering effect with faster aspart versus insulin aspart are preserved across a broad range of doses and consistently observed from day to day. CLINICALTRIALS. GOV IDENTIFIER: NCT02033239.

A Comparison of Pharmacokinetic and Pharmacodynamic Properties Between Faster-Acting Insulin Aspart and Insulin Aspart in Elderly Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: Due to population aging, an increasing number of elderly patients with diabetes use insulin. It is therefore important to investigate the characteristics of new insulins in this population. Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with faster absorption. This study investigated the pharmacological properties of faster aspart in elderly subjects with type 1 diabetes mellitus (T1DM). METHODS: In a randomised, double-blind, two-period crossover trial, 30 elderly (≥65 years) and 37 younger adults (18-35 years) with T1DM received single subcutaneous faster aspart or IAsp dosing (0.2 U/kg) and underwent an euglycaemic clamp (target 5.5 mmol/L) for up to 12 h. RESULTS: The pharmacokinetic and pharmacodynamic time profiles were left-shifted for faster aspart versus IAsp. In each age group, onset of appearance occurred approximately twice as fast (~3 min earlier) and early exposure (area under the concentration-time curve [AUC] for serum IAsp from time zero to 30 min [AUCIAsp,0-30 min]) was greater (by 86% in elderly and 67% in younger adults) for faster aspart than for IAsp. Likewise, onset of action occurred 10 min faster in the elderly and 9 min faster in younger adults, and early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 30 min [AUCGIR,0-30 min]) was greater (by 109%) for faster aspart than for IAsp in both age groups. Total exposure (AUCIAsp,0-t) and the maximum concentration (C max) for faster aspart were greater (by 30 and 28%, respectively) in elderly than in younger adults. No age group differences were seen for the total (AUCGIR,0-t) or maximum (GIRmax) glucose-lowering effect. CONCLUSION: This study demonstrated that the ultra-fast pharmacological properties of faster aspart are similar in elderly subjects and younger adults with T1DM. ClinicalTrials.gov Identifier: NCT02003677.

Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval.

OBJECTIVES: Since population-based data on prognostic factors affecting survival in patients with breast cancer with bone metastasis (BM) are currently limited, we conducted this nationwide retrospective cohort study to examine the prognostic role of disease stage at breast cancer diagnosis and length of BM-free interval (BMFI). SETTING: Denmark. PARTICIPANTS: 2427 women with a breast cancer diagnosis between 1997 and 2011 in the Danish Cancer Registry and a concurrent or subsequent BM diagnosis in the Danish National Registry of Patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Survival (crude) based on Kaplan-Meier method and mortality risk (crude and adjusted for age, year of diagnosis, estrogen receptor status and comorbidity) based on Cox proportional hazards regression analyses by stage of disease at breast cancer diagnosis and by length of BMFI (time from breast cancer to BM diagnosis), following patients from BM diagnosis until death, emigration or until 31 December 2012, whichever came first. RESULTS: Survival decreased with more advanced stage of disease at the time of breast cancer diagnosis; risk of mortality during the first year following a BM diagnosis was over two times higher for those presenting with metastatic versus localised disease (adjusted HR=2.12 (95% CI 1.71 to 2.62)). With respect to length of BMFI, survival was highest in women with a BMFI <1 year (ie, in those who presented with BM at the time of breast cancer diagnosis or were diagnosed within 1 year). However, among patients with a BMFI ≥1 year, survival increased with longer BMFI (1-year survival: 39.9% (95% CI 36.3% to 43.6%) for BMFI 1 to <3 years and 52.6% (95% CI 47.4% to 57.6%) for BMFI ≥5 years). This pattern was also observed in multivariate analyses. CONCLUSIONS: Stage of disease at breast cancer diagnosis and length of BMFI appear to be important prognostic factors for survival following BM.

Long-term mortality and recurrence after colorectal cancer surgery with preoperative stenting: a Danish nationwide cohort study.

BACKGROUND AND STUDY AIMS: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination, and thereby increasing recurrence risk and long-term mortality. The aim of this study was to compare overall mortality and CRC recurrence in patients receiving preoperative SEMS vs. patients undergoing urgent resection. PATIENTS AND METHODS: This was a Danish, nationwide, population-based cohort study (2005 - 2010). For patients with CRC who survived the first 30 days after resection, the long-term survival in terms of mortality rate ratios was assessed using Cox regression with adjustment for important covariates. For patients with Dukes' A - C disease only, recurrence risk was similarly assessed using incidence rate ratios. RESULTS: The 5-year survival was 49 % among 581 patients with preoperative SEMS and 40 % among 3333 patients undergoing urgent resection, corresponding to an adjusted mortality rate ratio of 0.98 (95 % confidence interval [CI] 0.90 to 1.07). For patients with Dukes' stage A - C disease, the 5-year recurrence risk was 39 % among 286 patients after preoperative SEMS and 30 % among 1627 patients after urgent resection, corresponding to an adjusted incidence rate ratio of 1.12 (95 %CI 0.99 to 1.28). CONCLUSIONS: Long-term mortality associated with the use of SEMS as a bridge to surgery was comparable to that of urgent resection. SEMS use may be associated with an increased CRC recurrence risk.

Bone metastasis, skeletal-related events, and mortality in lung cancer patients: a Danish population-based cohort study.

OBJECTIVES: To estimate the incidence rate of bone metastasis and subsequent skeletal-related events (SREs) (radiation to bone, spinal cord compression, fracture, and surgery to bone) in lung cancer patients and to quantify their impact on mortality. MATERIALS AND METHODS: We conducted a nationwide cohort study of patients diagnosed with lung cancer between 1999 and 2010 in Denmark. We computed the cumulative incidence (%) of bone metastasis and subsequent SREs (treating death as a competing risk) and corresponding incidence rates (per 1000 person-years). Survival was evaluated using the Kaplan-Meier method for three dynamic lung cancer patient cohorts-no bone metastasis; bone metastasis without SREs; and bone metastasis with SREs. Based on a Cox proportional hazards model, we computed mortality rate ratios (MRRs) comparing mortality rates between these patient cohorts, adjusting for age, comorbidity, stage, and histology. Analyses were conducted for the lung cancer patient cohort overall and by histologic subtype. RESULTS: We identified 29,720 patients with incident lung cancer (median follow-up: 7.3 months). The 1-year cumulative incidence of bone metastasis was 5.9%, and the 1-year cumulative incidence of subsequent SREs was 55.0%. The incidence of bone metastasis and SREs was higher in patients with non-small cell lung cancer (NSCLC) versus SCLC. One-year survival was 37.4% in patients with no bone metastasis; 12.1% in patients with bone metastasis without SREs; and 5.1% in patients with both bone metastasis and SREs. When mortality rates between patients with bone metastasis with and without an SRE were compared, 2-month mortality rates were similar, but the >2-month adjusted MRR was 2.0 (95% confidence interval: 1.7-2.2). CONCLUSION: Bone metastases predict a poor prognosis in lung cancer patients. The majority of lung cancer patients with bone metastasis will also experience an SRE, which may further increase the rate of mortality.

Comorbidity and survival of Danish breast cancer patients from 2000-2011: a population-based cohort study.

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.

Comorbidity and survival of Danish lung cancer patients from 2000-2011: a population-based cohort study.

OBJECTIVE: To examine lung cancer survival and the impact of comorbidity in the Central Denmark Region from 2000 to 2011. METHODS: We performed a population-based cohort study of lung cancer patients diagnosed during four 3-year calendar periods (2000-2002, 2003-2005, 2006-2008, and 2009-2011) in the Central Denmark Region. The Danish National Registry of Patients was used to identify 9,369 incident lung cancer patients, and to obtain data on their Charlson comorbidity index score, categorized as no (score = 0), medium (score = 1-2), or high (score ≥3) level comorbidity. We calculated 1- and 5-year survival in different calendar time periods overall, and by age, sex, and level of comorbidity, and used Cox regression to compute mortality rate ratios (MRR) for each level of comorbidity versus no comorbidity in different calendar time periods. RESULTS: Overall 1-year survival increased from 31% in 2000-2002 to 37% in 2009-2011, while the 5-year survival increased from 10% in 2000-2002 to predicted 13% in 2009-2011 with the largest improvement observed for women and patients less than 80 years. The adjusted 1-year MRR in patients with high comorbidity compared with those without comorbidity was 1.23 (95% confidence interval [CI]: 1.05-1.46) in 2000-2002 and 1.35 (95% CI: 1.17-1.56) in 2009-2011. The corresponding adjusted 5-year MRRs were 1.21 (95% CI: 1.04-1.40) in 2000-2002 and 1.26 (95% CI: 1.11-1.42) in 2009-2011. CONCLUSION: Lung cancer patients' survival increased from 2000 to 2011 in the Central Denmark Region, most prominently for women under 80 years and patients with no, or medium level of comorbidity. Their prognosis remained nonetheless dismal with overall 5-year survival of 13%, and comorbidity remained a negative prognostic factor.

Comorbidity and survival of Danish prostate cancer patients from 2000-2011: a population-based cohort study.

OBJECTIVE: We investigated temporal changes in overall survival among prostate cancer (PC) patients and the impact of comorbidity on all-cause mortality. METHODS: We conducted a population-based cohort study in the Central Denmark Region (1.2 million inhabitants). Using medical registries, we identified 7,654 PC patients with first-time PC diagnosis within the period 2000-2011 and their corresponding comorbidities within 10 years prior to the PC diagnosis. We estimated 1- and 5-year survival in four consecutive calendar periods using a hybrid analysis and plotted Kaplan-Meier survival curves. We used Cox proportional hazards regression to compute 1- and 5-year age-adjusted mortality rate ratios (MRRs) for different comorbidity levels. All estimates are reported with their corresponding 95% confidence intervals (CI). RESULTS: The annual number of PC cases doubled over the 12-year study period. Men aged <70 years accounted for the largest proportional increase (from 33% to 47%). The proportion of patients within each comorbidity category remained constant over time. One-year survival increased from 82% (CI: 80%-84%) in 2000-2002 to 92% (CI: 90%-93%) in 2009-2011, while 5-year survival increased from 43% (CI: 40%-46%) to 65% (CI: 62%-67%) during the same time intervals. Improvements in 5-year survival were most prominent among patients aged <80 years and among those with no comorbidity (from 51% to 73%) and medium comorbidity (from 32% to 54%). Improvements in survival were much smaller for those with high comorbidity (from 33% to 39%). The 1-year age-adjusted MRR for patients with high comorbidity (relative to patients with no comorbidity) increased over time from 1.84 (CI: 1.19-2.84) to 3.67 (CI: 2.49-5.41), while the 5-year age-adjusted MRR increased from 1.73 (CI: 1.34-2.23) to 2.38 (CI: 1.93-2.94). CONCLUSION: Overall survival of PC improved substantially during 2000-2011, although primarily among men with low comorbidity. All-cause mortality was highest among PC patients with high comorbidity, and their relative 1- and 5-year mortality increased over time compared to those without comorbidity.

Comorbidity and survival of Danish patients with colon and rectal cancer from 2000-2011: a population-based cohort study.

OBJECTIVE: To evaluate recent trends in the prevalence and impact of comorbidity on colorectal cancer (CRC) survival in the Central Region of Denmark. MATERIAL AND METHODS: Using the Danish National Registry of Patients, we identified 5,777 and 2,964 patients with a primary colon or rectal cancer, respectively, from 2000 through 2011. We estimated survival according to Charlson Comorbidity Index scores and computed mortality rate ratios (MRRs) using Cox proportional hazard regression analysis, adjusting for age and sex. RESULTS: More than one-third of CRC patients had comorbidity at diagnosis. During the study period, 1-year survival increased substantially in colon cancer patients with Charlson score 0 (72% to 80%) and modestly for Charlson score 3+ patients (43% to 46%). Using colon cancer patients with Charlson score 0 as reference, adjusted 1-year MRRs in patients with Charlson score 3+ were 2.19 (95% confidence interval [CI]: 1.57-3.05) in 2000-2002 and 2.56 (95% CI: 1.96-3.35) in 2009-2011. One-year survival after rectal cancer improved from 81% to 87% in patients with Charlson score 0 and from 56% to 60% in Charlson score 3+. Corresponding MRRs in patients with Charlson 3+ were 2.21 (95% CI: 1.33-3.68) in 2000-2002 and 3.09 (95% CI: 1.91-5.00) in 2009-2011 using Charlson score 0 as reference. Five-year MRRs did not differ substantially from 1-year MRRs. CONCLUSION: Comorbidity was common among CRC patients and was associated with poorer prognosis. We observed improved survival from 2000 to 2011 for all comorbidity levels, with least improvement for colon cancer patients with comorbid conditions.

Comorbidity and survival of Danish ovarian cancer patients from 2000-2011: a population-based cohort study.

OBJECTIVE: To examine the prevalence of comorbidity among patients diagnosed with epithelial ovarian cancer in the Central Denmark Region and to study the impact of comorbidity on cancer survival over time. METHODS: We included women recorded with a first-time diagnosis of epithelial ovarian cancer in the Danish National Registry of Patients in the Central Denmark region between 2000 and 2011. We followed their survival through the Danish Civil Registration System. We estimated 1- and 5-year survival overall and stratified by Charlson Comorbidity Index score. We used Cox proportional hazard regression analyses to compute adjusted mortality rate ratios (MRRs) within different calendar time periods overall and by comorbidity level. RESULTS: We identified 1,540 patients. In 2000-2002, 25% of the newly diagnosed ovarian cancer patients had a comorbidity diagnosis compared with 35% in 2009-2011. Median age increased from 61 to 66 years. One-year overall survival changed from 73% (95% confidence interval [CI]: 69-78) in 2000-2002 to 69% (95% CI: 63-73) in 2009-2011, corresponding to an age- and comorbidity-adjusted MRR of 1.03 (95% CI: 0.79-1.36). Five-year survival changed only slightly during the study period, from 37% (95% CI: 32-42) in 2000-2002 to 39% (95% CI: 34-44) in 2009-2011. In patients with Charlson score ≥3, 1-year survival changed from 63% (95% CI: 35-81) in 2000-2002 to 41% (95% CI: 24-57) in 2003-2005 and thereafter stabilized. One-year survival changed from 56% (95% CI: 44-66) to 64% (95% CI: 53-74) in patients with Charlson score 1-2. Compared with Charlson score 0, adjusted 1-year MRRs for Charlson score ≥3 were 1.44 (95% CI: 0.62-3.36) in 2000-2002 and 2.11 (95% CI: 1.27-3.51) in 2009-2011, whereas adjusted 1-year MRRs for Charlson score 1-2 changed from 2.04 (95% CI: 1.33-3.14) in 2000-2002 to 1.09 (95% CI: 0.69-1.71) in 2009-2011. CONCLUSION: Comorbidity increased among ovarian cancer patients over time and was associated with poor survival. One- and 5-year overall survivals changed only little and an expected decrease in survival, following increased prevalence of comorbidity and increasing age of patients, may have been counteracted by more aggressive surgery.

25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study.

OBJECTIVES: To examine 25 year trends in first time hospitalisation for acute myocardial infarction in Denmark, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity. DESIGN: Nationwide population based cohort study using medical registries. SETTING: All hospitals in Denmark. SUBJECTS: 234,331 patients with a first time hospitalisation for myocardial infarction from 1984 through 2008. MAIN OUTCOME MEASURES: Standardised incidence rate of myocardial infarction and 30 day and 31-365 day mortality by sex. Comorbidity categories were defined as normal, moderate, severe, and very severe according to the Charlson comorbidity index, and were compared by means of mortality rate ratios based on Cox regression. RESULTS: The standardised incidence rate per 100,000 people decreased in the 25 year period by 37% for women (from 209 to 131) and by 48% for men (from 410 to 213). The 30 day, 31-365 day, and one year mortality declined from 31.4%, 15.6%, and 42.1% in 1984-8 to 14.8%, 11.1%, and 24.2% in 2004-8, respectively. After adjustment for age at time of myocardial infarction, men and women had the same one year risk of dying. The mortality reduction was independent of comorbidity category. Comparing patients with very severe versus normal comorbidity during 2004-8, the mortality rate ratio, adjusted for age and sex, was 1.96 (95% CI 1.83 to 2.11) within 30 days and 3.89 (3.58 to 4.24) within 31-365 days. CONCLUSIONS: The rate of first time hospitalisation for myocardial infarction and subsequent short term mortality both declined by nearly half between 1984 and 2008. The reduction in mortality occurred for all patients, independent of sex and comorbidity. However, comorbidity burden was a strong prognostic factor for short and long term mortality, while sex was not.

Use of penicillin and other antibiotics and risk of multiple sclerosis: a population-based case-control study.

A 2006 study from the United Kingdom found that penicillin use may decrease the risk of multiple sclerosis (MS). To confirm this finding, the authors conducted a nationwide case-control study in Denmark, using the Danish Multiple Sclerosis Registry to identify 3,259 patients with MS onset from 1996 to 2008, and selected 10 population controls per case (n = 32,590), matched on sex and age. Through the National Prescription Database, prescriptions for antibiotics redeemed from 1995 to 2008 and before the date of first MS symptom/index date were identified. Conditional logistic regression analysis was used to compute odds ratios associating antibiotic use with MS occurrence. In total, 1,922 patients (59%) redeemed penicillin prescriptions before the index date and 2,292 (70%) redeemed any type of antibiotic prescription. Penicillin use was associated with an increased risk of MS (odds ratio = 1.21, 95% confidence interval: 1.10, 1.27). Use of any type of antibiotic was similarly associated with an increased risk of MS (odds ratio = 1.41, 95% confidence interval: 1.29, 1.53). The odds ratios for different types of antibiotics ranged between 1.08 and 1.83. Thus, this study found that penicillin use and use of other antibiotics were similarly associated with increased risk of MS, suggesting that the underlying infections may be causally associated with MS.

Survival of patients with primary liver cancer in central and northern Denmark, 1998-2009.

OBJECTIVE: Primary liver cancer (PLC) is a serious disease with high mortality. During the last decade, improvements in the diagnostic procedures and treatment of PLC may have improved survival. However, few updated longitudinal studies examined this issue. In a population-based setting, we studied changes in the prognoses over time. METHODS: Between 1998 and 2009, we identified all patients with PLC in the central and northern Denmark regions, with a combined population of 1.8 million. We determined age- and period-stratified survival, and computed mortality rate ratios (MRRs) with 95% confidence intervals (CIs), using Cox proportional hazard regression to assess changes over time, while controlling for age and gender. We conducted the analyses for PLC overall and separately for hepatocellular carcinoma (HCC) and cholangiocarcinoma, respectively. RESULTS: We included 1064 patients with PLC. Their median age was 69 years (range 17-94 years). The number of patients diagnosed with PLC in the period 2007-2009 was approximately 40% higher than the number in 1998-2000. One-year survival increased from 16% in 1998-2000 to 28% in 2007-2009, corresponding to an adjusted 1-year MRR of 0.65 (95% CI: 0.54-0.79). In patients aged <60 years, we found the most pronounced increase in 1-year survival, from 14% to 49% in women and from 19% to 41% in men. The 3- and 5-year survival in the entire cohort increased from 5% to a predicted 11% and from 2% to a predicted 7% during our study period, respectively. Accordingly, the expected 3- and 5-year adjusted MRRs were 0.68 (95% CI: 0.57-0.82) and 0.68 (95% CI: 0.57-0.81), respectively. One-, 3-, and 5-year survival improved during the study period for both HCC and cholangiocarcinoma. CONCLUSION: PLC survival remains poor in the Danish population, although we observed an increase over the period 1998-2009, particularly in young people.

Survival in patients with synchronous liver metastases in central and northern Denmark, 1998 to 2009.

OBJECTIVE: In Denmark, the strategy for treatment of cancer with metastases to the liver has changed dramatically during the period 1998 to 2009, when multidisciplinary care and a number of new treatments were introduced. We therefore examined the changes in survival in Danish patients with colorectal carcinoma (CRC) or other solid tumors (non-CRC) who had liver metastases at time of diagnosis. STUDY DESIGN AND METHODS: We included patients diagnosed with liver metastases synchronous with a primary cancer (ie, a solid cancer diagnosed at the same date or within 60 days after liver metastasis diagnosis) during the period 1998 to 2009 identified through the Danish National Registry of Patients. We followed those who survived for more than 60 days in a survival analysis (n = 1021). Survival and mortality rate ratio (MRR) at 1, 3, and 5 years stratified by year of diagnosis were estimated using Cox proportional hazards regression analysis. RESULTS: In the total study population of 1021 patients, 541 patients had a primary CRC and 480 patients non-CRC. Overall, the 5-year survival improved from 3% (95% confidence interval [CI]: 1%-6%) in 1998-2000 to 10% (95% CI: 6%-14%) in 2007 to 2009 (predicted value). The 5-year survival for CRC-patients improved from 1% (95% CI: 0%-5%) to 11% (95% CI: 6%-18%) whereas survival for non-CRC patients only increased from 5% (95% CI: 1%-10%) to 8% (95% CI: 4%-14%). CONCLUSION: We observed improved survival in patients with liver metastases in a time period characterized by introduction of a structured multidisciplinary care and improved treatment options. The survival gain was most prominent for CRC-patients.

Survival of prostate cancer patients in central and northern Denmark, 1998-2009.

OBJECTIVE: Prostate cancer is the most common noncutaneous cancer among Danish men. During the last decade, use of prostate specific antigen (PSA) testing has increased, and in clinically localized prostate cancer, curative intended treatment has gained a footing. Our aim was to examine possible changes in the short- and long-term survival of patients with prostate cancer during 1998-2009. STUDY DESIGN AND SETTING: From two Danish regions (population, 1.8 million) we included all patients (N = 10,547) with an incident diagnosis of prostate cancer retrieved from the Danish National Registry of Patients. We determined survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox proportional hazard regression to assess changes over time, controlling for age. RESULTS: During the study period, the annual number of incident prostate cancer patients more than doubled, and the median age at diagnosis decreased from 74 to 70 years. The survival improved over the study period, particularly in the last half of the period (2004-2009). Thus, 1-year survival increased from 80% (1998-2000) to 90% (2007-2009), corresponding to an age-adjusted MRR of 0.54 (95% confidence interval CI: 0.46-0.63). The expected increase in 3- and 5-year survival was even more pronounced: 47%-73% and 34%-60%, respectively. This corresponded to a 3-year age-adjusted MRR of 0.46 (95% CI: 0.42-0.51) and a 5-year MRR of 0.50 (95% CI: 0.46-0.54). The 1-, 3-, and 5-year overall survival increased in all age groups (<70 years, 70-79 years, ≥80 years). CONCLUSION: Survival after prostate cancer has improved in Denmark within the last decade. Although diagnosis and treatment improvements could explain this, length and lead time bias are likely to have influenced our results.

Survival of patients with kidney cancer in central and northern Denmark, 1998-2009.

OBJECTIVE: For decades, kidney cancer patients in Denmark have had lower survival than patients in the other Scandinavian countries. Our aim was to study possible changes in survival of patients with kidney cancer after implementation of two national Danish cancer plans. STUDY DESIGN AND SETTING: From 1998 through 2009 we included all patients (N = 2659) with an incident diagnosis of kidney cancer in two Danish regions (population 1.8 million). Data were retrieved from the Danish National Registry of Patients. We computed survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox regression to assess changes over time, controlling for age and gender. We lacked data on stage distribution. Among patients who had a nephrectomy we also computed 30-day mortality and 30-day MRRs. RESULTS: During the study period, we identified 2659 patients with kidney cancer. The annual number of patients increased from 583 in the period 1998-2000 to 853 in the period 2007-2009. The median age at diagnosis was 69 years throughout the study period. The overall 1-year survival improved from 56% (1998-2000) to 63% (2007-2009), corresponding to an adjusted MRR of 0.78 (95% confidence interval [CI] 0.66-0.93). We predicted the 3-year survival to increase from 40% to 51% and the 5-year survival to increase from 33% to 42%, corresponding to predicted MRRs of 0.76 (95% CI 0.66-0.87) and 0.77 (95% CI 0.68-0.89), respectively. Survival increased in all age groups (15-59 years, 60-74 years, 75+ years) and in both genders, except for men below 60 years, for whom the 1-year survival declined from 76% to 69%. The 30-day mortality after nephrectomy declined from 4% to 2% during the study period. CONCLUSION: We observed an improvement in the survival and relative mortality in kidney cancer patients, although not in men younger than 60 years.

Survival of patients with ovarian cancer in central and northern Denmark, 1998-2009.

OBJECTIVE: To examine time trends of survival and mortality of ovarian cancer in the central and northern Denmark regions during the period 1998-2009. STUDY DESIGN AND SETTING: We conducted a cohort study including women recorded with a first-time diagnosis of ovarian cancer in the Danish National Registry of Patients (DNRP) between 1998 and 2009. Patients were followed for survival through the Danish Civil Registration System. We determined survival stratified by age, and used Cox proportional hazard regression analyses to obtain mortality rate ratios (MRRs) to assess changes over time. RESULTS: We found no improvement in overall ovarian cancer survival between 1998 and 2009. One-year survival was 71% in 1998-2000 and 68% in 2007-2009. Three-year survival declined from 48% in 1998-2000 to 46% in 2007-2009 (predicted), and 5-year survival declined from 40% in 1998-2000 to 37% in 2007-2009 (predicted). Compared with the period 1998-2000, the age-adjusted 1-year MRR was 1.05 (95% confidence interval CI: 0.86-1.28) for the period 2007-2009, and the predicted age-adjusted 3- and 5-year MRRs were 0.96 (95% CI: 0.83-1.12) and 0.99 (95% CI: 0.86-1.14), respectively. Results are not adjusted for tumor stage as this information was not available. We also observed a decline in the annual number of incident ovarian cancer patients during the study period, most pronounced in the youngest age group. CONCLUSION: The survival of ovarian cancer patients did not improve during the study period. This lack of improvement contrasts with the national cancer strategies implemented during this last decade, focusing on improving the survival of ovarian cancer patients.

Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007).

Bone lesions as a consequence of bone metastases in breast cancer patients can increase risk for skeletal-related events (SREs) (i.e., radiation to the bone, a pathological or osteoporotic fracture event, hypercalcemia, spinal cord compression, or surgery to the bone). The mortality risk for breast cancer patients with SREs subsequent to bone metastases is unclear. We assessed this relationship in a large, population-based cohort of breast cancer patients in Denmark. We identified 35,912 newly diagnosed breast cancer patients from January 1, 1999 to December 31, 2007 in the Danish National Patient Registry (DNPR) and followed them through April 1, 2008. Information on stage and treatment was obtained from the Danish Cancer Registry. We used the Kaplan-Meier method to estimate survival, and Cox's regression analysis to estimate the mortality rate ratio (MRR) by the presence of bone metastases with and without SREs, adjusting for age and comorbidity. The 5-year survival was 75.8% for breast cancer patients without bone metastases, 8.3% for patients with bone metastases, and 2.5% for those with both bone metastases and SREs. The adjusted MRR was 10.5 [95% confidence interval (CI) 9.5-11.6] for breast cancer patients with bone metastases, and 14.4 (95% CI 13.1-15.8) for those with bone metastases and SREs, compared with breast cancer patients with no bone metastases but possibly other sites of metastases. A similar pattern persisted when analyses were stratified by stage or treatment. Breast cancer patients with bone metastases and SREs have a poor prognosis compared to those with and without bone metastases regardless of cancer treatment or stage of disease at diagnosis.

Non-melanoma skin cancer and ten-year all-cause mortality: a population-based cohort study.

Confounding from comorbidity and socioeconomic status may have biased earlier findings of all-cause mortality among patients with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We therefore examined all-cause mortality among 72,295 Danish patients with BCC, 11,601 with SCC, and 383,714 age- and gender-matched population control cohort subjects with extensive control for comorbidity and socioeconomic status. Data on cancer, death, and socioeconomic status were obtained from medical databases and Statistics Denmark. We analysed data using Cox regression analysis, with estimation of 10-year mortality rate ratios (MRRs) and 95% confidence intervals (CI). Mortality was reduced among patients with BCC (10-year MRR = 0.91 (95% CI: 0.89-0.92) and did not vary by age, comorbidity, or socioeconomic status. Mortality among patients with SCC was increased and varied by age, selected chronic diseases, but not socioeconomic status. The reduced mortality observed among patients with BCC and the increased mortality among patients with SCC persisted even after extensive control for comorbidity and socioeconomic status.