Risk of Synchronous and Metachronous Colorectal Cancer: Population-Based Estimates in Denmark with Focus on Non-Hereditary Cases Diagnosed After Age 50.

BACKGROUND AND AIMS: The risk of synchronous and metachronous colorectal cancer is influenced by heritable and environmental factors. As a basis for comparative studies, we provide population-based estimates of synchronous and metachronous colorectal cancer with a focus on non-heritable cases. MATERIAL AND METHODS: Based on data from national Danish cancer registers, we estimated the proportion of synchronous colorectal cancer and the incidence rates and risks for metachronous colorectal cancer in 28,504 individuals, who developed 577 metachronous colorectal cancer above age 50. RESULTS: Synchronous colorectal cancer was diagnosed in 1.3% of the cases. The risk of metachronous colorectal cancer was associated with sex, tumor location, and age with the strongest influence from the latter. The incidence rate ratios for metachronous colorectal cancer ranged from above 6 in patients below age 65 to <1-3.2 in patients above age 65. The absolute risk of metachronous colorectal cancer was ⩾10% in patients below age 65 and 1.0%-8.0% in patients above age 65. CONCLUSION: Individuals who develop sporadic, non-inherited colorectal cancer above age 50 are at a significantly increased risk of metachronous colorectal cancer with risk estimates that are strongly affected by age. This observation underscores the need for development of targeted surveillance in the most common clinical subset of colorectal cancer.

Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study.

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0-3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%. Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early-stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.

Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population.

OBJECTIVES: Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). A recent publication found that WLWH in Denmark attend the national ICC screening programme less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark compared with that in women in the general population. METHODS: We studied a nationwide cohort of WLWH and a cohort of 15 age-matched women per WLWH from the general population for the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank, which contains nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology result to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. RESULTS: We followed 1140 WLWH and 17 046 controls with no prior history of ICC or hysterectomy for 9491 and 156 865 person-years, respectively. Compared with controls, the overall incidences of CIN1 or worse (CIN1+), CIN2+ and CIN3+, but not ICC, were higher in WLWH and predicted by young age and a CD4 count < 200 cells/µL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, when we compared subgroups of WLWH and controls where women in both groups were adherent to the national ICC screening programme and had a normal baseline cytology, incidences of CIN and ICC were comparable. CONCLUSIONS: Overall, WLWH developed more cervical disease than controls. Yet, in WLWH and controls adherent to the national ICC screening programme and with normal baseline cytology, incidences of CIN and ICC were comparable.

Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome.

BACKGROUND AND PURPOSE: Brain tumors represent a rare and relatively uncharacterized tumor type in Lynch syndrome. METHODS: The national Danish Hereditary Nonpolyposis Colorectal Cancer Register was utilized to estimate the cumulative life-time risk for brain tumors in Lynch syndrome, and the mismatch repair (MMR) status in all tumors available was evaluated. RESULTS: Primary brain tumors developed in 41/288 families at a median age of 41.5 (range 2-73) years. Biallelic MMR gene mutations were linked to brain tumor development in childhood. The risk of brain tumors was significantly higher (2.5%) in MSH2 gene mutation carriers compared to patients with mutations in MLH1 or MSH6. Glioblastomas predominated (56%), followed by astrocytomas (22%) and oligodendrogliomas (9%). MMR status was assessed in 10 tumors, eight of which showed MMR defects. None of these tumors showed immunohistochemical staining suggestive of the IDH1 R132H mutation. CONCLUSION: In Lynch syndrome brain tumors occurred in 14% of the families with significantly higher risks for individuals with MSH2 gene mutations and development of childhood brain tumors in individuals with constitutional MMR defects.

Risk of a venous thromboembolic episode due to caesarean section and BMI: a study in northern Denmark covering 2000-2010.

BMI significantly influences the risk of venous thromboembolism after emergency caesarean delivery compared with vaginal delivery.

Genetic variation in toll-like receptors and retinoic acid-inducible gene I and outcome of hepatitis C virus infection: a candidate gene association study.

We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis were performed. srs2233437, rs730775 and rs28362857 in Inhibitor of NF-kB ε (IkBε) and rs352140 in TLR9 were associated with spontaneous HCV resolution (P ≤ 0.05) in the discovery cohort (n = 308). In the validation cohort (n = 216), we replicated a significant association with HCV resolution for two SNPs in the IkBε, rs2233437 and rs730775. Presence of one or two of the variant allele in rs2233437 had more than twofold higher odds of resolution in adjusted logistic regression (adjusted odds ratio (aOR), 2.6; (95% CI, 1.4, 4.8) P = 0.002). We identified polymorphisms in the IkBε gene associated with spontaneous HCV resolution in two independent cohorts.

Effect of high-dose preoperative methylprednisolone on recovery after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: High-dose glucocorticoid may reduce postsurgical pain and improve recovery. We hypothesized that 125 mg methylprednisolone (MP) would reduce time to meet functional discharge criteria after total hip arthroplasty (THA). METHODS: Forty-eight patients undergoing unilateral THA under spinal anaesthesia were consecutively included in this randomized, double-blind, placebo-controlled trial receiving preoperative i.v. MP or saline. All patients received a standardized, multimodal analgesic regime with paracetamol, celecoxib, and gabapentin. The primary outcome was time to meet well-defined functional discharge criteria. Secondary outcomes were handgrip strength and endurance, pain, nausea, vomiting, fatigue, sleep quality, and rescue analgesic-, antiemetic-, and hypnotic medicine requirements. The inflammatory response measured by C-reactive protein (CRP) and actual length of stay were also registered. Discharge criteria were assessed twice daily (at 09:00 and 14:00 h) until discharge. Other outcomes were assessed at 2, 4, 6, 8, and 24 h after operation, and also in a questionnaire from postoperative day (POD) 1-4. RESULTS: Time to meet discharge criteria was [median (IQR) (95% CI), MP vs placebo]: 23.5 (23.3-23.7) (17.8-43.8) vs 23.5 (23.0-23.8) (20.0-46.8) h, the mean difference (95% CI) being -1.3 (-4.7 to 2.2) h, P=0.65. Overall pain for the first 24 h after surgery was significantly reduced in the MP vs the placebo group (P<0.01), as was CRP at 24 h (P<0.0001). No other between-group differences were observed. No drug-related complications were observed at follow-up on POD30. CONCLUSIONS: MP 125 mg i.v. before surgery added to a multimodal oral analgesic regime did not reduce time to meet functional discharge criteria after THA, but improved analgesia for the first 24 h.

The association between aortic augmentation index and cardiovascular risk factors in a large unselected population.

The augmentation index (AIx) is a measure of systemic arterial stiffness, and previous studies have demonstrated an association between AIx and risk factors of cardiovascular disease (CVD). However, there is limited knowledge about the age and gender differences of the observed associations. Therefore, the aim of the present study is to examine the association's consistency at different ages and to see if the associations are the same in men and women. This study is based on 3432 subjects from The Copenhagen City Heart Study, a prospective epidemiological survey of a representative population in Denmark. All subjects had AIx measured non-invasively by the SphygmoCor device (SphygmoCor, West Ryde, Australia). To analyse the association between AIx and CVD risk factors multiple linear regression analyses were used stratified by gender and age. The main determinants of AIx were age, heart rate, height and systolic blood pressure in both age groups with few gender differences. Associations between AIx and cardiovascular risk factors further differed by age: In young subjects AIx was associated with cholesterol, high-sensitive C-reactive protein, current smoking, low weight, poor education and physical inactivity, whereas in subjects above age 60 AIx was associated with weight and current smoking in men. We found a modest association between AIx and traditional CVD risk factors and the association attenuated in subjects >60 years. Further longitudinal studies are needed to determine whether AIx is primarily a marker of CVD in younger subjects.

Major but differential decline in the incidence of Staphylococcus aureus bacteraemia in HIV-infected individuals from 1995 to 2007: a nationwide cohort study*.

OBJECTIVES: Incidence rates (IRs) of Staphylococcus aureus bacteraemia (SAB) are known to be higher in HIV-infected individuals than in the general population, but have not been assessed in the era of highly active antiretroviral therapy. METHODS: From 1 January 1995 to 31 December 2007, all Danish HIV-infected individuals (n=4871) and population controls (n=92 116) matched on age and sex were enrolled in a cohort and all cases of SAB were registered. IRs and risk factors were estimated using time-updated Poisson regression analysis. RESULTS: We identified 329 cases of SAB in 284 individuals, of whom 132 individuals were infected with HIV and 152 were not [crude IR ratio (IRR) 24.2; 95% confidence interval (CI) 19.5-30.0, for HIV-infected vs. non-HIV-infected individuals]. Over time, IR declined for HIV-infected individuals (IRR 0.40). Injecting drug users (IDUs) had the highest incidence and the smallest decline in IR, while men who have sex with men (MSM) had the largest decline over time. Among HIV-infected individuals, a latest CD4 count <100 cells/µL was the strongest independent predictor of SAB (IRR 10.2). Additionally, HIV transmission group was associated with risk of SAB. MSM were more likely to have hospital-acquired SAB, a low CD4 cell count and AIDS at the time of HIV acquisition compared with IDUs. CONCLUSIONS: We found that the incidence of SAB among HIV-infected individuals declined during the study period, but remained higher than that among HIV-uninfected individuals. There was an unevenly distributed burden of SAB among HIV transmission groups (IDU>MSM). Low CD4 cell count and IDU were strong predictors of SAB among HIV-infected individuals.

Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.

BACKGROUND: Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. OBJECTIVE: The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. DESIGN: This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. SETTING: General adult Caucasian population. PARTICIPANTS: The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. MEASUREMENTS: Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. RESULTS: Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. LIMITATION: Further validation in ethnic populations other than Caucasians is needed. CONCLUSION: The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

Improved survival after rectal cancer in Denmark.

OBJECTIVE: In 1995, an analysis showed an inferior prognosis after rectal cancer in Denmark compared with the other Scandinavian countries. The Danish Colorectal Cancer Group (DCCG) was established with the aim of improving the prognosis, and in this study we present a survival analysis of patients treated from 1994 to 2006. METHOD: The study was based on the National Rectal Cancer Registry and the National Colorectal Cancer Database, supplemented with data from the Central Population Registry. The analysis included actuarial overall and relative survival. RESULTS: A total of 10 632 patients were operated on. The overall 5-year survival increased from 0.37 in 1994 to 0.51% in 2006; the improvement was greater in men (20% points) than in women (10% points), and greatest in stage III (20% points). The relative 5-year survival increased from 0.46 to 0.62, including an improvement of 23% points in men and 9% points in women and the greatest in stage III (22% points). CONCLUSIONS: The prognosis has improved substantially, probably mainly because of initiatives taken by the DCCG, among which implementation of total mesorectal excision, improved staging and centralized treatment are considered most important.

Relative validity of a food frequency questionnaire used in the Inter99 study.

OBJECTIVE: To evaluate the validity of the Inter99 food frequency questionnaire (FFQ) compared with a 28-days' diet history and biomarkers. SUBJECTS: A random sample of 13 016 individuals were drawn from a general population and invited for a health screening programme. Participation rate was 52.5%. All high-risk individuals were re-invited for assessment after 1 and 3 years and completed a 198-item FFQ at all three occasions. Participants attending for 3 years follow-up were invited to participate in the validation study, including a 28-days' diet history, a 24-h urine collection and a fasting blood sample. Overall, 264 subjects participated. RESULTS: Spearman's rank correlation coefficients between the two dietary methods ranged from 0.31(beta-carotene) to 0.64 (fruits) in men and from 0.31 (polyunsaturated fat and sodium) to 0.64 (fruits) for women. The proportion of individuals classified in the same or adjacent quintiles were, on average, 72% for men and 69% for women. Gross misclassification was found on average in 2%. The correlation coefficients of the residuals ranged from 0.27 (sodium) to 0.61 (fruits) for men and from 0.21 (sodium) to 0.62 (B12-vitamin) for women. Correlation coefficients between fruit and vegetable intake and carotenoids ranged from -0.08 (lycopene) to 0.44 (alpha-carotene). For the residuals the correlation coefficients ranged from -0.004 (lycopene) to 0.47 (alpha-carotene). CONCLUSION: The Inter99 FFQ and the residuals of the intake provide acceptable classification of individuals according to their dietary intakes and the FFQ gives a good quantitative measurement of key dietary components.

Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people.

Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF-alpha and IL-6 on survival in the following 6 years. A total of 133 participants died during this follow-up period. TNF-alpha was associated with mortality in men, but not in women, whereas low-grade elevations in IL-6 were associated strongly with mortality in both sexes. TNF-alpha explained only 7% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate that at least in old populations chronic elevated levels of TNF-alpha and IL-6 have different biological functions that trigger age-associated pathology and cause mortality.