Steen Ladelund

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

Abstract.  Eugen‐Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbæk S, Fenger M, Olsen MH, Hildebrandt PR, Borch‐Johnsen K, Jørgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308.

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‐α) initiates the inflammatory cascade and has been linked to several age‐associated disorders. It remains, however, unknown if TNF‐α is associated with mortality in old populations. The aim of the present study was to investigate if serum levels of TNF‐α 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‐α and IL‐6 on survival in the following 6 years. A total of 133 participants died during this follow‐up period. TNF‐α 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‐α 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‐α and IL‐6 have different biological functions that trigger age‐associated pathology and cause mortality.

The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis

Abstract Background. In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. Methods. In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated. Results. Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09). Conclusions. Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.

Smoking behavior among hospital staff still influences attitudes and counseling on smoking.

Smoking among health professionals has been shown to influence smoking-related knowledge and counseling in clinical practice. The evidence regarding smoking as a risk factor has increased in the past decade. The present study was carried out in 2000 and investigated the associations between individual smoking behavior among hospital staff and (a). smoking-related knowledge, (b). attitudes toward counseling on smoking, and (c). self-reported smoking-related counseling provided by the staff. The study was based on a survey using self-administered questionnaires given to all hospital staff in a large university hospital in Denmark. Altogether, 82% of staff (2561) returned a completed questionnaire. Analyses focused on a subsample consisting of health professionals in the clinical wards (1429). Multivariate analyses were performed in which smoking-related knowledge, attitudes toward smoking-related counseling, smoking-related counseling practices, and self-rated qualifications for counseling were main outcome measures. Health professionals who were current smokers systematically underestimated the health consequences of smoking and differed significantly from nonsmokers in their assessments of smoking as a risk factor. Nonsmokers might overestimate smoking as a risk factor. Nonsmokers gave patients advice on smoking cessation significantly more often than did current smokers (ex-smokers, OR=2.5, 95% CI=1.8-3.4; never-smokers, OR=1.5, 95% CI=1.1-2.0). Ex-smokers and smokers felt significantly more qualified to counsel patients about smoking than did never-smokers (ex-smokers, OR=1.8, 95% CI=1.3-2.5; smokers, OR=1.4, 95% CI=1.0-1.9). Individual smoking behavior among hospital staff was strongly associated with smoking-related knowledge, attitudes, and counseling practices. Lack of self-rated qualifications was a major barrier to professional counseling on smoking in a hospital framework.

Aortic augmentation index: reference values in a large unselected population by means of the SphygmoCor device.

BACKGROUND Arterial stiffness and pulse wave reflection are associated with cardiovascular disease (CVD). Pulse wave analyses (PWAs) allow the estimation of the central augmentation index (AIx), a measurement of pulse wave reflection. To understand the predictive role of AIx, reference values for AIx are needed. METHODS This population study is based on 4,561 subjects from The Copenhagen City Heart Study, an ongoing epidemiological survey started in 1976, including subjects randomly chosen from the population in Copenhagen, Denmark. We calculated and internally validated reference values of AIx measured by the SphygmoCor device in a cohort without known CVD or diabetes, and with low risk of CVD according to HeartScore using gender-specific multiple regression analyses adjusting for age, heart rate, and height. RESULTS AIx was significantly higher in women than in men, 30% vs. 22%, (P < 0.001) and the increase in AIx with age was curvilinear. There were 972 subjects in the low-risk cohort with mean AIx 28% in women (N = 565) and 18% in men (N = 407) (P < 0.001). We report the following internally validated reference equations for AIx: men: AIx = 79.20 + 0.63 (age) - 0.002 (age(2)) - 0.28 (heart rate) - 0.39 (height). Women: AIx = 56.28 + 0.90 (age) - 0.005 (age(2)) - 0.34 (heart rate) - 0.24 (height). AIx appeared to increase with increasing risk of CVD according to HeartScore. CONCLUSIONS We report a novel and internally validated gender-specific equation including age, heart rate, and height to calculate reference values for AIx.

Level of Fecal Calprotectin Correlates With Endoscopic and Histologic Inflammation and Identifies Patients With Mucosal Healing in Ulcerative Colitis

BACKGROUND & AIMS In patients with ulcerative colitis (UC), mucosal healing is an important goal of treatment. However, mucosal healing is difficult to determine on the basis of clinical evaluation alone, and endoscopy is uncomfortable and can cause complications. Fecal calprotectin (FC) is a marker of inflammation, and its levels have been associated with disease activity. We investigated the association between level of FC and mucosal healing and clinical disease activity in patients with UC. METHODS We performed an observational cross-sectional study of 120 patients with active or inactive UC who underwent sigmoidoscopy at Copenhagen University Hospital Hvidovre from September 2012 through 2014. Endoscopic inflammation was evaluated by using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histologic inflammatory activity by a slightly modified Harpaz Index, which measures acute inflammation. The Partial Mayo Score was used to measure the clinical disease activity. RESULTS A cutoff level of FC of 192 mg/kg identified patients with endoscopic evidence of mucosal healing, which was based on the MES and UCEIS, with positive predictive values of 0.71 and 0.65, respectively; negative predictive values were 0.90 and 0.93, respectively. A cutoff level of 171 mg/kg identified patients with histologic evidence of mucosal healing, with positive predictive value of 0.75 and negative predictive value of 0.90. Levels of FC increased significantly with increases in endoscopic and histologic disease activity. There was high concordance between MES and UCEIS as well as between MES or UCEIS and histologic inflammatory activity. The histologic activity index had an interobserver variation of 4.35%. CONCLUSIONS Level of FC identifies patients with UC who have endoscopic and histologic features of mucosal healing and correlates with endoscopic and histologic inflammatory activity. The UCEIS seems to be as accurate as the MES in identifying patients with mucosal healing and as easy to use. The histologic activity index had a high concordance with recognized endoscopic score systems.

Do patient characteristics, disease, or treatment explain social inequality in survival from colorectal cancer? ☆

This paper investigates the association between individually measured socioeconomic status (SES) and all-cause survival in colorectal cancer patients, and explores whether factors related to the patient, the disease, or the surgical treatment mediate the observed social gradient. The data were derived from a nationwide clinical database of all adenocarcinomas of the colon or rectum diagnosed in Denmark between 2001 and 2004 (inclusive). These data were linked to those from several central registries providing information on income, education, and housing status, as well as to data on comorbidity from previous hospitalizations and use of medication. Only patients with colorectal cancer as their first primary tumour and those born after 1920 were included. A total of 8763 patients were included in the study. Cox proportional hazard regression models revealed a positive social gradient in survival for increasing levels of education and income, and in owners versus renters of housing. A series of regression analyses were used to test potential mediators of the association between the socioeconomic indicators and survival by stepwise inclusion of lifestyle factors (smoking, alcohol intake, body mass index), comorbidity, stage of disease, mode of admission, type of operation, specialization of the surgeon, and curative versus palliative resection. A causal diagram guided the analyses. Inclusion of comorbidity, and to a lesser extent lifestyle, reduced the variation associated with SES, while no evidence of a mediating effect was found for disease or surgical treatment factors. This indicates that the difference in survival among colorectal cancer patients from different social groups was probably not caused by unintentional differences in treatment factors related to surgery, and suggests that primary prevention of chronic diseases among the socially deprived might be one way to reduce social differences in prognosis.

Nutritional counselling in primary health care: a randomized comparison of an intervention by general practitioner or dietician

Aims To compare health effects and risk reduction in two different strategies of nutritional counselling in primary health care for patients at high risk of ischaemic heart disease. Methods In a cluster-randomized trial 60 general practitioners (GPs) in the Copenhagen County were randomized to give nutritional counselling or to refer patients to a dietician. Patients were included after opportunistically screening (n = 503 patients), and received nutritional counselling by GP or dietician over 12 months. Health effects were measured by changes in weight, waist circumference and blood lipids. Risk of cardiovascular disease was calculated by The Copenhagen Risk Score. Data on use of medicine and primary health care was obtained from central registers. Results Altogether 339 (67%) patients completed the intervention. Weight loss was larger in the dietician group (mean 4.5 kg vs. 2.4kg), and increase of HDL-cholesterol was larger in the GP group (mean 0.13mmol/l vs. 0.03mmol/l). The reduction of the cardiovascular risk score was significantly larger in the GP group (P = 0.0005). Other health outcomes were not significantly different. Conclusions GPs were aware of substantial risk factors of cardiovascular disease and addressed these when counselling. The guidance from a GP was of significant importance for risk reduction in relation to IHD. However, a long-term lifestyle intervention by GP was difficult to implement. In the case of obesity it was effective to refer to long-term nutritional counselling by a dietician.

The impact of socioeconomic factors on 30-day mortality following elective colorectal cancer surgery: a nationwide study.

We investigated postoperative mortality in relation to socioeconomic status (SES) in electively operated colorectal cancer patients, and evaluated whether social inequalities were explained by factors related to patient, disease or treatment. Data from the nationwide database of Danish Colorectal Cancer Group were linked to individual socioeconomic information in Statistics Denmark. Patients born before 1921 and those having local surgical or palliative procedures were excluded. A total of 7160 patients, operated on in the period 2001-2004, were included, of whom 342 (4.8%) died within 30 days of surgery. Postoperative mortality was significantly lower in patients with high income (odds ratio (OR)=0.82 (0.70-0.95) for each increase in annual income of EUR 13,500), higher education versus short education (OR)=0.60 (0.41-0.87), and owner-occupied versus rental housing (OR)=0.73 (0.58-0.93). Differences in comorbidity and to a lesser extent lifestyle characteristics accounted for the excess risk of postoperative death among low-SES patients.

The impact of a population-based multi-factorial lifestyle intervention on changes in long-term dietary habits: the Inter99 study.

OBJECTIVE To evaluate the effectiveness of a population-based multi-factorial lifestyle intervention on long-term changes in dietary habits compared to a non-intervention control group. METHODS The study was a randomized controlled lifestyle intervention study, Inter99 (1999-2006), Copenhagen, Denmark, using a high-risk strategy. Participants in the intervention group (n=6 091) had at baseline a medical health-examination and a face-to-face lifestyle counselling. Individuals at high risk of ischemic heart disease were repeatedly offered both individual and group-based counselling. The control group (n=3 324) was followed by questionnaires. Dietary habits were measured by a validated 48-item food frequency questionnaire and changes were analyzed by multilevel analyses. RESULTS At the 5-year follow-up the intervention group compared to the control group had significantly increased their intake of vegetables (men: net-change: 23 g/week; p=0.04; women: net-change: 27 g/week; p=0.005) and decreased the intake of highly saturated fats used on bread and for cooking (men: OR=0.59 (0.41-0.86); women: OR=0.42 (0.30-0.59)). Significant effects on fruit and fish intake were found at the 3-year follow-up but the effect attenuated at the 5-year follow-up. CONCLUSION A population-based multi-factorial lifestyle intervention promoted significant greater beneficial long-term dietary changes compared to the control group, especially the intake of vegetables and saturated fat was improved.