Michael Edlinger

Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults

Initial studies have indicated diabetes and obesity to be risk factors for hepatocellular carcinoma; but the association between other metabolic risk factors and primary liver cancer (PLC) has not been investigated. The metabolic syndrome and cancer project (Me‐Can) includes cohorts from Norway, Austria and Sweden with data on 578,700 subjects. We used Cox proportional hazard models to calculate relative risks (RRs) of PLC by body mass index (BMI), blood pressure and plasma levels of glucose, cholesterol and triglycerides as continuous standardized variables (z‐score with mean = 0 and standard deviation (SD) = 1) and their standardized sum of metabolic syndrome (MetS) z‐score. RRs were corrected for random error in measurements. During an average follow‐up of 12.0 years (SD = 7.8), 266 PLCs were diagnosed among cohort members. RR of liver cancer per unit increment of z‐score adjusted for age, smoking status and BMI and stratified by birth year, sex and sub‐cohorts, was for BMI 1.39 (95% confidence interval (CI) 1.24–1.58), mid blood pressure 2.08 (0.95–4.73), blood glucose 2.13 (1.55–2.94) cholesterol 0.62 (0.51–0.76) and serum triglycerides 0.85 (0.65–1.10). The RR per one unit increment of the MetS z‐score was 1.35 (1.12–1.61). BMI, glucose and a composite MetS score were positively and cholesterol negatively associated with risk of liver cancer.

Total serum cholesterol and cancer incidence in the Metabolic syndrome and Cancer Project (Me-Can).

Objective To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can). Methods Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation. Results In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph−/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph−/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83). Conclusion TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.

Evaluation of the PI-RADS Scoring System for Classifying mpMRI Findings in Men with Suspicion of Prostate Cancer

Purpose. To evaluate the ESUR scoring system (PI-RADS) for multiparametric MRI of the prostate in clinical routine and to define a reliable way to generate an overall PI-RADS score. Methods. Retrospective analysis of all patients with a history of negative prebiopsies, who underwent 3 Tesla multiparametric MRI from October 2011 to April 2013 (n = 143): PI-RADS scores for each single modality were defined. To generate the overall PI-RADS score, an algorithm based approach summing up each single-modality score to a sum-score was compared to a more subjective approach, weighting the single modalities dependent on the radiologists impression. Because of ongoing cancer suspicion 73 patients underwent targeted mpMRI-ultrasound image fusion rebiopsy. For this group thresholds for tumor incidences and malignancy were calculated. Results. 39 (53%) out of 73 targeted rebiopsies were cancer positive. The PI-RADS score correlated well with tumor incidence (AUC of 0.86, 95% CI 0.78 to 0.94) and malignancy (AUC 0.84, 95% CI 0.68 to 0.99). Regarding the sum-score a threshold of ≥10 turned out to be reliable for cancer detection (sensitivity 90%, specificity 62%) and for ≥13 for indicating higher malignancy (Gleason ≥4 + 3) (sensitivity 80%, specificity 86%). To generate the overall PI-RADS score, the use of an algorithm based approach was more reliable than that of the approach based on the radiologists impression. Conclusion. The presented scoring system correlates well with tumor incidence and malignancy. To generate the overall PI-RADS score, it seems to be advisable to use an algorithm based instead of a subjective approach.

Blood pressure and other metabolic syndrome factors and risk of brain tumour in the large population-based Me-Can cohort study

Objectives: Brain tumour has few established determinants. We assessed to which extent risk of brain tumour was related to metabolic syndrome factors in adults. Methods: In the Me-Can project, 580 000 individuals from Sweden, Austria, and Norway were followed for a median of 10 years after baseline measurement. Data on brain tumours were obtained from national cancer registries. The factors of metabolic syndrome (BMI, SBP and DBP, and blood levels of glucose, cholesterol, and triglycerides), separately and combined, were analysed in quintiles and for transformed z-scores (mean transformed to 0 and standard deviation to 1). Cox proportional hazards multivariate regression models were used, with corrections for measurement error. Results: During follow-up, 1312 primary brain tumours were diagnosed, predominantly meningioma (n = 348) and high-grade glioma (n = 436). For meningioma, the hazard ratio was increased for z-scores of SBP [hazard ratio = 1.27 per unit standard deviation, 95% confidence interval (CI) 1.03–1.57], of DBP (hazard ratio = 1.29, 95% CI 1.04–1.58), and of the combined metabolic syndrome score (hazard ratio = 1.31, 95% CI 1.11–1.54). An increased risk of high-grade glioma was found for DBP (hazard ratio = 1.23, 95% CI 1.01–1.50) and triglycerides (hazard ratio = 1.35, 95% CI 1.05–1.72). For both meningioma and high-grade glioma, the risk was more than double in the fifth quintiles of DBP compared to the lowest quintile. For meningioma this risk was even larger for SBP. Conclusion: Increased blood pressure was associated with risk of brain tumours, especially of meningiomas.

A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study.

Objective To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC). Methods The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements. Results During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73). Conclusion This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can)

Background  Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC).

The impact of distension pressure on acute endothelial cell loss and neointimal proliferation in saphenous vein grafts

OBJECTIVES We aimed to determine the extent of acute endothelial cell loss and neointimal proliferation in the long-term in saphenous vein grafts (SVGs) exposed to defined distension pressures. METHODS During routine competence testing of SVGs for coronary artery bypass grafting (CABG), blinded peak pressure measurements were performed in 10 patients. In an experimental set-up, distension pressure-related endothelial damage was studied in the SVGs of 20 patients. In a subgroup (n = 10), each patients SVG was divided into segments and subjected to four constant pressures (50, 100, 150 and 300 mmHg) for 30 min each. In another subgroup (n = 10), SVGs were exposed to a short phase of high pressure (low pressure followed by 300 mmHg for 5 min). Acute endothelial cell loss was quantified by CD31-immunostaining. After 2 weeks of organ culture, the neointimal proliferation was evaluated using histomorphometry. Pressure-related damage was compared with damage at baseline (0 mmHg). RESULTS During routine competence testing for CABG, we revealed a median peak pressure of 355 mmHg (range: 240-639 mmHg). In the experimental set-up, significant acute endothelial cell loss occurred at all tested distension pressures: at 50 mmHg, the median endothelial cell loss was 29% (range: 20-51%, P = 0.015), at 100 mmHg 54% (range: 37-69%, P < 0.001), at 150 mmHg 75% (range: 41-88%, P < 0.001), at 300 mmHg 91% (range: 63-100%, P < 0.001) and at short high-pressure exposure 65% (range: 49-82%, P < 0.001) in comparison with 20% (range: 0-44%) at baseline. Significant neointimal proliferation occurred when a distension pressure of 50 mmHg was exceeded: at 50 mmHg, median neointimal proliferation was 97 µm (range: 60-380 µm, P = 0.176), at 100 mmHg 168 µm (range: 100-600 µm, P = 0.001), at 150 mmHg 183 µm (range: 160-440 µm, P < 0.001) at 300 mmHg 347 µm (range: 190-590 µm, P < 0.001) and at short high-pressure exposure 130 µm (range: 60-410 µm, P = 0.02) in comparison with 90 µm (range: 60-170 µm) at baseline. CONCLUSIONS In vitro exposure of SVGs to low distension pressure ranges causes significant acute endothelial cell loss and crucial long-term damage, namely neointimal proliferation.

Mediation analysis of the relationship between sex, cardiovascular risk factors and mortality from coronary heart disease: Findings from the population-based VHM&PP cohort.

BACKGROUND In Europe, annually about 77,000 women, but 253,000 men die prematurely from coronary heart disease (CHD) before the age of 65 years. This gap narrows with increasing age and disappears after the eighth life decade. However, little is known regarding the contribution of cardiovascular risk factors to this sex difference. OBJECTIVE We investigated to what extent mens higher risk of dying from CHD is explained through a different risk factor profile, as compared to women. METHODS Mediation analysis technique was used to assess the specific contributions of blood pressure, cholesterol, glucose, and smoking to the difference between men and women regarding CHD mortality in a large Austrian cohort consisting of 117,264 individuals younger than 50 years (as a proxy for pre-menopausal status) and 54,998 older ones, with 3892 deaths due to CHD during a median follow-up of 14.6 years. RESULTS Adjusting for age and year of examination, we observed a male versus female CHD mortality hazard ratio (HR) of 4.7 (95% CI: 3.4-5.9) in individuals younger than 50 years, of which 40.9% (95% CI: 27.1%-54.7%) was explained through risk factor pathways, mainly through blood pressure. In older participants, there was a HR of 1.9 (95% CI: 1.8-2.0) of which 8.2% (95% CI: 4.6%-11.7%) was mediated through the risk factors. CONCLUSION The extent to which major risk factors contribute to the sex difference regarding CHD mortality decreases with age. The female survival advantage was explained to a substantial part through the pathways of major risk factors only in younger individuals.

Interface Management between General Practitioners and Rheumatologists—Results of a Survey Defining a Concept for Future Joint Recommendations

Objective To measure the views of general practitioners (GPs) and rheumatologists in a nationwide evaluation, so as to optimise their cooperation in managing patients with inflammatory rheumatic diseases. Methods A questionnaire covering aspects of collaboration was sent, both by mail and/or by email, to all GPs and rheumatologists in Austria. Topics covered were (i) examinations and interventions to be performed before referral, (ii) the spectrum of diseases to be referred, and (iii) the role of GPs in follow-up and continuous management of patients. Results 1,229 GPs of the 4,016 GPs (31%) and 110 of the 180 rheumatologists (61%) responded to the questionnaire. In cases of suspected arthritis, 99% of the GPs and 92% of the rheumatologists recommended specific laboratory tests, and 92% and 70%, respectively, recommended X-rays of affected joints before referral. Rheumatoid arthritis and spondyloarthritis, psoriatic arthritis and connective tissue disease were unanimously seen as indications for referral to a rheumatologist. Only 12% of rheumatologists felt responsible for the treatment of hand osteoarthritis and fibromyalgia. 80% of GPs and 85% of rheumatologists were of the opinion that treatment with disease-modifying drugs should be initiated by a specialist. Subsequent drug prescription and administration by GPs was supported by a majority of GPs and rheumatologists, with a concomitant rheumatologist follow-up every three to six months. Conclusion The considerable consensus between the two professional groups constitutes a solid base for future joint recommendations, with the aim to accelerate the diagnostic process and the initiation of adequate therapy.

Lifestyle-related biomarkers and endometrial cancer survival: Elevated gamma-glutamyltransferase as an important risk factor

BACKGROUND Lifestyle seems to play an important role in endometrial cancer mortality, but it remains unclear which biomarkers are involved. The aim of this study was to assess the extent of the association between lifestyle-related biomarkers and the survival of endometrial cancer patients. METHODS A sub-cohort of 242 endometrial cancer patients, from a population-based study of the more than 90,000 female participants of the Vorarlberg Health Monitoring and Promotion Programme, was followed for a median duration of twelve years. Besides age, tumour staging, and histology, also pre-diagnostic levels of body mass index, blood pressure, triglycerides, total cholesterol, glucose, gamma-glutamyltransferase (GGT), and serum uric acid were analysed in Cox proportional hazards regression models to estimate multivariate mortality risks. RESULTS During follow-up 89 deaths occurred of which 49 were cancer-related. Survival was associated with age, tumour stage, and histology. Of the biomarkers, log10-transformed GGT showed a large effect on cancer-related mortality (HR = 3.35, 95% CI 1.12-10.03), whereas the other parameters did not appear with significant effects after adjustment for the other factors. CONCLUSION Elevated level of GGT, a lifestyle-related marker, was associated with poor survival among endometrial cancer patients.