Susan van Dieren

Cohort Profile: The EPIC-NL study

A major scientific challenge for the next few decades is to understand the interaction between genetic susceptibility and environmental factors in the aetiology of chronic diseases. The most promising approach to discover these interactions requires a combined effort of epidemiology and molecular genetics and large sample sizes for sufficient power. Already in the early 90s, the European Prospective Investigation Into Cancer and Nutrition (EPIC) was initiated in 10 European countries to create a large cohort to study the aetiology of chronic diseases. The Netherlands has contributed two cohort studies to EPIC: the Prospect cohort of 17 357 women of the Julius Center in Utrecht, and the Monitoring Project on Risk Factors for Chronic Diseases (MORGEN) cohort of 22 654 men and women of the National Institute for Public Health and the Environment (RIVM) in Bilthoven. In the design phase, both cohorts collaborated closely to obtain maximal synergy in the design of the questionnaires and to follow identical protocols in the collection of biological samples. Because of the efficiency gain in maintaining the cohort infrastructure and in conducting scientific analyses, the Julius Center and the RIVM decided to combine efforts to maintain and expand the cohorts and biobanks by merging them into one EPICNetherlands (EPIC-NL) study.

Laparoscopic peritoneal lavage or sigmoidectomy for perforated diverticulitis with purulent peritonitis : a multicentre, parallel-group, randomised, open-label trial

BACKGROUND Case series suggest that laparoscopic peritoneal lavage might be a promising alternative to sigmoidectomy in patients with perforated diverticulitis. We aimed to assess the superiority of laparoscopic lavage compared with sigmoidectomy in patients with purulent perforated diverticulitis, with respect to overall long-term morbidity and mortality. METHODS We did a multicentre, parallel-group, randomised, open-label trial in 34 teaching hospitals and eight academic hospitals in Belgium, Italy, and the Netherlands (the Ladies trial). The Ladies trial is split into two groups: the LOLA group comparing laparoscopic lavage with sigmoidectomy and the DIVA group comparing Hartmanns procedure with sigmoidectomy plus primary anastomosis. The DIVA section of this trial is still underway but here we report the results of the LOLA section. Patients with purulent perforated diverticulitis were enrolled for LOLA, excluding patients with faecal peritonitis, aged older than 85 years, with high-dose steroid use (≥20 mg daily), and haemodynamic instability. Patients were randomly assigned (2:1:1; stratified by age [<60 years vs ≥60 years]) using secure online computer randomisation to laparoscopic lavage, Hartmanns procedure, or primary anastomosis in a parallel design after diagnostic laparoscopy. Patients were analysed according to a modified intention-to-treat principle and were followed up after the index operation at least once in the outpatient setting and after sigmoidoscopy and stoma reversal, according to local protocols. The primary endpoint was a composite endpoint of major morbidity and mortality within 12 months. This trial is registered with ClinicalTrials.gov, number NCT01317485. FINDINGS Between July 1, 2010, and Feb 22, 2013, 90 patients were randomly assigned in the LOLA section of the Ladies trial when the study was terminated by the data and safety monitoring board because of an increased event rate in the lavage group. Two patients were excluded for protocol violations. The primary endpoint occurred in 30 (67%) of 45 patients in the lavage group and 25 (60%) of 42 patients in the sigmoidectomy group (odds ratio 1·28, 95% CI 0·54-3·03, p=0·58). By 12 months, four patients had died after lavage and six patients had died after sigmoidectomy (p=0·43). INTERPRETATION Laparoscopic lavage is not superior to sigmoidectomy for the treatment of purulent perforated diverticulitis. FUNDING Netherlands Organisation for Health Research and Development.

Gamma‐glutamyltransferase, cardiovascular disease and mortality in individuals with diabetes mellitus

Increased plasma activity of gamma‐glutamyltransferase (GGT) is associated with cardiovascular diseases (CVD) and mortality in the general population. We investigated the association between GGT, CVD and mortality in individuals with diabetes mellitus.

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus

Background We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors. Methods and Results We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition‐NL (EPIC‐NL). The associations of 23 biomarkers (adiponectin, C‐reactive protein, epidermal‐type fatty acid binding protein, heart‐type fatty acid binding protein, basic fibroblast growth factor, soluble FMS‐like tyrosine kinase‐1, soluble intercellular adhesion molecule‐1 and ‐3, matrix metalloproteinase [MMP]‐1, MMP‐3, MMP‐9, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E‐selectin, P‐selectin, tissue inhibitor of MMP‐1, thrombomodulin, soluble vascular cell adhesion molecule‐1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c‐statistic and net reclassification index (NRI; continuous and based on 10‐year risk strata 0–10%, 10–20%, 20–30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, and MMP‐3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c‐statistic with 0.03 (95% CI 0.01–0.05), and the continuous NRI was 0.37 (95% CI 0.21–0.52). In EPIC‐NL, the multimarker model increased the c‐statistic with 0.03 (95% CI 0.00–0.03), and the continuous NRI was 0.44 (95% CI 0.23–0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03–0.21) in SMART and 0.07 (95% CI −0.04–0.17) in EPIC‐NL. Conclusions Of the 23 evaluated biomarkers from different pathophysiological pathways, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, MMP‐3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited.

Outcome and Learning Curve in 159 Consecutive Patients Undergoing Total Laparoscopic Hemihepatectomy

Importance Widespread implementation of laparoscopic hemihepatectomy is currently limited by its technical difficulty, paucity of training opportunities, and perceived long and harmful learning curve. Studies confirming the possibility of a short and safe learning curve for laparoscopic hemihepatectomy could potentially benefit the further implementation of the technique. Objective To evaluate the extent and safety of the learning curve for laparoscopic hemihepatectomy. Design, Setting, and Participants A prospectively collected single-center database containing all laparoscopic liver resections performed in our unit at the University Hospital Southampton National Health Service Foundation Trust between August 2003 and March 2015 was retrospectively reviewed; analyses were performed in December 2015. The study included 159 patients in whom a total laparoscopic right or left hemihepatectomy procedure was started (intention-to-treat analysis), including laparoscopic extended hemihepatectomies and hemihepatectomies with additional wedge resections, at a tertiary referral center specialized in laparoscopic hepato-pancreato-biliary surgery. Main Outcomes and Measures Primary end points were clinically relevant complications (Clavien-Dindo grade ≥III). The presence of a learning curve effect was assessed with a risk-adjusted cumulative sum analysis. Results Of a total of 531 consecutive laparoscopic liver resections, 159 patients underwent total laparoscopic hemihepatectomy (105 right and 54 left). In a cohort with 67 men (42%), median age of 64 years (interquartile range [IQR], 51-73 years), and 110 resections (69%) for malignant lesions, the overall median operation time was 330 minutes (IQR, 270-391 minutes) and the median blood loss was 500 mL (IQR, 250-925 mL). Conversion to an open procedure occurred in 17 patients (11%). Clinically relevant complications occurred in 17 patients (11%), with 1% mortality (death within 90 days of surgery, n = 2). Comparison of outcomes over time showed a nonsignificant decrease in conversions (right: 14 [13%] and left: 3 [6%]), blood loss (right: 550 mL [IQR, 350-1150 mL] and left: 300 mL [IQR, 200-638 mL]), complications (right: 15 [14%] and left: 4 [7%]), and hospital stay (right: 5 days [IQR, 4-7 days] and left: 4 days [IQR, 3-5 days]). Risk-adjusted cumulative sum analysis demonstrated a learning curve of 55 laparoscopic hemihepatectomies for conversions. Conclusions and Relevance Total laparoscopic hemihepatectomy is a feasible and safe procedure with an acceptable learning curve for conversions. Focus should now shift to providing adequate training opportunities for centers interested in implementing this technique.

Preoperative biliary drainage in perihilar cholangiocarcinoma: identifying patients who require percutaneous drainage after failed endoscopic drainage

BACKGROUND AND STUDY AIMS Preoperative biliary drainage is often initiated with endoscopic retrograde cholangiopancreatography (ERCP) in patients with potentially resectable perihilar cholangiocarcinoma (PHC), but additional percutaneous transhepatic catheter (PTC) drainage is frequently required. This study aimed to develop and validate a prediction model to identify patients with a high risk of inadequate ERCP drainage. PATIENTS AND METHODS Patients with potentially resectable PHC and (attempted) preoperative ERCP drainage were included from two specialty center cohorts between 2001 and 2013. Indications for additional PTC drainage were failure to place an endoscopic stent, failure to relieve jaundice, cholangitis, or insufficient drainage of the future liver remnant. A prediction model was derived from the European cohort and externally validated in the USA cohort. RESULTS Of the 288 patients, 108 (38%) required additional preoperative PTC drainage after inadequate ERCP drainage. Independent risk factors for additional PTC drainage were proximal biliary obstruction on preoperative imaging (Bismuth 3 or 4) and predrainage total bilirubin level. The prediction model identified three subgroups: patients with low risk (7%), moderate risk (40%), and high risk (62%). The high-risk group consisted of patients with a total bilirubin level above 150 µmol/L and Bismuth 3a or 4 tumors, who typically require preoperative drainage of the angulated left bile ducts. The prediction model had good discrimination (area under the curve 0.74) and adequate calibration in the external validation cohort. CONCLUSIONS Selected patients with potentially resectable PHC have a high risk (62%) of inadequate preoperative ERCP drainage requiring additional PTC drainage. These patients might do better with initial PTC drainage instead of ERCP.

HbA1c measured in stored erythrocytes is positively linearly associated with mortality in individuals with diabetes mellitus.

Introduction Observational studies have shown that glycated haemoglobin (HbA1c) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA1c measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality. Methods Within the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA1c was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA1c in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles. Results After a median follow-up of 9.3 years, 460 participants died. Higher HbA1c was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity =0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA1c and medication. Conclusion This prospective study showed that persons with lower HbA1c had better survival than those with higher HbA1c. The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA1c appears to be associated with reduced mortality risk.

Effects of blood pressure lowering on cardiovascular outcomes in different cardiovascular risk groups among participants with type 2 diabetes

AIMS To asses differences in treatment effects of a fixed combination of perindopril-indapamide on major clinical outcomes in patients with type 2 diabetes across subgroups of cardiovascular risk. METHODS 11,140 participants with type 2 diabetes, from the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The Framingham equation was used to calculate 5-year CVD risk and to divide participants into two risk groups, moderate-high risk (<25% and no history of macrovascular disease), very high risk (>25% and/or history of macrovascular disease). Endpoints were macrovascular and microvascular events. RESULTS The mean age of participants was 66 years (42.5% female). 1000 macrovascular and 916 microvascular events were recorded over follow-up of 4.3 years. Relative treatment effects were similar across risk groups, (all P-values for heterogeneity ≥0.38). Hazard ratios for combined macro- and microvascular events were 0.89 (0.77-1.03) for the moderate-high risk and 0.92 (0.81-1.03) for the very high risk. Absolute treatment effects tended to be greater in the high risk groups although differences were not statistically significant (P>0.05). CONCLUSIONS Relative effects of blood pressure lowering with perindopril-indapamide on cardiovascular outcomes were similar across risk groups whilst absolute effects trended to be greater in the high risk group.

Continuous wound infiltration or epidural analgesia for pain prevention after hepato-pancreato-biliary surgery within an enhanced recovery program (POP-UP trial): study protocol for a randomized controlled trial

BackgroundPostoperative pain prevention is essential for the recovery of surgical patients. Continuous (thoracic) epidural analgesia (CEA) is routinely practiced for major abdominal surgery, but evidence is conflicting on its benefits in this setting. Potential disadvantages of epidural analgesia are a) perioperative hypotension, frequently requiring additional intravenous fluid boluses or prolonged use of vasopressors; b) relatively high failure rates, with periods of inadequate analgesia; and c) the risk of rare but serious, at times persistent, neurologic complications (hematoma and abscess). In recent years, continuous (subfascial) wound infiltration (CWI) plus patient-controlled analgesia (PCA) has been suggested as a safe and reliable alternative, which does not have the previously mentioned disadvantages, but evidence from multicenter trials targeting a specific surgical population is lacking. We hypothesize that CWI+PCA is equally as effective as CEA, without the mentioned disadvantages.Methods/designPOP-UP is a randomized controlled noninferiority multicenter trial, recruiting adult patients scheduled for elective hepato-pancreato-biliary surgery via laparotomy in an enhanced recovery setting. A total of 102 patients are being randomly allocated to CWI+PCA or (P)CEA. Our primary endpoint is the Overall Benefit of Analgesic Score (OBAS), a composite endpoint of pain intensity, opioid-related adverse effects and patient satisfaction, during postoperative days 1 to 5. Secondary endpoints include length of the hospital stay, number of patients with severe pain, and the use of rescue medication.DiscussionPOP-UP is a pragmatic trial that will provide evidence of whether CWI+PCA is noninferior as compared to (P)CEA after elective hepato-pancreato-biliary surgery via laparotomy in an enhanced recovery setting. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of this technique, especially when the described disadvantages of epidural analgesia are less often observed with CWI+PCA.Trial registrationNetherlands Trial Register NTR4948 (registry date 2 January 2015).

Effect of goal-directed therapy on outcome after esophageal surgery: A quality improvement study

Background Goal-directed therapy (GDT) can reduce postoperative complications in high-risk surgery patients. It is uncertain whether GDT has the same benefits in patients undergoing esophageal surgery. Goal of this Quality Improvement study was to evaluate the effects of a stroke volume guided GDT on post-operative outcome. Methods and findings We compared the postoperative outcome of patients undergoing esophagectomy before (99 patients) and after (100 patients) implementation of GDT. There was no difference in the proportion of patients with a complication (56% vs. 54%, p = 0.82), hospital stay and mortality. The incidence of prolonged ICU stay (>48 hours) was reduced (28% vs. 12, p = .005) in patients treated with GDT. Secondary analysis of complication rate showed a decrease in pneumonia (29 vs. 15%, p = .02), mediastinal abscesses (12 vs. 3%, p = .02), and gastric tube necrosis (5% vs. 0%, p = .03) in patients treated with GDT. Patients in the GDT group received significantly less fluids but received more colloids. Conclusions The implementation of GDT during esophagectomy was not associated with reductions in overall morbidity, mortality and hospital length of stay. However, we observed a decrease in pneumonia, mediastinal abscesses, gastric tube necrosis, and ICU length of stay.