Centre Of Amsterdam Research Articles

Standard Pre- and Postoperative Determination of Chromogranin A in Resectable Non-Functioning Pancreatic Neuroendocrine Tumors - Diagnostic Accuracy: NF-pNET and Low Tumor Burden

Background: Chromogranin A (CgA) is often used in metastatic patients with nonfunctioning pancreatic neuroendocrine tumors (NF-pNET). The aim of this study is to assess the diagnostic accuracy of CgA in patients with low tumor burden. Methods: Resectable patients with NF-pNET without metastases at time of diagnosis were included between 2002 and 2013 in the Academic Medical Center of Amsterdam. CgA was determined at time of diagnosis and during follow-up according to a standardized method. The upper reference range was 94 µg/l. Results: Overall, 47 patients were included in this study. CgA was elevated preoperatively in only 10 patients (27%). In the detection of metastases during follow-up, the positive predictive value for CgA was 50% and negative predictive value was 81%. In 50% of the patients with an elevated CgA during follow-up, this test result was false-positive. Conclusions: The diagnostic accuracy of CgA was low preoperatively in patients with resectable NF-pNET and low tumor burden. In the detection of recurrent disease after curative resection of NF-pNET, the diagnostic accuracy of CgA was moderate (50%). We conclude that the routine measurement of CgA at time of diagnosis or during follow-up after curative resection had limited value in patients with resectable NF-pNET.

SSRIs increase risk of blood transfusion in patients admitted for hip surgery.

BackgroundRecent studies have shown that an increased bleeding tendency can be caused by Selective Serotonin Reuptake Inhibitors (SSRI) use. We aimed to investigate the occurrence and risk of blood transfusion in SSRI users compared to non-SSRI users in a cohort of patients admitted for hip-surgery.MethodsWe conducted a retrospective cohort study of patients who underwent planned or emergency hip surgery from 1996 to 2011 in the Academic Medical Center in Amsterdam. Primary outcome measure was risk of blood transfusion. Secondary outcome measures were pre- and postoperative hemoglobin level. Multivariate logistic regression was used to adjust for potential confounders.ResultsOne-hundred and fourteen SSRI users were compared to 1773 non-SSRI users. Risk of blood transfusion during admission was increased for SSRI users in multivariate analyses (OR 1.7 [95% CI 1.1–2.5]). Also, pre-operative hemoglobin levels were lower in SSRI users (7.8±1.0 mmol/L) compared to non-SSRI users (8.0±1.0 mmol/L) (p = 0.042)), as were postoperative hemoglobin levels (6.2±1.0 mmol/L vs. 6.4±1.0 mmol/L respectively) (p = 0.017)).ConclusionsSSRI users undergoing hip surgery have an increased risk for blood transfusion during admission, potentially explained by a lower hemoglobin level before surgery. SSRI use should be considered as a potential risk indicator for increased blood loss in patients admitted for hip surgery. These results need to be confirmed in a prospective study.

Shared Responsibility in International Law: A Conceptual Framework

his paper explores the phenomenon of the sharing of international responsibilities among multiple actors who contribute to injury to third parties. It examines the manifestations of shared responsibility, identifies the normative questions that it raises, assesses its possible consequences for international law and legal doctrine and sets forth a conceptual framework that allows us to analyze questions of shared responsibility. By doing so, the paper lays out the foundations, scope and ambitions of the SHARES Project - a five-year research project funded by the European Research Council and carried out by a research group at the Amsterdam Center for International Law. The paper more particularly explores the current framework of international state responsibility, how it can apply to situations of shared responsibility and what are its limits. It then suggests revisiting the foundations of international responsibility and proposes, in light of its public/private nature and objectives to move away from a unitary to differentiated regimes of international responsibility. It is within this new framework that some key normative questions, both substantial and procedural, that arise in situations of shared responsibility are discussed (joint and several liability, relationship between multiple wrongdoers, changes to the bilateral nature of international dispute settlement). The paper concludes with a 'semantic toolbox' of shared responsibility, defining concepts such as 'shared accountability', 'shared attribution or 'shared liability' which will provide a useful point of reference for subsequent research on the topic.

Striatal dopamine receptor binding in morbidly obese women before and after gastric bypass surgery and its relationship with insulin sensitivity

Striatal dopamine receptor binding in morbidly obese women before and after gastric bypass surgery and its relationship with insulin sensitivity

Editorial introductions

Editorial introductions

Safety and effectiveness using dexmedetomidine versus propofol TCI sedation during oesophagus interventions: a randomized trial

BackgroundEndoscopic treatment of early neoplastic lesions in oesophagus has evolved as a valid and less invasive alternative to surgical resection. These endoscopic interventions are minimal invasive treatment options usually done with sedation on an outpatient basis. The aim of this trial is to determine the safety and effectiveness of dexmedetomidine sedation compared to the standard used propofol TCI sedation during endoscopic oesophageal interventions.MethodsThe study will be performed as a randomized controlled trial. The first 64 consenting patients will be randomized to either the propofol or the dexmedetomidine group. Following endoscopy patients and gastroenterologists have to fill in questionnaires (PSSI, CSSI) (see abbreviations) about their sedation experiences. Additionally, patients have to accomplish the Trieger test before and after the procedure. Patient monitoring includes time adapted HR, SO2, ECG, NIBP, exCO2, NICO, sweat conductance measurement, OAA/S, and the Aldrete score. Effectiveness of sedation, classified by satisfaction levels and pain and sedation score measured by questionnaires is the primary outcome parameter. Respiratory and hemodynamic complications are surrogate parameters for the secondary outcome parameter “safety”.DiscussionThe acceptance level among patients after propofol sedation is high. Dexmedetomidine is a relatively new representative for procedural sedation. Has this new form of conscious sedation the potential to be safer and more effective for patients and endoscopists than propofol during endoscopic oesophageal interventions?Trial registrationThis trial is registered in the ISRCTN Register (ISRCTN 68599804). It will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Departments of Anesthesiology and Gastroenterology & Hepatology of the Academic Medical Center of Amsterdam are responsible for the design and conduct of the trial.

High-Resolution Anoscopy

High-resolution anoscopy is increasingly advocated to screen HIV+ men who have sex with men for anal cancer and its precursor lesions, anal intraepithelial neoplasia. A systematic comparison between clinical features and the histopathology of suspect lesions is lacking. This study aims to analyze interobserver agreement in classifying features of intra-anal lesions suspect for anal intraepithelial neoplasia and to compare these features with their histopathological outcome. This study is a cross-sectional survey regarding high-resolution anoscopy with images and biopsies of suspect lesions. Two dermatologists experienced in high-resolution anoscopy, blinded for histopathological outcome, independently classified the lesions on clinical features. This investigation was conducted at the Dermatology outpatient clinic of the Academic Medical Center in Amsterdam, The Netherlands. Included in the study were 163 HIV+ men who have sex with men, older than 18 years, with no history of anal cancer. The primary outcomes measured were the κ-coefficient for interobserver agreement and the proportions of anal intraepithelial neoplasia per clinical feature. Three hundred four biopsies were taken from 163 patients. One hundred sixty-eight biopsies (55%) showed anal intraepithelial neoplasia, and 67/304 (22%) showed high-grade anal intraepithelial neoplasia. The κ-coefficient was 0.65 for condylomatous lesions, 0.14 for surface configuration, 0.54 for punctation, 0.08 for mosaicism, and 0.43 for atypical vessels. Condylomatous lesions showed high-grade anal intraepithelial neoplasia in 18% (95% CI, 11%-27%). In lesions with flat leukoplakia, punctation, and atypical vessels, high-grade anal intraepithelial neoplasia was seen in 25%, 30%, and 23%. In lesions with the combination punctation/atypical vessels and punctation/flat leukoplakia/atypical vessels, high-grade anal intraepithelial neoplasia was found in 38% and 40%. We did not take biopsies of healthy-looking mucosa. Furthermore, the real-time description of features during high-resolution anoscopy, instead of the use of images, would improve the recognition of subtle mucosal abnormalities. A moderate to substantial interobserver agreement was demonstrated in recognizing condylomas, punctation, and atypical vessels. Furthermore, high-grade anal intraepithelial neoplasia is present in a high proportion of intra-anal condylomata. A combination of punctation, flat leukoplakia, and atypical vessels is the best predictor for high-grade anal intraepithelial neoplasia.

Seroepidemiology of High-Risk HPV in HIV-Negative and HIV-Infected MSM: The H2M Study

Men who have sex with men (MSM), in particular HIV-infected MSM, are at increased risk for diseases related to human papilloma virus (HPV). Our goal was to assess the effect of HIV status on the presence of type-specific antibodies against seven high-risk HPV types in HPV-unvaccinated MSM. Moreover, we compared determinants of HPV seropositivity between HIV-negative and HIV-infected MSM. MSM ≥18 years of age were recruited from the Amsterdam Cohort Studies, a sexually transmitted infection clinic, and an HIV-treatment center in Amsterdam, the Netherlands. Participants completed a risk-factor questionnaire; serum samples were analyzed using a fluorescent bead-based multiplex assay. MSM (n = 795) were recruited in 2010 to 2011; 758 MSM were included in this analysis. Median age was 40.1 years (interquartile range 34.8-47.5) and 308 MSM (40.6%) were HIV-infected. Seroprevalence of HPV-16 was 37.1% in HIV-negative and 62.7% in HIV-infected MSM (P < 0.001); seroprevalence of HPV-18 was 29.1% in HIV-negative MSM and 42.5% in HIV-infected MSM (P < 0.001). Similar patterns of seroprevalence were observed for HPV types 31, 33, 45, 52, and 58. In multivariable analyses, HPV seropositivity was associated with HIV infection [adjusted OR = 2.1; 95% confidence interval, 1.6-2.6]. In multivariable analyses stratified by HIV status, increasing age and number of lifetime male sex partners were significantly associated with HPV seropositivity in HIV-negative, but not HIV-infected MSM. Seroprevalence of high-risk HPV types is high among unvaccinated MSM. HIV infection is a strong and independent determinant for HPV seropositivity, which we hypothesize is because of increased persistence of HPV infection in HIV-infected MSM.

Uncertain Inheritance: Transgenerational Effects of Environmental Exposures

Andrea Cupp made a serendipitous discovery when she was a postdoctoral fellow at Washington State University: While investigating how chemicals affect sex determination in embryonic animals, she bred the offspring of pregnant rats that had been dosed with an insecticide called methoxyclor. When the males from that litter grew into adults, they had decreased sperm counts and higher rates of infertility. Cupp had seen these same abnormalities in the animals’ fathers, which had been exposed to methoxyclor in the womb. But this latest generation hadn’t been exposed that way, which suggested that methoxyclor’s toxic effects had carried over generations. “At first I couldn’t believe it,” says Cupp’s advisor, Michael Skinner, a biochemist and Washington State professor. “But then we repeated the breeding experiments and found that the results held up.” Skinner and Cupp, who is now a professor at the University of Nebraska–Lincoln, published their findings in 2005.1 Since that paper—which showed that reproductive effects not just from methoxyclor but also from the fungicide vinclozolin persisted for at least four generations—the number of published articles reporting similar transgenerational findings has increased steadily. “In the last year and half there’s been an explosion in studies showing transgenerational effects from exposure to a wide array of environmental stressors,” says Lisa Chadwick, a program administrator at the National Institute of Environmental Health Sciences (NIEHS). “This is a field that’s really starting to take off.” According to Chadwick, the new findings compel a reevaluation of how scientists perceive environmental health threats. “We have to think more long-term about the effects of chemicals that we’re exposed to every day,” she says. “This new research suggests they could have consequences not just for our own health and for that of our children, but also for the health of generations to come.” Figure 1 Glossary The NIEHS recently issued requests for applications totaling $3 million for research on transgenerational effects in mammals.2 Chadwick says funded studies will address two fundamental data needs, one pertaining to potential transgenerational mechanisms and another to the number of chemicals thought to exert these effects. These studies will extend to what’s known as the F3 generation—the great-grandchildren of the originally exposed animal. That’s because chemicals given to pregnant females (the F0 generation) interact not only with the fetal offspring (the F1 generation) but also the germ cells developing within those offspring, which mature into the sperm and eggs that give rise to the F2 generation. Thus, the F3 animals are the first generation to be totally unexposed to the original agent. Effects that extend to the F2 generation are known as “multigenerational,” whereas those that extend to the F3 generation are known as “transgenerational.”3 Transgenerational effects have now been reported for chemicals including permethrin, DEET, bisphenol A, certain phthalates, dioxin, jet fuel mixtures, nicotine, and tributyltin, among others. Most of these findings come from rodent studies.4,5,6,7 But preliminary evidence that chemical effects can carry over generations in humans is also emerging, although no F3 data have been published yet. Given the challenges of tracking effects over multiple human lifespans, the evidence is more difficult to interpret, particularly with respect to potential mechanisms, says Tessa Roseboom, a professor of early development and health at the Academic Medical Center in Amsterdam, the Netherlands. Still, some reports have linked nutritional deficiencies from famine and exposure to diethylstilbestrol (DES)—a nonsteroidal estrogen used to protect against miscarriage from the 1940s to the 1970s—to effects that persist among the grandchildren of exposed women.8,9,10,11,12,13

Diffusion capacity and BMPR2 mutations in pulmonary arterial hypertension

To the Editor: Pulmonary arterial hypertension (PAH) is a disease in which remodelling of the small pulmonary arteries leads to an increase in pulmonary artery pressure (PAP). The most important genetic predisposing factor related to PAH is a mutation in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ) [1, 2]. BMPR2 mutation carriers are known to present with disease at an earlier age and with worse haemodynamics [3]. We recently showed in a cohort of patients with idiopathic and hereditary PAH that a very low diffusion capacity for carbon monoxide ( D LCO) is exclusively found in some of the patients without identified BMPR2 mutations, whereas BMPR2 mutation carriers have a relatively preserved D LCO [4]. D LCO is a noninvasive marker of the quality of the alveolar capillary structure [5] and the observed difference in D LCO supports the hypothesis that distinct vascular disease processes are at play in BMPR2 mutation-related PAH and non BMPR2 mutation-related idiopathic PAH. Until recently, insufficient availability of lung samples has prohibited the performance of a detailed comparison of the pulmonary vascular pathologies in these two disease groups [6]. Therefore, we sought, in the present study, to confirm the previously found influence of BMPR2 mutations on diffusion capacity in a much larger multinational patient cohort. We performed a retrospective collaborative study at the VU University Medical Center in Amsterdam, the Netherlands and the Universite Paris-Sud, Assistance Publique Hopitaux de Paris, Le Kremlin-Bicetre, France. Patients were eligible for this study when classified in the database with idiopathic or familial PAH, and when the results from BMPR2 mutation analysis and D LCO measurements were available. Patients were diagnosed with idiopathic …

The Gathering Momentum of International and Supranational Action against Aggressive Tax Planning and Harmful Tax Competition: The State of Play of Recent Work of the OECD and European Union This article is an updated version of M.F. Nouwen, International and Supranational Action against Aggressive Tax Planning and Harmful Tax Competition Is Gaining Momentum Fast: The State of Play of Recent

The author explores the current state of play of global and EU efforts to address aggressive tax planning and harmful tax competition. He concludes that there is currently unprecedented consensus amongst the media, public, policymakers, non-governmental organizations and other tax activists in general to address this phenomenon, resulting in increasing national, supranational and international action and initiatives.

Determinants of adverse in-hospital outcome after cardiac surgery in adults with congenital heart disease

Purpose: Patients with congenital heart disease (CHD) often undergo right-sided surgery, and contribution of the right ventricle (RV) to their cardiac pump function is essential. We aimed to identify determinants of adverse outcome after cardiac surgery. Methods: 503 consecutive adults (56% male, median age 36 years) with CHD operated between January 2001 and January 2011 in the Academic Medical Center in Amsterdam were studied. RV function was considered normal for levels of TAPSE and TDI S' above 15mm and 11 cm/s respectively. RV failure was defined as combination of (1) elevated jugular venous pressure, (2) impaired RV function on transthoracic echocardiography and (3) diagnosis of RV failure was documented in the medical charts. Intensive care stay was prolonged if it exceeded four days. The composite end point of an adverse in-hospital outcome was operative mortality, RV failure, inotropes on intensive care, a prolonged intensive care stay, or all. Determinants of adverse outcome were evaluated by logistic regression analysis. Results: Nine patients (1,8%) died peri-operatively, 19 had RV failure, 83 needed inotropic therapy on intensive care and 21 had prolonged intensive care stay. The composite end point was reached in 91 patients (18,1%). Significant pre-operative determinants are shown in the Table. View this table: Table 1. Pre operative determinants of adverse outcome after congenital cardiac surgery Conclusion: Supraventricular arrhythmia, renal function and ventricular function were determinants of adverse in-hospital outcome after congenital cardiac surgery.

FRI0062 Evaluation of a multi-biomarker disease activity (vectra ™ da algorithm) in early rheumatoid arthritis and unclassified arthritis patients

BackgroundAccurate and frequent assessment of rheumatoid arthritis (RA) is critical for optimal treatment planning and would benefit from the availability of an objective, sensitive and robust way to measure disease...

Jay Donald Ostrow: The yellow giant

Jay Donald Ostrow: The yellow giant

3D Atlas of Human Embryology; creating an application as a new learning tool

Proper understanding of the complex morphogenetic processes underlying embryonic development is intimately associated with good three-dimensional insight into the developing structures. This, in turn, is exceedingly difficult to acquire with the currently available study tools. As a first attempt to provide such a learning tool we made an application, containing a 3D developmental series of human embryos. Digital images of serial sections of 34 human embryos of the Carnegie Collection between Carnegie stages 7 (15–17 days) and 23 (56–60 days) are used to create 3D reconstructions of all developing organ systems. The 3D reconstruction program Amira is used to align the sections and to manually annotate all structures in order to create the 3D models. Subsequently, game-development students used the program Blender to create low-poly surfaces, based on the original reconstructions and without the loss of necessary detail. This application is created by students, for students. Over 45 students contributed to this labor-intensive project, investing about 20,000 hours of work. The result is an impressive atlas covering the entire embryonic period and also containing additional quizzes and short textual explanations per stage and organ system. This study is supported in part by a grant from the Academic Medical Center in Amsterdam, The Netherlands. Grant Funding Source: AAA/AMC

The caregivers’ perspective on the end-of-life phase of glioblastoma patients

Glioblastoma multiforme (GBM) still harbors a fatal prognosis. The involvement of the neurocognition and psyche poses unique challenges for care provision by relatives. We lack data about the caregivers' perspective on the end-of-life (EOL) phase of GBM patients to improve counseling and support. In this study we investigated the experiences of 52 caregivers of deceased GBM patients treated in Austria. We used a questionnaire developed by the University Medical Centre of Amsterdam for exploration of the EOL-phase in glioma patients. The caregivers (17 men, 34 women) completed the questionnaire in median three years after the patients' death. 29 % of caregivers reported that they felt incompletely prepared for their tasks, however, those with higher education levels felt significantly better informed. 29 % suffered from financial difficulties, which was associated with burnout (60 %) and reduced quality of life (QOL). The patients' most common symptoms reported by caregivers were fatigue (87 %), reduced consciousness (81 %) and aphasia (77 %). 22 % of patients were bedbound during their last three months increasing to 80 % in the last week of life. The reported QOL of caregivers was very low and did not differ between caregivers of patients, who died at home (40 %) and caregivers of patients, who died in hospital (46 %). The caregiver reported that their QOL was only slightly better than the QOL they attributed to the patients. Furthermore, the high frequency of financial difficulties, burnout symptoms and feelings of insufficient information emphasize the urgent need for support and training dedicated to caregivers.

E. de Wet and J. Vidmar (eds), Hierarchy in International Law: The Place of Human Rights

The book under review, Hierarchy in International Law: The Place of Human Rights, is one outcome of a research project at the Amsterdam Center for International Law. The broader project has the title: ‘The emerging international constitutional order: the implications of hierarchy in international law for the coherence and legitimacy of international decision-making’. The debate on whether and in what manner the international legal order should be conceptualised in constitutional terms is long running and includes various theoretical perspectives. Hierarchy in International Law does not attempt to add another strand of theory to this debate. Rather it seeks to contribute to the debate by examining how international human rights law has been treated by judicial bodies when it conflicts with other international law. The premise of the book is that if international human rights law is treated by courts in a favourable manner when it conflicts with other international...

The Negative Predictive Value of Clinical Examination With or Without Anesthesia Versus Magnetic Resonance Imaging for Parametrial Infiltration in Cervical Cancer Stages IB1 to IIA

This study aimed to compare the negative predictive value (NPV) of clinical examination with or without anesthesia and magnetic resonance imaging (MRI) in identifying patients with cervical carcinoma without parametrial infiltration. This retrospective cohort study was conducted at the Academic Medical Center in Amsterdam. The medical files of 203 patients diagnosed with cervical cancer stages IB1-IIA, who underwent surgical treatment between January 1, 2003, and January 31, 2011, were reviewed. We compared clinical International Federation of Gynecology and Obstetrics staging and MRI during the staging procedure. The results were compared with the parametrial status by surgical-pathological investigation, which was considered to be the reference standard. Based on the surgical-pathological findings, 16.7% of the patients treated surgically had parametrial infiltration. For parametrial infiltration, examination under anesthesia (EUA) had an NPV of 65.3% and MRI of 76.9%, respectively. We found no significant difference between these NPVs. Examination under anesthesia and MRI are equal in identifying cervical cancer patients without parametrial infiltration with a tendency for MRI to perform better than EUA. When outpatient clinical staging is considered inconclusive, pretreatment staging may be limited to MRI. In these cases, EUA seems to have no additional value.

Regulatory Competition in Contract Law: Empirical Evidence and Normative ImplicationsThis article is a revised version of a paper presented at the Cambridge Centre of European Legal Studies, the Oxford Comparative Law Discussion Group and the Amsterdam Centre for the Study of European Contract Law. I thank all participants for their valuable comments. All remaining errors are mine.

Regulatory competition has been high on the agenda of lawyers and economists for several years. Initially, the focal point of the debate was corporate law. Only recently the attention has shifted to other areas of law, notably contract law. However, in contrast to corporate law where there is little doubt that states do compete for corporate charters both in the United States and in Europe, it is hotly debated whether there is – or whether there can be – regulatory competition in contract law. In the first part of the following article I argue that this question must be answered in the affirmative: empirical evidence shows that there is regulatory competition in contract law just like in other areas of law, notably corporate law. Most importantly, empirical evidence shows that businesses and consumers actually choose the applicable contract law based on the quality of the law and that states actually respond to these choices by adjusting their contract laws. With this finding, however, the discussion about regulatory competition in contract law has not yet reached its end. To the contrary: the fact that states actually do compete for application of their contract law raises a number of normative questions. Should regulatory competition be promoted because it induces a race to the top? Should it be banned because it induces a race to the bottom? In the second part of the paper I argue that regulatory competition in contract law will generally induce a race to the top. It should, therefore, generally be promoted. However, I also argue that regulatory competition may induce a race to the bottom in some cases, namely where a choice of law does not account for the interests of all parties affected by the choice. In these cases, I conclude, that regulatory competition should be regulated. More specifically, I argue that it should be regulated on the level of private international law by limiting freedom of choice.

High-sensitivity Troponin T Is Associated with Poor Outcome in Adults with Pulmonary Arterial Hypertension due to Congenital Heart Disease

Pulmonary arterial hypertension due to congenital heart disease (CHD-PAH) has a poor prognosis. We sought to determine whether the biomarker high-sensitivity troponin T (hsTnT) measured on routine visit at the outpatient clinic is associated with prognosis. Consecutive adult CHD-PAH (86% Eisenmenger syndrome) patients referred for advanced medical therapy between January 2005 and March 2007 in the Academic Medical Center in Amsterdam. Patients with severe renal impairment were excluded. The primary outcome was mortality. Of all 31 patients (mean age 45 ± 12 years) with CHD-PAH, eight patients died during a median follow-up of 5.6 (range 1.6 to 6.8) years. A hsTnT level >0.014 μg/L was the 99th percentile cutoff of the normal distribution and therefore defined as elevated. At baseline, elevated levels of hsTnT were found in eight patients (26%). In univariate Cox regression, hsTnT elevated at baseline, NT-pro-BNP and right ventricular function were determinants of death (P < .05 for all). Patients with elevated levels of hsTnT showed a significantly higher mortality rate as compared to patients with normal hsTnT levels (62% vs. 13%, P = .005). Levels of hsTnT were abnormal in a substantial proportion of CHD-PAH patients. A significant inverse relationship was found between hsTnT and survival.