http://repub.eur.nl/res/aut/4113/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/7217/ 2006-01-11T00:00:00Z In chapter 1 a brief description of the scientific strategy followed in the papers that form the main part of this thesis is given, along with a division in study categories. Here this division will be followed. There are 3 descriptive studies, 3 hypothesis-generating observational studies and 2 hypothesis-testing observational studies. The distinction between these study types is, however, not always very clear. Both the descriptive and the hypothesis-testing studies contain elements that can be regarded as hypothesis-generating. The first descriptive study can be found in chapter 2. It marks the field by describing the group of patients referred to the Erasmus Medical Center Rotterdam department of Hepatology for liver transplantation from 1986 through 2002, as well as the treatment decisions and outcomes in this group. Also, the fields covered by the studies in the following chapters are pointed out. No attempt is made here to generate hypotheses. Three exceptional patients that have survived for more than 10 years after heterotopic liver transplantation are described in chapter 4b. Heterotopic liver transplantation is a surgical technique designed to solve some of the problems of the conventional orthotopic procedure by avoiding the removal of the patient's own liver. Heterotopic transplantation has never become a viable alternative for orthotopic transplantation, and was abandoned even in Rotterdam after 23 were done in the 5-year period between 1986 and 1990. In this paper the possibility is raised that recipients of heterotopic liver grafts are protected from hepatocellular carcinoma development in their own liver by the nearly complete atrophy of this organ. Admittedly, this statement can hardly be called a hypothesis because it cannot really be tested. Chapter 5b hosts the last descriptive paper. Here details are given on the long-term follow up of patients transplanted for acute liver failure. The main finding is that complete rehabilitation is the rule rather than the exception in patients that survive after transplantation, though there are some frequently occurring complications that become even more prevalent over 109 CHAPTER 8: Summary the period from 5 to 10 years after the operation. These complications are obesity, dyslipidemia, hypertension and a moderate decline of the renal function. The hypothesis that can be distilled a from our data is that modification and minimisation of the immunosuppressive treatment might reduce the number and severity of long-term complications. The hypothesis-generating part starts with chapter 3a, where the Model for End-stage Liver Disease (MELD) developed by the Mayo Clinics in the United States is examined. The hypothesis arising from this study is that a simplified model containing only two of the factors used in MELD transformed into their natural logarithms predicts mortality on the waiting list for liver transplantation better than MELD does in its original form. In the same paper partial external validation of this new model is presented. The effect of disease severity in patients with Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis on the outcome after enlistment for liver transplantation is the subject of study in chapter 3b. Here it is shown that the optimal timing of transplantation depends on the choice of the starting point for the analysis and of the outcome measure. The best absolute survival is found when low-risk patients are transplanted, but the largest survival benefit is found in the high-risk group. The resulting hypothesis is that transplanting patients with chronic cholestatic liver diseases before they reach a more advanced stage of their disease is the optimal strategy, at least from the perspective of the patient. A type of study similar to that in chapter 3a is presented in chapter 6. Here we identify the factors associated with the occurrence of early acute rejection after liver transplantation in our patient group using the Cox proportional hazard rate model. The resulting hypothesis is that a risk score derived from this model can be used to separate patient groups with low and high risks of acute rejection, that could possibly benefit from a level of postoperative immunosuppression adjusted to this risk. Two studies can be qualified as hypothesis-testing. In chapter 4a the claim that the results of heterotopic liver transplantation for end-stage chronic liver disease are superior to those of the conventional orthotopic procedure is examined in an observational study covering a relatively long period and using a case-control approach. This study has a number of shortcomings, but still provides the best evidence available that the hypothesis should be rejected, at least for the specific liver diseases forming the indication for transplantation in our patients. In hindsight, a somewhat more definitive answer would have been given by a less complex analysis of patient survival on an intention-to-treat basis, disregarding the crossover of one patient from the case group to the control group at the time of retransplantation. Apart from that, based on the observations in this study CHAPTER 8: Summary two other hypotheses can be formulated. One is that the use of a partial liver graft in patients at a more-than-average risk of developing malignant diseases further increases this risk. The second one, explicitly stated in chapter 7, is that heterotopic transplantation may still be superior to orthotopic transplantation in the setting of a living related donor program. Finally, in chapter 3a the hypothesis that emergency liver transplantation improves the survival for patients with acute liver failure is tested in another observational study. Although the alternative hypothesis that there is no effect cannot be rejected on statistical grounds, our data strongly suggest that the original hypothesis is correct. It should be noted that it is hard to reach statistical significance here because of the relatively small number of patients that died before they could be transplanted in our single-centre study. Our paper does, however, point out the optimal statistical method to test the hypothesis in a larger study that does not rely on historical controls. http://repub.eur.nl/res/pub/13287/ 2004-01-01T00:00:00Z Focal nodular hyperplasia (FNH) is the second most common benign liver tumor after hemangioma. FNH is classified into two types: classic (80% of cases) and nonclassic (20%). Distinction between FNH and other hypervascular liver lesions such as hepatocellular adenoma, hepatocellular carcinoma, and hypervascular metastases is critical to ensure proper treatment. An asymptomatic patient with FNH does not require biopsy or surgery. Magnetic resonance (MR) imaging has higher sensitivity and specificity for FNH than does ultrasonography or computed tomography. Typically, FNH is iso- or hypointense on T1-weighted images, is slightly hyper- or isointense on T2-weighted images, and has a hyperintense central scar on T2-weighted images. FNH demonstrates intense homogeneous enhancement during the arterial phase of gadolinium-enhanced imaging and enhancement of the central scar during later phases. Familiarity with the proper MR imaging technique and the spectrum of MR imaging findings is essential for correct diagnosis of FNH. http://repub.eur.nl/res/pub/3848/ 2002-02-11T00:00:00Z A human monoclonal antibody type IgG4, designated 1Ff4, was obtained by Epstein Barr virus transformation of peripheral blood lymphocytes from a hepatitis B vaccinee (HB-VAX: plasma-derived vaccine) after one boost of yeast recombinant DNA derived vaccine (Engerix-B). 1Ff4 binds preferentially to HBsAg/adw(2) and HBsAg/ayw(1). In binding experiments, it competes with antibodies induced by vaccination with HB-VAX-DNA (yeast recombinant) and HB-VAX (plasma-derived vaccine). 1Ff4 competes in part with a monoclonal antibody for the w/r region. Partial inhibition of binding of HBsAg/adw(2) to solid phase anti-HBs was detected, resembling inhibition obtained using other human monoclonal specific for the "a"-loop. 1Ff4 does not bind to linear peptides covering the two "a"-loops or to an adw(2)/G145R mutant, its binding to wild type HBsAg strongly depends on the presence of disulphide bonds. In a large series of HBsAg-positive samples from an endemic area, 1Ff4 antibodies were successfully used to discriminate between an adw(2) and an adrq+ strain. The characterisation of 1Ff4 and other human monoclonal anti-HBs antibodies may help to understand the fine specificity of protective antibodies elicited by immunization.