http://repub.eur.nl/res/aut/13813/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30047/ 2008-03-01T00:00:00Z Testicular germ cell tumors of adolescents and adults (TGCTs) can be classified into seminomatous and nonseminomatous tumors. Various nonseminomatous cell lines, predominantly embryonal carcinoma, have been established and proven to be valuable for pathobiological and clinical studies. So far, no cell lines have been derived from seminoma which constitutes more than 50% of invasive TGCTs. Such a cell line is essential for experimental investigation of biological characteristics of the cell of origin of TGCTs, i.e., carcinoma in situ of the testis, which shows characteristics of a seminoma cell. Before a cell line can be used as model, it must be verified regarding its origin and characteristics. Therefore, a multidisciplinary approach was undertaken on TCam-2 cells, supposedly the first seminoma cell line. Fluorescence in situ hybridization, array comparative genomic hybridization, and spectral karyotyping demonstrated an aneuploid DNA content, with gain of 12p, characteristic for TGCTs. Genome wide mRNA and microRNA expression profiling supported the seminoma origin, in line with the biallelic expression of imprinted genes IGF2/H19 and associated demethylation of the imprinting control region. Moreover, the presence of specific markers, demonstrated by immunohistochemistry, including (wild type) KIT, stem cell factor, placental alkaline phosphatase, OCT3/4 (also demonstrated by a specific Q-PCR) and NANOG, and the absence of CD30, SSX2-4, and SOX2, confirms that TCam-2 is a seminoma cell line. Although mutations in oncogenes and tumor suppressor genes are rather rare in TGCTs, TCam-2 had a mutated BRAF gene (V600E), which likely explains the fact that these cells could be propagated in vitro. In conclusion, TCam-2 is the first well-characterized seminoma-derived cell line, with an exceptional mutation, rarely found in TGCTs. http://repub.eur.nl/res/pub/30120/ 2008-01-01T00:00:00Z A 40-year-old woman presented with blurred vision and diplopia, followed by slowly progressive left-sided motor and sensory disturbances. She also suffered from memory loss and had mild spatial and temporal disorientation. A T2-weighted MRI showed a large area of high signal intensity in the periventricular white matter of the right more than the left occipital region and the corpus callosum, without enhancement on T1-weighted images after gadolinium administration and without mass effect. A stereotacticbiopsy of the intracerebral lesion showed blast-like neoplastic cells within a mononuclear infiltrate. No diagnosis could be made based on morphology and immunohistochemistry using a large series of markers. However, based on positive OCT3/4 nuclear staining, the tumor was diagnosed as a germinoma (seminoma of the brain). The patient was treated accordingly and her condition improved, although focal deficits remained. http://repub.eur.nl/res/pub/10637/ 2007-11-14T00:00:00Z Genesis of a new individual starts by fusion of the female egg and male sperm forming the fertilized egg called the zygote. This single cell will divide and the repeated division of its daughter cells will eventually give rise to approximately 100 million million cells that constitute an adult human being. Along this path of development the cells will acquire specialized features and skills necessary for performing their specific function within the organism; the cells have differentiated. If and how a cell will differentiate is dependent on the potency of the cell and the stimuli it receives from the environment. The first cell(s) of the embryo can differentiate to the complete gamut of somatic cells and germ cells, and are therefore pluripotent. The process of differentiation of germ cells starts in the first weeks of embryonal development and culminates in the formation of highly specialized germ cells, i.e. egg and spermatozoon, around puberty. Germ cells that fail to properly differentiate during development can give rise to germ cell tumors. Depending on the time point of derailment of normal germ cell development, different types of germ cell tumors can arise. This thesis focuses on germ cell tumors of adolescents and young adults that derive from an early germ cell that has not yet differentiated to a cell committed to male or female germ cell development. Reminiscent of their origin these tumors are pluripotent and have features that are only present in cells of early embryonic development. This includes the presence of proteins involved in regulation of pluripotency like OCT3/4, also known as POU5F1. Because OCT3/4 is unique to stem cells and germ cells in the early embryo and normally not present in the adult human, we can use OCT3/4 in diagnosis of germ cell tumors in adults. http://repub.eur.nl/res/pub/31904/ 2002-04-03T00:00:00Z Part one of this thesis contains the general introduction to partial and whole liver transplantation. Chapter 2 addresses the concept of auxiliary partial liver transplantation. Auxiliary partial heterotopic liver transplantation was first introduced as a less invasive procedure for patients who could not tolerate a standard orthotopic liver transplantation. Later on the technique was proposed for patients with acute liver failure in whom regeneration of the native liver was expected, but due to its complications it never gained wide acceptance. Since 1990 a new concept of auxiliary partial liver transplantation was introduced where the graft is placed in the orthotopic position. In chapter 3 the development and current surgical technique of orthotopic liver transplantation are discussed. Initially the diseased liver was removed with the vena cava and replaced by a whole liver graft. With increasing waiting lists for donor organs, surgical techniques were developed to split the donor liver and transplant both partial liver grafts in the orthotopic position. In part two three studies regarding experimental auxiliary partial liver transplantation are presented. In chapter 4 we report the long-term correction of an inborn error of metabolism with an auxiliary partial liver graft placed in a heterotopic position. Since the distribution of portal blood flow between liver graft and native liver remains controversial in auxiliary liver transplantation, the success of metabolic correction was related to four different forms of portal inflow. With the introduction of auxiliary partial orthotopic liver transplantation several disadvantages of the placement of the graft in heterotopic liver transplantation were overcome. In chapter 5 we therefore assess the importance of portal flow diversion in an experimental model of auxiliary partial liver transplantation in the orthotopic position. The portal blood flow was measured with Doppler ultrasonography and changes in portal flow distribution were recorded after surgical intervention in the portal blood flow. In chapter 6 the metabolic correction following these interventions in portal flow were reported. Part three contains three studies performed in patients receiving an orthotopic whole liver transplantation. In chapter 7 we present the problem of graft dysfunction in the first 7 days after liver transplantation. We report our data on mitochondrial dysfunction in patients with primary graft dysfunction and the relation with toxic reaction products of the nitric oxide radical. In chapter 8 we report an increased incidence of fibrinolysis, the most prominent coagulation disorder during orthotopic liver transplantation, after introduction of virus inactivated plasma. Consequences of fibrinolysis and treatment options are discussed. In chapter 9 we evaluate patient and graft survival between patients transplanted with standard liver replacement or a vena cava preserving technique. Chapter 10 provides an overview of the development of different techniques for splitting of the donor liver in an attempt to alleviate the shortage of donor organs in paediatric and adult liver transplantation. Chapter 11 summarises the previous studies, bringing the data in perspective and provides future perspectives.