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Adam en Eva en andere verhalen over genetica.
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ISBN: 9058560139 Year: 2000 Publisher: Oostkamp Stichting kunstboek

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Het genetische onderzoek dat wetenschappelijke vorsers uitvoeren, is niet langer een zaak voor het laboratorium maar hoort thuis in het hart van onze maatschappij. Genetische technologie wordt gebruikt bij gerechtelijk onderzoek en als bewijs van historische vooronderstellingen. Bovendien wil de mens ook een keuze maken in de bepaling van zijn biologische oorsprong. Kinderen op maat gemaakt lijken plots niet meer veraf. Ingrepen in onze genetica hebben evenwel ook hun invloed op verzekerbaarheid, tewerkstelling en de privé-sfeer in het algemeen. De cruciale vraag dringt zich dan ook op of genetische testen leed voorkomen dan wel dat leed eerder veroorzaken. In hun boek Adam en Eva en andere verhalen over genetica schetsen David en Jean-Jacques Cassiman een duidelijk beeld van de Menselijke Erfelijkheid aan het begin van een nieuwe eeuw. Op een uiterst toegankelijke en intrigerende manier maken zij een balans op en plaatsen ze de feiten tegenover de emoties.


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The neural/neuroendocrine compartment of the liver : differentiation potential of the hepatic stellate cell
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ISBN: 9058671836 Year: 2001 Volume: 248 Publisher: Leuven Leuven university press,

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Dissertation
Analysis of market access of orphan drugs for rare diseases
Authors: --- --- --- --- --- et al.
Year: 2014 Publisher: Leuven KU Leuven. Faculty of Pharmaceutical Sciences

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This project carries out an analysis of market access of orphan drugs for rare diseases. In the European Union (EU), orphan drugs are intended for the diagnosis, prevention or treatment of rare diseases. These rare diseases are life-threatening or chronically seriously debilitating conditions affecting no more than five in 10,000 persons in the EU. Worldwide, policies are available to stimulate the development and marketing of orphan drugs. Such policies serve to compensate industry for the risks and lower potential return on investment due to the low number of patients. Part 1 of this project, the general introduction, provides the definitions and background related to orphan drugs and rare diseases and presents an overview of the different steps of market access of orphan drugs in the EU. The contents of this project reflect these steps, i.e. orphan designation and marketing authorization are discussed in part 2, pricing is discussed in part 3, reimbursement in part 4 and uptake in part 5. The general introduction also provides an overview of the arguments for and against attributing special status to orphan drugs. Studies on the registration of orphan drugs are reported in part 2. An evaluation of the orphan drug policies in the EU by orphan drug experts is provided in chapter 2.1. Experts perceive the orphan drug policies in the EU as useful. Within the context of continuing to optimize patient access to orphan drugs, several policy recommendations were formulated such as defining the concept of sufficiently profitable in the context of reducing the period of market exclusivity for highly profitable orphan drugs, determining the level of clinical evidence needed to authorize orphan drugs, etc. Chapter 2.2 describes the development and validation of a new tool, COMPASS, to assess the quality of orphan drugs clinical evidence presented for orphan drugs at the time of marketing authorization. The tool was drawn up based on elements derived from existing checklists supplemented with items specifically related to rare diseases and orphan drugs as recommended by six experts. The COMPASS tool can for example be used by local reimbursement agencies for the review of clinical evidence in orphan drug registration dossiers or by clinicians and pharmacists upon considering a (new) orphan drug treatment.The COMPASS tool was used in chapter 2.3 to quantitatively evaluate the characteristics and quality of pivotal studies presented for orphan drugs authorised in the EU before July 1st, 2012. These studies were found to exhibit methodological flaws such as lack of blinding in the study design, lack of QoL-related endpoints as outcome, use of surrogate endpoints, etc. Additionally, there were important shortcomings in the reporting of those studies, which further complicates the interpretation of the clinical evidence. This study shows that a more demanding regulatory process for orphan drugs is needed.Studies on the pricing of orphan drugs are reported in part 3. The influence of orphan designation status on prices of drugs for rare indications is demonstrated in chapter 3.1. The analysis showed that the median price per defined daily dose was higher for drugs with an orphan designation (138.56) than for drugs without an orphan designation used for rare indications (16.55). Chapter 3.2 provides several examples of repurposed drugs for rare indications for which the effectiveness evidence was published prior to the application for orphan designation status. Upon comparing Belgian hospital prices per defined daily dose of selected drugs for common diseases with the price of repurposed drugs for the rare disease indication, differences of up to 200 fold were reported. This pricing practice adds to the budget impact of treating rare diseases. An overview of the international scientific literature on the drivers of pricing of ultra-orphan drugs in described in chapter 3.3. Ultra-rare diseases constitute an informal subcategory, within rare diseases, to describe very rare diseases (i.e. occurring in less than one per 50,000 individuals). The pricing process of ultra-orphan drugs is a complex and non-transparent issue. Evidence in the literature seems to indicate that ultra-orphan drugs are priced based on rarity of the indication and the number of available alternatives.Chapter 3.4 shows how various drug- and disease-specific variables relate to annual treatment costs per patient and per orphan drug indication in six EU Member States. Additionally, it was investigated if certain country-specific pricing and reimbursement policies affect the price level of orphan drugs. Repurposed orphan drugs, orally administered orphan drugs or orphan drugs for which an alternative treatment is available are associated with lower annual treatment costs. Orphan drugs with multiple orphan indications, for chronic treatments or for which an improvement in overall survival or quality-of-life has been demonstrated, are associated with higher annual treatment costs. No association was found between annual treatments cost of orphan drugs across countries and the different pricing and reimbursement systems. Current debate about the affordability of high-priced orphan drugs highlights the need for more transparency in orphan drug price setting.The topic of reimbursement of orphan drugs is discussed in part 4. Because of their high price and difficulties in demonstrating effectiveness, orphan drugs are often perceived as not able to provide value for money. In chapter 4.1 an overview of the evidence on the value for money of orphan drugs is given. Results show that orphan drugs can provide value for money. Considering a threshold of £30,000 per quality-adjusted life years (QALY) (i.e. threshold for reimbursement applied in England and Wales) ten out of a total of nineteen orphan drugs for which data was available, offer value for money.Factors other than cost-effectiveness are also taken into account at the time of reimbursement In chapter 4.2 qualitative research methods were applied to establish that various official (i.e. therapeutic value, budget impact, price and impact in clinical practice) and non-official (i.e. pricing and reimbursement in other countries, interference by patient organisations and experts, arguments related to quality of pharmaceutical compounding, media attention, innovative character, economic importance, ethical arguments and the political climate) factors might influence reimbursement decisions for orphan drugs in Belgium. The identification of these factors is crucial in the development of a transparent and consistent framework which will guide future decision-making for reimbursement of orphan drugs.A study on the uptake of orphan drugs is reported in part 5. Chapter 5.1 shows that the uptake of orphan drugs varies across EU Member States. The highest volumes of orphan drugs in the first year occurred in Member States with a high gross domestic product (GDP) and implicitly, a higher budget for health care, independently of the existence of a formal health technology assessment (HTA) organisation. In contrast, in countries with a low GDP, orphan drugs were less available in countries with a formal HTA-organisation. There, budgetary restrictions can cause the exclusion of less cost-effective orphan drugs. These variations have important implications with respect to access to orphan drugs. Recommendations for a sustainable orphan drug market are proposed in the general discussion in part 6. These recommendations relate to one (or more) of the steps of market access. Several recommendations to improve quality of clinical evidence (for instance by setting trial standards imposing the use of at least one hard endpoint) are formulated. Furthermore, to capture what is valued by patients, patient(s) (organizations) should be able to provide input in an early stage on what endpoints should be considered when developing a new drug for a rare disease. Development of new orphan drugs can be improved by adopting a public-private partnership approach for orphan drug development. Patient registries are an important tool to gather knowledge about the natural course of a rare disease and/or the long-term effectiveness of an orphan drug. Long-term data is required for marketing authorization and to guide reimbursement decisions. Recommendations relating to pricing of orphan drugs include measures to increase transparency in orphan drug pricing, a proposal to prescribe repurposed orphan drugs by international non-proprietary name and a call to revise orphan drug status of sufficiently profitable orphan drugs. Timely access to new orphan drugs can be achieved by implementing managed entry agreements to deal with the uncertainty about cost-effectiveness and by optimizing reimbursement procedures for orphan drugs across EU Member States. Finally, there is a need to define priorities in funding and reimbursement of orphan drugs. Upcoming challenges for the orphan drug pharmaceutical industry are also discussed. For instance, adaptive licensing is expected to reduce the overall cost of development and to have a positive effect on timely access to new drugs. Future research could focus on pricing and budget impact orphan drugs, an issue of continued importance in the aftermath of the financial and economic crisis.

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Dissertation
The diagnostic accuracy of alpha-1-antitrypsin immunohistochemical staining for alpha-1- antitrypsin deficiency related liver disease compared to the golden standard of genotyping: a single centre retrospective analysis.
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Year: 2016 Publisher: Leuven KU Leuven. Faculteit Geneeskunde

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Abstract: Objectives In clinical practice serologic, immunologic and storage screening blood tests, including serum levels for alpha-1-antitrypsin (AAT), are performed in order to attain the aetiology of liver disease. If these tests fail to retain a diagnosis, liver biopsy is indicated. As AAT is an acute-phase protein and therefore often elevated in the setting of inflammation and liver disease, AAT deficiency is often missed and sometimes incorrectly ruled out upon initial screening tests. The aim is to compare the diagnostic accuracy of immunostaining to the golden standard of genotyping in AAT deficiency related liver disease, looking whether immunostaining can replace genotyping in certain conditions. Methods A single centre retrospective analysis was performed. Patients who had a diagnosis based on genotype and had an immunostain on liver biopsy were included. Results In all patients (n=42) immunostaining for AAT was positive (sensitivity = 100%) regardless of genotype. 13 out of 27 serum levels (48.14%) where normal. When comparing outcome variables between heterozygous and homozygous patients no significant difference was found other than for cirrhosis solely due to AAT deficiency. Conclusion Immunostaining for AAT on liver biopsy is found to accurately diagnose AAT deficiency by identifying the accumulation of mutated AAT in hepatocytes. As accumulation itself is the cause of liver damage and the knowledge of genotype does not have a significant impact on clinical daily practice, a genetic screening is deemed irrelevant once accumulation is confirmed by immunostaining.

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Dissertation
Betekenis en gevolgen van het interleukine-28B-polymorfisme voor de behandeling van een infectie met het hepatitis C-virus: stand van zaken.

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In 2009 werd voor het eerst een groep van „single nucleotide”-polymorfismen (SNP’s) nabij de genlocus van het interleukine-28B (IL-28B) beschreven. Vier onafhankelijke genoomassociatiestudies hebben het verband aangetoond tussen deze polymorfismen en de doeltreffendheid van virale klaring bij patiënten chronisch geïnfecteerd met het hepatitis C-virus (HCV) genotype 1 die behandeld werden met gepegyleerd interferon (peg-IFN) en ribavirine. Dezelfde polymorfismen bleken later ook geassocieerd te zijn met een spontane HCV-klaring. De polymorfismen die het meest beschreven worden in de literatuur, zijn het rs12979860- en het rs8099917-SNP. Het IL-28B-genotype en het bereiken van een snelle virologische klaring op week vier van de therapie („rapid virologic response” – RVR) vormen twee belangrijke factoren in het voorspellen van een volledige virale klaring („sustained virologic response” – SVR) of genezing door de huidige standaardtherapie bij patiënten geïnfecteerd met HCV genotype 1. Het verband tussen het IL-28B-genotype en de HCV-klaring kan een belangrijke rol spelen in het beslissingsproces omtrent het starten van de huidige standaardtherapie, de interpretatie van klinische studies, het economische aspect van de behandeling en de ontwikkeling van nieuwe antivirale agentia werkzaam in de behandeling van HCV. Achtereenvolgens worden het HCV, het IL-28B-polymorfisme, de huidige behandeling en de tekortkomingen besproken. Daarnaast wordt er aandacht besteed aan de toekomstige behandelingsstrategieën bij chronische infecties met HCV.

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Dissertation
Vascular mediators in cirrhotic portal hypertension.

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Dissertation
Towards organization of care for patients with hereditary haemochromatosis

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Hereditary haemochromatosis (HH) is a disorder of iron homeostasis with an autosomal recessive inheritance. The prevalence is 1/200 to 1/400 in Northern Europe and the carrier frequency is 1/10. The penetrance of HH is rather low. Homozygous carriers of the p.C282Y mutation may remain asymptomatic and have a normal quality of life (QoL). But iron accumulation can cause organ damage, resulting in liver dysfunction (fibrosis, cirrhosis, hepatocellular carcinoma), arthropathy, diabetes mellitus, and this can have an impact on the QoL. Complications and symptoms can regress by intensive treatment reducing the iron overload of the body.The most common treatment is phlebotomy every week/fortnight during the depletion phase and every three to six months as maintenance therapy and consists of bloodletting of approximately 500 ml of whole blood (representing about 250 mg of iron). Secondly, erythrocytapheresis can be performed and is a treatment by which red blood cells are removed using an apheresis device. This is used in patients who do not tolerate phlebotomies for several reasons.There are different guidelines on the topics of diagnosis and treatment of HH but they do not always correspond well and recommendations are frequently based on expert opinion (guidelines from the European Association for the Study of the Liver; the American Association from the Study of Liver Diseases; Dutch guideline). Related to the diverse presenting symptoms, patients are followed by different specialized healthcare providers, varying from gastro-enterologists, hematologists, rheumatologist to endocrinologists, internists, but also general practitioners, which results in differential follow-up and treatment strategies. There is a lack of congruence in follow-up strategies, as well as a gap in information transfer, continuity and care coordination. Cases from teaching hospitals are known where HH patients had developed cirrhosis and HCC, while cirrhosis was not diagnosed and therefore surveillance screening of the liver with ultrasound had not been performed.HH is a chronic condition and several care models for the management of chronic diseases exist, with their specific focus areas. The Chronic Care Model (CCM) of Wagner as well as the Innovative Care for Chronic Conditions (ICCC) are already used in several settings to optimize care for patients with chronic conditions as HIV/AIDS, hypertension, diabetes, depression. t also in care for patients with HH there is an urgent need for the development of a management model, organized from a chronic care perspective. Initial treatment in a (university) hospital setting should be followed by a phase of maintenance treatment, in order to sustain the positive effects of the initial more intense treatment phase and improve outcomes on the short and long-term.The overall aim of this doctoral project is to evaluate the current care for patients with hereditary haemochromatosis, resulting in four research questions (RQ).RQ 1: What is the quality of the existing guidelines for hereditary haemochromatosis?RQ2: Which treatment and follow-up is required to ensure good quality of care in HH patients?RQ3: How is the current care at the University hospital Leuven, Gasthuisberg for patients with hereditary haemochromatosis, based on predefined key-interventions (RQ2)?RQ4: Does the intake of proton pump inhibitors decrease phlebotomy need?


Dissertation
Hypophosphatasia in adults: the experience of a single academic center

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ABSTRACT Background and objectives: Hypophosphatasia (HPP) is a rare disorder caused by mutations in the alkaline phosphatase (ALP) gene, and characterized by low ALP levels and musculoskeletal, dental and systemic manifestations. Awareness of the diagnosis is important e.g. to avoid inappropriate treatment. Here we describe a case series of HPP patients known at the University Hospitals of Leuven. Secondly, we investigated the feasibility and the ethical aspects of a case finding strategy. Methods: Patients with HPP were identified through medical record review. Inclusion criteria were: 1) age ≥ 16 years; 2) low serum ALP level not explained by secondary causes; 3) one or more of the following additional supporting elements: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; or genetic testing positive for a known HPP mutation. Secondly, the laboratory database of our hospital was searched for patients within the Internal Medicine department with persistently low serum ALP levels. Results: 18 patients met our inclusion criteria. Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in 7 patients (39%), 3 of which had been previously categorized as having chronic fatigue syndrome. Seven patients (39%) were inappropriately treated or planned to be treated with antiresorptive treatment. Patients detected by family screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower serum ALP levels and higher substrate levels. In the laboratory database, the prevalence of a persistently low serum ALP level was 0.1%. Detailed medical record review found no secondary causes of persistently low ALP values in a subgroup of 100/190 patients (52.6%). Conclusion: Our case series helps to understand the spectrum of HPP disease severity. Since disease recognition is low in HPP, a case finding strategy based on low serum ALP levels can be defended. Further research into the prevalence of HPP and the risks of case finding is required.

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Dissertation
Het klinische spectrum van aantasting bij samengesteld heterozygote hemochromatose C282Y/H63D: Literatuuronderzoek en cohortstudie in UZ Leuven

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Bij hereditaire hemochromatose type 1 liggen autosomaal recessieve mutaties in het HFE-gen aan de basis van deze primaire ijzerstapelingsziekte. Een minderheid van wie genetisch voorbeschikt is, ontwikkelt biochemische afwijkingen, ziekteverschijnselen of orgaanschade. Bij samengesteld heterozygoten C282Y/H63D zouden zelden of nooit symptomen ontstaan, tenzij beïnvloedende factoren zoals persoonskenmerken, omgevingsinvloeden of genvarianten in het spel zijn. Deze observationele, retrospectieve cohortstudie brengt het klinische spectrum bij samengesteld heterozygoten C282Y/H63D in UZ Leuven in kaart. Gegevensanalyse suggereert dat milde ziekte-expressie en orgaanschade, zoals levercirrose of osteoporose, kunnen optreden. Een mogelijke invloed van geslacht, leeftijd en overgewicht lijkt naar voren te komen, ook zonder overmatig alcoholgebruik. Geassocieerde genetische polymorfismen worden niet nagegaan. Een gepersonaliseerde benadering van het risicoprofiel zou in de klinische praktijk een antwoord kunnen bieden op vragen omtrent de intensiteit en de aandachtspunten van het beleid in deze groep. Om het individuele belang van mogelijke beïnvloedende factoren in te schatten, zijn bijkomende prospectieve multivariate analyses op grotere schaal cruciaal. Het is de taak van referentiecentra, zoals UZ Leuven, om deze multifactoriële aandoening verder in kaart te brengen, om samen te werken bij de ontwikkeling van richtinggevende adviezen voor verwijzende zorgverstrekkers en om de zorgkwaliteit te bevorderen.

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Dissertation
Patiënten met mucopolysaccharidose: klinisch verloop, diagnostiek en behandeling

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De mucopolysaccharidosen (MPS) zijn erfelijke, metabole aandoeningen die behoren tot de groep van lysosomale stapelingsziekten. Ze worden gekenmerkt door een grote klinische heterogeniteit, zowel qua symptomatologie als behandeling en prognose. In dit artikel illustreren we de belangrijkste kenmerken van MPS aan de hand van 15 patiënten met MPS gekend in het Universitair Ziekenhuis Leuven. Patiënten met MPS komen terecht bij verschillende specialisaties binnen het artsenberoep gezien de presentatie van de ziekte zeer variabel kan zijn. De gouden standaard bij de diagnose van MPS is de bepaling van residuele enzymactiviteit, al dan niet aan te vullen met verdere genetische analyse. Op vlak van behandeling zijn er meerdere opties mogelijk elk met hun voor- en nadelen, maar tot op heden is er geen enkele die de ziekte volledig geneest. Verder onderzoek naar andere mogelijke behandelingen wordt volop gevoerd. In de tussentijd is verlichting van de ziektelast door middel van verscheidene symptomatische interventies een belangrijk onderdeel in de behandeling.

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