[Harmonisation of regulatory requirements for clinical trials on medicinal products for human use in the Directive 2001/20/EC and complementary guidance. Implementation of the 12th Law Amending the German Drug Law]. / Angleichung der regulatorischen Anforderungen für die klinische Prüfung von Arzneimitteln am Menschen in der EU Die Richtlinie 2001/20/EG und die diese ergänzenden Verordnungen und Empfehlungen: die 12. Novelle zum AMG.

Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 aims to harmonise national regulations governing clinical trials of medicinal products for human use in the European Union. This aim is to be achieved by harmonising the legal regulations and administrative provisions in force in the Member States, especially with respect to the requirements for starting and conducting clinical trials, taking into account international ethical and scientific standards (Good Clinical Practice). The goal is to further improve the protection of participants in clinical trials and to promote clinical research within the European Union. In Germany, the necessary transposition into the national Drug Law has taken place in the form of the 12th Law Amending the Drug Law of 30 July 2004 as well as complementary implementation provisions. The amendments to the German Drug Law affect in particular the official authorisation procedure, the involvement of ethics committees as well as the conduct of clinical trials on minors. The Directive's requirements have been transposed into German law while maintaining the high level of protection for the participants in clinical trials which had already existed in German legislation.

A model for hepatocarcinogenesis with clonal expansion of three successive phenotypes of preneoplastic cells.

The two-stage model with clonal expansion of intermediate cells has often been used to describe the carcinogenesis process. The model hypothesizes that cells have to undergo two mutations on their way from the normal to the malignant stage. Biological experiments indicate the existence of three types of preneoplastic cells in hepatocarcinogenesis representing three successive intermediate stages in the development of malignant cells from normal cells. This finding suggests that hepatocarcinogenesis should be described by a multi-stage model with three intermediate stages, leading to a four-stage mutation model with clonal expansion of all types of intermediate cells. This model is presented and mathematical approximations for the number and size of nonextinct premalignant clones of the different cell types are derived. The model is applied to focal lesion data from a rat hepatocarcinogenesis experiment.

Familial aggregation in Behçet's disease: high frequency in siblings and parents of pediatric probands.

OBJECTIVE: To examine familial aggregation of Behçet's disease (BD) in pediatric compared with non-pediatric patients. METHODS: A retrospective study was conducted to analyze data collected from 572 patients with BD in whom the diagnosis was made with criteria defined by the International Study Group for BD. The age of attaining criteria (the age at which the patient met the study group criteria) was evaluated for each patient. Recurrence risks were calculated for the pediatric group from information provided by 45 families. RESULTS: Of the 505 patients from whom the age of attaining criteria could be ascertained, 106 showed definitive BD before the age of 16 years and were considered as pediatric patients with BD; the other 399 were classified as non-pediatric patients. Thirteen of the 106 pediatric patients (12.3%) and only 9 of the 399 non-pediatric patients (2.2%) had relatives affected by BD. This excess of familial cases in the pediatric group compared with the non-pediatric group was significant (P <.0001, chi2 analysis). Moreover, the mean age of attaining criteria in familial cases (17. 95 years [SD = 8.62]) was significantly lower than in sporadic cases (27.28 years [SD = 11]; P <.0001, Student t test). The recurrence risk among siblings and parents who met the International Study Group criteria was 0.1. CONCLUSION: Our data support the hypothesis of a genetic component in the pathogenesis of BD, and we propose the inclusion of familial history in the definition of pediatric BD.

[Strategic cytogenetic aids in oncologic diagnosis and individual therapy control]. / Strategische zytogenetische Hilfen für die onkologische Diagnostik und eine individuelle Therapieführung.

The main cytogenetic markers of haemoblastoses and other myelo- and lymphoproliferative disorders as well as an oncologically relevant gene map of the human chromosomes were demonstrated taking as a basis own data and corresponding literature. We have tried to describe the current prognostic value of several karyotypic traits and trends for the use of clinicians, especially for oncologists, from the cytogenetic point of view. We particularly consider the dynamics and the development, the competition between various cell-lines of the bone-marrow with different changes of the karyotypes. Further attempts to a clear understanding of the nature and the significance of clonal chromosome changes in haemoblastoses and other tumours as well as of the risk of neoplastic development determined by distinct chromosomal abnormalities should take into consideration the molecular mechanisms of translocation and also the consequences of gene dosis, such as of immunologic systems. At present cytogenetic tumour markers seem to be a strategic aid for diagnosis and prognosis as well as for the understanding of the mechanisms, initiating the chromosome aberrations and leading to further changes during the development of the tumour.