Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (+/- 0.10) and 45% (+/- 0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials

Analysis of the concept of semiquantitative CYP2D6-gene dose in ultrarapid metabolizers compared to extensive metabolizers according to the pharmacokinetic of S- and R-metoprolol

GesamtdissertationDiese Arbeit baut auf einer klinischen Studie zum Einfluss der CYP2D6-Genduplikation auf die Pharmakokinetik von Metoprolol in gesunden Probanden auf. Ziel der Arbeit war es durch eine erweiterte Genotypisierung von CYP2D6-Allelen, welche eine verminderte oder eine erhöhte CYP2D6-Aktivität bedingen, eine über die übliche Einteilung in Schnell- (EM) und Ultraschnell- Metabolisierer (UM) hinausgehende genauere Klassifikation für den Metabolisierungsstatus von CYP2D6 zu finden. Hierfür wurde das Konzept der semiquantitativen Gendosis von CYP2D6 erstellt und anhand des Einflusses auf den Metabolismus von Metoprolol in vivo enantioselektiv untersucht. Genotypisiert wurden neben den vermindert aktiven Allelen CYP2D6*9, *10 und *41 auch die aktiven Allele CYP2D6*2 und CYP2D6*35. Die pharmakokinetischen Daten von R- und S-Metoprolol sowie deren Metaboliten (SS-Metoprolol, SR- Metoprolol, RS-Metoprolol, RR-Metoprolol) wurden mittels High Performance Liquid Chromatographie (HPLC) erhoben. Für die Feinklassifizierung der CYP2D6-Aktivität in semiquantitative Gendosen wurde jedem Allel entsprechend der vorhergesagten Enzymaktivität ein Wert zwischen 0 und 1 zugeordnet und die semiquantitative Gendosis anhand des Genotyps als Summenwert der einzelnen Allele errechnet. Das Vorliegen einer Duplikation führte jeweils zu einer Verdopplung des Punktwertes des dupliziert vorliegenden Allels. So erhielten die für den EM-Phänotyp kodierenden Genotypen 1,5 oder 2, die für den UM- Phänotyp kodierenden Genotypen 2,5 oder 3 Punkte. Anschließend wurde diese Einteilung anhand pharmakokinetischer Parameter von Metoprolol überprüft, wobei sich ein signifikanter Einfluss der semiquantitativen CYP2D6-Gendosis zeigte. Eine Enantioselektivität des Einflusses konnte dabei nicht festgestellt werden. Um genauere Aussagen über die Aktivität von CYP2D6 machen zu können, sollte eine Genotypisierung, insbesondere für die Abgrenzung Schnell- versus Ultraschnell-Metabolisierer, auch die Bestimmung der Allele mit herabgesetzter und erhöhter Enzymaktivität erfassen.The background of this thesis was a clinical study on metoprolol as a CYP2D6 probe drug studying the influence of the CYP2D6 gene-duplication on pharmacokinetics of metoprolol in healthy volunteers. The aim of our study was to generate a more precise classification of the activitiy of CYP2D6 taking the contribution of alleles with decreased or increased activity into account. For this reason we further genotyped the study participants for CYP2D6, and established a concept of semiquantitative gene dosages validated with the pharmacokinetic data on metoprolol which was additionally analysed in an enantioselective way. We genotyped the reduced active alleles CYP2D6*9, *10 and *41 as well as the active alleles CYP2D6*2 and *35. Pharmacokinetic data of R- and S-Metoprolol as well as of the metabolites (SS-Metoprolol, SR- Metoprolol, RS-Metoprolol and RR-Metoprolol) were detected using High Performance Liquid Chromatographie (HPLC). To categorize the CYP2D6-activity into semiquantitative genedoses we assigned each allele a value between 0 and 1 according to the predicted enzyme activity and calculated the semiquantitative genedoses with the genotype as cumulative value of the individual alleles. The existance of a duplication led to a duplication of the value of the duplicated allele. Therefore the genotypes, which encoded for the EM-phenotype received 1.5 or 2.0, the genotypes, which encoded for the UM- phenotype received 2.5 or 3.0 points. The correlation between CYP2D6 activity score and pharmacokinetic parameters of racemic metoprolol was stronger than with the classical classification into ultrarapid and extensive metabolizer. The influence of CYP2D6 on kinetics of the enantiomers of metoprolol was neglectible. To specify the CYP2D6-activity, especially for the differentiation between extensive and ultrarapid metabolizers, the genotyping should include the alleles which encode for reduced as well as for increased enzyme activity

Neural correlates of erotic stimulation under different levels of female sexual hormones.

Previous studies have demonstrated variable influences of sexual hormonal states on female brain activation and the necessity to control for these in neuroimaging studies. However, systematic investigations of these influences, particularly those of hormonal contraceptives as compared to the physiological menstrual cycle are scarce. In the present study, we investigated the hormonal modulation of neural correlates of erotic processing in a group of females under hormonal contraceptives (C group; N = 12), and a different group of females (nC group; N = 12) not taking contraceptives during their mid-follicular and mid-luteal phases of the cycle. We used functional magnetic resonance imaging to measure hemodynamic responses as an estimate of brain activation during three different experimental conditions of visual erotic stimulation: dynamic videos, static erotic pictures, and expectation of erotic pictures. Plasma estrogen and progesterone levels were assessed in all subjects. No strong hormonally modulating effect was detected upon more direct and explicit stimulation (viewing of videos or pictures) with significant activations in cortical and subcortical brain regions previously linked to erotic stimulation consistent across hormonal levels and stimulation type. Upon less direct and less explicit stimulation (expectation), activation patterns varied between the different hormonal conditions with various, predominantly frontal brain regions showing significant within- or between-group differences. Activation in the precentral gyrus during the follicular phase in the nC group was found elevated compared to the C group and positively correlated with estrogen levels. From the results we conclude that effects of hormonal influences on brain activation during erotic stimulation are weak if stimulation is direct and explicit but that female sexual hormones may modulate more subtle aspects of sexual arousal and behaviour as involved in sexual expectation. Results may provide a basis for future imaging studies on sexual processing in females, especially in the context of less explicit erotic stimulation

Differential brain activation contrasting erotic minus non-erotic stimulation.

<p>Depicted are contrasts from experimental runs with video (A), picture (B) and picture expectation (C) stimuli during luteal and follicular phase of the menstrual cycle and under oral contraceptives. The rightmost panel depicts the conjunction of the three conditions. For demonstration purposes, all thresholds were set at p<0.005 uncorrected. Even at such a more lenient threshold, no differential brain activation was found under contraceptives upon picture expectation.</p

Sample characteristics: Hormonal levels and questionnaires.

<p>Values are means and standard deviations (in rounded brackets) of serum estrogen and progesterone levels, subjective ratings of sexual dysfunction as assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire (MGH-SFQ), subjective ratings of erotic and non-erotic pictures as presented during fMRI (visual analogue scale 1–9 with 1: not sexually arousing at all, 9: very sexually arousing) and symptoms of depression as measured with the ADS scale in the group taking contraceptives (C) and in the group without contraceptives during the follicular (nC-F) or luteal (nC-L) phase of the menstrual cycle; <i>p</i>: significance of group differences computed from paired and unpaired t-tests.</p