Im metastasierten Melanom sind bei Vorhandensein einer BRAF V600 Mutation zielgerichtete Therapien mit BRAF+MEK-Inhibitoren sowie Immuntherapien (ICB), die Immuncheckpoints wie PD-1 blockieren, zugelassen. Aktuell gibt es keine evidenzbasierte Empfehlung welche Therapie in der Erstlinie im BRAF V600 mutierten Melanom eingesetzt werden sollte. Bis jetzt wurde der Stellenwert PD-1 basierter Immuncheckpoint Blockade in der Zweitlinie nach Progress unter BRAF+MEK-Inhibition nicht beschrieben. Es ist auch unklar, ob die Kombinations-ICB (PD-1 plus CTLA-4 Blockade) mit einer Verbesserung des Ansprechens und Überlebens gegenüber einer PD-1 Monotherapie assoziiert ist, wie für das therapie-naive Melanom beschrieben. Wir haben eine retrospektive, multizentrische Studie durchgeführt um die Wirksamkeit von PD-1 basierten Immuntherapien nach Progress unter zielgerichteter Therapie zu explorieren. In unserer Untersuchung zeigten PD-1 Monotherapie und die kombinierte PD-1 plus CTLA-4 Blockade eine ähnliche Wirksamkeit in Patienten mit BRAFi+MEKi-Resistenz. Die Kombinationstherapie war dagegen mit einem deutlich höheren Risiko für schwerwiegende immunvermittelte Nebenwirkungen im Vergleich zu PD-1 Monotherapie assoziiert. Unsere Daten indizieren, dass eine PD-1 Blockade einer Kombinations-ICB in der Zweitlinie nach Progress unter zielgerichteter Therapie im fortgeschrittenen BRAF V600 mutierten Melanom vorzuziehen ist. / Targeted therapies employing dual inhibition of the MAPK pathway (BRAFi+MEKi) as well as immunotherapies blocking immune checkpoints (ICB) such as PD-1 are approved for metastatic BRAF V600 mutant melanoma. There is no evidence-based recommendation which therapy should be used first-line. The efficacy of second-line PD-1 blocking agents after failure of dual MAPKi has not been characterized. It is not clear whether a combinational ICB (PD-1 plus CTLA-4 blockade) is associated with an improvement in responses and survival compared to single agent PD-1 inhibition, as reported for treatment-naive melanoma. To this end, we conducted a retrospective, multicenter study to explore the outcome of melanoma patients receiving second-line PD-1 based ICB regimes after progression on targeted therapy. In our study PD-1 monotherapy and combined PD-1 plus CTLA-4 blockade showed similar activity in melanoma patients resistant to BRAF plus MEK inhibition. However, combined PD-1 plus CTLA-4 blockade was associated with a higher rate of treatment-related adverse events than monotherapy. Our data indicate that PD-1 monotherapy might be preferred over combined ICB as second-line treatment after progression on targeted therapy in metastatic BRAF V600 mutant melanoma with poor prognosis.

Die vorliegende Dissertation beschäftigt sich mit den tumorbedingten Überlebensdaten der Melanompatient:innen am Hauttumorzentrum Leipzig mit Primärdiagnose in den Stadien II bis IV zwischen 2006 bis Ende 2019. Aufgrund der im letzten Jahrzehnt etablierten neuen innovativen Therapiemöglichkeiten für die Stadien III bis IV wird angenommen, dass sich ab 2011 für Patient:innen in diesen Stadien Verbesserungen der Überlebensdaten eingestellt haben. In der Kontrollgruppe von Patient:innen im Tumorstadium II hingegen wird bei nahezu gleichgebliebenen Therapieoptionen keine Änderung der Mortalitätsraten im Gesamtbetrachtungszeitraum von 2006 bis 2019 erwartet. Die Auswertung erfolgte retrospektiv anhand der am Klinisches Krebsregister Leipzig (KKRL) erhobenen Daten. Es sind 840 Melanompatient:innen eingeschlossen. Von diesen erhielten 554 Patient:innen die Erstdiagnose im Stadium II, 250 im Stadium III und 36 im Stadium IV. Verglichen werden die Zeiträume 2006 bis 2010 (Ära der Chemotherapien, Gruppe 1, 292 Patient:innen), 2011 bis 2013 (Zulassung der ersten neuen innovativen Therapien im fortgeschrittenen Tumorstadium, Gruppe 2, 161 Patient:innen) und 2014 bis 2019 (umfängliches zugelassenes Arsenal neuer innovativer Therapien einschließlich adjuvanter Therapien, Gruppe 3, 387 Patient:innen). Kaplan Meier Darstellungen sowie Log Rank Tests betrachten die Fragestellung in Hinblick auf statistisch signifikante Unterschiede. Auswertungen zur Gruppenzusammensetzung und zu den Beobachtungszeiträumen ermöglichen eine Aussage über die Vergleichbarkeit der drei Patient:innengruppen. Betrachtet werden das Gesamtüberleben (OS), das progressionsfreie Überleben (PFS) in Hinblick auf den Tumorstadien-Shift von III zu IV sowie das rezidivfreie Überleben (RFS). Im Ergebnis können für Patient:innen im Tumorstadium III Veränderungen hinsichtlich des OS, PFS sowie RFS im Vergleich der drei Zeiträume aufgezeigt werden. Für das OS kann ein statistisch signifikanter Vorteil der Patient:innen für den letzten Zeitraum nachgewiesen werden. In Gruppe 3 überleben prozentual und statistisch signifikant die meisten Patient:innen bis zum fünften Jahr. Bei der Betrachtung des PFS tritt der Stadien-Shift bei Melanom-Patient:innen in den beiden letzten Zeiträumen später und prozentual weniger auf, wobei noch kein Nachweis einer statistischen Signifikanz gelingt. Für das RFS kann ebenfalls keine statistische Signifikanz berechnet werden. Zwar ist ein Anstieg der Mediane von Gruppe 1 zu 3 zu verzeichnen, jedoch gleicht sich der prozentuale Anteil der Rezidive bis zum fünften Jahr über alle drei Zeiträume hinweg an. Damit kann für die am Hauttumorzentrum Leipzig behandelten Patient:innen im Tumorstadien III in der Ära der neuen Therapeutika eine Verbesserung der Gesamt- und progressionsfreien Überlebensdaten demonstriert werden. Diese Real-life Daten entsprechen den Studiendaten der Literatur und unterstreichen den Überlebensvorteil im Stadium III nicht zuletzt aufgrund der adjuvanten Therapien. Das sich über alle Zeiträume angleichende RFS hingegen weist darauf hin, dass das Krankheitsrezidiv weniger beeinflusst wird. Bei der Auswertung des OS im fernmetastasierten Tumorstadium IV zeigen sich eine Verdreifachung der 5-Jahres-Überlebensrate (5-JÜR) von Gruppe 3 zu Gruppe 1 sowie ein Anstieg der Mediane und Mittelwerte. Diese Berechnungen sind hinweisend auf einen Benefit der neuen Immuntherapeutika im Tumorstadium IV, wenngleich ein statistisch signifikanter Unterschied nicht nachgewiesen werden kann. Das RFS kann aufgrund des häufig frühzeitigen Todeseintritts im fortgeschrittenen Stadium IV nicht ausreichend beurteilt werden. In der Kontrollgruppe Stadium II kann wie erwartet bei dem Vergleich des OS zwischen den drei Zeiträumen kein statistisch signifikanter Unterschied ermittelt werden. Bei der Berechnung der Mittelwerte des OS sowie der JÜR zeigt sich eine tendenzielle Verschlechterung der Überlebensdaten von Gruppe 1 zu 3. Allerdings sind die Beobachtungszeiträume von einem Teil der Patient:innen in der letzten Gruppe zum Zeitpunkt der Auswertung noch kurz, was die Auswertbarkeit einschränkt. Unerwartet aber statistisch signifikant verschlechtert sich ebenfalls das RFS der Stadium II Patient:innen von Gruppe 1 zu 3. Möglicher Grund für diese Entwicklung könnte der langsame Rückgang der adjuvanten Interferon-Therapie über den Beobachtungszeitraum sein, welche aufgrund der schwachen und uneinheitlichen weltweiten Studiendaten auch in Deutschland zunehmend verlassen wurde und welche zuletzt aufgrund der Einstellung der Produktion durch die Pharmahersteller zudem nicht mehr verfügbar war. Es ist demzufolge anzunehmen, dass eine Roferon-Therapie möglicherweise doch einen positiven Einfluss auf das OS sowie RFS in Leipzig hat. Wünschenswert für die abschließende Darstellung der Leipziger Überlebensdaten wäre die erneute Auswertung nach längeren Beobachtungszeiten für die letzte Gruppe. Einen ersten Ausblick hierfür gibt der Vergleich der Berechnungen der Daten aktualisiert bis zum 01.01.2021 und bis zum 01.04.2022. Insbesondere im Tumorstadium III des letzten Zeitraums sind Zunahmen der Mittelwerte sowie Mediane des OS, RFS und PFS zu verzeichnen. Damit kann der Nachweis eines statistisch signifikanten Unterschiedes insbesondere für das RFS sowie PFS im Stadium III in zukünftigen Auswertungen und im Hinblick auf die vielversprechenden Angaben in der Literatur erwartet werden.:Abkürzungsverzeichnis Abbildungsverzeichnis 1 Einleitung 2 Aufgabenstellung 3 Materialien und Methoden 4 Ergebnisse 4.1 Patient:innenprofil 4.2 Therapeutika 4.3 Gesamtüberleben 4.3.1 Gesamtüberleben im primär diagnostizierten Tumorstadium II 4.3.2 Gesamtüberleben im primär diagnostizierten Tumorstadium III 4.3.3 Gesamtüberleben im primär diagnostizierten Tumorstadium IV 4.4 Tumorstadien-Shift vom primär diagnostizierten Stadium III zu IV 4.5 Rezidivfreies Überleben . 4.5.1 Rezidivfreies Überleben im primär diagnostizierten Tumorstadium II 4.5.2 Rezidivfreies Überleben im primär diagnostizierten Tumorstadium III 4.5.3 Rezidivfreies Überleben im primär diagnostiziertenTumorstadium IV 4.6 Beobachtungszeitraum 5 Diskussion 5.1 Patient:innenprofil 5.2 Gesamtüberleben 5.3 Tumorstadien-Shift von III zu IV 5.4 Rezidivfreies Überleben 5.5 Beobachtungszeitraum 6 Zusammenfassung Literaturverzeichnis Anhang Eigenständigkeitserklärung

Background Despite advances in the understanding of the disease and new treatment strategies, stage IV GC remains a relevant health issue worldwide. So far, treatment in stage IV GC has been limited to platinum-based chemotherapy. Furthermore, in the case of HER2 expression, the HER2-directed monoclonal antibody trastuzumab is an approved targeted drug for first line treatment. According to the pivotal randomized-controlled phase III registration study, trastuzumab is improving overall survival from 11.1 to 13.8 months. Unfortunately not all patients respond and almost all initial responders eventually develop resistance and experience tumor progression. The prospective multicenter VARIANZ study aimed to identify resistance biomarkers for HER2-targeted treatment in advanced gastric and esophagogastric junction cancer. More than 500 patients receiving medical treatment for stage IV GC were recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry (IHC) and chromogenic-in-situ-hybridization (ISH). Within the study a HER2 test deviation rate (22.3%) between central and local test was associated with negative impact on patient survival. Patients who received trastuzumab with centrally confirmed HER2+ status (central HER2+/local HER2+) lived significantly longer compared to patients who received trastuzumab for local HER2+ but central HER2 stage IV GC (20.5 months vs. 10.9 months, 95% CI [8.2, 14.4], p<0.001) [1]. In the present analysis, we investigated methodological and biological variables that may promote deviating HER2 test results. Methods We analyzed HER2 testing procedures and participation in quality assurance programs of 105 participating local pathology laboratories. Furthermore, tumor localization, histological subtypes and tested tumor material (for local and central test) were compared between patients with centrally confirmed (central HER2+/local HER2+, n=68) and unconfirmed HER2 status (central HER2-/local HER2+, n=68). Results Central confirmation of the local HER2 IHC scores were seen for the majority of locally HER2- IHC 0/1 (172/178; 96.6%), but less frequently for locally IHC3+ (57/124; 46.0%) cases. Neither use of specific IHC methods nor participation in round robin tests varied between cohorts with confirmed (central HER2+/local HER2+, n=68) or deviating (central HER2-/local HER2+, n=68) HER2 test results. We found seven IHC antibodies (HercepTest, 4B5, SP3, CB11, UMAB36, A0485, EP3) in routine use in Germany, with HercepTest and 4B5 being the most commonly used. 46 (43.8%) local pathology laboratories participated in quality assurance programs for HER2 testing in GC. The distribution of the tested tumor material (primary tumor biopsy, surgical specimen, or biopsy from metastasis), related to both local and central HER2 testing, was comparable between the cohorts studied. Regarding tumor characteristics, deviating test results were more frequently found in GC vs. EGJC (69.1% vs. 39.7%; p=0.001). Within the Laurén histological classification deviating status (central HER2-/local HER2+) was more often found in diffuse type GC (23.5% vs. 5.9% for confirmed HER2+, p=0.004). Conclusion and Interpretation VARIANZ study has shown that GC patients with deviating HER2 test results had poor trastuzumab benefit [1], so we dedicated this work to the important question of the underlying causes of HER2 test deviations in GC. Our analysis demonstrates that neither the antibody platform used for IHC nor participation in round robin tests of local pathology institutes correlated with the deviation rate for HER2 test results. In contrast, we found that tumor characteristics such as primary tumor location and histological phenotype had an impact on test deviations: more HER2 test deviations were seen in distal GC compared to EGJC as well as in the diffuse versus intestinal subtype according to Laurén’s classification. One main limitation of our study is the so far barely used IHC HER2-antibody CB11 for central testing. However, in our study its highly specific properties [2–4] enabled it to identify patients who benefited from trastuzumab. In contrast to breast cancer HER2 is very heterogeneously expressed in GC [5, 6]. Due to this different expression, the HER2 testing scheme was adapted for GC [7]. Nevertheless, the success of HER2-targeted therapy in GC lags significantly behind breast cancer therapy [5]. HER2 heterogeneity is a known issue in GC, even in early stages [8]. Although much has been published [6, 9–11] , there is no generally agreed definition for HER2 heterogeneity or diagnostic procedure to identify HER2 heterogeneity. There are different approaches, for example using the relative number of HER2+ stained tumor cells [10, 12] or the deviation in HER2 status in a set of primary biopsies [13]. HER2 heterogeneity has already been associated with limited trastuzumab benefit and decreased overall survival in trastuzumab treated patients [1, 13, 14]. We conclude that the central confirmation of the HER2 status is a correlate of lower HER2 heterogeneity and may serve as an indicator for better treatment efficacy of trastuzumab. Further we assume that for distal GC location and for the diffuse subtype where HER2 positivity in general is less common [2, 15–18] weak HER2 expression and intratumoral heterogeneity account for more deviating test results. In our view, HER2 diagnostic scheme for GC should be adapted. Adaption of HER2 thresholds to identify patients benefiting from trastuzumab treatment has been already postulated [1, 17]. Our data suggests that only patients with low HER2 heterogeneity may benefit from trastuzumab treatment. For the selection of patients with low HER2 heterogeneity, the above tumor characteristics, such as tumor localization and histological subtype, should be reported. EGJC and the intestinal subtype are positive indicators of the presence of low HER2 heterogeneity. The use of highly specific IHC antibodies should be preferred. Furthermore, a positive result in IHC should always be confirmed by the examination of a paired specimen and the percentage of positive stained tumor cells should be reported. This might improve survival outcomes with targeted treatment, prevent overtreatment and associated side effects and costs and may enable successful studies of other promising HER2 targeting drugs.

No description available.

Alcohol use disorder (AUD) is a widespread mental disease denoted by chronic alcohol use despite significant negative consequences for a person’s life. It affected more than 14 million persons in Europe alone and accounted for more than 5% of deaths worldwide in 2011-2012. Understanding the psychological and neurobiological mechanisms driving the development and maintenance of pathological alcohol use is key to conceptualizing new programs for prevention and therapy of AUD. There has been a variety of etiological models trying to describe and relate these mechanisms. Lately, the view of AUD as a disorder of learning and decision making has received much support proposing dual systems to be at work in AUD – one system being deliberate, forward-planning, and goal-directed and the other one reflexive, automatic, and habitual. Both systems supposedly work in parallel in a framework of value-based decision making and their balance can be flexibly adjusted in healthy agents, while a progressive imbalance favoring habitual over goal-directed choice strategies is assumed in AUD. This imbalance has been theoretically associated to neural adaptations to chronic alcohol use in corticostriatal pathways involved in reward processing, especially in ventral striatum. However, these theoretical models are grounded strongly on animal research while empirical research in the human domain remains rather sparse and inconclusive. Furthermore, alterations in value-based decision-making processes and their neural implementation might not only result from prolonged alcohol misuse but may also represent premorbid interindividual differences posing a risk factor for the development of AUD. Therefore, I here present three studies investigating the relation of alcohol use with the balance between goal-directed and habitual decision systems and with parameters modulating option valuation processes of these systems, namely delay, risk, and valence of option outcomes. To separate the investigation of these decision processes as predisposing risk for or consequence of alcohol use, two samples were examined: one sample of 201 eighteen-year-old men being neither abstinent from nor dependent on alcohol as well as one sample of 114 AUD patients in detoxification treatment and 98 control participants matched for age, sex, educational background, and smoking status. Both samples had a baseline assessment of several behavioral tasks, questionnaires, and neuropsychological testing and were followed-up over one year to examine drinking trajectories in the sample of young men and relapse in detoxified patients. The behavioral tasks included a sequential choice task using model-free and model-based reinforcement learning as operationalization of habitual and goal-directed decision making, respectively, during functional magnetic resonance imaging and four tasks probing participants’ delay discounting, probability discounting for gains and losses, and loss aversion. Study 1 presents the cross-sectional analysis of the sequential choice task in relation to baseline drinking behavior of the young-adult sample. These analyses did not reveal an association between non-pathological alcohol use and habitual and goal-directed control on neither a behavioral nor neural level except for one exploratory finding of increased BOLD responses to model-free habitual learning signals in participants with earlier onset of drinking. Study 2 examined the same task in AUD patients compared to control participants showing no difference in behavioral control or neural correlates between those groups. However, prospectively relapsing AUD patients showed lower BOLD responses associated to model-based goal-directed control than abstaining patients and control participants. Additionally, the interaction of goal-directed control and positive expectancies of alcohol effects discriminated subsequently relapsing and abstaining patients revealing an increased risk of relapse for those patients who showed higher levels of goal-directed control and low alcohol expectancies or low levels of goal-directedness and high expectancies. Study 3 examined modulating features of goal-directed and habitual option valuation – delay, risk, and valence of options – in association to alcohol use in the young-adult sample and AUD status in the sample of patients and matched control participants on a cross-sectional as well as longitudinal level. This study revealed no relation of delay, risk, and loss aversion with current alcohol use and consumption one year later in the young men. In contrast, AUD patients showed systematically more impulsive choice behavior than control participants in all four tasks: a higher preference for immediate rewards, more risky choices when facing gains and less when facing losses, and lower loss aversion. Furthermore, a general tendency to overestimate the probability of uncertain losses could predict relapse risk over the following year in AUD patients. Taken together, these results do not support the hypothesis that mechanisms of value-based decision making might be predisposing risk factors for alcohol consumption. The findings for patients already suffering from AUD are mixed: while choice biases regarding delays, risks, and valence of option outcomes seem to be altered systematically in AUD, there was no indication of an imbalance of habitual and goal-directed control. These findings challenge the assumption of a generalized outcome-unspecific shift of behavioral control from goal-directed to habitual strategies during the development of AUD and point towards several possible future avenues of research to modify or extend the theoretical model.

Alcohol use disorder (AUD) is a widespread mental disease denoted by chronic alcohol use despite significant negative consequences for a person’s life. It affected more than 14 million persons in Europe alone and accounted for more than 5% of deaths worldwide in 2011-2012. Understanding the psychological and neurobiological mechanisms driving the development and maintenance of pathological alcohol use is key to conceptualizing new programs for prevention and therapy of AUD. There has been a variety of etiological models trying to describe and relate these mechanisms. Lately, the view of AUD as a disorder of learning and decision making has received much support proposing dual systems to be at work in AUD – one system being deliberate, forward-planning, and goal-directed and the other one reflexive, automatic, and habitual. Both systems supposedly work in parallel in a framework of value-based decision making and their balance can be flexibly adjusted in healthy agents, while a progressive imbalance favoring habitual over goal-directed choice strategies is assumed in AUD. This imbalance has been theoretically associated to neural adaptations to chronic alcohol use in corticostriatal pathways involved in reward processing, especially in ventral striatum. However, these theoretical models are grounded strongly on animal research while empirical research in the human domain remains rather sparse and inconclusive. Furthermore, alterations in value-based decision-making processes and their neural implementation might not only result from prolonged alcohol misuse but may also represent premorbid interindividual differences posing a risk factor for the development of AUD. Therefore, I here present three studies investigating the relation of alcohol use with the balance between goal-directed and habitual decision systems and with parameters modulating option valuation processes of these systems, namely delay, risk, and valence of option outcomes. To separate the investigation of these decision processes as predisposing risk for or consequence of alcohol use, two samples were examined: one sample of 201 eighteen-year-old men being neither abstinent from nor dependent on alcohol as well as one sample of 114 AUD patients in detoxification treatment and 98 control participants matched for age, sex, educational background, and smoking status. Both samples had a baseline assessment of several behavioral tasks, questionnaires, and neuropsychological testing and were followed-up over one year to examine drinking trajectories in the sample of young men and relapse in detoxified patients. The behavioral tasks included a sequential choice task using model-free and model-based reinforcement learning as operationalization of habitual and goal-directed decision making, respectively, during functional magnetic resonance imaging and four tasks probing participants’ delay discounting, probability discounting for gains and losses, and loss aversion. Study 1 presents the cross-sectional analysis of the sequential choice task in relation to baseline drinking behavior of the young-adult sample. These analyses did not reveal an association between non-pathological alcohol use and habitual and goal-directed control on neither a behavioral nor neural level except for one exploratory finding of increased BOLD responses to model-free habitual learning signals in participants with earlier onset of drinking. Study 2 examined the same task in AUD patients compared to control participants showing no difference in behavioral control or neural correlates between those groups. However, prospectively relapsing AUD patients showed lower BOLD responses associated to model-based goal-directed control than abstaining patients and control participants. Additionally, the interaction of goal-directed control and positive expectancies of alcohol effects discriminated subsequently relapsing and abstaining patients revealing an increased risk of relapse for those patients who showed higher levels of goal-directed control and low alcohol expectancies or low levels of goal-directedness and high expectancies. Study 3 examined modulating features of goal-directed and habitual option valuation – delay, risk, and valence of options – in association to alcohol use in the young-adult sample and AUD status in the sample of patients and matched control participants on a cross-sectional as well as longitudinal level. This study revealed no relation of delay, risk, and loss aversion with current alcohol use and consumption one year later in the young men. In contrast, AUD patients showed systematically more impulsive choice behavior than control participants in all four tasks: a higher preference for immediate rewards, more risky choices when facing gains and less when facing losses, and lower loss aversion. Furthermore, a general tendency to overestimate the probability of uncertain losses could predict relapse risk over the following year in AUD patients. Taken together, these results do not support the hypothesis that mechanisms of value-based decision making might be predisposing risk factors for alcohol consumption. The findings for patients already suffering from AUD are mixed: while choice biases regarding delays, risks, and valence of option outcomes seem to be altered systematically in AUD, there was no indication of an imbalance of habitual and goal-directed control. These findings challenge the assumption of a generalized outcome-unspecific shift of behavioral control from goal-directed to habitual strategies during the development of AUD and point towards several possible future avenues of research to modify or extend the theoretical model.:Table of Contents List of Figures List of Tables List of Abbreviations Abstract Chapter 1. Perspectives on alcohol use disorder 1.1 The size of alcohol use disorder 1.1.1 Terminology of alcohol-use related disorders 1.1.2 Size and burden of alcohol consumption and alcohol use disorders 1.2 Cognitive psychological perspectives on alcohol use disorder 1.2.1 A unified framework for addiction 1.2.2 Value-based decision making 1.2.3 Goal-directed and habitual systems 1.3 Neurobiological perspectives on alcohol use disorders 1.3.1 Neural underpinnings of the reward circuit 1.3.2 Neural underpinning of goal-directed and habitual decision making 1.3.3 Striatal adaptations associated with chronic alcohol consumption 1.4 Synopsis and research questions Chapter 2. Study 1 2.1 Abstract 2.2 Introduction 2.3 Material and methods 2.3.1 Participants and procedure 2.3.2 Measures of goal-directed and habitual behavioral control 2.3.3 Measure of alcohol consumption 2.3.4 Behavioral statistical analyses 2.3.5 Functional magnetic resonance imaging data acquisition and analysis 2.4 Results 2.4.1 Sample characteristics 2.4.2 Behavioral results 2.4.3 Functional magnetic resonance imaging results 2.5 Discussion Chapter 3. Study 2 3.1 Abstract 3.2 Introduction 3.3 Methods and materials 3.3.1 Participants 3.3.2 Procedure 3.3.3 Alcohol Expectancy Questionnaire 3.3.4 Task 3.3.5 Magnetic Resonance Imaging 3.3.6 Follow-up procedure 3.3.7 Data analysis 3.3.8 fMRI analysis 3.4 Results 3.4.1 Sample characteristics 3.4.2 Task-related group differences 3.4.3 Interaction between alcohol expectancies and model-based control 3.4.4 fMRI results 3.5 Discussion Chapter 4. Study 3 4.1 Abstract 4.2 Introduction 4.3 Study 3.1 4.3.1 Material and methods 4.3.2 Results 4.4 Study 3.2 4.4.1 Material and methods 4.4.2 Results 4.5 Discussion Chapter 5. General discussion 5.1 Summary of findings and discussion 5.1.1 Goal-directed and habitual decision making and alcohol use (disorder) 5.1.2 Neuroimaging correlates of goal-directed and habitual control 5.1.3 Modulators of the valuation systems and alcohol use (disorders) 5.1.4 Integration of findings 5.2 Limitations 5.2.1 Methodological critique of the Two-Step task 5.3 Outlook for future studies 5.3.1 Tentative framework for future studies 5.4 Conclusions References Appendix A Supplementary Information of Study 1 A.1 Supplementary Methods 1 - behavioral A.2 Supplementary Methods 2 - fMRI A.3 Supplementary Results - behavioral A.4 Supplementary results - fMRI B Supplementary Information of Study 2 B.1 Computational fits B.2 Preprocessing of the functional imaging data B.3 Exclusion criteria for different analyses B.4 First level analysis of the functional imaging analysis B.5 Voxel-based morphometry B.6 Drinking Motives Questionnaire B.7 Model-free comparisons B.8 Association with time to relapse B.9 Number of detoxifications and model-based control: behavioral and neuroimaging analyses C Supplementary Information of Study 3 C.1 Differences between VBDM version used in this study compared to the VBDM version reported in Pooseh et al. (under review) C.2 Additional correlational analyses D Supplementary Information for additional analyses

Durch den exzessiven Gebrauch von Antibiotika haben sich in den letzten Jahren zunehmend Resistenzen herausgebildet. Eine potentielle Alternative zu konventionellen Antibiotika sind prädatorische Bakterien. Das Bakterium Bdellovibrio bacteriovorus hat einen zweiphasigen Lebenszyklus bestehend aus einer Angriffsphase, in der es andere gram-negative Bakterien jagt, und einer Wachstumsphase, in der es das Zytoplasma eines Wirtes für die eigene Reproduktion nutzt. Für einen künftigen Einsatz von B. bacteriovorus als Antibiotikum müssen die Prozesse des Lebenszyklus verstanden werden. Das Proteom von B. bacteriovorus wurde bisher jedoch nur sehr wenig untersucht. Daher wurden in dieser Arbeit mithilfe der Massenspektrometrie Proteine von verschiedenen Zeitpunkten des Lebenszyklus von B. bacteriovorus relativ quantifiziert. Es konnten zahlreiche Proteine identifiziert werden, die zu spezifischen Zeitpunkten des Lebenszyklus hoch- oder herabreguliert werden. Die größten Unterschiede im Proteinmuster konnten zwischen der Angriffs- und der Wachstumsphase beobachtet werden. In der Angriffsphase sind einige Proteine herabreguliert, die mit der Proteinexpression im Zusammenhang stehen. Weiterhin wurde bestätigt, dass sich junge und gealterte Zellen der Angriffsphase deutlich voneinander unterscheiden, womit die Angriffsphase eigentlich aus zwei Phasen besteht. Auf Grundlage der Ergebnisse und eines Vergleiches mit Transkriptionsdaten wurde die Vermutung aufgestellt, dass B. bacteriovorus Proteine, welche spezifisch für die Angriffsphase sind, bereits während der Wachstumsphase synthetisiert. Im Zusammenhang mit der Forschung an B. bacteriovorus konnten auch neue Impulse bezüglich der MeCAT-basierten massenspektrometrischen Proteinquantifizierung angestoßen werden. In dieser Arbeit wurde unter anderem ein MeCAT-Reagenz mit Acrylamidfunktionalität entwickelt, welches erfolgreich als interner Standard für die Laserablation-ICP-MS von Polyacrylamidgelen verwendet werden kann. / Due to the excessive use of antibiotics, antibiotic resistance has increased over the last years. A potential alternative to conventional antibiotics are predatory bacteria. The predatory bacterium Bdellovibrio bacteriovorus has a biphasic life cycle consisting of an attack phase in which it hunts other gram-negative bacteria, and a growth phase in which it uses the cytoplasm of a prey cell as a substrate for its own reproduction. For future application of B. bacteriovorus as an antibiotic, it is necessary to understand the processes that occur during the life cycle. However, almost no information has been obtained regarding the proteome of B. bacteriovorus yet. Using mass spectrometry and an isotopic labelling strategy, proteins from different time points in the life cycle of B. bacteriovorus were quantified relatively to each other in this work. Numerous proteins were identified that are up- or down-regulated at specific time points in the life cycle. The largest differences in protein pattern existed between the attack phase and the growth phase, whereas only minor differences occurred within the growth phase. For instance, several proteins that appear to be down-regulated during the attack phase are related to protein expression. Furthermore, it was confirmed that there is a significant difference between young and aged cells of the attack phase. Therefore, the attack phase actually consists of two phases. Based on the results and on a comparison with transcription data, it was suggested that attack phase specific proteins of B. bacteriovorus are already synthesized during the growth phase. In connection with the research on B. bacteriovorus, new impulses regarding the MeCAT based protein quantification with mass spectrometry could be initiated. In this work, a MeCAT reagent with acrylamide functionality was developed, which can be used successfully as an internal standard for laser ablation ICP-MS of polyacrylamide gels.

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During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.