Hepatische vs. Peritoneale Metastasierung beim Kolorektalen Karzinom

Das kolorektale Karzinom ist eine der häufigsten Krebsarten in der westlichen Welt und zeichnet sich durch seine hohe Mortalität aus. Prognosebestimmend ist die Entwicklung von Fernmetastasen, die schlechteste Prognose haben dabei Tumore, die eine Peritonealkarzinose entwickeln. Dies ist verglichen mit einer Lebermetastasierung ein seltenes Ereignis, aber aufgrund der unterschiedlichen therapeutischen Interventionsmöglichkeiten ist eine frühzeitige Unterscheidung von hoher Relevanz. Ziel dieser Arbeit ist deshalb die Identifizierung von Biomar-kern die mit den einzelnen Metastasierungsmustern korrelieren. Möglich ist das beispielsweise durch eine molekularpathologischen Klassifikation der Tumore: Als vielversprechend gilt die Analyse von Mutationen im Epidermal Growth Fac-tor Receptor (EGFR)-Signaltransduktionsweg, Tumorsuppressorgenen, den Mismatch Reparatur Defekt (MMRD)-Genen und vor allem die der Expression von Stammzellmarkern. Mutationen im EGFR-Signaltransdukionsweg wie die der Protoonkogene KRAS oder BRAF beeinflussen möglicherweise das Ausbreitungs-muster und sind relevant für das Ansprechen auf die Therapie mit Anti-EGFR-Antikörpern. Eine Mutation des Tumorsupressorgens p53 stellt einen wichtigen Schritt in der Karzinogenese dar und es gibt Hinweise darauf, dass sich die bis heute bekannten Karzinogenesewege hinsichtlich des Vorhandenseins der p53 Mutation unterscheiden. Auch anhand des Auftretens eines MMR-Defekts lassen sich aktuell schon Rückschlüsse auf Wachstum und Prognose ziehen. Als sehr erfolgsversprechend gilt die Analyse der Expression des Signal- und Strukturpro-teins ß-Catenin und besonders die der Stammzellmarker CD133 und CD44. Sie könnten eine Klassifikation der einzelnen Subgruppen erlauben und gelten als potentielle Ziele neuer Therapien. In dieser Arbeit machte man sich bereits be-stehende Erkenntnisse zu Nutze um eine spezielle Auswahl an zu untersuchenden Markern zu treffen. Ziel war die Identifizierung von Biomarkern, die mit dem Metastasierungsmuster korrelieren und die Überprüfung der sehr heterogenen Aussagen bezüglich der Relevanz der einzelnen untersuchten Marker. Dazu wur-den in einer retrospektiven Fall-Kontrollstudie insgesamt 124 Primärtumore un-tersucht. 37 Fälle des Kollektivs wiesen eine Lebermetastasierung auf, 18 Fälle eine Peritonealkarzinose und 13 Fälle wiesen beides auf. Als Kontrollgruppe fun-gierten 56 Fälle die in einem 5-Jahres Follow-up keine Metastasen entwickelten. Es konnte nachgewiesen werden, dass Tumore die Lebermetastasen entwickelten eine signifikant erhöhte Expression der untersuchten Biomarker aufwiesen, wobei die Kombination der Stammzellmarker mit ß-Catenin die Signifikanz noch verbesserte. In dieser Gruppe traten auch vermehrt Mutationen im p53 Gen auf. In der Gruppe der Peritonealkarzinosen ließ sich keine erhöhte Expression der Marker ß-Catenin, CD133 und CD44 nachweisen, aber vermehrt Mutationen im BRAF Gen

Blood–brain barrier dysfunction and folate and vitamin B12 levels in first-episode schizophrenia-spectrum psychosis: a retrospective chart review

Vitamin deficiency syndromes and blood–brain barrier (BBB) dysfunction are frequent phenomena in psychiatric conditions. We analysed the largest available first-episode schizophrenia-spectrum psychosis (FEP) cohort to date regarding routine cerebrospinal fluid (CSF) and blood parameters to investigate the association between vitamin deficiencies (vitamin B12 and folate) and BBB impairments in FEP. We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with an ICD-10 diagnosis of a first-episode F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture, blood-based vitamin status diagnostics and neuroimaging within the clinical routine. 222 FEP patients were included in our analyses. We report an increased CSF/serum albumin quotient (Qalb) as a sign of BBB dysfunction in 17.1% (38/222) of patients. White matter lesions (WML) were present in 29.3% of patients (62/212). 17.6% of patients (39/222) showed either decreased vitamin B12 levels or decreased folate levels. No statistically significant association was found between vitamin deficiencies and altered Qalb. This retrospective analysis contributes to the discussion on the impact of vitamin deficiency syndromes in FEP. Although decreased vitamin B12 or folate levels were found in approximately 17% of our cohort, we found no evidence for significant associations between BBB dysfunction and vitamin deficiencies. To strengthen the evidence regarding the clinical implications of vitamin deficiencies in FEP, prospective studies with standardized measurements of vitamin levels together with follow-up measurements and assessment of symptom severity in addition to CSF diagnostics are needed

Cathodal tDCS Over Motor Cortex Does Not Improve Tourette Syndrome: Lessons Learned From a Case Series

Introduction: Current pathophysiological hypotheses of Gilles de la Tourette Syndrome (GTS) refer to temporally abnormal neuronal activation in cortico-striato-thalamo-cortical (CSTC) networks. Modifying cortical activity by non-invasive brain-stimulation appears to be a new treatment option in GTS. Background: Previous studies suggested therapeutic effects of cathodal transcranial direct current stimulation (tDCS) to pre-supplementary motor areas (SMA), however, treatment modalities concerning electrode placement, current intensity and stimulation-rate have not been systematically explored. Aim of this study was to assess efficacy of an alternative stimulation regime on GTS symptoms in a pilot study. To test a treatment protocol with tDCS twice a day, we administered 10 sessions over 5 days of bilateral cathodal tDCS (30 min, 2 mA) over the pre-SMA in three patients with severe GTS. Tic severity as well as obsessive-compulsive (OC) symptoms and affective scales were rated before and after tDCS treatment. Discussion: Only one out of three patients showed a 34.5% reduction in tic severity. The two other patients showed an increase in tic severity. All patients showed a mild increase in positive affect and a reduction in negative affect, OC symptom changes were heterogeneous. Our results do not support earlier findings of extensive therapeutic effects of cathodal tDCS on tics in patients with GTS and show that prediction of stimulation effects on a targeted brain area remains inaccurate. Concluding Remarks: Future research will have to focus on the determination of most effective stimulation modes regarding site, polarity and frequency of tDCS in GTS patients

Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia - a cross-sectional study

Negative symptoms and cognitive deficits are common in individuals with schizophrenia, greatly affect their outcome, and have been associated with alterations in cerebral gray and white matter volume (GMV, WMV). In the last decade, aerobic endurance training has emerged as a promising intervention to alleviate these symptoms and improved aerobic fitness has been suggested as a key moderator variable. In the present study, we investigated, whether aerobic fitness is associated with fewer cognitive deficits and negative symptoms and with GMVs and WMVs in individuals with schizophrenia in a cross-sectional design. In the largest study to date on the implications of fitness in individuals with schizophrenia, 111 participants at two centers underwent assessments of negative symptoms, cognitive functioning, and aerobic fitness and 69 underwent additional structural magnetic resonance imaging. Multilevel Bayesian partial correlations were computed to quantify relationships between the variables of interest. The main finding was a positive association of aerobic fitness with right hippocampal GMV and WMVs in parahippocampal and several cerebellar regions. We found limited evidence for an association of aerobic fitness with cognitive functioning and negative symptoms. In summary, our results strengthen the notion that aerobic fitness and hippocampal plasticity are interrelated which holds implications for the design of exercise interventions in individuals with schizophrenia

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat