Pharmako- und/oder Psychotherapie bei posttraumatischer Belastungsstörung: Systematischer Überblick zu Therapieansätzen und ihrer Effektivität

Die psychotherapeutischen Behandlungsansätze der posttraumatischen Belastungsstörung („posttraumatic stress disorder“, PTSD) wurden in den letzten 20 Jahren beständig weiterentwickelt und überprüft. Ihre positiven Effekte sind mittlerweile weitgehend gut und übereinstimmend belegt. Der Nutzen pharmakologischer Behandlungsmöglichkeiten ist weniger gut evaluiert, und die Datenlage ist widersprüchlicher. Der vorliegende Beitrag präsentiert einen Überblick über den gegenwärtigen Forschungsstand der störungsorientierten psychotherapeutischen und pharmakologischen Ansätze der PTSD und deren Effektivität. Zunächst erfolgt ein Überblick über die Metaanalysen der letzten 10 Jahre zur Effektivität der Psychotherapie und der Pharmakotherapie der PTSD. Im Weiteren wird die aktuelle Datenlage aus Vergleichsstudien zu Pharmako- und Psychotherapie vorgestellt. Die präsentierten Studien zeigen durchgängig relativ geringe Effektstärken bei Pharmakotherapie als Monotherapie (zumeist placebokontrolliert) und relativ geringe Effektstärkengewinne in Verbindung mit Psychotherapie gegenüber Psychotherapie allein. Beim Vergleich Psychotherapie vs. Pharmakotherapie bestätigt die aktuelle Studienlage keine Äquivalenz bezüglich der Effekte. Auf der Basis der aktuellen Studienlage erscheint es angezeigt, dass Fachgesellschaften eventuell noch fortbestehende Empfehlungen der Pharmakotherapie als Behandlung erster Wahl einer Revision unterziehen und generell pharmakotherapeutische Optionen mit größerer Zurückhaltung vertreten. Abstract Over the last 20 years psychotherapeutic treatment approaches for posttraumatic stress disorder (PTSD) have constantly been refined and reviewed. Nowadays, the positive effects of psychotherapy in PTSD are consistent across studies and well-documented; however, the benefits of pharmacological treatment approaches in PTSD are less well evaluated and the available data are more inconsistent. This article provides an overview over the current state of research on the disorder-oriented psychotherapeutic and pharmacological approaches in PTSD along with their effectiveness. Firstly, an overview of meta-analyses published in the last 10 years on the effectiveness of psychotherapy and pharmacotherapy of PTSD is presented. Furthermore, the currently available literature on comparative studies regarding pharmacotherapy and psychotherapy in PTSD is summarized. All of the presented studies only show relatively small effect sizes for pharmacotherapy as monotherapy (mostly placebo controlled) and relatively small gains in effect size when combined with psychotherapy as opposed to psychotherapy alone. The current study situation confirms that there is no equivalency with respect to the effects when comparing psychotherapy versus pharmacotherapy in PTSD. On the basis of the current state of research, the potentially still persisting recommendation by various expert associations to consider the pharmacotherapy of PTSD as first-line treatment should be revised. In general, pharmacotherapeutic options in PTSD should be advocated with restraint

Metabolic tumor constitution is superior to tumor regression grading for evaluating response to neoadjuvant therapy of esophageal adenocarcinoma patients

The response to neoadjuvant therapy can vary widely between individual patients. Histopathological tumor regression grading (TRG) is a strong factor for treatment response and survival prognosis of esophageal adenocarcinoma (EAC) patients following neoadjuvant treatment and surgery. However, TRG systems are usually based on the estimation of residual tumor but do not consider stromal or metabolic changes after treatment. Spatial metabolomics analysis is a powerful tool for molecular tissue phenotyping but has not been used so far in the context of neoadjuvant treatment of esophageal cancer. We used imaging mass spectrometry to assess the potential of spatial metabolomics on tumor and stroma tissue for evaluating therapy response of neoadjuvant-treated EAC patients. With an accuracy of 89.7%, the binary classifier trained on spatial tumor metabolite data proved to be superior for stratifying patients when compared with histopathological response assessment, which had an accuracy of 70.5%. Sensitivities and specificities for the poor and favorable survival patient groups ranged from 84.9% to 93.3% using the metabolic classifier and from 62.2% to 78.1% using TRG. The tumor classifier was the only significant prognostic factor (HR 3.38, 95% CI 1.40-8.12, p = 0.007) when adjusted for clinicopathological parameters such as TRG (HR 1.01, 95% CI 0.67-1.53, p = 0.968) or stromal classifier (HR 1.86, 95% CI 0.81-4.25, p = 0.143). The classifier even allowed us to further stratify patients within the TRG1-3 categories. The underlying mechanisms of response to treatment have been figured out through network analysis. In summary, metabolic response evaluation outperformed histopathological response evaluation in our study with regard to prognostic stratification. This finding indicates that the metabolic constitution of the tumor may have a greater impact on patient survival than the quantity of residual tumor cells or the stroma. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

Metabolic tumor constitution is superior to tumor regression grading for evaluating response to neoadjuvant therapy of esophageal adenocarcinoma patients.

The response to neoadjuvant therapy can vary widely between individual patients. Histopathological tumor regression grading (TRG) is a strong factor for treatment response and survival prognosis of esophageal adenocarcinoma (EAC) patients following neoadjuvant treatment and surgery. However, TRG systems are usually based on the estimation of residual tumor but do not consider stromal or metabolic changes after treatment. Spatial metabolomics analysis is a powerful tool for molecular tissue phenotyping but has not been used so far in the context of neoadjuvant treatment of esophageal cancer. We used imaging mass spectrometry to assess the potential of spatial metabolomics on tumor and stroma tissue for evaluating therapy response of neoadjuvant-treated EAC patients. With an accuracy of 89.7%, the binary classifier trained on spatial tumor metabolite data proved to be superior for stratifying patients when compared to histopathological response assessment which had an accuracy of 70.5%. Sensitivities and specificities for the poor and favorable survival patient groups ranged from 84.9 to 93.3% using the metabolic classifier and from 62.2 to 78.1% using TRG. The tumor classifier was the only significant prognostic factor (HR 3.38, 95% CI = 1.40-8.12, P = 0.007) when adjusted for clinicopathological parameters such as TRG (HR 1.01, 95% CI = 0.67-1.53, P = 0.968) or stromal classifier (HR 1.856, 95% CI = 0.81-4.25, P = 0.143). The classifier even allowed to further stratify patients within the TRG1-3 categories. The underlying mechanisms of response to treatment has been figured out through network analysis. In summary, metabolic response evaluation outperformed histopathological response evaluation in our study with regard to prognostic stratification. This finding indicates that the metabolic constitution of tumor may have a greater impact on patient survival than the quantity of residual tumor cells or the stroma. This article is protected by copyright. All rights reserved

Light sheet fluorescence microscopy guided MALDI-imaging mass spectrometry of cleared tissue samples.

Light sheet fluorescence microscopy (LSFM) of optically cleared biological samples represents a powerful tool to analyze the 3-dimensional morphology of tissues and organs. Multimodal combinations of LSFM with additional analyses of the identical sample help to limit the consumption of restricted specimen and reduce inter-sample variation. Here, we demonstrate the proof-of-concept that LSFM of cleared brain tissue samples can be combined with Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) for detection and quantification of proteins. Samples of freshly dissected murine brain and of archived formalin-fixed paraffin-embedded (FFPE) human brain tissue were cleared (3DISCO). Tissue regions of interest were defined by LSFM and excised, (re)-embedded in paraffin, and sectioned. Mouse sections were coated with sinapinic acid matrix. Human brain sections were pre-digested with trypsin and coated with α-cyano-4-hydroxycinnamic acid matrix. Subsequently, sections were subjected to MALDI-time-of-flight (TOF)-MSI in mass ranges between 0.8 to 4 kDa (human tissue sections), or 2.5–25 kDa (mouse tissue sections) with a lateral resolution of 50 µm. Protein- and peptide-identities corresponding to acquired MALDI-MSI spectra were confirmed by parallel liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis. The spatial abundance- and intensity-patterns of established marker proteins detected by MALDI-MSI were also confirmed by immunohistochemistry

Patterns of Carbon-Bound Exogenous Compounds in Patients with Lung Cancer and Association with Disease Pathophysiology.

Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy. SIGNIFICANCE: This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology

Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis.

Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism

Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis

Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra-and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hind-limb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism