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Testing Bayesian models of belief updating in the context of depressive symptomatology
No full textPredictive processing approaches to belief updating in depression propose that depression is related to more negative and more precise priors. Also, belief updating is assumed be negatively biased in comparison to normative Bayesian updating. There is a lack of efficient methods to mathematically model belief updating in depression.
We validated a novel performance belief updating paradigm in a nonclinical sample (N = 133). Participants repeatedly participated in a non-self-related emotion recognition task and received false feedback. Effects of the feedback manipulation and differences in depressive symptoms on belief updating were analysed in Bayesian multilevel analyses.
Beliefs were successfully manipulated through the feedback provided. Depressive symptoms were associated with more negative updating than normative Bayesian updating but results were influenced by few cases. No evidence of biased change in beliefs or overly precise priors was found. Depressive symptoms were associated with more negative updating of generalised performance beliefs.
There was cautious support for negatively biased belief updating associated with depressive symptoms, especially for generalised beliefs. The content of the task may not be self-relevant enough to cause strong biases. Further explication of Bayesian models of depression and replication in clinical samples is needed.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Untersuchung des Einflusses von Toll-like Rezeptor 5 auf humane hepatische und pankreatische Sternzellen
No full textFibrose, die übermäßige Zunahme von Extrazellulärmatrix im menschlichen Körper, ist eine Folge anhaltender entzündlicher Gewebereaktionen. Besonders in der Leber und im Pankreas fördert eine Vielzahl an akuten und chronischen Erkrankungen, wie z. B. die Alkoholische und Nicht-Alkoholische Steatohepatitis, Virushepatitis, Autoimmunhepatitis, Pankreatitis und Pankreaskarzinome, die Fibroseentwicklung, die sich durch komplexe Pathophysiologie auszeichnet und im Verlauf von einem dramatischen Verlust von funktionalem Gewebe begleitet sein kann. Die bedeutsamsten Mediatoren der Fibrose und Hauptquelle von extrazellulären Matrixproteinen, wie Kollagen, sind humane Sternzellen, deren Aktivierung eine etablierte Schlüsselrolle in der Fibroseentstehung spielt. Quieszente hepatische und pankreatische Sternzellen halten in ihrem ruhendem Zustand als epitheliale Zellen im Leberparenchym bzw. Pankreastroma neben der Speicherung von Vitamin A wichtige Aufgaben zum Erhalt und Gleichgewicht der Gewebeintegrität und Immunregulation inne. Ihre Aktivierung führt zur Transdifferenzierung in mesenchymale Myofibrolasten und damit zur vermehrten Bildung von Extrazellulärmatrix, zur parenchymalen Migration, Chemotaxis, Proliferation, Phagozytose, Tumorinteraktion bzw. -förderung uvm. Diese Mechanismen führen über fibrotische Umbauprozesse bzw. desmoplastische Gewebereaktionen zum Verlust der physiologischen Organarchitektur und können unbehandelt in Zirrhose, Karzinogenese bzw. Tumorprogress münden. Als immunkompetente Zellen exprimieren humane Sternzellen diverse Toll-like Rezeptoren (TLR), die sie zur Erkennung pathologischer mikrobieller Strukturen befähigen. Mittels der Expression von TLR 5 sind sie dazu in der Lage das bakterielle Geißelprotein Flagellin spezifisch zu binden und über TLR-spezifische Signalwege so inflammatorische Gewebereaktionen zu generieren und zu verstärken. Diese Eigenschaft stellt ein interessantes Bindeglied zwischen Sternzell-assoziierter Fibroseentstehung und mikrobieller Besiedelung des Gastrointestinaltraktes dar. Diese Studie hebt eine mögliche Kommunikation zwischen Sternzellen und anderen Pankreas- bzw. Leberzellen, sowie dem Mikrobiom mittels TLR 5 hervor. Aus in vitro Studien ist bekannt, dass die Behandlung immortalisierte LX-2 und hPSC 2.2. Sternzellen mit geringen Mengen des Wachstumsfaktors TGF-β1 zur Transdifferenzierung in Myofibroblasten führen kann. TGF-β1 war dazu in der Lage die Aktivierung der Sternzellen stimulieren und damit ihren charakteristischen Wandel vom quieszenten zum aktiven Zustand, der sie im hepatischen und pankreatischen Milieu auszeichnet, zu fördern. Die Empfänglichkeit für TGF-β1 zeigt somit, dass Sternzellen auch über Signale aus ihrer Umgebung, sowie von weiter entfernten Zellen aktiviert werden können. Vor allem die Anwesenheit von Tumorzellen im umliegendem Gewebe könnte für eine Sternzellaktivierung durch die Sekretion verschiedener Wachstumsfaktoren, wie TGF-β1, verantwortlich sein. Um einen Einfluss von TLR 5 auf die Aktivierbarkeit von hepatischen und pankreatischen Sternzellen zu belegen, wurde ein TLR 5 Knockdown in LX-2 und hPSC 2.2.-Zellen durchgeführt. Die Aktivierung wurde durch unterschiedliche Konzentrationen TGF-β1 induziert. In der quantitativen RT-PCR zeigte sich eine Induktion von TLR 5 nach Aktivierung der Zellen mit TGF-β1. Außerdem nach TLR 5 Knockdown und TGF-β1 Behandlung eine Ineffizienz der TGF-β1 Wirkung bei der Aktivierung der Zellen. Dies konnte durch Westernblots auf Proteinebene bestätigt werden, bei der sich eine vermehrte TLR 5 Expression bei aktivierten Zellen, sowie eine verminderte Proteinexpression der Aktivitätsmarker nach TLR 5 Inhibierung präsentierte, die durch TGF-β1 nicht auf das Niveau des aktiven Zustandes gesteigert werden konnte. Diese Ergebnisse bestätigten sich ebenfalls in der indirekten Immunfluoreszenz. Das Proliferationsverhalten wurde zusätzlich durch eine Echtzeitbildgebung mittels Incucyte® beobachtet. Hier zeigte sich über einen Zeitraum von 48 Stunden eine verminderte Proliferationsrate nach TLR 5 Inhibierung und Behinderung der TGF-β1 Effizienz. Diese Ergebnisse bestätigen das aktivierende Potenzial von TGF-β1 und heben die Bedeutsamkeit von TLR 5 bei der Aktivierung von Sternzellen hervor und eröffnen damit neue Perspektiven zum besseren Verständnis von Mechanismen die im Gewebe mit einer Beteiligung von Sternzellen einhergeht; im Speziellen hinsichtlich der Sensibilität humaner Sternzellen gegenüber mikrobieller Stimuli und der Fähigkeit von Mikroorganismen molekulare und morphologische Zellveränderungen zu initiieren, die ein wichtige Rolle für Gewebestruktur und Funktionalität spielen. Des weiteren bietet das weitere Verständnis von Mechanismen der Fibroseentstehung im Zusammenhang mit der Karzinogenese und der Einflussnahme des Mikrobioms neue Hinweise für zukünftige Therapien und Maßnahmen zur Behandlungen von Erkrankungen des oberen Gastrointestinaltraktes.Fibrosis, the increased deposition of extracellular matrix in human body, is a result of sustained inflammatory tissue response. Particularly in liver and pancreas a variety of acute and chronic diseases, including alcoholic and non-alcoholic steatohepatitis, viral and autoimmune hepatitis, pancreatitis and pancreatic carcinoma, can promote the complex pathophysiologic process of fibrogenesis, and by that lead to a dramatic loss of functional parenchyma. The most significant mediators of fibrosis and main source of extracellular matrix proteins like collagen are human stellate cells, whose activation plays a well established key role of fibrogenesis. Quiescent hepatic and pancreatic stellate cells are characterised by epithelial morphology and storage of Vitamin A and carry out various functions contributing to functional tissue integrity and immunity. Their activation causes the transdifferentation to mesenchymal myofibroblasts with ability to deposit extracellular matrix by collagen secretion, parenchymal migration, contractility, proliferation, phagocytosis, etc.; which can lead to to liver fibrosis, cirrhosis, and tumourigenesis. Past studies indicated the resemblance of pancreatic stellate cells and their hepatic relatives in functionality and morphologic appearance. In the context of pancreatic ductal carcinoma pancreatic stellte cells not only contrive the characteristic desmoplastic tissue formation but they also interact with carcinoma cells and participate considerably in the tumor metabolism and development. As immunocompetent cells, human stellate cells express a various amount of Toll-like receptors (TLR) with whom pathogen molecular patterns can be recognized. Via the expression of TLR 5 human stellate cells can bind specifically the bacterial flagella protein Flagellin leading to intracellular TLR signaling and promoting tissue inflammation; a characteristic feature which indicates an interesting link between stellate cell-mediated fibrogenesis and microbial colonization of the gastrointestinal tract. This study highlights a possible intercommunication existing between the stellate cells, other pancreatic and liver cells and the microbiota via TLR 5. In vitro studies showed that LX-2 and HPSC 2.2 immortalised stellate cells can be easily treated with a low amount of transforming growth factor beta 1 (TGF-β1), leading to their transdifferentiation into myofibroblasts. TGF-β1 was able to stimulate the stellate cells, promote their activation, and their change from a quiescent state to an active one, which characterises these cells in their liver and pancreatic tissue environment. The responsiveness to TGF-β1 highlights the fact that the stellate cells can be activated by signaling coming from both neighbouring and more distant cells. In particular, the presence of tumour cells in the surrounding parenchyma could be also responsible for stellate cell activation through the secretion of several growth stimulating factors, including TGF-β1. To show that TLR 5 influences the activation of hepatic and pancreatic stellate cells, TLR 5 was knocked down in LX-2 and hPSC 2.2. cell lines. Additionally, different concentrations of TGF-β1 were used to stimulate the cell activation. The quantitative RT-PCR showed an increased expression of TLR 5 after cell activation with TGF-β1 and a disabled TGF-β1 activation efficacy during TLR 5 knockdown; consequently the inhibition of TLR 5 caused an inefficiency of TGF-β1. These data could be confirmed by protein level of western blot analysis; activated cells presented an increased expression of TLR 5 and a decreased expression of the activity marker after inhibiting TLR 5, which could not be rehabilitated. These results were also confirmed by indirect immunofluorescence. Additionally, the cell proliferation was observed by real time imaging system Incucyte® revealing a decreased proliferation rate and TGF-β1 efficacy during TLR 5 knockdown during 48 hours. These results confirm the activating potential of TGF-β1, highlight the importance of TLR 5 for stellate cell activation and offer new perspectives for understanding the mechanisms underlying stellate cells’ involvement in the tissue environment; in particular, the sensitivity of human stellate cells to stimuli coming from microorganisms populating the host body and the ability of micro-organisms to activate molecular and morphological changes in cells that play a specific role in the structure and functioning of the tissue or organ. Understanding the mechanisms of organ fibrogenesis in correlation with tumourigenesis and the influence of microbiota will open new directions for future treatment of diseases affecting the upper-midgut area of the human body
Measuring Anti-trafficking Policy - Integrating Text and Statistical Analysis
No full textThis paper reviews the existing indices on anti-trafficking policy and proposes the integration of statistical indicators into the indices coded from qualitative texts in order to improve the objectivity of evaluation. Examining the validity of the existing indices, the 3P Index and the GRETA-Scorecard, the results suggest that these measurements are not free from subjectivity regarding the selection of policy requirements and evaluation standards. To enhance objectivity, the utilization of the European Statistics is proposed and the validity of these statistics is investigated through multi-covariate analysis. The results show that the EU statistics are relevant indicators reflecting the quality of anti-trafficking policy, suggesting that, by integrating text and statistical information, an index on anti-trafficking policy canenhance its comprehensiveness and objectivity
Empirical Analysis of the Assessment of Innovation Effects in U.S. Merger Cases
No full textIn this empirical study all mergers that have been challenged by the U.S. antitrust agencies FTC and DOJ between 1995 and 2008 were analyzed in regard to the question to what extent and how the agencies assessed the innovation effects of mergers. Theoretical background is the still open question how negative effects of mergers on innovation should be taken into account in merger policy. Although we can show in our study that in one third of all challenged mergers also innovation concerns were raised, the results also point to a still existing large degree of uneasiness and inconsistencies of the agencies in regard to the assessment of innovation effects. A particularly interesting result is that - despite the wide-spread rejection of the "innovation market approach" in the antitrust debate - the agencies used more an innovationspecific assessment approach that includes also innovation in the market definition than the pure traditional product market concept. Additionally, we also found significant differences between the assessment approaches of the FTC and the DOJ
Cephalometric Screening Assessment for Superior Airway Space Narrowing : Added Value of Three-Dimensional Imaging
No full textAssessing the morphology of the superior airway space is a crucial diagnostic
step in the treatment planning of patients with obstructive sleep apnea syndrome (OSAS) or prior to
orthognathic surgery. The aim of this study is to evaluate the necessary scope of a two-dimensional
cephalometric assessment and the necessity of three-dimensional imaging in the identification of
superior airway space narrowing (SASN). Methods: The computed tomography studies of 100 nonobese,
non-OSAS patients were evaluated and analyzed retrospectively. Multiplanar reconstructions
were created and underwent cephalometric evaluation. The three-dimensional superior airway
morphology was segmented and measured for the minimal cross-sectional area (Amin) and volume
(V0). Patients were grouped according to Amin < 80 mm2 and V0 < 12 cm3. Cephalometric parameters
(CPs) were analyzed according to Amin and V0 with an unpaired t-test, Pearson correlation, and
ROC-curve analysis. Results: The CPs regarding sagittal airway space dimensions (IPAS, MPAS,
SPAS) and mandibular body length (GoGn) show the strongest correlation to the three-dimensional
minimal cross-sectional area (Amin). The ROC-curve analysis classifying for SASN led to an AUC
of 0.86 for IPAS, 0.87 for MPAS, 0.88 for SPAS, and 0.63 for GoGn. Three-dimensional imaging may
further improve the diagnostic accuracy in the identification of SASN for IPAS below 13.5 mm, MPAS
below 10.2 mm, SPAS below 12.5 mm, and GoGn below 90.2 mm. Conclusions: Two-dimensional
cephalometric sagittal airway space diameters and mandibular body length are useful initial screening
parameters in the identification of superior airway space narrowing. Nevertheless, as the correlation
of two-dimensional cephalometric parameters with three-dimensional upper airway space narrowing
is varying and highly dependent on acquisition circumstances, indications for three-dimensional
imaging, if possible, in the supine position to evaluate upper airway space morphology should
be provided generously, especially in patients with low but normal airway space parameters in
two-dimensional cephalometry.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Streptococcus pneumoniae disrupts the structure of the golgi apparatus and subsequent epithelial cytokine response in an H2O2‑dependent manner
No full textLung infections caused by Streptococcus pneumonia are a global leading cause of death. The reactive oxygen species H2O2 is one of the virulence factors of Streptococcus pneumoniae. The Golgi apparatus is essential for the inflammatory response of a eukaryotic cell. Golgi fragmentation was previously shown to be induced by bacterial pathogens and in response to H2O2 treatment. This led us to investigate whether the Golgi apparatus is actively involved and targeted in host–pathogen interactions during pneumococcal infections.
Following in vitro infection of BEAS-2B bronchial epithelial cells with Streptococcus pneumoniae for 16 h, the structure of the Golgi apparatus was assessed by fluorescence staining of the Golgi-associated protein, Golgin-97. To investigate the effect of H2O2 production on Golgi structure, BEAS-2B cells were treated with H2O2 or the H2O2 degrading enzyme Catalase, prior to Golgi staining. Artificial disruption of the Golgi apparatus was induced by treatment of cells with the GBF1 inhibitor, Golgicide A. A proinflammatory cellular response was induced by treatment of cells with the bacterial cell wall component and TLR4 ligand lipoteichoic acid.
In vitro infection of bronchial epithelial cells with wild type Streptococcus pneumoniae led to a disruption of normal Golgi structure. Golgi fragmentation was not observed after deletion of the pneumococcal H2O2-producing gene, spxB, or neutralization of H2O2 by catalase treatment, but could be induced by H2O2 treatment. Streptococcus pneumoniae infection significantly reduced host cell protein glycosylation and artificial disruption of Golgi structure significantly reduced bacterial adherence, but increased bacterial counts in the supernatant. To understand if this effect depended on cell-contact or soluble factors, pneumococci were treated with cell-supernatant of cells treated with Golgicide A and/or lipoteichoic acid. This approach revealed that lipoteichoic acid conditioned medium inhibits bacterial replication in presence of host cells. In contrast, artificial Golgi fragmentation by Golgicide A treatment prior to lipoteichoic acid treatment rescued bacterial replication. This effect was associated with an increase of IL-6 and IL-8 in the supernatant of lipoteichoic acid treated cells. The increased cytokine release was abolished if cells were treated with Golgicide A prior to lipoteichoic acid treatment.
Streptococcus pneumoniae disrupts the Golgi apparatus in an H2O2-dependent manner, thereby inhibiting paracrine anti-infective mechanisms.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
High expression of insulinoma-associated protein 1 (INSM1) distinguishes colorectal mixed and pure neuroendocrinecarcinomas from conventional adenocarcinomas with diffuseexpression of synaptophysin
No full textComplementary to synaptophysin and chromogranin A, insulinoma-associated protein 1 (INSM1) has emerged as a sensitive marker for the diagnosis of neuroendocrine neoplasms. Since there are no comparative data regarding INSM1 expression in conventional colorectal adenocarcinomas (CRCs) and colorectal mixed adenoneuroendocrine carcinomas/neuroendocrine carcinomas (MANECs/NECs), we examined INSM1 in a large cohort of conventional CRCs and MANECs/NECs. In conventional CRC, we put a special focus on conventional CRC with diffuse expression of synaptophysin, which carry the risk of being misinterpreted as a MANEC or a NEC. We investigated INSM1 according to the immunoreactive score in our main cohort of 1,033 conventional CRCs and 21 MANECs/NECs in comparison to the expression of synaptophysin and chromogranin A and correlated the results with clinicopathological parameters and patient survival. All MANECs/NECs expressed INSM1, usually showing high or moderate expression (57% high, 34% moderate, and 9% low), which distinguished them from conventional CRCs, which were usually INSM1 negative or low, even if they diffusely expressed synaptophysin. High expression of INSM1 was not observed in conventional CRCs. Chromogranin A was negative/low in most conventional CRCs (99%), but also in most MANECs/NECs (66%). Comparable results were observed in our independent validation cohorts of conventional CRC (n = 274) and MANEC/NEC (n = 19). Similar to synaptophysin, INSM1 expression had no prognostic relevance in conventional CRCs, while true MANEC/NEC showed a highly impaired survival in univariate and multivariate analyses (e.g. disease-specific survival: p < 0.001). MANECs/NECs are a highly aggressive variant of colorectal cancer, which must be reliably identified. High expression of INSM1 distinguishes MANEC/NEC from conventional CRCs with diffuse expression of the standard neuroendocrine marker synaptophysin, which do not share the same dismal prognosis. Therefore, high INSM1 expression is a highly specific/sensitive marker that is supportive for the diagnosis of true colorectal MANEC/NEC.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Validation of an algorithm for an app for appointments in a vascular medicine outpatient clinic
No full textZiel der Arbeit war die Validierung einer App für die Terminvereinbarung in einer gefäßmedizinischen Ambulanz. Für die häufigsten Verdachtsdiagnosen einer gefäßmedizinischen Sprechstunde wurden elf Algorithmen entwickelt und in eine App programmiert. Die Überprüfung der Dringlichkeitseinstufung der Abfrage-Algorithmen im Vergleich mit der Terminfindung durch zwei erfahrene Fachärztinnen ergab, dass die Algorithmen eine sehr hohe Übereinstimmung mit dem Facharztstandard haben und somit als valide angesehen werden können.
Im Gegensatz zu den beiden Fachärztinnen zeigten die üblicherweise zur Terminvereinbarung eingesetzten medizinischen Fachangestellten eine sehr heterogene Dringlichkeitseinstufung. Auf den klinischen Alltag übertragen bedeutet dies einerseits eine Patientengefährdung bei zu später, andererseits eine Effektivitätsminderung der Sprechstunde bei zu früher Terminvereinbarung. Bei Verwendung der App als Abfragealgorithmus konnte die Terminvergabe nahezu vollständig die Vorgaben der Referenz erreichen. Damit führte sie zu einer sicheren, und konsistenten Terminvergabe, die wissensunabhängig vom Anwender war und zu einer deutlichen Handlungssicherheit beitrug. Darüber hinaus war der Zeitaufwand aufgrund der strukturierten Führung der Patientenabfrage deutlich geringer.
Da sich ein klarer Nutzen für die Terminvereinbarung mit Hilfe der Algorithmen in der App zeigte, ist im nächsten Schritt die Zulassung und Verwendung im klinischen Alltag geplant.The aim of the doctoral thesis was to validate an app for making appointments in a vascular medicine outpatient clinic. Eleven algorithms were developed and programmed into an app for the most common suspected diagnoses in a vascular medicine consultation. The review of the urgency classification of the algorithms in comparison with the appointment scheduling by two experienced specialists showed that the algorithms have a very high level of agreement with the specialist standard and can therefore be regarded as valid.
In contrast to the two specialists, the medical assistants who usually used to make appointments showed a very heterogeneous urgency classification. Applied to everyday clinical practice, it means that on the one hand that patients are at risk if appointments are made too late and on the other hand that the effectiveness of the consultation is reduced if appointments are made too early. When using the app as an algorithm, the appointment allocation was able to almost completely reach the requirements of the reference. This led to reliable and consistent appointment allocation, which was independent of the user's knowledge. In addition, the time required was significant reduced due to the structured management of patient queries.
There was a clear benefit for making appointments with the help of the algorithms in the app, so the next step is to obtain the approval to use it in everyday clinical practice
“When one has no REAL illness”—analysis of the knowledge component of mental health literacy in children and adolescents of parents with a mental illness
No full textIntroduction and objective: Mental Health Literacy (MHL) is important in promoting youth mental health. One key aspect of MHL is knowledge about mental disorders, which is particularly relevant for populations at risk for developing mental disorders, such as children of parents with a mental illness (COPMI), representing a mechanism within the transgenerational transmission. Currently, COPMI’s level of disorder knowledge in general, and about the specific parental disorder has not been comprehensively researched. We, therefore, aimed to assess COPMI’s disorder knowledge and clarify its association with COPMI’s age and sex exploratively. To assess both general and disorder-specific knowledge, we took a novel approach that makes disorder knowledge comparable across samples and over time.
Methods: A mixed method analysis of N = 181 semi-structured MHL interviews with COPMI (aged 5 to 17 years) was carried out in the COMPARE—family study in Germany. We conducted a DSM-oriented deductive qualitative content analysis to assess COPMI’s general and specific disorder knowledge. Chi-square tests served to identify age and sex differences.
Results: Children revealed limited knowledge of mental disorders in general, whereas adolescents displayed more knowledge that was also partly consistent with descriptions of classification systems like the DSM-5. The level of specific knowledge about the parent’s disorder depended on the disorder group. More children displayed adequate knowledge of somatic and anxiety disorders compared to trauma and depressive disorders, and more adolescents displayed adequate knowledge of depressive and anxiety disorders. COPMI’s age and sex were found to be significantly associated with disorder knowledge: adolescents exhibited higher levels of adequate general and specific disorder knowledge, and males exhibited higher levels of adequate general disorder knowledge.
Conclusion: Assessing COPMI’s disorder knowledge and identifying associated age and sex differences yield valuable insights into the knowledge component of the MHL theory. Our findings can help to improve psychoeducational interventions for COPMI by orienting them to their prevailing levels of disorder knowledge. We recommend employing and extending the DSM-oriented deductive approach to assess knowledge within MHL. Analyses involving additional assessments within the COMPARE—family study are in preparation to identify potential knowledge gains over time, and associations to COPMI’s own well-being and mental health symptoms.Gefördert durch den Open-Access-Publikationsfonds der UB Marburg
Langzeitergebnisse zur Strahlentherapie nach radikaler Prostatektomie als adjuvante Radiatio versus Salvage-Radiatio bei Persistenz des prostataspezifischen Antigens
No full textHintergrund: Patienten mit Prostatakarzinom (PCa) kann, bei entsprechend vorliegenden histopathologischen Risikofaktoren, nach radikaler Prostatektomie (RPE) die Radiatio der Prostataloge angeboten werden. Diese kann mit urogenitalen sowie gastrointestinalen Akut- und Spättoxizitäten verbunden sein. Definitionsgemäß erhalten Patienten ohne Persistenz des prostataspezifischen Antigens (PSA) nach RPE eine adjuvante Radiotherapie (ART), während die Radiatio bei Patienten mit PSA-Persistenz nach RPE als Salvage-Radiotherapie (SRT) bezeichnet wird.
Fragestellung: Ziel der vorliegenden Arbeit war die Evaluation der onkologischen Langzeitergebnisse von PCa-Patienten nach RPE und anschließender Radiatio der Prostataloge als ART nach Erreichen des definierten PSA-Nullbereichs nach RPE oder als SRT bei PSA-Persistenz nach RPE. Hierbei wurde der Einfluss der PSA-Persistenz nach RPE auf die onkologischen Langzeitergebnisse untersucht. Mögliche Nebenwirkungen der Radiatio wie urogenitale sowie gastrointestinale Akut- und Spättoxizität, toxizitätsbedingte Zystektomie und Auftreten von vesikourethralen Anastomosenstrikturen (VUAS) wurden analysiert. Abschließend erfolgte der Vergleich der Ergebnisse mit in der Literatur beschriebenen Studiendaten.
Material und Methoden: In dieser retrospektiven Arbeit wurden 261 am Klinikum Fulda behandelte PCa-Patienten identifiziert, die nach offener retropubischer RPE bei Vorliegen von positiven chirurgischen Schnitträndern (R1) und/oder eines kapselüberschreitenden PCa (≥ pT3) im Zeitraum vom 01.01.2004 bis zum 31.12.2018 eine Radiatio der Prostataloge erhielten. Patienten mit neoadjuvanter antihormoneller Therapie, histologisch nachgewiesenen Lymphknotenmetastasen (pN1) oder nicht erfolgter pelviner Lymphadenektomie (pNx) wurden ausgeschlossen. In die Auswertung wurden somit 180 PCa-Patienten einbezogen und abhängig von einer bestehenden PSA-Persistenz nach RPE in ART- oder SRT-Gruppe eingeteilt. Hierbei galt ein PSA- Wert > 0,1 ng/ml vor Radiatio als PSA-Persistenz nach RPE. Die perkutane Radiatio erfolgte durch einen Linearbeschleuniger mit Photonenstrahlung in 3D-konformaler oder intensitätsmodulierter Technik mit einer geplanten Gesamtdosis von 59,4 Gray (Gy); 64,8 Gy; 66,6 Gy oder 70,2 Gy mit einer Fraktionierung von 1,8 Gy pro Tag an 5 Tagen pro Woche.
Ergebnisse: Das mediane Alter der Patienten zum Zeitpunkt der RPE lag bei 65,8 Jahren (44,3-80 Jahre). Das untersuchte Gesamtkollektiv von 180 Patienten konnte mit einer medianen Nachbeobachtungszeit von 8,3 Jahren (0,1-17,6 Jahre) nachverfolgt werden. Das biochemisch rezidivfreie 2-, 5- und 10-Jahres Überleben der Patienten mit ART betrug 96,4 %, 85,8 % und 75,7 %. Da nach Abschluss der SRT 47,1 % der Patienten weiterhin eine PSA-Persistenz oder -Progredienz mit einem PSA-Wert über dem definierten Grenzwert für ein biochemisches Rezidiv (BCR) aufwiesen, wurde das BCR-freie Überleben in der SRT-Gruppe nicht erhoben. Im Vergleich zu Patienten ohne PSA-Persistenz zeigten Patienten mit PSA-Persistenz nach RPE ungünstigere onkologische Langzeitergebnisse mit einem signifikant schlechteren metastasenfreien Überleben, karzinomspezifischen Überleben und Gesamtüberleben. So lag das metastasenfreie 2-, 5- und 10-Jahres Überleben von Patienten mit ART vs. SRT bei 99,3%, 98.5% und 87,1% vs. 91%, 64,3% und 36,4% (p<0,0000005). Das karzinomspezifische 2-, 5- und 10-Jahres Überleben von Patienten mit ART vs. SRT betrug 100 %, 100 % und 97,6 % vs. 100 %, 92,7 % und 68,5 % (p < 0,000000005). Das 2-, 5- und 10-Jahres Gesamtüberleben von Patienten mit ART vs. SRT lag bei 97,9 %, 94 % und 84 % vs. 100 %, 83,7 % und 61,8 % (p = 0,042). Darüber hinaus wiesen Patienten mit PSA-Persistenz im Vergleich zu Patienten ohne PSA-Persistenz nach RPE signifikant höhere präoperative PSA-Werte und ungünstigere Gleason-Scores auf. Urogenitale und gastrointestinale Akut- bzw. Spättoxizitäten ≥ Grad 3 wurden in insgesamt 3,3 % bzw. 5 % der Fälle beobachtet. Sechs Patienten (3,3 %) wurden aufgrund einer urogenitalen Spättoxizität zystektomiert. Bei 16,1 % der Patienten traten behandlungsbedürftige VUAS auf.
Schlussfolgerung: Die onkologischen Ergebnisse der ART sind exzellent. Bei PCa- Patienten mit RPE und nachfolgender Radiatio der Prostataloge ist eine PSA-Persistenz nach RPE mit signifikant schlechteren onkologischen Langzeitergebnissen vergesellschaftet. Darüber hinaus ist die Radiatio der Prostataloge nach RPE mit einer nicht zu vernachlässigenden Rate an Akut- und Spättoxizitäten assoziiert. Bei einer hohen Gesamtüberlebensrate hat ein Großteil der PCa-Patienten die Chance, mögliche Spätfolgen der Radiatio tatsächlich zu erleben, sodass der Einsatz dieser wohlüberlegt erfolgen sollte.Background: The radiation of the prostate fossa can be offered to patients with prostate cancer (PCa) and appropriate histopathological risk factors after radical prostatectomy (RPE). This can be associated with genitourinary and gastrointestinal acute and late toxicities. By definition, patients without a persisting prostate-specific antigen (PSA) after RPE receive an adjuvant radiotherapy (ART), while radiation in patients with persisting PSA after RPE is called salvage radiotherapy (SRT).
Objectives: The aim of the present work was to evaluate the oncological long-term outcomes of PCa patients after RPE and subsequent radiation of the prostate fossa as ART after reaching the defined PSA zero range after RPE or as SRT if PSA persists after RPE. The influence of PSA persistence after RPE on long-term oncological outcomes was examined. Possible side effects of radiation such as genitourinary and gastrointestinal acute and late toxicity, toxicity-related cystectomy and occurrence of vesicourethral anastomotic strictures (VUAS) were analysed. Finally, the results were compared with data described in the literature.
Materials and Methods: In this retrospective work, 261 PCa patients, treated at the General Hospital Fulda, were identified, who underwent open retropubic RPE and thereafter received radiation of the prostate fossa in the presence of positive surgical margins (R1) and/or PCa extending beyond the capsule (≥ pT3) in the period from January 1st, 2004 to December 31st, 2018. Patients with neoadjuvant antihormonal therapy, histologically proven lymph node metastases (pN1) or no pelvic lymphadenectomy (pNx) were excluded. Ultimately, 180 PCa patients were included in the analysis and divided into ART- or SRT-group depending on existing PSA persistence after RPE. A PSA value > 0.1 ng/ml before radiation was considered as PSA persistence after RPE. Percutaneous radiation was carried out using linear accelerator with photon radiation using 3D-conformal- or intensity-modulated technology with a planned total dose of 59.4 Gray (Gy); 64.8 Gy; 66.6 Gy or 70.2 Gy with a fractionation of 1.8 Gy per day, 5 day per week.
Results: The median age of the patients at the time of RPE was 65.8 years (44.3- 80 years). The total group of 180 patients examined was followed up with a median time of 8.3 years (0.1-17.6 years). The 2-, 5- and 10-year biochemical recurrence-free survival of Patients with ART was 96.4 %, 85.8 % and 75.7 %. Since 47.1 % of the patients in the SRT-group continued to have PSA persistence or progression with a PSA value above the defined cutoff for biochemical recurrence (BCR) after completion of SRT, BCR-free survival was not analysed in the SRT-group. Compared to patients without PSA persistence, patients with PSA persistence after RPE showed worse long-term oncological outcomes with significantly worse metastasis-free survival, cancer-specific free survival and overall survival. The 2-, 5- and 10-year metastasis-free survival of patients with ART vs. SRT was 99.3 %, 98.5 % and 87.1 % vs. 91 %, 64.3 % and 36.4 % (p < 0.0000005). Cancer-specific 2-, 5- and 10-year survival of patients with ART vs. SRT was 100 %, 100 % and 97.6 % vs. 100 %, 92.7 % and 68.5 % (p < 0.000000005). The 2-, 5- and 10-year overall survival of Patients with ART vs. SRT was 97.9 %, 94 % and 84% vs. 100%, 83.7% and 61.8% (p=0.042). In addition, patients with PSA persistence had significantly higher preoperative PSA values and less favourable Gleason scores compared to patients without PSA persistence after RPE. Genitourinary and gastrointestinal acute and late toxicities ≥ grade 3 were observed in a total of 3.3 % and 5% cases respectively. Six patients (3.3%) underwent cystectomy due to genitourinary late toxicity. VUAS requiring treatment occurred in 16.1 % of patients.
Conclusion: The oncological results of ART are excellent. In patients with RPE and subsequent radiation of the prostate fossa, PSA persistence after RPE is related to significantly worse long-time oncological outcomes. In addition, radiation of the prostate fossa after RPE is associated with a non-negligible rate of acute and late toxicities. With a high overall survival rate, a majority of PCa patients have the chance to actually experience possible long-term effects of radiation. Therefore, its use should be carefully considered