Definition and Independent Validation of a Proteomic-Classifier in Ovarian Cancer

Simple Summary: The heterogeneity of epithelial ovarian cancer and its associated molecular biological characteristics are continuously integrated in the development of therapy guidelines. In a next step, future therapy recommendations might also be able to focus on the patient's systemic status, not only the tumor's molecular pattern. Therefore, new methods to identify and validate host-related biomarkers need to be established. Using mass spectrometry, we developed and independently validated a blood-based proteomic classifier, stratifying epithelial ovarian cancer patients into good and poor survival groups. We also determined an age dependence of the prognostic performance of this classifier and its association with important biological processes. This work highlights that, just like molecular markers of the tumor itself, the systemic condition of a patient (partly reflected in proteomic patterns) also influences survival and therapy response and could therefore be integrated into future processes of therapy planning. Abstract: Mass-spectrometry-based analyses have identified a variety of candidate protein biomarkers that might be crucial for epithelial ovarian cancer (EOC) development and therapy response. Comprehensive validation studies of the biological and clinical implications of proteomics are needed to advance them toward clinical use. Using the Deep MALDI method of mass spectrometry, we developed and independently validated (development cohort: n = 199, validation cohort: n = 135) a blood-based proteomic classifier, stratifying EOC patients into good and poor survival groups. We also determined an age dependency of the prognostic performance of this classifier, and our protein set enrichment analysis showed that the good and poor proteomic phenotypes were associated with, respectively, lower and higher levels of complement activation, inflammatory response, and acute phase reactants. This work highlights that, just like molecular markers of the tumor itself, the systemic condition of a patient (partly reflected in proteomic patterns) also influences survival and therapy response in a subset of ovarian cancer patients and could therefore be integrated into future processes of therapy planning

Prognostic markers in epithelial ovarian cancer

Das epitheliale Ovarialkarzinom (EOC) ist eine heterogene Tumorerkrankung, gekennzeichnet durch eine komplexe Tumorbiologie. Trotz kontinuierlicher Forschung und Verbesserung der therapeutischen Möglichkeiten, stehen wir nach wie vor einer beunruhigend hohen Mortalität gegenüber. Prognostische Marker würden hier helfen, Patientinnen die von einer individuelleren tumorspezifischen Therapie profitieren könnten, zu selektieren. Die folgende Dissertation beschreibt eine weiterführende Evaluierung von potentiell interessanten prognostischen Markern in dieser komplexen Tumorentität. Ein neues Subklassifizierungs-systems, wobei anhand einer Gensignatur Ovarialkarzinompatientinnen in zwei Gruppen mit signifikant unterschiedlicher Prognose unterteilt wurden, konnte erfolgreich validiert werden. Die biologische Interpretation der Microarray-Daten identifizierte den Pathway der fokalen Adhäsionskinase (FAK) als signifikant überrepräsentierten Pathway. Folglich wurde die prognostische Bedeutung der aktivierten, phosphorylierten Form von FAK - bereits als therapeutisches Target beforscht - analysiert. Auch Hormonrezeptoren sowie Pathways in Mitochondrien werden als interessante therapeutische Targets diskutiert. Zusätzlich wurde daher die Expression und prognostische Rolle des Hormonrezeptor Co-Regulators PELP1 und des mitochondrialen Chaperons TRAP1 untersucht. Die vorliegende Dissertation gibt einen Überblick über mehrere interessante biologische Marker im Ovarialkarzinom und stellt beispielhaft dar, dass in dieser Tumor Entität eine "tumorspezifische" Therapie mit Vorsicht maßgeschneidert werden muss.Epithelial ovarian cancer (EOC) is a heterogeneous disease with a distinctive biology and behavior. Despite improvements in the therapeutic setting, we still have to face an alarmingly high mortality rate. Markers to adequately define patients that will benefit from an individualized "tumor-tailored" treatment approach are urgently needed. This thesis focused on the continuative evaluation of potential prognostic markers in this complex malignancy. The validation of a new subclassification approach, stratifying patients into subclasses with tremendous different prognosis was successful, additionally a significance analysis of microarrays and functional analysis of the differences between the two subclasses revealed the focal adhesion kinase (FAK) pathway as overrepresented. Therefore, the role of the FAK and the activated phosphorylated FAK - investigated as therapeutic target - was determined. Similarly, the mitochondrial pathway as well as hormone receptors are discussed as therapeutic targets but their role in EOC has not been fully elucidated yet. As little is known about the role of the mitochondrial pathway and the chaperone TRAP1 in the complex system of human EOC, the role of this mitochondrial chaperone was evaluated. Additionally, the expression and prognostic role of the estrogen receptor co-regulator PELP1 was investigated. This thesis gives an overview over a sample of interesting prognostic markers that might very well have an ambivalent role in EOC and exemplifies, that in this tumor entity a "tumor-specific-therapy" has to be tailored with caution.submitted by Stefanie AustAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersWien, Med. Univ., Diss., 2014OeBB(VLID)171393

The interrelation of organisation and professional competencies. An analysis of pedagogical competencies through the combined assessment of attitudes, knowledge and skills and their connection to organisational research

Der Aufsatz nimmt das Aufeinander-Verwiesen-Sein von Organisation und Profession im Handeln zum Ausgangspunkt und fokussiert die professionellen Kompetenzen. Er fragt, ob und wenn ja, wie professionelle Kompetenzen von Lehrenden in der Hochschule organisational variieren. Dabei werden zwei Zielrichtungen verfolgt: Theoretisch und forschungsmethodisch gilt es exemplarisch an einem Forschungsprojekt darzustellen, wie Professions- und Organisationsforschung in Theorieanlage und Methode miteinander verbunden sind. Aufbauend darauf weisen empirisch ausgewählte Ergebnisse darauf hin, dass professionelle Kompetenzen von Lehrenden und die Wahrnehmung der Hochschule als unterstützenden versus hemmenden Kontext organisationsbezogen variieren. Auf diese Weise werden der theoretische, methodische und empirische Mehrwert einer Verbindung beider Stränge sichtbar.The essay takes the interrelation of organisation and professional competencies as a starting point and focuses on professional competencies. It asks whether and, if so, how professional competencies of teachers in higher education vary organisationally. Two directions are pursued: Theoretically and methodologically, a research project is used as an example to illustrate how professional and organisational research are linked in terms of theory and method. Building on this, selected results empirically show that professional competencies of teachers in higher education and perceptions of the university as a supportive versus inhibiting context vary depending on the organisation. In this way, the theoretical, methodological and empirical added value of linking the two strands becomes visible

Defining Models to Classify between Benign and Malignant Adnexal Masses Using Routine Laboratory Parameters

Discrimination between benign and malignant adnexal masses is essential for optimal treatment planning, but still remains challenging in a routine clinical setting. In this retrospective study, we aimed to compare albumin as a single parameter to calculate models by analyzing laboratory parameters of 1552 patients with an adnexal mass (epithelial ovarian cancer (EOC): n= 294; borderline tumor of the ovary (BTO): n = 66; benign adnexal mass: n = 1192) undergoing surgery. Models comprising classical laboratory parameters show better accuracies (AUCs 0.92–0.93; 95% CI 0.90–0.95) compared to the use of single markers, and could easily be implemented in clinical practice by containing only readily available markers. This has been incorporated into a nomogram

NECTIN4 (PVRL4) as Putative Therapeutic Target for a Specific Subtype of High Grade Serous Ovarian Cancer—An Integrative Multi-Omics Approach

In high grade serous ovarian cancer patients with peritoneal involvement and unfavorable outcome would benefit from targeted therapies. The aim of this study was to find a druggable target against peritoneal metastasis. We constructed a planar—scale free small world—co-association gene expression network and searched for clusters with hub-genes associated to peritoneal spread. Protein expression and impact was validated via immunohistochemistry and correlations of deregulated pathways with comprehensive omics data were used for biological interpretation. A cluster up-regulated in miliary tumors with NECTIN4 as hub-gene was identified and impact on survival validated. High Nectin 4 protein expression was associated with unfavorable survival and (i) reduced expression of HLA genes (mainly MHC I); (ii) with reduced expression of genes from chromosome 22q11/12; (iii) higher BCAM in ascites and in a high-scoring expression cluster; (iv) higher Kallikrein gene and protein expressions; and (v) substantial immunologic differences; locally and systemically; e.g., reduced CD14 positive cells and reduction of different natural killer cell populations. Each three cell lines with high (miliary) or low NECTIN4 expression (non-miliary) were identified. An anti-Nectin 4 antibody with a linked antineoplastic drug−already under clinical investigation−could be a candidate for a targeted therapy in patients with extensive peritoneal involvement

Factors associated with post-relapse survival in patients with recurrent cervical cancer : the value of the inflammation-based Glasgow Prognostic Score

Purpose The aim of the present study was to assess the value of the Glasgow Prognostic Score (GPS) as a prognostic tool for predicting post-relapse survival (PRS) in patients with recurrent cervical cancer. Methods We retrospectively evaluated the data of 116 patients with recurrent cervical cancer in whom serologic biomarkers had been assessed at the time of relapse. The GPS was calculated as follows: patients with elevated serum C-reactive protein levels and hypoalbuminemia were allocated a score of 2, and those with 1 or no abnormal value were allocated a score of 1 and 0, respectively. To assess the association between factors including the GPS and PRS, we performed uni- and multivariate survival analyzes. Results After a median follow-up of 20.9 months from recurrence, a 5-year PRS rate of 25% (SE 4.7%) was observed. Only in 29.8% of the patients, recurrence was limited to the pelvis. In uni- and multivariate survival analyzes, the GPS [HR 1.6 (95% CI 0.92.4), p=0.01], a history of radiation therapy as part of initial treatment [HR 2.7 (95% CI 1.16.9), p=0.03], and the presence of peritoneal carcinomatosis or multiple sites of relapse [HR 4.2 (95% CI 1.99.3), p<0.001] were associated with shorter PRS. The GPS correlated with higher squamous cell carcinoma antigen levels (p=0.001), shorter median PRS (p=0.009), and less intensive treatment for relapse (p=0.02). Conclusions A higher GPS at the time of relapse, a history of radiation therapy, and the presence of peritoneal carcinomatosis or multiple sites of relapse are independently associated with shorter PRS in patients with recurrent cervical cancer.(VLID)365858