Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-29031 Wissenschaftlicher Artikel Lüke, Florian; Haller, Florian; Utpatel, Kirsten; Krebs, Markus; Meidenbauer, Norbert; Scheiter, Alexander; Spoerl, Silvia; Heudobler, Daniel; Sparrer, Daniela; Kaiser, Ulrich; Keil, Felix; Schubart, Christoph; Tögel, Lars; Einhell, Sabine; Dietmaier, Wolfgang; Huss, Ralf; Dintner, Sebastian; Sommer, Sebastian; Jordan, Frank; Goebeler, Maria-Elisabeth; Metz, Michaela; Haake, Diana; Scheytt, Mithun; Gerhard-Hartmann, Elena; Maurus, Katja; Brändlein, Stephanie; Rosenwald, Andreas; Hartmann, Arndt; Märkl, Bruno; Einsele, Hermann; Mackensen, Andreas; Herr, Wolfgang; Kunzmann, Volker; Bargou, Ralf; Beckmann, Matthias W.; Pukrop, Tobias; Trepel, Martin; Evert, Matthias; Claus, Rainer; Kerscher, Alexander Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy. 2022 Cancers 14 20 urn:nbn:de:bvb:20-opus-290311 10.3390/cancers14205040 Urologische Klinik und Poliklinik OPUS4-30498 Wissenschaftlicher Artikel Schulmeyer, Carla E.; Fasching, Peter A.; Häberle, Lothar; Meyer, Julia; Schneider, Michael; Wachter, David; Ruebner, Matthias; Pöschke, Patrik; Beckmann, Matthias W.; Hartmann, Arndt; Erber, Ramona; Gass, Paul Expression of the immunohistochemical markers CK5, CD117, and EGFR in molecular subtypes of breast cancer correlated with prognosis Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort-case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS. 2023 Diagnostics 13 3 urn:nbn:de:bvb:20-opus-304987 10.3390/diagnostics13030372 Pathologisches Institut OPUS4-13567 Wissenschaftlicher Artikel Otto, Wolfgang; Rubenwolf, Peter C.; Burger, Maximilian; Fritsche, Hans-Martin; Rößler, Wolfgang; May, Matthias; Hartmann, Arndt; Hofstädter, Ferdinand; Wieland, Wolf F.; Denzinger, Stefan Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer Background: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. Method: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. Results: 59% of patients were shown to exhibit AQP3-positive tumours, whereas 41% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20% vs. 72%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). Conclusions: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC. 2012 BMC Cancer 12 459 urn:nbn:de:bvb:20-opus-135679 10.1186/1471-2407-12-459 Urologische Klinik und Poliklinik OPUS4-11416 Dissertation Hartmann, Matthias Optimization and Design of Network Architectures for Future Internet Routing At the center of the Internet's protocol stack stands the Internet Protocol (IP) as a common denominator that enables all communication. To make routing efficient, resilient, and scalable, several aspects must be considered. Care must be taken that traffic is well balanced to make efficient use of the existing network resources, both in failure free operation and in failure scenarios. Finding the optimal routing in a network is an NP-complete problem. Therefore, routing optimization is usually performed using heuristics. This dissertation shows that a routing optimized with one objective function is often not good when looking at other objective functions. It can even be worse than unoptimized routing with respect to that objective function. After looking at failure-free routing and traffic distribution in different failure scenarios, the analysis is extended to include the loop-free alternate (LFA) IP fast reroute mechanism. Different application scenarios of LFAs are examined and a special focus is set on the fact that LFAs usually cannot protect all traffic in a network even against single link failures. Thus, the routing optimization for LFAs is targeted on both link utilization and failure coverage. Finally, the pre-congestion notification mechanism PCN for network admission control and overload protection is analyzed and optimized. Different design options for implementing the protocol are compared, before algorithms are developed for the calculation and optimization of protocol parameters and PCN-based routing. The second part of the thesis tackles a routing problem that can only be resolved on a global scale. The scalability of the Internet is at risk since a major and intensifying growth of the interdomain routing tables has been observed. Several protocols and architectures are analyzed that can be used to make interdomain routing more scalable. The most promising approach is the locator/identifier (Loc/ID) split architecture which separates routing from host identification. This way, changes in connectivity, mobility of end hosts, or traffic-engineering activities are hidden from the routing in the core of the Internet and the routing tables can be kept much smaller. All of the currently proposed Loc/ID split approaches have their downsides. In particular, the fact that most architectures use the ID for routing outside the Internet's core is a poor design, which inhibits many of the possible features of a new routing architecture. To better understand the problems and to provide a solution for a scalable routing design that implements a true Loc/ID split, the new GLI-Split protocol is developed in this thesis, which provides separation of global and local routing and uses an ID that is independent from any routing decisions. Besides GLI-Split, several other new routing architectures implementing Loc/ID split have been proposed for the Internet. Most of them assume that a mapping system is queried for EID-to-RLOC mappings by an intermediate node at the border of an edge network. When the mapping system is queried by an intermediate node, packets are already on their way towards their destination, and therefore, the mapping system must be fast, scalable, secure, resilient, and should be able to relay packets without locators to nodes that can forward them to the correct destination. The dissertation develops a classification for all proposed mapping system architectures and shows their similarities and differences. Finally, the fast two-level mapping system FIRMS is developed. It includes security and resilience features as well as a relay service for initial packets of a flow when intermediate nodes encounter a cache miss for the EID-to-RLOC mapping. 2015 urn:nbn:de:bvb:20-opus-114165 10.25972/OPUS-11416 Institut für Informatik OPUS4-14873 Wissenschaftlicher Artikel Philipp-Abbrederis, Kathrin; Herrmann, Ken; Knop, Stefan; Schottelius, Margret; Eiber, Matthias; Lückerath, Katharina; Pietschmann, Elke; Habringer, Stefan; Gerngroß, Carlos; Franke, Katharina; Rudelius, Martina; Schirbel, Andreas; Lapa, Constantin; Schwamborn, Kristina; Steidle, Sabine; Hartmann, Elena; Rosenwald, Andreas; Kropf, Saskia; Beer, Ambros J; Peschel, Christian; Einsele, Hermann; Buck, Andreas K; Schwaiger, Markus; Götze, Katharina; Wester, Hans-Jürgen; Keller, Ulrich In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination andpoor prognosis. We evaluated the novel CXCR4 probe [\(^{68}\)Ga]Pentixafor for invivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [\(^{68}\)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [\(^{68}\)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [\(^{18}\)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34\(^{+}\) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [\(^{68}\)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases. 2015 477-487 EMBO Molecular Medicine 7 4 urn:nbn:de:bvb:20-opus-148738 10.15252/emmm.201404698 Klinik und Poliklinik für Nuklearmedizin OPUS4-21850 Wissenschaftlicher Artikel Appelt-Menzel, Antje; Oerter, Sabrina; Mathew, Sanjana; Haferkamp, Undine; Hartmann, Carla; Jung, Matthias; Neuhaus, Winfried; Pless, Ole Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development? Translating basic biological knowledge into applications remains a key issue for effectively tackling neurodegenerative, neuroinflammatory, or neuroendocrine disorders. Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) still poses a demanding challenge for drug development targeting central nervous system diseases. Validated in vitro models of the BBB could facilitate effective testing of drug candidates targeting the brain early in the drug discovery process during lead generation. We here review the potential of mono- or (isogenic) co-culture BBB models based on brain capillary endothelial cells (BCECs) derived from human-induced pluripotent stem cells (hiPSCs), and compare them to several available BBB in vitro models from primary human or non-human cells and to rodent in vivo models, as well as to classical and widely used barrier models [Caco-2, parallel artificial membrane permeability assay (PAMPA)]. In particular, we are discussing the features and predictivity of these models and how hiPSC-derived BBB models could impact future discovery and development of novel CNS-targeting therapeutics. 2020 Current Protocols in Stem Cell Biology 55 1 urn:nbn:de:bvb:20-opus-218509 10.1002/cpsc.122 Lehrstuhl für Tissue Engineering und Regenerative Medizin OPUS4-32406 Wissenschaftlicher Artikel Löb, Sanja; Linsmeier, Eva; Herbert, Saskia-Laureen; Schlaiß, Tanja; Kiesel, Matthias; Wischhusen, Jörg; Salmen, Jessica; Kranke, Peter; Quenzer, Anne; Kurz, Florian; Weiss, Claire; Gerhard-Hartmann, Elena; Wöckel, Achim; Diessner, Joachim Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody-drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. 2023 5417-5428 Journal of Cancer Research and Clinical Oncology 149 8 urn:nbn:de:bvb:20-opus-324068 10.1007/s00432-022-04486-0 Frauenklinik und Poliklinik OPUS4-31934 Wissenschaftlicher Artikel Stephan, Marlene; Tascilar, Koray; Yalcin-Mutlu, Melek; Hagen, Melanie; Haschka, Judith; Reiser, Michaela; Hartmann, Fabian; Kleyer, Arnd; Hueber, Axel J.; Manger, Bernhard; Figueiredo, Camille; Cobra, Jayme Fogagnolo; Tony, Hans-Peter; Finzel, Stephanie; Kleinert, Stefan; Wendler, Jörg; Schuch, Florian; Ronneberger, Monika; Feuchtenberger, Martin; Fleck, Martin; Manger, Karin; Ochs, Wolfgang; Schmitt-Haendle, Matthias; Lorenz, Hannes Martin; Nüsslein, Hubert; Alten, Rieke; Henes, Joerg; Krüger, Klaus; Schett, Georg; Rech, Jürgen Physical function of RA patients tapering treatment — a post hoc analysis of the randomized controlled RETRO trial Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline. 2023 Journal of Clinical Medicine 12 11 urn:nbn:de:bvb:20-opus-319349 10.3390/jcm12113723 Medizinische Klinik und Poliklinik II