@article{RiedmeierDecarolisHaubitzetal.2021, author = {Riedmeier, Maria and Decarolis, Boris and Haubitz, Imme and M{\"u}ller, Sophie and Uttinger, Konstantin and B{\"o}rner, Kevin and Reibetanz, Joachim and Wiegering, Armin and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Wiegering, Verena}, title = {Adrenocortical carcinoma in childhood: a systematic review}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248507}, year = {2021}, abstract = {Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65\% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80\% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89\%). Most patients were diagnosed with localized disease, whereas 23\% had metastasis at primary diagnosis. Only 72\% of the patients achieved complete resection. In 334 children (23\%), recurrent disease was reported: 81\% — local recurrence, 19\% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.}, language = {en} } @article{BauerOpitzFilseretal.2019, author = {Bauer, Maria and Opitz, Anne and Filser, J{\"o}rg and Jansen, Hendrik and Meffert, Rainer H. and Germer, Christoph T. and Roewer, Norbert and Muellenbach, Ralf M. and Kredel, Markus}, title = {Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications}, series = {BMC Anesthesiology}, volume = {19}, journal = {BMC Anesthesiology}, doi = {10.1186/s12871-019-0805-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200730}, pages = {132}, year = {2019}, abstract = {Background Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. Methods This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. Results Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0-17.3); first day: 17.8 (16.9-18.2), p < 0.004; third day: 17.4 (16.2-18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC\%predicted) (median: 93, 58, 64\%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC\%predicted on the third postoperative day (r = - 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC\%predicted was only decreased on the first postoperative day (median FVC\%predicted on the preoperative, first and third day: 85, 81 and 88\%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. Conclusions After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation.}, language = {en} } @article{GilbertSchneemannScholzetal.2018, author = {Gilbert, F. and Schneemann, C. and Scholz, C. J. and Kickuth, R. and Meffert, R. H. and Wildenauer, R. and Lorenz, U. and Kellersmann, R. and Busch, A.}, title = {Clinical implications of fracture-associated vascular damage in extremity and pelvic trauma}, series = {BMC Muscuskeletal Disorders}, volume = {19}, journal = {BMC Muscuskeletal Disorders}, number = {404}, doi = {10.1186/s12891-018-2333-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176252}, year = {2018}, abstract = {Background: Vascular damage in polytrauma patients is associated with high mortality and morbidity. Therefore, specific clinical implications of vascular damage with fractures in major trauma patients are reassessed. Methods: This comprehensive nine-year retrospective single center cohort study analyzed demography, laboratory, treatment and outcome data from 3689 patients, 64 patients with fracture-associated vascular injuries were identified and were compared to a control group. Results: Vascular damage occurred in 7\% of patients with upper and lower limb and pelvic fractures admitted to the trauma room. Overall survival was 80\% in pelvic fracture and 97\% in extremity fracture patients and comparable to non-vascular trauma patients. Additional arterial damage required substantial fluid administration and was visible as significantly anemia and disturbed coagulation tests upon admission. Open procedures were done in over 80\% of peripheral extremity vascular damage. Endovascular procedures were predominant (87\%) in pelvic injury. Conclusion: Vascular damage is associated with high mortality rates especially in combination with pelvic fractures. Initial anemia, disturbed coagulation tests and the need for extensive pre-clinical fluid substitution were observed in the cohort with vascular damage. Therefore, fast diagnosis and early interventional and surgical procedures are necessary to optimize patient-specific outcome.}, language = {en} } @article{WagnerEikenHaubitzetal.2019, author = {Wagner, Johanna and Eiken, Barbara and Haubitz, Imme and Lichthardt, Sven and Matthes, Niels and L{\"o}b, Stefan and Klein, Ingo and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Suprapubic bladder drainage and epidural catheters following abdominal surgery—a risk for urinary tract infections?}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0209825}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177731}, pages = {e0209825}, year = {2019}, abstract = {Background Epidural catheters are state of the art for postoperative analgesic in abdominal surgery. Due to neurolysis it can lead to postoperative urinary tract retention (POUR), which leads to prolonged bladder catheterization, which has an increased risk for urinary tract infections (UTI). Our aim was to identify the current perioperative management of urinary catheters and, second, to identify the optimal time of suprapubic bladder catheter removal in regard to the removal of the epidural catheter. Methods We sent a questionnaire to 102 German hospitals and analyzed the 83 received answers to evaluate the current handling of bladder drainage and epidural catheters. Then, we conducted a retrospective study including 501 patients, who received an epidural and suprapubic catheter after abdominal surgery at the University Hospital W{\"u}rzburg. We divided the patients into three groups according to the point in time of suprapubic bladder drainage removal in regard to the removal of the epidural catheter and analyzed the onset of a UTI. Results Our survey showed that in almost all hospitals (98.8\%), patients received an epidural catheter and a bladder drainage after abdominal surgery. The point in time of urinary catheter removal was equally distributed between before, simultaneously and after the removal of the epidural catheter (respectively: ~28-29\%). The retrospective study showed a catheter-associated UTI in 6.7\%. Women were affected significantly more often than men (10,7\% versus 2,5\%, p<0.001). There was a non-significant trend to more UTIs when the suprapubic catheter was removed after the epidural catheter (before: 5.7\%, after: 8.4\%). Conclusion The point in time of suprapubic bladder drainage removal in relation to the removal of the epidural catheter does not seem to correlate with the rate of UTIs. The current handling in Germany is inhomogeneous, so further studies to standardize treatment are recommended.}, language = {en} } @article{BartmannJanakiRamanFloeteretal.2018, author = {Bartmann, Catharina and Janaki Raman, Sudha R. and Fl{\"o}ter, Jessica and Schulze, Almut and Bahlke, Katrin and Willingstorfer, Jana and Strunz, Maria and W{\"o}ckel, Achim and Klement, Rainer J. and Kapp, Michaela and Djuzenova, Cholpon S. and Otto, Christoph and K{\"a}mmerer, Ulrike}, title = {Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation}, series = {Cancer \& Metabolism}, volume = {6}, journal = {Cancer \& Metabolism}, number = {8}, doi = {10.1186/s40170-018-0180-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175607}, year = {2018}, abstract = {Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro. Methods: Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5\% oxygen) or normoxia (21\% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed. Results: 3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation. Conclusions: We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.}, language = {en} } @article{BurkardMeirKannapinetal.2021, author = {Burkard, Natalie and Meir, Michael and Kannapin, Felix and Otto, Christoph and Petzke, Maximilian and Germer, Christoph-Thomas and Waschke, Jens and Schlegel, Nicolas}, title = {Desmoglein2 Regulates Claudin2 Expression by Sequestering PI-3-Kinase in Intestinal Epithelial Cells}, series = {Frontiers in Immunology}, volume = {12}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2021.756321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247059}, year = {2021}, abstract = {Inflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesion and upregulation of Claudin2 in Caco2 cells challenged with TNFα. In Dsg2-deficient Caco2 cells basal expression of Claudin2 was increased which was paralleled by reduced transepithelial electrical resistance and by augmented phosphorylation of AKT\(^{Ser473}\) under basal conditions. Inhibition of phosphoinositid-3-kinase proved that PI-3-kinase/AKT-signaling is critical to upregulate Claudin2. In immunostaining PI-3-kinase dissociated from Dsg2 under inflammatory conditions. Immunoprecipitations and proximity ligation assays confirmed a direct interaction of Dsg2 and PI-3-kinase which was abrogated following TNFα application. In summary, Dsg2 regulates Claudin2 expression by sequestering PI-3-kinase to the cell borders in intestinal epithelium.}, language = {en} } @article{DiersWagnerBaumetal.2020, author = {Diers, J. and Wagner, J. and Baum, P. and Lichthardt, S. and Kastner, C. and Matthes, N. and Matthes, H. and Germer, C.-T. and L{\"o}b, S. and Wiegering, A.}, title = {Nationwide in-hospital mortality rate following rectal resection for rectal cancer according to annual hospital volume in Germany}, series = {BJS Open}, volume = {4}, journal = {BJS Open}, number = {2}, doi = {10.1002/bjs5.50254}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212878}, pages = {310 -- 319}, year = {2020}, abstract = {Background The impact of hospital volume after rectal cancer surgery is seldom investigated. This study aimed to analyse the impact of annual rectal cancer surgery cases per hospital on postoperative mortality and failure to rescue. Methods All patients diagnosed with rectal cancer and who had a rectal resection procedure code from 2012 to 2015 were identified from nationwide administrative hospital data. Hospitals were grouped into five quintiles according to caseload. The absolute number of patients, postoperative deaths and failure to rescue (defined as in-hospital mortality after a documented postoperative complication) for severe postoperative complications were determined. Results Some 64 349 patients were identified. The overall in-house mortality rate was 3·9 per cent. The crude in-hospital mortality rate ranged from 5·3 per cent in very low-volume hospitals to 2·6 per cent in very high-volume centres, with a distinct trend between volume categories (P < 0·001). In multivariable logistic regression analysis using hospital volume as random effect, very high-volume hospitals (53 interventions/year) had a risk-adjusted odds ratio of 0·58 (95 per cent c.i. 0·47 to 0·73), compared with the baseline in-house mortality rate in very low-volume hospitals (6 interventions per year) (P < 0·001). The overall postoperative complication rate was comparable between different volume quintiles, but failure to rescue decreased significantly with increasing caseload (15·6 per cent after pulmonary embolism in the highest volume quintile versus 38 per cent in the lowest quintile; P = 0·010). Conclusion Patients who had rectal cancer surgery in high-volume hospitals showed better outcomes and reduced failure to rescue rates for severe complications than those treated in low-volume hospitals.}, language = {en} } @article{ZaitsevaHoffmannOttoetal.2022, author = {Zaitseva, Olena and Hoffmann, Annett and Otto, Christoph and Wajant, Harald}, title = {Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy}, series = {Frontiers in Pharmacology}, volume = {13}, journal = {Frontiers in Pharmacology}, issn = {1663-9812}, doi = {10.3389/fphar.2022.935086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290238}, year = {2022}, abstract = {Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome.}, language = {en} } @article{SchmidtDenkWiegering2020, author = {Schmidt, Stefanie and Denk, Sarah and Wiegering, Armin}, title = {Targeting protein synthesis in colorectal cancer}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {5}, issn = {2072-6694}, doi = {10.3390/cancers12051298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206014}, year = {2020}, abstract = {Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.}, language = {en} } @article{HankirSeyfriedSchellingeretal.2021, author = {Hankir, Mohammed K. and Seyfried, Florian and Schellinger, Isabel N. and Schlegel, Nicolas and Arora, Tulika}, title = {Leaky gut as a potential culprit for the paradoxical dysglycemic response to gastric bypass-associated ileal microbiota}, series = {Metabolites}, volume = {11}, journal = {Metabolites}, number = {3}, issn = {2218-1989}, doi = {10.3390/metabo11030153}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234085}, year = {2021}, abstract = {Altered host-intestinal microbiota interactions are increasingly implicated in the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We previously found, however, that RYGB-associated ileal microbiota can paradoxically impair host glycemic control when transferred to germ-free mice. Here we present complementary evidence suggesting that this could be due to the heightened development of systemic endotoxemia. Consistently, application of ileal content from RYGB-treated compared with sham-operated rats onto Caco-2 cell monolayers compromised barrier function and decreased expression of the barrier-stabilizing proteins claudin-4 and desmoglein-2. Our findings raise the possibility that RYGB-associated ileal microbiota produce and release soluble metabolites which locally increase intestinal permeability to promote systemic endotoxemia-induced insulin resistance, with potential implications for the treatment of RYGB patients who eventually relapse onto type 2 diabetes.}, language = {en} } @article{KredelKunzmannSchlegeletal.2017, author = {Kredel, Markus and Kunzmann, Steffen and Schlegel, Paul-Gerhardt and W{\"o}lfl, Matthias and Nordbeck, Peter and B{\"u}hler, Christoph and Lotz, Christopher and Lepper, Philipp M. and Wirbelauer, Johannes and Roewer, Norbert and Muellenbach, Ralf M.}, title = {Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock}, series = {American Journal of Case Reports}, volume = {18}, journal = {American Journal of Case Reports}, doi = {10.12659/AJCR.902485}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158193}, pages = {723-727}, year = {2017}, abstract = {Background: The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. Case Report: A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. Conclusions: In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option.}, language = {en} } @phdthesis{Zeeb2022, author = {Zeeb, Luisa}, title = {Bedeutung der Expression von MMP-1 und MMP-13 beim Barrett assoziierten Adenokarzinom}, doi = {10.25972/OPUS-27872}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278723}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Es wird vermutet, dass das {\"o}sophageale Adenokarzinom (EAC) durch gastroosophagealen Reflux auf dem Boden des Barrett-{\"O}sophagus (BE) entsteht. Bei der Tumorprogression k{\"o}nnten Matrix-Metalloproteasen eine wichtige Rolle spielen. Die Expression von MMP-1 und MMP-13 wurde im {\"O}sophaguskarziom (n=41 EAC mit BE, n=19 EAC ohne BE, n=10 Plattenepithelkarzinom, ESCC) sowie im nicht-dysplastischen BE (n=18) untersucht. Die Koexpression von MMP-1 und Cdx-2 (intestinale Metaplasie) und die Koexpression von MMP-1 und Ki-67 (Proliferation) wurde mittels Immunhistochemie und auf mRNA-Ebene untersucht. Die Ergebnisse wurde mit klinisch-pathologischen Eigenschaften korreliert. Im gesunden Plattenepithel wurde weder MMP-1 noch MMP-13 exprimiert. In allen EAC ohne BE wurde MMP-1 exprimiert (100\%). Im EAC mit BE, war in 95\% MMP-1 im EAC nachweisbar. Die Expression von MMP-1 im BE ohne IN lag bei 56\%. Das ESCC exprimierte in 60\% MMP-1. Bei der quantitativen Analyse zeigten sich 48\% MMP-1 positive Zellen im EAC mit BE und 35\% im angrenzendem BE (p<0,05). Mit 44\% MMP-1 positiver Zellen im EAC ohne BE, lag die Expression signifikant {\"u}ber der im BE mit EAC (p<0,05). Im ESCC (32\% MMP-1 positiv) lag eine im Vergleich zu allen EACs signifikant geringere Expression vor. Im BE ohne IN waren 4\% der Zellen MMP-1 positiv. Die RT-PCR best{\"a}tigte die Ergebnisse der IHC auf mRNA-Ebene. Eine Pr{\"a}parate waren negativ f{\"u}r MMP-13. Die Untersuchung der Koexpression von MMP-1 in Ki-67 positiven Zellen zeigte eine starke direkte Korrelation (r=0,943 f{\"u}r BE und r= 0,811 f{\"u}r EAC). Eine hohe MMP-1 Expression war mit einem positiven Lymphknotenstatus assoziiert aber nicht mit einem schlechterem {\"U}berleben (p=0,307). Die Ergebnisse zeigen, dass MMP-1 eine wichtige Rolle bei der Invasion und Metastasierung des Barrett assoziierten EAC spielen k{\"o}nnte. Die Assoziation eines positiven Lymphknotenstatus mit hoher MMP-1-Expression spricht daf{\"u}r, dass MMP-1 ein wichtiger Faktor bei der malignen Progression sein k{\"o}nnte.}, subject = {Adenocarcinom}, language = {de} } @article{BaurBuentemeyerMegerleetal.2017, author = {Baur, Johannes and B{\"u}ntemeyer, Tjark-Ole and Megerle, Felix and Deutschbein, Timo and Spitzweg, Christine and Quinkler, Marcus and Nawroth, Peter and Kroiss, Matthias and Germer, Christoph-Thomas and Fassnacht, Martin and Steger, Ulrich}, title = {Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study}, series = {BMC Cancer}, volume = {17}, journal = {BMC Cancer}, number = {522}, doi = {10.1186/s12885-017-3506-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159409}, year = {2017}, abstract = {Background: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15\%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8\%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome.}, language = {en} } @article{KressBaurOttoetal.2018, author = {Kress, Sebastian and Baur, Johannes and Otto, Christoph and Burkard, Natalie and Braspenning, Joris and Walles, Heike and Nickel, Joachim and Metzger, Marco}, title = {Evaluation of a miniaturized biologically vascularized scaffold in vitro and in vivo}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {4719}, doi = {10.1038/s41598-018-22688-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176343}, year = {2018}, abstract = {In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine.}, language = {en} } @article{WallstabeBussemerGroeberBeckeretal.2020, author = {Wallstabe, Julia and Bussemer, Lydia and Groeber-Becker, Florian and Freund, Lukas and Alb, Mirian and Dragan, Mariola and Waaga-Gasser, Ana Maria and Jakubietz, Rafael and Kneitz, Hermann and Rosenwald, Andreas and Rebhan, Silke and Walles, Heike and Mielke, Stephan}, title = {Inflammation-Induced Tissue Damage Mimicking GvHD in Human Skin Models as Test Platform for Immunotherapeutics}, series = {ALTEX}, volume = {37}, journal = {ALTEX}, number = {3}, doi = {10.14573/altex.1907181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229974}, pages = {429-440}, year = {2020}, abstract = {Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.}, language = {en} } @article{KippnichSchorscherKredeletal.2020, author = {Kippnich, Maximilian and Schorscher, Nora and Kredel, Markus and Markus, Christian and Eden, Lars and Gassenmaier, Tobias and Lock, Johann and Wurmb, Thomas}, title = {Dual‑room twin‑CT scanner in multiple trauma care: first results after implementation in a level one trauma centre}, series = {European Journal of Trauma and Emergency Surgery}, journal = {European Journal of Trauma and Emergency Surgery}, issn = {1863-9933}, doi = {10.1007/s00068-020-01374-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232390}, year = {2020}, abstract = {Purpose The trauma centre of the Wuerzburg University Hospital has integrated a pioneering dual-room twin-CT scanner in a multiple trauma pathway. For concurrent treatment of two trauma patients, two carbon CT examination and intervention tables are positioned head to head with one sliding CT-Gantry in the middle. The focus of this study is the process of trauma care with the time to CT (tCT) and the time to operation (tOR) as quality indicator. Methods All patients with suspected multiple trauma, who required emergency surgery and who were initially diagnosed by the CT trauma protocol between 05/2018 and 12/2018 were included. Data relating to time spans (tCT and tOR), severity of injury and outcome was obtained. Results 110 of the 589 screened trauma patients had surgery immediately after finishing primary assessment in the ER. The ISS was 17 (9-34) (median and interquartile range, IQR). tCT was 15 (11-19) minutes (median and IQR) and tOR was 96.5 (75-119) minutes (median and IQR). In the first 30 days, seven patients died (6.4\%) including two within the first 24 h (2\%). There were two ICU days (1-6) (median and IQR) and one (0-1) (median and IQR) ventilator day. Conclusion The twin-CT technology is a fascinating tool to organize high-quality trauma care for two multiple trauma patients simultaneously}, language = {en} } @article{BachmannEhlertBeckeretal.2020, author = {Bachmann, Julia and Ehlert, Elias and Becker, Matthias and Otto, Christoph and Radeloff, Katrin and Blunk, Torsten and Bauer-Kreisel, Petra}, title = {Ischemia-like stress conditions stimulate trophic activities of adipose-derived stromal/stem cells}, series = {Cells}, volume = {9}, journal = {Cells}, number = {9}, issn = {2073-4409}, doi = {10.3390/cells9091935}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211233}, year = {2020}, abstract = {Adipose-derived stromal/stem cells (ASCs) have been shown to exert regenerative functions, which are mainly attributed to the secretion of trophic factors. Upon transplantation, ASCs are facing an ischemic environment characterized by oxygen and nutrient deprivation. However, current knowledge on the secretion capacity of ASCs under such conditions is limited. Thus, the present study focused on the secretory function of ASCs under glucose and oxygen deprivation as major components of ischemia. After exposure to glucose/oxygen deprivation, ASCs maintained distinct viability, but the metabolic activity was greatly reduced by glucose limitation. ASCs were able to secrete a broad panel of factors under glucose/oxygen deprivation as revealed by a cytokine antibody array. Quantification of selected factors by ELISA demonstrated that glucose deprivation in combination with hypoxia led to markedly higher secretion levels of the angiogenic and anti-apoptotic factors IL-6, VEGF, and stanniocalcin-1 as compared to the hypoxic condition alone. A conditioned medium of glucose/oxygen-deprived ASCs promoted the viability and tube formation of endothelial cells, and the proliferation and migration of fibroblasts. These findings indicate that ASCs are stimulated by ischemia-like stress conditions to secrete trophic factors and would be able to exert their beneficial function in an ischemic environment.}, language = {en} } @phdthesis{Morgenroth2020, author = {Morgenroth, Stephanie}, title = {Die Wertigkeit der pr{\"a}operativen Breischluckuntersuchung bei der Antirefluxchirurgie und der Chirurgie der Hiatushernien}, doi = {10.25972/OPUS-21733}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217335}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die radiologische Breischluckuntersuchung wird derzeit noch vor einer Antirefluxchirurgie und Chirurgie der Hiatushernien zur Detektion und Klassifikation einer Hiatushernie empfohlen. Ziel der Arbeit war es zu untersuchen, ob die pr{\"a}operative Breischluckuntersuchung bei der Diagnostik und Klassifikation von Hiatushernien einen zus{\"a}tzlichen Nutzen hat und diese Befunde dann mit Endoskopie und schnittbildgebenden Verfahren zu vergleichen.}, subject = {Gastro{\"o}sophagealer Reflux}, language = {de} } @article{SchickSchlegel2022, author = {Schick, Martin Alexander and Schlegel, Nicolas}, title = {Clinical implication of phosphodiesterase-4-inhibition}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms23031209}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284511}, year = {2022}, abstract = {The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.}, language = {en} } @article{HankirBruneauJr2022, author = {Hankir, Mohammed Khair and Bruneau Jr., Michael}, title = {Periphery-brain interactions and leptin in the regulation of whole-body energy metabolism}, series = {Nutrients}, volume = {14}, journal = {Nutrients}, number = {8}, issn = {2072-6643}, doi = {10.3390/nu14081594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270581}, year = {2022}, abstract = {No abstract available}, language = {en} } @article{OttoSchmidtKastneretal.2019, author = {Otto, C. and Schmidt, S. and Kastner, C. and Denk, S. and Kettler, J. and M{\"u}ller, N. and Germer, C.T. and Wolf, E. and Gallant, P. and Wiegering, A.}, title = {Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells}, series = {Neoplasia}, volume = {21}, journal = {Neoplasia}, number = {11}, doi = {10.1016/j.neo.2019.10.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202451}, pages = {1110-1120}, year = {2019}, abstract = {The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.}, language = {en} } @article{LichthardtWagnerLoebetal.2020, author = {Lichthardt, Sven and Wagner, Johanna and L{\"o}b, Stefan and Matthes, Niels and Kastner, Caroline and Anger, Friedrich and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Pathological complete response due to a prolonged time interval between preoperative chemoradiation and surgery in locally advanced rectal cancer: analysis from the German StuDoQ|Rectalcarcinoma registry}, series = {BMC Cancer}, volume = {20}, journal = {BMC Cancer}, number = {1}, doi = {10.1186/s12885-020-6538-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229334}, year = {2020}, abstract = {Background Preoperative chemoradiotherapy is the recommended standard of care for patients with local advanced rectal cancer. However, it remains unclear, whether a prolonged time interval to surgery results in an increased perioperative morbidity, reduced TME quality or better pathological response. Aim of this study was to determine the time interval for best pathological response and perioperative outcome compared to current recommended interval of 6 to 8 weeks. Methods This is a retrospective analysis of the German StuDoQ|Rectalcarcinoma registry. Patients were grouped for the time intervals of "less than 6 weeks", "6 to 8 weeks", "8 to 10 weeks" and "more than 10 weeks". Primary endpoint was pathological response, secondary endpoint TME quality and complications according to Clavien-Dindo classification. Results Due to our inclusion criteria (preoperative chemoradiation, surgery in curative intention, M0), 1.809 of 9.560 patients were suitable for analysis. We observed a trend for increased rates of pathological complete response (pCR: ypT0ypN0) and pathological good response (pGR: ypT0-1ypN0) for groups with a prolonged time interval which was not significant. Ultimately, it led to a steady state of pCR (16.5\%) and pGR (22.6\%) in "8 to 10" and "more than 10" weeks. We were not able to observe any differences between the subgroups in perioperative morbidity, proportion of rectal extirpation (for cancer of the lower third) or difference in TME quality. Conclusion A prolonged time interval between neoadjuvant chemoradiation can be performed, as the rate of pCR seems to be increased without influencing perioperative morbidity.}, language = {en} } @phdthesis{Schulz2019, author = {Schulz, Christian Andreas}, title = {Tissue Engineering einer autologen Neofaszie in Kombination mit synthetischen Netzen im dynamischen Bioreaktor: Morphometrie und explorative Gen-Expressionsanalyse}, doi = {10.25972/OPUS-19187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191876}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Zusammenfassung Einleitung: Die Inzidenz von Narbenhernien (operativ erworbene Schwachstellen der Bauchwand) ist abh{\"a}ngig von der Art der vorhergegangen Operation, nach Laparaskopien ist sie um einiges niedriger als nach Laparotomien, wird aber mit 2-20\% in der Literatur angegeben. Aufgrund der m{\"o}glichen Komplikationen (Platzbauch, Darminkarzeration, Schmerzen, Funktionseinschr{\"a}nkung, …) stellen Narbenhernien oftmals große Belastungen f{\"u}r die Patienten dar. Die operative Sanierung, in Abh{\"a}ngigkeit von Gr{\"o}ße und Lage, wird zumeist durch einbringen eines Netzgewebes erreicht. Dieser Fremdk{\"o}rper kann seinerseits wieder Komplikationen hervorrufen (Infektionen, Funktionsverlust, Schmerzen, Fisteln), die bis zur Explantation des Netzgewebes f{\"u}hren k{\"o}nnen. Das Risiko f{\"u}r das Auftreten von Narbenhernien bzw. deren Rezidiven h{\"a}ngt von vielen Faktoren ab, als Risikofaktoren wurden unter anderem Rauchen, m{\"a}nnliches Geschlecht, Alter >45 Jahre und ein BMI >25 kg/cm² ausgemacht. Ein Teilbereich des Tissue Engineerings ist die Entwicklung von Modellen, anhand derer in vitro Prozesse des menschlichen K{\"o}rpers nachvollzogen werden k{\"o}nnen. Mit dieser Arbeit soll ein Modell etabliert werden Anhand dessen die Untersuchung der Kollagenproduktion und der Netzinkorporation bzw. die Auswirkungen verschiedener Risikofaktoren auf diese Prozesse in vitro erm{\"o}glicht werden soll. Weiterhin wurden Studienfragen formuliert, die sich sowohl mit der Durchf{\"u}hrbarkeit dieser Methode abzielten, als auch gezielt nach der St{\"u}tzung der These der „guten und schlechten Heiler" durch diese Arbeit abzielten. Sowie nach der Vergleichbarkeit der Ergebnisse mit bekannten Kollagenmustern die aus Netzexplantaten bekannt sind. Material und Methode: F{\"u}r die vorliegende Arbeit wurden Biopsien von Faszien bzw. Narbenhernien im Rahmen einer Operation gewonnen, aus diesen wurden die Fibroblasten isoliert und anschliessend entweder eingefroren bzw. expandiert, um sie in einer Rattenkollagenmatrix mit und ohne synthetischem Netz im dynamisch mechanischen Bioreaktor zu kultivieren. Die Biopsien wurden Anhand der Kollagen I/III Ratio in „gute und schlechte Heiler" eingruppiert. Anschließend wurden die so gez{\"u}chteten Neofaszien HE und Pikrosiriusrot gef{\"a}rbt um zum einen einen Eindruck von der Verteilung der Fibroblasten innerhalb der Neofaszie zu gewinnen, als auch Aussagen zum Kollagenmuster, der Kollagen I/III Ratio und zur Kollagendensit{\"a}t treffen zu k{\"o}nnen. Die Dicke der kultivierten Neofaszien wurde sowohl in Sirius als auch in HE F{\"a}rbung untersucht. Weiterhin wurden RT-PCR und Gene Arrays von Nativgeweben und von Neofaszien mit unterschiedlichen Netztypen durchgef{\"u}hrt. Ergebnisse: Bei gesunden Probanden konnten oftmals nicht gen{\"u}gend Zellen aus den Faszienbiopsaten gewonnen werden, deshalb wurde im Verlauf der Arbeit auf die Gewinnung von gesundem Fasziengewebe als Vergleichsgruppe verzichtet. Fibroblasten von als „schlechten Heilern" klassifizierten Patienten zeigten meist ein langsameres Wachstum in der Expansionsphase. Der Bioreaktor bereitete kaum Probleme (ein paar Faszien trockneten anf{\"a}nglich aus, dieses Problem lies sich durch bei Bedarf verk{\"u}rzten Medienwechselintervallen in den Griff bekommen. Probleme mit Kontaminationen traten nicht auf. Bei den Histologischen Untersuchungen der Neofaszien waren Fibroblasten {\"u}ber den gesamten Bereich der Neofaszie zu sehen, auch in unmittelbarer Umgebung der Netzstrukturen. Die Kollagenmuster stimmten in Ans{\"a}tzen mit den aus klinischen Netzexplantaten bekannten Mustern {\"u}berein (Polydirektional bei Polyesternetz, Konzentrisch um die Netzstrukturen bei Polypropylen). Weiterhin war eine verst{\"a}rkte Kollagenbildung quer zur Druckrichtung des Bioreaktors zu erkennen. Bei der Betrachtung der Dicke der Neofaszien zeigte sich (unter Vorbehalt, aufgrund der geringen Probenanzahl) eine Tendenz zu meist d{\"u}nneren Faszien bei „schlechten Heilern" w{\"a}hrend die Neofaszien von „guten Heilern" meist eine kleinere Streuung um den Mittelwert zeigten (einheitlicher waren). Die Kollagendensit{\"a}t und auch die Kollagen I/III Ratio lieferten Ergebnisse Anhand derer Gesagt werden kann, dass je h{\"o}her die Ausgangswerte im Nativgewebe waren, diese mit h{\"o}herer Wahrscheinlichkeit von den Neofaszien nicht erreicht werden konnten. qRT-PCR und Gene Array zeigten in der Rangkorrelation nach Spearman große {\"U}bereinstimmungen. Beantwortung der Studienfragen: Es konnte gezeigt werden, dass es m{\"o}glich ist Neofaszien mit synthetischen Netzen zu z{\"u}chten, die {\"u}ber den gesamten Bereich mit Fibroblasten besiedelt waren. Die Ergebnisse der Kollagenmorphologie zeigten in Ans{\"a}tzen die aus Netzexplantaten bekannten Muster. Bei Kollagen I/III Ratio und Densit{\"a}t war lediglich erkennbar, dass je h{\"o}her die Ausgangswerte waren, diese mit zunehmender Wahrscheinlichkeit nicht reproduziert werden konnten. Es ließ sich keine Verbindung zwischen der Kollagen I/III Ratio der Histologischen Gewebeproben und den Molekularbiologischen Ergebnissen feststellen. Weiterhin konnte die Theorie der „guten und schlechten Heiler" molekularbiologisch nicht gest{\"u}tzt werden, da die Proben der als „schlechte Heiler" Klassifizierten Biopsien st{\"a}rkere Gemeinsamkeiten mit als „gute Heiler" Klassifizierten Biopsien aufwiesen als untereinander. Es konnte gezeigt werden dass die Kultur auf die MMP-8 und Elastinproduktion keinen Einfluss zu haben scheint. Diskussion: Im Verlauf der Diskussion wurde darauf hingewiesen, dass die Kollagensynthese, und Sekretion ein komplexes und h{\"o}chst aktives System darstellt, welches im Rahmen der Wundheilung durch Co-Signalling, und der Interaktion zwischen Fibroblasten und Immunzellen (Makrophagen…) nochmals ver{\"a}ndert wird, auch dadurch bedingt, dass Fibroblasten im Verlauf der Wundheilung selbst als immunmodulierende Zellen in Erscheinung treten k{\"o}nnen. So k{\"o}nnen weiterhin die Kollagen kodierenden Gene (Col1A1, Col1A2, Col3A1) als Marker f{\"u}r die Kollagenaktivit{\"a}t herangezogen werden, da aber zwischen Synthese und Sekretion des Kollagens ein nicht zu vernachl{\"a}ssigender Teil bereits intrazellul{\"a}r wieder abgebaut wird kann nur durch Betrachtung dieser Gene die Theorie der „guten und schlechten Heiler" nicht gest{\"u}tzt werden. Durch die hohe Korrelation der Ergebnisse aus gene-Array und qRT-PCR k{\"o}nnte f{\"u}r die Zukunft vorl{\"a}ufig auf die Durchf{\"u}hrung von qRT-PCR verzichtet werden, um eventuell unterschiedliche Pathways mit dem Gene-Array zu identifizieren. Offene Fragen Ausblick und Perspektiven: Da das System der Wundheilung und Kollagensynthese und -Sekretion sehr komplex ist sollte f{\"u}r die Zukunft durch eine Kokultur mit Makrophagen bzw. durch die Zugabe von TNF-α, IL-6, PDGF, G-CSF, GM-CSF, Vitamin C oder Lysyloxidase zum Kulturmedium, gepr{\"u}ft werden ob sich eine Aktivit{\"a}tsver{\"a}nderung der Fibroblasten und damit eine andere Neofaszienstruktur erreichen l{\"a}sst. Weiterhin sollte um einer Verf{\"a}lschung der Ergebnisse durch das f{\"u}r die Gele verwendete Rattenkollagen vorzubeugen, entweder die Kulturdauer verl{\"a}ngert werden (mit dem Gedanken dass dann das gesamte Rattenkollagen durch humanes ersetzt wurde) bzw. ein Kollagenfreies Gel als Tr{\"a}gerstruktur entwickelt und verwendet werden. Um eine bessere Vergleichbarkeit der Ergebnisse des Gene-Arrays aus Spenderbiopsie und Neofaszie zu erreichen sollten die zur RNA-Gewinnung verwendeten Anteile der Biopsie noch innerhalb des OP in RNA-later bzw. in fl{\"u}ssigen Stickstoff gegeben werden, um einer verst{\"a}rkten Degradation vorzubeugen.}, subject = {Hernie}, language = {de} } @phdthesis{Eiken2020, author = {Eiken, Barbara}, title = {Auswirkung von Epiduralkatheter und suprapubischer Harnableitung in Bezug auf die Inzidenz von Katheter-assoziierten Harnwegsinfektionen nach abdominalchirurgischen Eingriffen}, doi = {10.25972/OPUS-20883}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208836}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Einleitung Periduralkatheter (PDK) werden häufig zur postoperativen Analgesie angewendet. Deren Anwendung kann zu einem Harnverhalt f{\"u}hren, was oftmals zu einer längeren Liegedauer des Blasenkatheters f{\"u}hrt. Ziel Unser Ziel war es den optimalen Zeitpunkt f{\"u}r die Entfernung des Blasenkatheters zu identifizieren, um das Risiko f{\"u}r Komplikationen im Sinne von Harnwegsinfekten (HWI) zu minimieren. Methodik Insgesamt wurden 501 Patienten in diese retrospektive Studie eingeschlossen, die einen Periduralkatheter sowie einen suprapubischen Blasenkatheter im Rahmen eines allgemeinchirurgischen Eingriffs erhalten hatten. Die Patienten wurde anhand des Zeitpunktes der Entfernung des Blasenkatheters in Bezug zum Zeitpunkt der Entfernung des PDKs aufgeteilt und das Auftreten eines HWIs analysiert. Zusätzlich haben wir eine Umfrage an 102 deutschen Kliniken durchgef{\"u}hrt und die 83 erhaltenen Antworten hinsichtlich der aktuellen Handhabung von PDK und Harnableitung evaluiert. Ergebnis In unserem Patientenkollektiv zeigte sich in 6,7 \% ein Katheter-assoziierter HWI. Signifikant mehr Frauen als Männer hatten einen HWI (7,8 \% männlich versus 20,1 \% weiblich, p = 0,0001). Es zeigte sich ein Trend zur erhöhten Rate an HWIs, wenn der Blasenkatheter nach dem PDK entfernt wurde, jedoch ohne statistische Signifikanz (vor PDK-Entfernung: 29,5 \%, zeitgleich 16,2 \%, nach PDK-Entfernung 54,3 \%). Die deutschlandweite Umfrage konnte zeigen, dass in fast allen Krankenhäusern (98,8 \%), die Patienten einen PDK und eine Harnableitung nach einem größeren abdominalchirugischen Eingriff erhalten hatten. Es wurde häufiger ein transurethraler als ein suprapubischer Katheter verwendet. Der Zeitpunkt der Entfernung der Harnableitung war gleichmäßig verteilt auf die Zeitpunkte vor, zeitgleich und nach Entfernung des PDKs. Schlussfolgerung Der Zeitpunkt der Entfernung der Harnableitung in Bezug zum Zeitpunkt der Entfernung des PDKs scheint keinen statistisch signifikanten Einfluss auf die Entstehung eines Harnweginfektes zu haben. Es zeigt sich lediglich ein Trend zu einer leicht erhöhten Rate an HWIs, wenn der Blasenkatheter nach dem PDK entfernt wurde. Die aktuelle Handhabung in Deutschland zeigt sich sehr inhomogen, sodass weitere Studien notwendig sind, um die postoperative Versorgung zur standardisieren.}, subject = {Harnwegsinfektion}, language = {de} } @article{WeberGlutschGeissingeretal.2020, author = {Weber, J. and Glutsch, V. and Geissinger, E. and Haug, L. and Lock, J.F. and Schneider, F. and Kneitz, H. and Goebeler, M. and Schilling, B. and Gesierich, A.}, title = {Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease}, series = {British Journal of Dermatology}, volume = {183}, journal = {British Journal of Dermatology}, number = {3}, doi = {10.1111/bjd.18739}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213520}, pages = {559-563}, year = {2020}, abstract = {The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1) combined with nivolumab (3 mg kg-1), pathological responses were observed in 77\% of patients, while only 20\% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far.}, language = {en} } @article{KelmSeyfriedReimeretal.2017, author = {Kelm, M. and Seyfried, F. and Reimer, S. and Krajinovic, K. and Miras, A. D. and Jurowich, C. and Germer, C. T. and Brand, M.}, title = {Proximal jejunal stoma as ultima ratio in case of traumatic distal duodenal perforation facilitating successful EndoVAC\(^{®}\) treatment: a case report}, series = {International Journal of Surgery Case Reports}, volume = {41}, journal = {International Journal of Surgery Case Reports}, doi = {10.1016/j.ijscr.2017.11.022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159292}, pages = {401-403}, year = {2017}, abstract = {Introduction: During damage control surgery for blunt abdominal traumata simultaneous duodenal perforations can be missed making secondary sufficient surgical treatment challenging. Endoluminal vacuum (EndoVAC™) therapy has been shown to be a revolutionary option but has anatomical and technical limits. Presentation of the case: A 59-year old man with hemorrhagic shock due to rupture of the mesenteric root after blunt abdominal trauma received damage control treatment. Within a scheduled second-look, perforation of the posterior duodenal wall was identified. Due to local and systemic conditions, further surgical treatment was limited. Decision for endoscopic treatment was made but proved to be difficult due to the distal location. Finally, double-barreled jejunal stoma was created for transstomal EndoVAC™ treatment. Complete leakage healing was achieved and jejunostomy reversal followed subsequently. Discussion: During damage control surgery simultaneous bowel injuries can be missed leading to life-threatening complications with limited surgical options. EndoVAC™ treatment is an option for gastrointestinal perforations but has anatomical limitations that can be sufficiently shifted by a transstomal approach for intestinal leakage. Conclusion: In trauma related laparotomy complete mobilization of the duodenum is crucial. As ultima ratio, transstomal EndoVAC™ is a safe and feasible option and can be considered for similar cases.}, language = {en} } @article{NothhaftKlepperKneitzetal.2019, author = {Nothhaft, Matthias and Klepper, Joerg and Kneitz, Hermann and Meyer, Thomas and Hamm, Henning and Morbach, Henner}, title = {Hemorrhagic bullous Henoch-Sch{\"o}nlein Purpura: case report and review of the literature}, series = {Frontiers in Pediatrics}, volume = {6}, journal = {Frontiers in Pediatrics}, doi = {10.3389/fped.2018.00413}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201435}, pages = {413}, year = {2019}, abstract = {Henoch-Sch{\"o}nlein Purpura (HSP) or IgA vasculitis is the most common systemic vasculitis of childhood and may affect skin, joints, gastrointestinal tract, and kidneys. Skin manifestations of HSP are characteristic and include a non-thrombocytopenic palpable purpura of the lower extremities and buttocks. Rarely, HSP may initially present as or evolve into hemorrhagic vesicles and bullae. We present an otherwise healthy 5-year-old boy with an acute papulovesicular rash of both legs and intermittent abdominal pain. After a few days the skin lesions rapidly evolved into palpable purpura and hemorrhagic bullous lesions of variable size and severe hemorrhagic HSP was suspected. A histological examination of a skin biopsy showed signs of a small vessel leukocytoclastic vasculitis limited to the upper dermis and direct immunofluorescence analysis revealed IgA deposits in vessel walls, compatible with HSP. To further characterize the clinical picture and treatment options of bullous HSP we performed an extensive literature research and identified 41 additional pediatric patients with bullous HSP. Two thirds of the reported patients were treated with systemic corticosteroids, however, up to 25\% of the reported patients developed skin sequelae such as hyperpigmentation and/or scarring. The early use of systemic corticosteroids has been discussed controversially and suggested in some case series to be beneficial by reducing the extent of lesions and minimizing sequelae of disease. Our patient was treated with systemic corticosteroids tapered over 5 weeks. Fading of inflammation resulted in healing of most erosions, however, a deep necrosis developing from a large blister at the dorsum of the right foot persisted so that autologous skin transplantation was performed. Re-examination 11 months after disease onset showed complete clinical remission with re-epithelialization but also scarring of some affected areas.}, language = {en} } @article{GrimmigMoenchKreckeletal.2016, author = {Grimmig, Tanja and Moench, Romana and Kreckel, Jennifer and Haack, Stephanie and Rueckert, Felix and Rehder, Roberta and Tripathi, Sudipta and Ribas, Carmen and Chandraker, Anil and Germer, Christoph T. and Gasser, Martin and Waaga-Gasser, Ana Maria}, title = {Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {12}, doi = {10.3390/ijms17122060}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165743}, pages = {2060}, year = {2016}, abstract = {Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.}, language = {en} } @article{WollbornWunderStixetal.2015, author = {Wollborn, Jakob and Wunder, Christian and Stix, Jana and Neuhaus, Winfried and Bruno, Rapahel R. and Baar, Wolfgang and Flemming, Sven and Roewer, Norbert and Schlegel, Nicolas and Schick, Martin A.}, title = {Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression}, series = {Journal of Pharmacology and Pharmacotherapeutics}, volume = {6}, journal = {Journal of Pharmacology and Pharmacotherapeutics}, number = {1}, doi = {10.4103/0976-500X.149138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149336}, pages = {13-23}, year = {2015}, abstract = {Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.}, language = {en} } @article{MeirKannapinDiefenbacheretal.2021, author = {Meir, Michael and Kannapin, Felix and Diefenbacher, Markus and Ghoreishi, Yalda and Kollmann, Catherine and Flemming, Sven and Germer, Christoph-Thomas and Waschke, Jens and Leven, Patrick and Schneider, Reiner and Wehner, Sven and Burkard, Natalie and Schlegel, Nicolas}, title = {Intestinal epithelial barrier maturation by enteric glial cells is GDNF-dependent}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms22041887}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258913}, year = {2021}, abstract = {Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAP\(^{cre}\) x Ai14\(^{floxed}\) mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.}, language = {en} } @phdthesis{Scheler2022, author = {Scheler, Maximilian Heinrich Julius}, title = {Die operative Versorgung des Thoraxmagens - Eine Langzeitanalyse von 2008-2015}, doi = {10.25972/OPUS-25301}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-253018}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Der Thoraxmagen beschreibt eine zirkul{\"a}re Schwachstelle der phreniko{\"o}sophagealen Membran mit einer schrittweisen Dislozierung der Magenkardia und des {\"O}sophagus nach mediastinal. Die Therapie des Thoraxmagens kann konservativ im Sinne des „watchful waiting" oder operativ erfolgen. Aufgrund der m{\"o}glichen Komplikationen wird die elektive Operation durch die amerikanischen Leitlinien empfohlen. Ein zentrales Problem der Hiatushernienchirurgie stellt die hohe Anzahl an Rezidiven dar. Ob die Gr{\"u}nde hierf{\"u}r in der Zwerchfellrekonstruktion, Speiser{\"o}hrenl{\"a}nge, Fundoplicatio oder Netzaugmentation liegen, wird nach wie vor kontrovers diskutiert. In dieser Arbeit wurde die operative Versorgung des Thoraxmagens von 124 Patienten des Universit{\"a}tsklinikums W{\"u}rzburg im Zeitraum von September 2008 bis Juni 2015 untersucht. Hierf{\"u}r war neben den perioperativen Daten auch die Rezidiv- und Letalit{\"a}tsrate von Relevanz. Das Patientenkollektiv wurde sowohl in Hinblick auf das Lebensalter als auch auf die verschiedenen Versorgungsarten analysiert. Um die postoperative Lebensqualit{\"a}t zu beurteilen, erfolgte die Patientenbefragung mit Hilfe eines Symptomfragebogens und dem Gastrointestinalen Lebensqualit{\"a}tsindex nach Eypasch (GIQLI). Zus{\"a}tzlich wurden 17 Patienten postoperativ mittels MRT untersucht, um eine optimierte MRT-Sequenz zur Beurteilung der Hiatusregion zu evaluieren. Im Vergleich der Altersgruppen zeigte sich trotz einer erh{\"o}hten Komorbidit{\"a}tsrate bei dem Patientenkollektiv ≥ 75 Jahre (p=0,002) kein signifikanter Unterschied bei Betrachtung der intraoperativen Komplikationen. Die Rezidivrate lag unabh{\"a}ngig vom Alter bei 20,2\% im Untersuchungszeitraum, jedoch konnte eine verminderte Rezidivrate bei Patienten mit U-Shape Versorgung (p=0,015) festgestellt werden. In der postoperativen Patientenbefragung zeigten sich 87,0\% der Patienten, unabh{\"a}ngig vom Alter und der Versorgungsart, zufrieden mit dem Operationsergebnis und beschrieben ihren Zustand im Vergleich zu pr{\"a}operativ als gebessert. Die Ergebnisse des GIQLI erbrachten in dem untersuchten Patientenkollektiv ein gegen{\"u}ber der Allgemeinbev{\"o}lkerung erniedrigten Wert mit 95,4 Punkten. Die optimierte MRT-Sequenz zeichnete sich durch eine hohe diagnostische Konfidenz bei guter Bildqualit{\"a}t, kurzer Untersuchungsdauer und gleichzeitig hoher Akzeptanz der Patienten gegen{\"u}ber dieser Art der Diagnostik aus. Zusammenfassend stellt die operative Versorgung von Thoraxm{\"a}gen, unabh{\"a}ngig des Patientenalters, eine sichere Therapieform dar, die zu einer hohen Patientenzufriedenheit f{\"u}hrt. Die modifizierte MRT-Untersuchung hat sich als diagnostische Methode bew{\"a}hrt und stellt eine Alternative zu strahlenexponierenden oder von Seiten der Patienten weniger gut tolerierten Untersuchungsmodalit{\"a}ten dar.}, subject = {Zwerchfellkrankheit}, language = {de} } @phdthesis{Nordbeck2022, author = {Nordbeck, Arno Wilhelm}, title = {Roux-en-Y Magenbypass spezifische metabolomische Ver{\"a}nderungen in Urin, Faeces und Plasma - Charakterisierung im Zucker (fa/fa) Rattenmodel}, doi = {10.25972/OPUS-26869}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268694}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Es wurde ein etabliertes Tiermodell mit Zucker Ratten (fa/fa) verwendet, um postoperative, gewichtsverlustunabh{\"a}ngige metabolomische Effekte des Roux-en-Y Magenbypass (RYGB) zu ermitteln. Es galt Hypothesen zu generieren, welche globalen Metabolite die positiven Auswirkungen des Magenbypass verursachen k{\"o}nnen. Beispielsweise war γ-Amino-Butters{\"a}ure (GABA) f{\"a}kal nach RYGB vermehrt nachweisbar und somit ein potentieller Mediator f{\"u}r einen Bypass-spezifischen Effekt. Die Ergebnisse zeigen die Komplexit{\"a}t der metabolomischen Ver{\"a}nderungen durch RYGB und Nahrungsrestriktion. Die genauen Mechanismen nach metabolisch-bariatrischer Operation, die zu dem therapeutischen Effekt f{\"u}hren, bleiben weiterhin unklar, sodass es weiterer Studien bedarf, um kausale Zusammenh{\"a}nge nachzuweisen.}, subject = {Tiermodell}, language = {de} } @article{WiegeringRiegelWagneretal.2017, author = {Wiegering, Armin and Riegel, Johannes and Wagner, Johanna and Kunzmann, Volker and Baur, Johannes and Walles, Thorsten and Dietz, Ulrich and Loeb, Stefan and Germer, Christoph-Thomas and Steger, Ulrich and Klein, Ingo}, title = {The impact of pulmonary metastasectomy in patients with previously resected colorectal cancer liver metastases}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0173933}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158036}, pages = {e0173933}, year = {2017}, abstract = {Background 40-50\% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases. Methods 137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection. Results 39\% of all patients with liver resection due to CRLM developed additional lung metastases. 44\% of these patients underwent subsequent pulmonary resection. Patients undergoing pulmonary metastasectomy showed a significantly better five-year survival compared to patients not qualified for curative resection (5-year survival 71.2\% vs. 28.0\%; p = 0.001). Interestingly, the 5-year survival of these patients was even superior to all patients with CRLM, who did not develop pulmonary metastases (77.5\% vs. 63.5\%; p = 0.015). Patients, whose pulmonary metastases were not resected, were more likely to redevelop liver metastases (50.0\% vs 78.6\%; p = 0.034). However, the rate of distant metastases did not differ between both groups (54.5 vs.53.6; p = 0.945). Conclusion The occurrence of colorectal lung metastases after curative liver resection does not impact patient survival if pulmonary metastasectomy is feasible. Those patients clearly benefit from repeated resections of the liver and the lung metastases.}, language = {en} } @phdthesis{Widder2022, author = {Widder, Anna Ursula}, title = {Einfluss unterschiedlicher Lehrmethoden zum Vermitteln laparoskopischer Fertigkeiten - eine randomisierte, kontrollierte Studie}, doi = {10.25972/OPUS-27186}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271869}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Hintergrund. Training an Simulatoren ist eine effektive Methode zum Erlernen laparoskopischer Fertigkeiten. Dennoch besteht weiterhin die Notwendigkeit, Lehrmethoden zu optimieren, um praktischen {\"U}bungsaufwand zu reduzieren. In dieser Studie wurde die Auswirkung der mentalen {\"U}bung "deconstruction into key steps" (DIKS) auf die f{\"u}r den Erwerb laparoskopischer Fertigkeiten ben{\"o}tigte Zeit untersucht. Methoden. Medizinstudierende des 10. Fachsemesters nahmen an einem Laparoskopiekurs teil und wurden in zwei Gruppen randomisiert. Dabei wurde in der Experimentalgruppe (EG) eine Verk{\"u}rzung der praktischen {\"U}bungszeit um 58\% im Vergleich zur KG zu Gunsten des mentalen Trainings DIKS untersucht. Die laparoskopischen Eingangsfertigkeiten wurden an Simulatoren getestet (t0). Anschließend wurde der Lernerfolg in einer zweiten Pr{\"u}fung kontrolliert (t1). Nach neun Tagen erfolgte eine dritte Pr{\"u}fung (t2). Alle Messzeitpunkte wurden per Videomittschnitt nach validierten Kriterien bewertet. Potenzielle Pr{\"a}diktoren wurden mit Hilfe eines Fragebogens standardisiert erhoben. Ergebnisse. Sowohl die EG (n=58) als auch die KG (n=58) wiesen einen signifikanten Lernzuwachs auf (p<0,001). Es zeichnete sich jedoch ein signifikanter Unterschied im Lernzuwachs in bestimmten Zeitabschnitten ab. Die KG zeigte einen signifikant h{\"o}heren Lernzuwachs von t0-t1. Nach einer Woche wurde der Vorsprung der KG bei einem signifikant besseren Lernzuwachs der EG im zweiten Abschnitt egalisiert. Motivierte sowie geschickte Studierende zeigten eine signifikant bessere Leistung in Qualit{\"a}t und Quantit{\"a}t. M{\"a}nnern war es m{\"o}glich eine signifikant bessere Leistung in Qualit{\"a}t und Quantit{\"a}t zu erzielen. Schlussfolgerung. W{\"a}hrend initial ein verl{\"a}ngertes praktisches {\"U}ben zu einer unmittelbaren Leistungssteigerung f{\"u}hrte, wurde durch die zus{\"a}tzliche mentale {\"U}bung 'DIKS' bei gleichzeitig verk{\"u}rzter praktischer {\"U}bungszeit ein gleichwertiges Ergebnis erreicht.}, subject = {Laparoskopie}, language = {de} } @phdthesis{Schlueter2022, author = {Schl{\"u}ter, Dominique Carolin}, title = {Pr{\"a}operative Leberfunktionsevaluation mittels LiMAx Test beim Hepatozellul{\"a}ren Karzinom}, doi = {10.25972/OPUS-25447}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254478}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die Therapieentscheidung beim HCC richtet sich derzeit nach den BCLC-Kriterien. Die effektivste Therapieoption, eine Resektion, wird allerdings nur in den fr{\"u}hen Stadien empfohlen. Um postoperative Komplikationen zu vermeiden, ben{\"o}tigt es unter anderem eine effiziente pr{\"a}operative Leberfunktionsevaluation zur Auswahl der Resektionskandidaten. Fr{\"u}here Studien konnten zeigen, dass der LiMAx-Test hierf{\"u}r geeignet ist. Da aber Daten zu HCC-Patienten noch fehlen, war das Ziel dieser Studie zu untersuchen, ob der LiMAx-Test die pr{\"a}operative Evaluation von HCC-Patienten erleichtert und so die postoperative Morbidit{\"a}t und Mortalit{\"a}t insbesondere f{\"u}r Patienten mit Leberzirrhose gesenkt werden kann. Insgesamt erhielten 92 HCC Patienten zur Therapieevaluation eine LiMAx-Messung und wurden in eine Gruppe mit Zirrhose (LZ-Gruppe) und eine ohne (NL-Gruppe) eingeteilt und miteinander verglichen. Jeder Fall wurde in einer Tumorkonferenz besprochen und anhand der erhobenen Leberfunktionsparameter entschieden. 46 Patienten erhielten eine Resektion, 46 wurden abgelehnt, 17 aufgrund zu schlechter LiMAx-Ergebnisse. Die LiMAx-Werte der Resezierten waren mit 388 vs. 322µg/kg/h h{\"o}her als die der abgelehnten Patienten (p=0,004). Zudem waren sie ein unabh{\"a}ngiger Risikofaktor f{\"u}r eine Leberzirrhose und Pr{\"a}diktoren f{\"u}r eine unzureichende Leberfunktionsreserve. Ein unterer Grenzwert von 221µg/kg/h wurde ermittelt, bei welchem auch bei Zirrhosepatienten eine Resektion noch sicher durchgef{\"u}hrt werden kann. Generell gab es in der LZ-Gruppe nicht mehr postoperative Komplikationen als in der NL-Gruppe. Eine Vorhersage zur Entwicklung eines postoperativen Leberversagens durch den LiMAx-Test konnte in unserer Studie nicht gezeigt werden. Pr{\"a}operativ eingesetzt, erm{\"o}glicht der LiMAx-Test somit eine effektive und sichere Evaluation von HCC Patienten, die von einer Resektion profitieren, mit niedriger postoperativer Morbidit{\"a}ts- und Mortalit{\"a}tsrate, sowohl bei Patienten mit oder ohne Leberzirrhose.}, subject = {Leberfunktion}, language = {de} } @phdthesis{Doering2022, author = {D{\"o}ring, Anna Maria}, title = {Einfluss der minimalen Distanz zwischen Tumor und Resektatrand auf die Prognose kurativ resezierter Patienten mit hepatocellul{\"a}rem Carcinom}, doi = {10.25972/OPUS-27668}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276687}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Dies ist eine retrospektive unizentrische Analyse um den Einfluss des Resektionsabstandes auf prognostische Faktoren wie das rezidivfreie und Gesamt{\"u}berleben bei Patienten mit hepatocellul{\"a}ren Carcinom zu untersuchen. Es ließ sich kein Vorteil eines weiten (>5mm) tumorfreien Abstands zum Resektatrand gegen{\"u}ber einem schmalen (5mm) tumorfreien Abstand nachweisen. Allerdings wurden andere tumor- und patientenspezifische unabh{\"a}ngige Risikofaktoren f{\"u}r das rezidivfreie und Gesamt{\"u}berleben identifiziert. So ist ein pr{\"a}operativer AFP-Wert >15µg/l mit einem signifikant schlechteren krankheitsfreien und Gesamt{\"u}berleben assoziiert. Ebenso haben schlecht differenzierte (G3) HCCs, sowie HCC mit einer vaskul{\"a}ren Invasion (V1/V2) ein deutlich reduziertes rezidivfreies {\"U}berleben. Auch eine Tumorgr{\"o}ße >5cm war in dieser Studie ein unabh{\"a}ngiger Risikofaktor f{\"u}r ein verk{\"u}rztes Gesamt{\"u}berleben.}, subject = {Leberzellkrebs}, language = {de} } @phdthesis{Uttinger2022, author = {Uttinger, Konstantin Lukas}, title = {Der antiproliferative Effekt des RNA-Polymerase I Inhibitors CX-5461 in Zellen kolorektaler Karzinomzelllinien auf zellul{\"a}rer und molekularer Ebene}, doi = {10.25972/OPUS-26503}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265033}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die halbmaximale (Proliferations-) inhibitorische Konzentration (IC50) vom RNA-Polymerase I-Inhibitor CX-5461 liegt f{\"u}r die getesteten sieben humanen kolorektalen Karzinomzell¬linien zwischen 0,7 und 3,1 µmol/L, f{\"u}r nicht-transformierte Fibroblasten bei 8,1 µmol/L. Der deutlich st{\"a}rkere antiproliferative Effekt von CX-5461 auf Tumorzellen l{\"a}sst somit ein m{\"o}gliches therapeutisches Fenster erkennen. CX-5461 (1 µmol/L und weniger) induziert einen persistierenden Zellzyklus-arretierten Zellph{\"a}notyp mit Seneszenz-assoziierter (SA) -Galaktosidase-Aktivit{\"a}t (SA-β-Gal). Die durch CX-5461 ausgel{\"o}ste verringerte Synthese ribosomaler RNA (rRNA)-Transkripte im Nucleolus, ein Subkompartiment des Nucleus, in dem die Transkription der ribosomalen DNA und Bildung von Pr{\"a}-Ribosomen stattfinden, hat eine St{\"o}rung der Ribosomen¬biogenese zur Folge. Diese als nucleol{\"a}rer Stress bezeichnete Situation ist mit zahlreichen Einzelph{\"a}nomen assoziiert wie der Akkumulation ribosomaler Proteine aufgrund eines durch CX-5461 verursachten Missverh{\"a}ltnisses bei der Synthese ribosomaler Proteine und rRNAs. Auch kommt es bei nucleol{\"a}rem Stress zur Aktivierung Zellzykusarrest-f{\"u}hrender Signalwege vermittelt durch DNA-Damage-Response, p53 und Retinoblastom (Rb). Die durch CX-5461 induzieren seneszenten Zellen lassen sich durch Kombination mit dem Bcl-Inhibitor und Senotlytikum Navitoclax in Apoptose {\"u}berf{\"u}hren. Das kombinierte Strategiekonzept demonstriert, dass der pro-proliferative Ph{\"a}notyp von Tumorzellen mit CX-5461 durch Induktion von Seneszenz effektiv gestoppt werden kann, um anschließend diese Zellen mit dem Bcl-Inhibitor Navitoclax gezielt in Apoptose zu {\"u}berf{\"u}hren. Der durch CX-5461 ausgel{\"o}ste seneszente Zellph{\"a}notyp zeigt sich sensitiv gegen{\"u}ber dem Apoptose-ausl{\"o}senden Effekt von Navitoclax - im Ggs. zu nicht-seneszenten Zellen. Basierend auf diesem Konzept deutet sich eine potentielle neue Strategie f{\"u}r eine Tumortherapie an, deren Grundlage die kombinierte Adressierung der beiden antiproliferativen Ph{\"a}nomene Seneszenz und Apoptose in soliden Tumorzellen wie dem kolorektalen Karzinom darstellt.}, subject = {Dickdarmkrebs}, language = {de} } @article{KusanSuratKelmetal.2022, author = {Kusan, Simon and Surat, G{\"u}zin and Kelm, Matthias and Anger, Friedrich and Kim, Mia and Germer, Christoph-Thomas and Schlegel, Nicolas and Flemming, Sven}, title = {Microbial spectrum and antibiotic resistance in patients suffering from penetrating Crohn's disease}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {15}, issn = {2077-0383}, doi = {10.3390/jcm11154343}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281835}, year = {2022}, abstract = {Intraabdominal abscess formation occurs in up to 30\% of patients suffering from Crohn's disease (CD). While international guidelines recommend a step-up approach with a combination of empiric antibiotic therapy and percutaneous drainage to delay or even avoid surgery, evidence about microbial spectrum in penetrating ileitis is sparse. We retrospectively assessed outcomes of 46 patients with terminal penetrating Ileitis where microbial diagnostics have been performed and compared microbial spectrum and antibiotic resistance profile of CD patients with patients suffering from diverticulitis with intraabdominal abscess formation. In both groups, the most frequently isolated pathogen was the gram-negative bacterium E. coli belonging to the family of Enterobacterales. However, overall Enterobacterales were significantly more often verifiable in the control group than in CD patients. Furthermore, microbial analysis showed significant differences regarding isolation of anaerobic pathogens with decreased frequency in patients with CD. Subgroup analysis of CD patients to evaluate a potential influence of immunosuppressive therapy on microbial spectrum only revealed that Enterobacterales was less frequently detected in patients treated with steroids. Immunosuppressive therapy did not show any impact on all other groups of pathogens and did not change antibiotic resistance profile of CD patients. In conclusion, we were able to demonstrate that the microbial spectrum of CD patients does differ only for some pathogen species without increased rate of antibiotic resistance. However, the empiric antibiotic therapy for CD-associated intra-abdominal abscess remains challenging since different points such as local epidemiological and microbiological data, individual patient risk factors, severity of infection, and therapy algorithm including non-surgical and surgical therapy options should be considered before therapeutical decisions are made.}, language = {en} } @phdthesis{Schneemann2021, author = {Schneemann, Christina}, title = {Klinische Implikationen zur Versorgung von Schockraumpatienten - eine retrospektive Fall-Kontroll-Studie zu Fraktur-assoziierten Gef{\"a}ßverletzungen}, doi = {10.25972/OPUS-22334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223348}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Fraktur-assoziierte Gef{\"a}ßverletzungen sind seltene, aber potentiell lebensbedrohliche Unfallfolgen. Durch komplexe Verletzungsmuster stellen Fraktur-assoziierten Gef{\"a}ßverletzungen eine gef{\"a}ßchirurgische Notfallsituation dar und erfordern eine hohe Expertise seitens des behandelnden Schockraumteams. Diese retrospektive Studie untersuchte anhand von Patientendaten des Schockraums des Universit{\"a}tsklinikums W{\"u}rzburg im Zeitraum Dezember 2005 bis Dezember 2013, das Management von Patienten mit Fraktur-assoziierten Gef{\"a}ßverletzungen im Extremit{\"a}ten- und Beckenbereich. Es wurden Daten von N=64 Patienten mit Fraktur-assoziierten Gef{\"a}ßverletzungen im Bereich der Extremit{\"a}ten und des Beckens in einem Zeitraum von 8 Jahren ausgewertet. Diese Daten wurden mit Patientendaten von N=60 Patienten mit Frakturen im Bereich der Extremit{\"a}ten und des Beckens ohne Gef{\"a}ßbeteiligung verglichen. Insbesondere wurden Aussagen {\"u}ber Diagnostik, Therapie und Outcome gewonnen. Es konnte gezeigt werden, dass die unterschiedlichsten Trauma Score Systeme (GCS; ISS; RISC II) keine Hinweise auf das zus{\"a}tzliche Vorliegen einer Gef{\"a}ßverletzung liefern. Außerdem konnten erstmals die klinischen Auswirkungen einer zus{\"a}tzlichen Gef{\"a}ßverletzung auf das pr{\"a}klinische Fl{\"u}ssigkeitsmanagement und das Gerinnungssystem gezeigt werden. So k{\"o}nnten ein pr{\"a}klinisch erh{\"o}hter Fl{\"u}ssigkeitsbedarf und ver{\"a}nderte Gerinnungsparameter im Eingangslabor erste Hinweise auf eine zus{\"a}tzliche Gef{\"a}ßverletzung geben. Mit einer Gef{\"a}ßverletzung muss unabh{\"a}ngig von der Frakturlokalisation, dem Verletzungsausmaß und dem protokollierten Trauma Score gerechnet werden. Beim geringsten Verdacht sollte eine gef{\"a}ßchirurgische Vorstellung erfolgen.}, subject = {Gef{\"a}ßverletzung}, language = {de} } @phdthesis{Tillenburg2020, author = {Tillenburg, Wolfgang}, title = {Endovaskul{\"a}re Interventionen der unteren Extremit{\"a}ten in Spinalan{\"a}sthesie bei peripherer arterieller Verschlusskrankheit: {\"U}bertrieben, gef{\"a}hrlich oder doch sinnvoll?}, doi = {10.25972/OPUS-21901}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219012}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die H{\"a}ufigkeit der endovaskul{\"a}ren Interventionen (EI) an den unteren Extremit{\"a}ten zur Behandlung der peripheren arteriellen Verschlusskrankheit (pAVK) hat in den letzten Jahren zugenommen. Bei steigender Inzidenz der pAVK und bei gleichzeitiger Reduzierung der Rate mit operativen Interventionen (OI) profitieren die Patienten von der EI. Außerdem stieg die Anzahl der {\"a}lteren Patienten, die aufgrund einer pAVK im Krankenhaus einer EI zugef{\"u}hrt wurden. Es zeigt sich eine Erweiterung der Indikationen f{\"u}r eine EI von den Claudicanten hin zu den Patienten mit den Stadien der kritischen Isch{\"a}mie. Hierdurch werden gerade {\"a}ltere und morbidere Patienten mit komplexeren endovaskul{\"a}ren Prozeduren konfrontiert. Insbesondere im Krankenhaus ergibt sich die M{\"o}glichkeit, den pAVK-Patienten, die bisher eine OI mit einer an{\"a}sthesiologischen Begleitung erhielten, eine EI in SPA anzubieten. In der Regel werden EI in Lokalan{\"a}sthesie durchgef{\"u}hrt. Die Anwendung der SPA bei EI ist interessant, da es m{\"o}glicherweise neben der kompletten Schmerzausschaltung der unteren Extremit{\"a}ten bei erhaltener Kommunikation zu Synergieeffekten durch die periphere Vasodilatation kommen kann. Als ein seltenes Verfahren zur Verbesserung der peripheren Durchblutung hat dies die CT-gesteuerte tempor{\"a}re Sympathikolyse nach erfolgter EI gezeigt. Um prospektiv zu untersuchen, ob eine EI in SPA eine Verbesserung des Outcome und des Behandlungsablaufs mit sich bringt, ist zun{\"a}chst wichtig zu zeigen, dass die Anwendung von SPA bei EI nicht gef{\"a}hrlich ist. Hierzu stehen Daten aus der Allgemein-, Viszeral- und Gef{\"a}ßchirurgischen Abteilung des Klinikums Main-Spessart zur Verf{\"u}gung. Im Zeitraum vom 15.12.2009 bis 22.01.2015 wurden bei 59 Patienten EI in SPA durchgef{\"u}hrt. Bei keinem der 59 Patienten kam es durch die Anwendung der SPA zu an{\"a}sthesieabh{\"a}ngigen Komplikationen. Als zu erwartende Nebenwirkung trat der durch tempor{\"a}re Sympathikolyse ausgel{\"o}ste Blutdruckabfall bei allen Patienten auf. Im Mittel sank der Wert um 24,2 \% des Ausgangswerts, bei 13 Patienten (22,0 \%) wurde eine Korrektur des Blutdruckabfalls mit Akrinor® durchgef{\"u}hrt und gut beherrscht. F{\"u}r die St{\"a}rke des Blutdruckabfalls konnte keine Signifikanz bei der ASA-Einteilung, der Geschlechterverteilung und dem Alter nachgewiesen werden, somit besteht f{\"u}r eine EI in SPA keine Kontraindikation f{\"u}r den {\"a}lteren und kr{\"a}nkeren pAVK-Patienten. Die Ergebnisse dieser Dissertation zeigen, dass die Anwendung der SPA bei EI ein sicheres Verfahren ist. Die SPA kann, gerade bei zu erwartenden komplexen peripheren EI eine f{\"u}r den Patienten und Interventionisten angenehme und sichere Alternative zur Lokalan{\"a}sthesie sein. Der personelle und materialbedingte Aufwand einer EI in SPA, im Vergleich mit einer EI in Lokalan{\"a}sthesie, ist dabei deutlich erh{\"o}ht und scheint {\"u}bertrieben. Dass die EI in SPA Synergieeffekte mit sich bringt und deshalb sinnvoll ist, kann nur vermutet werden. Dieser Zusammenhang k{\"o}nnte im Rahmen einer prospektiven Studie, die beide An{\"a}sthesieverfahren f{\"u}r eine EI vergleicht, gezeigt werden.}, subject = {Endovascular Therapie}, language = {de} } @article{OttoKastnerSchmidtetal.2022, author = {Otto, Christoph and Kastner, Carolin and Schmidt, Stefanie and Uttinger, Konstantin and Baluapuri, Apoorva and Denk, Sarah and Rosenfeldt, Mathias T. and Rosenwald, Andreas and Roehrig, Florian and Ade, Carsten P. and Schuelein-Voelk, Christina and Diefenbacher, Markus E. and Germer, Christoph-Thomas and Wolf, Elmar and Eilers, Martin and Wiegering, Armin}, title = {RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells}, series = {Molecular Oncology}, volume = {16}, journal = {Molecular Oncology}, number = {15}, doi = {10.1002/1878-0261.13265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312806}, pages = {2788-2809}, year = {2022}, abstract = {Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.}, language = {en} } @article{KelmGermerSchlegeletal.2021, author = {Kelm, Matthias and Germer, Christoph-Thomas and Schlegel, Nicolas and Flemming, Sven}, title = {The revival of surgery in Crohn's disease — early intestinal resection as a reasonable alternative in localized ileitis}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {10}, issn = {2227-9059}, doi = {10.3390/biomedicines9101317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246296}, year = {2021}, abstract = {Crohn's disease (CD) represents a heterogeneous and complex disease with no curative therapeutic option available to date. Current therapy is mainly antibody-based focusing on the immune system while other treatment alternatives such as surgery are considered to be "last options". However, medical therapy for CD results in mild to severe side effects in a relevant amount of patients and some patients do not respond to the medication. Following that, quality of life is often significantly reduced in this patient cohort, thus, therapeutic alternatives are urgently needed. Updated evidence has revealed that surgery such as ileocecal resection (ICR) might be a potential therapeutic option in case of localized terminal ileitis since resection at early time points improves quality of life and significantly reduces the postoperative need for immunosuppressive medication with low rates of morbidity. In addition, new surgical approaches such as Kono-S anastomosis or inclusion of the mesentery result in significantly reduced rates of disease recurrence and reoperation. Based on the new evidence, the goal of this review is to provide an update on the role of surgery as a reasonable alternative to medical therapy in the interdisciplinary treatment of patients with CD.}, language = {en} } @article{KoehlerReeseKastneretal.2022, author = {K{\"o}hler, Franziska and Reese, Lena and Kastner, Carolin and Hendricks, Anne and M{\"u}ller, Sophie and Lock, Johan F. and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Surgical site infection following single-port appendectomy: a systematic review of the literature and meta-analysis}, series = {Frontiers in Surgery}, volume = {9}, journal = {Frontiers in Surgery}, issn = {2296-875X}, doi = {10.3389/fsurg.2022.919744}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276943}, year = {2022}, abstract = {Introduction Surgical site infections (SSIs) are one of the most common postoperative complications after appendectomy leading to recurrent surgery, prolonged hospital stay, and the use of antibiotics. Numerous studies and meta-analyses have been published on the effect of open versus conventional laparoscopic appendectomy (CLA) reporting faster postoperative recovery and less postoperative pain for CLA. A development from CLA has been the single-port appendectomy (SPA), associated with a better cosmesis but seemingly having a higher risk of wound infections. The aim of this systematic literature review and meta-analysis is to investigate whether reduced port or SPA alters the ratio of SSIs. Methods Pubmed, Embase, and Cochrane databases were screened for suitable articles. All articles published between January 1, 2002, and March 23, 2022, were included. Articles regarding children below the age of 18 were excluded as well as manuscripts that investigated solemnly open appendectomies. Articles were screened for inclusion criteria by two independent authors. Incidence of SSI was the primary outcome. Duration of operation and length of hospital stay were defined as secondary outcomes. Results A total of 25 studies were found through a database search describing 5484 patients. A total of 2749 patients received SPA and 2735 received CLA. There was no statistical difference in the rate of SSI (P = 0.98). A total of 22 studies including 4699 patients reported the duration of operation (2223 SPA and 2476 CLA). There was a significantly shorter operation time seen in CLA. The length of hospital stay was reported in 23 studies (4735 patients: 2235 SPA and 2500 CLA). A shorter hospital stay was seen in the SPA group (P < 0.00001). Separately performed analysis of randomized controlled trials could not confirm this effect (P = 0.29). Discussion SPA is an equally safe procedure considering SSI compared to CLA and does not lead to an increased risk of SSI. A longer operation time for SPA and a minor difference in the length of stay does lead to the use of SPA in selected patients only.}, language = {en} } @article{HendricksMeirHankiretal.2022, author = {Hendricks, Anne and Meir, Michael and Hankir, Mohammed and Lenschow, Christina and Germer, Christoph-Thomas and Schneider, Michael and Wiegering, Armin and Schlegel, Nicolas}, title = {Suppurative thyroiditis caused by ingested fish bone in the thyroid gland: a case report on its diagnostics and surgical therapy}, series = {BMC Surgery}, volume = {22}, journal = {BMC Surgery}, number = {1}, doi = {10.1186/s12893-022-01542-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299775}, year = {2022}, abstract = {Background Accidental ingestion of fish bone is a common cause of otolaryngological emergency. Migration of the ingested bone into the thyroid gland, however, occurs very rarely. The associated clinical presentation, symptoms and duration of discomfort are also highly variable between patients and can be diagnostically challenging. Case presentation Here, we report the case of a 71-year-old female patient presenting with an ingested fish bone that migrated into the right thyroid lobe as a rare cause of suppurative thyroiditis with the clinical features of sepsis. We outline the diagnostic approach, peri- and intraoperative management as well as complications. It is proposed that besides endoscopy, imaging methods such as ultrasound or computed tomography may be necessary to verify the diagnosis and location of an ingested fish bone. Prompt surgical removal of the foreign body and resection of the infectious focus is recommended to minimize the risk of local inflammation, recurrent nerve lesions and septic complications arising from the spread of infection. Conclusion Fish bone migration into the thyroid gland is an extremely rare event, the successful detection and surgical management of which can be achieved through a careful interdisciplinary approach.}, language = {en} } @article{WillmsSchwabvonWebskyetal.2022, author = {Willms, A. G. and Schwab, R. and von Websky, M. W. and Berrevoet, F. and Tartaglia, D. and S{\"o}relius, K. and Fortelny, R. H. and Bj{\"o}rck, M. and Monchal, T. and Brennfleck, F. and Bulian, D. and Beltzer, C. and Germer, C. T. and Lock, J. F.}, title = {Factors influencing the fascial closure rate after open abdomen treatment: Results from the European Hernia Society (EuraHS) Registry. Surgical technique matters}, series = {Hernia}, volume = {26}, journal = {Hernia}, number = {1}, organization = {EURAHS Open Abdomen Group}, issn = {1265-4906}, doi = {10.1007/s10029-020-02336-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234871}, pages = {61-73}, year = {2022}, abstract = {Purpose Definitive fascial closure is an essential treatment objective after open abdomen treatment and mitigates morbidity and mortality. There is a paucity of evidence on factors that promote or prevent definitive fascial closure. Methods A multi-center multivariable analysis of data from the Open Abdomen Route of the European Hernia Society included all cases between 1 May 2015 and 31 December 2019. Different treatment elements, i.e. the use of a visceral protective layer, negative-pressure wound therapy and dynamic closure techniques, as well as patient characteristics were included in the multivariable analysis. The study was registered in the International Clinical Trials Registry Platform via the German Registry for Clinical Trials (DRK00021719). Results Data were included from 630 patients from eleven surgical departments in six European countries. Indications for OAT were peritonitis (46\%), abdominal compartment syndrome (20.5\%), burst abdomen (11.3\%), abdominal trauma (9\%), and other conditions (13.2\%). The overall definitive fascial closure rate was 57.5\% in the intention-to-treat analysis and 71\% in the per-protocol analysis. The multivariable analysis showed a positive correlation of negative-pressure wound therapy (odds ratio: 2.496, p < 0.001) and dynamic closure techniques (odds ratio: 2.687, p < 0.001) with fascial closure and a negative correlation of intra-abdominal contamination (odds ratio: 0.630, p = 0.029) and the number of surgical procedures before OAT (odds ratio: 0.740, p = 0.005) with DFC. Conclusion The clinical course and prognosis of open abdomen treatment can significantly be improved by the use of treatment elements such as negative-pressure wound therapy and dynamic closure techniques, which are associated with definitive fascial closure.}, language = {en} } @article{MetznerHerzogHeckeletal.2022, author = {Metzner, Valentin and Herzog, Gloria and Heckel, Tobias and Bischler, Thorsten and Hasinger, Julia and Otto, Christoph and Fassnacht, Martin and Geier, Andreas and Seyfried, Florian and Dischinger, Ulrich}, title = {Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm11030753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255244}, year = {2022}, abstract = {Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.}, language = {en} } @article{KelmAngerEichlingeretal.2021, author = {Kelm, Matthias and Anger, Friedrich and Eichlinger, Robin and Brand, Markus and Kim, Mia and Reibetanz, Joachim and Krajinovic, Katica and Germer, Christoph-Thomas and Schlegel, Nicolas and Flemming, Sven}, title = {Early Ileocecal Resection Is an Effective Therapy in Isolated Crohn's Disease}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {4}, issn = {2077-0383}, doi = {10.3390/jcm10040731}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228822}, year = {2021}, abstract = {Despite the increasing incidence and prevalence of Crohn's Disease (CD), no curative options exist and treatment remains complex. While therapy has mainly focused on medical approaches in the past, growing evidence reveals that in cases of limited inflammation, surgery can suffice as an alternative primary treatment. We retrospectively assessed the disease course and outcomes of 103 patients with terminal Ileitis who underwent primary surgery (n = 29) or received primary medical treatment followed by surgery (n = 74). Primary endpoint was the need for immunosuppressive medication after surgical treatment (ileocecal resection, ICR) during a two-years follow-up. Rates for laparoscopic ICR were enhanced in case of early surgery, but no differences were seen for postoperative complications. In case of immunosuppressive medication, patients with ICR at an early state of disease needed significantly less anti-inflammatory medication during the two-year postoperative follow-up compared to patients who were primarily treated medically. Furthermore, in a subgroup analysis for patients with localized ileocecal disease manifestation, early surgery consistently resulted in a decreased amount of medical therapy postoperatively. In conclusion primary ICR is safe and effective in patients with limited CD, and the need for immunosuppressive medication during the postoperative follow-up is low compared to patients receiving surgery at a later stage of disease.}, language = {en} } @article{BankogluArnoldHeringetal.2018, author = {Bankoglu, Ezgi Eyluel and Arnold, Charlotte and Hering, Ilona and Hankir, Mohammed and Seyfried, Florian and Stopper, Helga}, title = {Decreased chromosomal damage in lymphocytes of obese patients after bariatric surgery}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {11195}, doi = {10.1038/s41598-018-29581-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177090}, year = {2018}, abstract = {The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.}, language = {en} } @phdthesis{Fieber2024, author = {Fieber, Tabea}, title = {Retrospektive unizentrische Analyse des Komplikationsmanagements bei Anastomoseninsuffizienz nach linksseitiger Kolon- und Rektumresektion}, doi = {10.25972/OPUS-36073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Eine gef{\"u}rchtete Komplikation nach Resektionen am Kolon mit Wiederherstellung der Kontinuit{\"a}t ist das Auftreten einer Anastomoseninsuffizienz (AI). Der Prozess der Diagnosestellung und das therapeutische Vorgehen sind zentrumsspezifisch und sehr heterogen. Ziel dieser Promotionsarbeit war die deskriptive Darstellung der Pr{\"a}valenz, Diagnostik und Therapie von AI, um anhand dieser Daten ein bestimmtes zu favorisierendes Vorgehen zur AI-Behandlung herauszuarbeiten. Es wurde eine retrospektive unizentrische Analyse durchgef{\"u}hrt. Diese umfasste eine Kohorte von 744 Patienten, welche von 2009 bis 2013 am Universit{\"a}tsklinikum W{\"u}rzburg unter Kontinuit{\"a}tserhalt kolorektal reseziert wurden. Es erfolgte eine deskriptive und statistische Auswertung mittels uni- und multivariater Analysen in Bezug auf Demographie, Risikofaktoren f{\"u}r die Entwicklung einer AI und den Erfolg der einzelnen Therapiekonzepte. W{\"a}hrend der Nachbeobachtungsphase vom im Mittel 2,5 Jahren entwickelten 10,48\% der Patienten eine AI. 60\% der Insuffizienzen wurden w{\"a}hrend der ersten 7 postoperativen Tage detektiert. Als Risikofaktoren konnten indikationsunabh{\"a}ngig m{\"a}nnliches Geschlecht, offener Zugangsweg und pulmonale Erkrankungen herausgearbeitet werden. Indikationsspezifisch zeigte sich eine Zunahme des AI-Risikos bei Divertikulitis-Patienten mit pulmonalen Erkrankungen (OR 4,5) und Cortisoneinnahme (OR 5,4). Auff{\"a}llig wurden Patienten mit AI durch heterogene und teils unspezifische Symptome - am h{\"a}ufigsten durch Fieber (28,21\%) und auff{\"a}llige Laborwerte (48,72\%). Eine folgende CT-Diagnostik best{\"a}tigte die Diagnose in 76,32\% der F{\"a}lle und war in 24,48\% falsch negativ. Patienten mit schlechtem AZ bei Diagnose der AI zeigten eine signifikant h{\"o}here Mortalit{\"a}t. Ein protektives Stoma konnte eine AI nicht verhindern, aber ihre Symptome und die Schwere des Verlaufs abmildern. Gemessen an der {\"U}berlebensrate und der Revisionspflichtigkeit unterschieden sich die durchgef{\"u}hrten Maßnahmen beim Versuch der kontinuit{\"a}tserhaltenden Therapie nicht in Bezug auf den Erfolg der Therapie. Wie Insuffizienz- und Mortalit{\"a}tsrate nach AI zeigen, ist diese unizentrische Analyse international vergleichbar. Die Ableitung einer generellen Empfehlung zur therapeutischen Vorgehensweise bei AI ist nicht m{\"o}glich. Vielmehr sind alle dargestellten Maßnahmen zur Beherrschung der AI sinnvoll, w{\"a}hrend die Wahl der Vorgehensweise weiterhin eine Individualentscheidung bleibt.}, subject = {Darmanastomose}, language = {de} } @article{BelicPageLazariotouetal.2019, author = {Belic, Stanislav and Page, Lukas and Lazariotou, Maria and Waaga-Gasser, Ana Maria and Dragan, Mariola and Springer, Jan and Loeffler, Juergen and Morton, Charles Oliver and Einsele, Hermann and Ullmann, Andrew J. and Wurster, Sebastian}, title = {Comparative Analysis of Inflammatory Cytokine Release and Alveolar Epithelial Barrier Invasion in a Transwell® Bilayer Model of Mucormycosis}, series = {Frontiers in Microbiology}, volume = {9}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2018.03204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252477}, year = {2019}, abstract = {Understanding the mechanisms of early invasion and epithelial defense in opportunistic mold infections is crucial for the evaluation of diagnostic biomarkers and novel treatment strategies. Recent studies revealed unique characteristics of the immunopathology of mucormycoses. We therefore adapted an alveolar Transwell® A549/HPAEC bilayer model for the assessment of epithelial barrier integrity and cytokine response to Rhizopus arrhizus, Rhizomucor pusillus, and Cunninghamella bertholletiae. Hyphal penetration of the alveolar barrier was validated by 18S ribosomal DNA detection in the endothelial compartment. Addition of dendritic cells (moDCs) to the alveolar compartment led to reduced fungal invasion and strongly enhanced pro-inflammatory cytokine response, whereas epithelial CCL2 and CCL5 release was reduced. Despite their phenotypic heterogeneity, the studied Mucorales species elicited the release of similar cytokine patterns by epithelial and dendritic cells. There were significantly elevated lactate dehydrogenase concentrations in the alveolar compartment and epithelial barrier permeability for dextran blue of different molecular weights in Mucorales-infected samples compared to Aspergillus fumigatus infection. Addition of monocyte-derived dendritic cells further aggravated LDH release and epithelial barrier permeability, highlighting the influence of the inflammatory response in mucormycosis-associated tissue damage. An important focus of this study was the evaluation of the reproducibility of readout parameters in independent experimental runs. Our results revealed consistently low coefficients of variation for cytokine concentrations and transcriptional levels of cytokine genes and cell integrity markers. As additional means of model validation, we confirmed that our bilayer model captures key principles of Mucorales biology such as accelerated growth in a hyperglycemic or ketoacidotic environment or reduced epithelial barrier invasion upon epithelial growth factor receptor blockade by gefitinib. Our findings indicate that the Transwell® bilayer model provides a reliable and reproducible tool for assessing host response in mucormycosis.}, language = {en} }