TY - JOUR A1 - Hankir, Mohammed K. A1 - Patt, Marianne A1 - Patt, Jörg T. W. A1 - Becker, Georg A. A1 - Rullmann, Michael A1 - Kranz, Mathias A1 - Deuther-Conrad, Winnie A1 - Schischke, Kristin A1 - Seyfried, Florian A1 - Brust, Peter A1 - Hesse, Swen A1 - Sabri, Osama A1 - Krügel, Ute A1 - Fenske, Wiebke T1 - Suppressed fat appetite after Roux-en-Y gastric bypass surgery associates with reduced brain mu-opioid receptor availability in diet-induced obese male rats JF - Frontiers in Neuroscience N2 - Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting. KW - bariatric surgery KW - caloric-restriction KW - fat appetite KW - Brain μ-opioid receptors KW - positron emission tomography imaging Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181130 VL - 10 ER - TY - JOUR A1 - Marx, Gernot A1 - Schindler, Achim W. A1 - Mosch, Christoph A1 - Albers, Joerg A1 - Bauer, Michael A1 - Gnass, Irmela A1 - Hobohm, Carsten A1 - Janssens, Uwe A1 - Kluge, Stefan A1 - Kranke, Peter A1 - Maurer, Tobias A1 - Merz, Waltraut A1 - Neugebauer, Edmund A1 - Quintel, Michael A1 - Senninger, Norbert A1 - Trampisch, Hans-Joachim A1 - Waydhas, Christian A1 - Wildenauer, Rene A1 - Zacharowski, Kai A1 - Eikermann, Michaela T1 - Intravascular volume therapy in adults guidelines from the association of the scientific medical societies in Germany JF - European Journal of Anaesthesiology N2 - No abstract available. KW - Predict fluid responsiveness KW - Randomized controlled-trial KW - 6-percent hydroxyethyl starch KW - Central venous-pressure KW - Elective cesarean-section KW - Critically-ill patients KW - Puls-pressure variation KW - Lactated ringers solution KW - Hypertonic saline 7.5-percent KW - Major abdominal surgery Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188223 VL - 33 IS - 7 ER - TY - JOUR A1 - Trujillo‐Viera, Jonathan A1 - El‐Merahbi, Rabih A1 - Schmidt, Vanessa A1 - Karwen, Till A1 - Loza‐Valdes, Angel A1 - Strohmeyer, Akim A1 - Reuter, Saskia A1 - Noh, Minhee A1 - Wit, Magdalena A1 - Hawro, Izabela A1 - Mocek, Sabine A1 - Fey, Christina A1 - Mayer, Alexander E. A1 - Löffler, Mona C. A1 - Wilhelmi, Ilka A1 - Metzger, Marco A1 - Ishikawa, Eri A1 - Yamasaki, Sho A1 - Rau, Monika A1 - Geier, Andreas A1 - Hankir, Mohammed A1 - Seyfried, Florian A1 - Klingenspor, Martin A1 - Sumara, Grzegorz T1 - Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity JF - EMBO Molecular Medicine N2 - Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. KW - chylomicron KW - fat absorption KW - intestine KW - obesity KW - protein kinase D2/PKD2/PRKD2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239018 VL - 13 IS - 5 ER - TY - JOUR A1 - Wagner, Johanna C. A1 - Wetz, Anja A1 - Wiegering, Armin A1 - Lock, Johan F. A1 - Löb, Stefan A1 - Germer, Christoph-Thomas A1 - Klein, Ingo T1 - Successful surgical closure of infected abdominal wounds following preconditioning with negative pressure wound therapy JF - Langenbeck's Archives of Surgery N2 - Purpose Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. Methods Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). Results One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care. Conclusion Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs. KW - open wound treatment KW - surgical site infections KW - secondary skin closure KW - negative pressure wound therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267541 SN - 1435-2451 VL - 406 IS - 7 ER - TY - JOUR A1 - Flemming, Sven A1 - Hankir, Mohammed K. A1 - Kusan, Simon A1 - Krone, Manuel A1 - Anger, Friedrich A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Safety of elective abdominal and vascular surgery during the COVID-19 pandemic: a retrospective single-center study JF - European Journal of Medical Research N2 - Background Patients with coronavirus disease 2019 (COVID-19) who undergo surgery have impaired postoperative outcomes and increased mortality. Consequently, elective and semi-urgent operations on the increasing number of patients severely affected by COVID-19 have been indefinitely postponed.in many countries with unclear implications on disease progression and overall survival. The purpose of this study was to evaluate whether the establishment of a standardized screening program for acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficient to ensure high-quality medical and surgical treatment of COVID-19 and non-COVID-19 patients while minimizing in-hospital SARS-CoV-2 transmission. Methods The screening program comprised polymerase chain reaction (PCR) testing of nasopharyngeal swabs and a standardized questionnaire about potential symptoms for SARS-CoV-2 infection. All elective and emergency patients admitted to the surgical department of a tertiary-care hospital center in Lower Franconia, Germany, between March and May 2020 were included and their characteristics were recorded. Results Out of the study population (n = 657), 509 patients (77.5%) had at least one risk factor for a potentially severe course of COVID-19 and 164 patients (25%) were active smokers. The average 7-day incidence in Lower Franconia was 24.0/100,000 during the observation period. Preoperative PCR testing revealed four asymptomatic positive patients out of the 657 tested patients. No postoperative SARS-CoV-2 infection or transmission could be detected. Conclusion The implementation of a standardized preoperative screening program to both COVID-19 and non-COVID-19 patients can ensure high-quality surgical care while minimizing infection risk for healthcare workers and potential in-hospital transmission. KW - SARS-CoV-2 KW - COVID-19 KW - elective surgery KW - screening KW - PCR Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264975 VL - 26 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Champ, Colin E. A1 - Otto, Christoph A1 - Kämmerer, Ulrike T1 - Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis JF - PLoS ONE N2 - Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ\(^{2}\) were MR = 0.85 (95% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors. KW - anti-tumor effects KW - ketogenic dients KW - mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167036 VL - 11 IS - 5 ER - TY - JOUR A1 - Wallaschek, Nina A1 - Reuter, Saskia A1 - Silkenat, Sabrina A1 - Wolf, Katharina A1 - Niklas, Carolin A1 - Özge, Kayisoglu A1 - Aguilar, Carmen A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Kircher, Stefan A1 - Rosenwald, Andreas A1 - Shannon-Lowe, Claire A1 - Bartfeld, Sina T1 - Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids JF - PLoS Pathogens N2 - Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection. KW - Organoids KW - ephitelial cells KW - gastrointestinal infections KW - cancers and neoplasms KW - Epstein-Barr virus KW - flow cytometry KW - epithelium Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259206 VL - 17 IS - 2 ER - TY - JOUR A1 - Hoffmann, Annett A1 - Ebert, Thomas A1 - Hankir, Mohammed K. A1 - Flehmig, Gesine A1 - Klöting, Nora A1 - Jessnitzer, Beate A1 - Lössner, Ulrike A1 - Stumvoll, Michael A1 - Blüher, Matthias A1 - Fasshauer, Mathias A1 - Tönjes, Anke A1 - Miehle, Konstanze A1 - Kralisch, Susan T1 - Leptin improves parameters of brown adipose tissue thermogenesis in lipodystrophic mice JF - Nutrients N2 - Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients. KW - lipodystrophy KW - leptin KW - brown adipose tissue KW - thermogenesis KW - uncoupling protein 1 KW - sympathetic nervous system Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242787 SN - 2072-6643 VL - 13 IS - 8 ER - TY - THES A1 - Kloos, Kerstin T1 - Über die Effekte von Hyperthermie und Zytostatika auf die Tumorzellproliferation, Apoptose und Expression von Heat Shock Proteinen im Kolonkarzinom T1 - Effects of hyperthermia and cytostatic drugs on tumor cell proliferation, apoptosis and expression of heat shock proteins in colon carcinoma N2 - Die Kombination aus zytoreduktiver Chirurgie und einer anschließenden hyperthermen intraperitonealen Chemoperfusion (HIPEC) stellt sich als vielversprechende Therapiestrategie bei ausgesuchten Patienten mit Peritonealkarzinose, z. B. des kolorektalen Karzinoms, dar. Die intraperitoneale Chemoperfusion kombiniert eine lokale Hochdosis-Chemotherapie mit einer Hyperthermie. Hitzeschockproteinen (HSP) kommt dabei eine bedeutende Rolle zu, da sie infolge von zellulären Stressfaktoren wie Hitze oder Zytostatika-bedingter Chemotoxizität induziert werden. HSPs setzen Reparatur- und Zellschutzmechanismen in Gang und vermindern so in einzelnen überlebenden Tumorzellen möglicherweise den gewünschten Therapieerfolg der HIPEC. Ziel der Arbeit war es, mithilfe eines bereits etablierten in vitro HIPEC-Modells die Auswirkungen der äußeren Stressoren Hyperthermie und Zytostatika auf die Expression von Hitzeschockproteinen (HSP27, HSP70 und HSP90) in drei humanen Kolonkarzinomzelllinien zu untersuchen. Dazu wurden die Zelllinien HT29, SW480 und SW620 jeweils mit und ohne Zytostatika (Mitomycin C, MMC und Oxaliplatin, OXA) für eine Stunde drei verschiedenen Temperaturstufen von 37°C als Normothermie, 41°C und 43°C als Hyperthermie ausgesetzt und nach einer Regenerationszeit von 30 min, 24 h, 48 h und 72 h mit Hilfe von RT-qPCR-Analysen und Western Blots untersucht. Zudem wurden nach gleichem Ablauf Effekte der HIPEC auf die Tumorzellproliferation und Apoptose mittels Proliferationsmarkern Ki-67, PCNA und MTS-Tests sowie dem antiapoptotischen Protein Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Patientenproben vor und nach HIPEC analysiert. Sowohl die einstündige Chemotherapie mit Mitomycin C oder Oxaliplatin unter hyperthermen Bedingungen als auch die isolierte Hyperthermiebehandlung führte im Vergleich zu normothermen Kontrollbedingungen bei 37°C zu einer signifikanten Überexpression der untersuchten HSPs in RTq-PCR-Analysenaller drei Kolonkarzinomzelllinien. Interessanterweise wurden vermehrte HSP Genexpressionsmuster noch drei Tage nach Behandlung beobachtet. Eine verstärkte Proteinexpression zeigte sich bestätigend insbesondere für HSP27 und HSP70 unter zytostatischer Behandlung mit MMC oder OXA und führte zu einer bis zu 3-fachen Expressionssteigerung wenn die Zellen hyperthermen Bedingungen ausgesetzt waren. Tumorzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden, zeigten interessanterweise zudem proliferative anstelle von anti-proliferativen Effekten. In durchgeführten MTS-Tests führte sowohl die Hyperthermie allein als auch die zusätzliche Zytostatikagabe zu einer deutlich erhöhten Zellviabilität im Vergleich zu normothermer Chemotherapie im Modellansatz. Übereinstimmend mit den Ergebnissen der MTS-Tests konnte eine Induktion der Proliferationsmarker PCNA und Ki-67 durch Hyperthermie und Chemotherapie auf Gen- und Proteinebene beobachtet werden. Im Falle von PCNA ließ sich eine verstärkte Proteinexpression in ex vivo Proben von Patienten nach klinisch durchgeführter HIPEC bestätigen. Zusätzliche Untersuchungen des anti-apoptotisch wirkenden Regulatorproteins Bcl-xL in in vitro Tumorzellansätzen sowie in ex vivo Proben von Patienten nach hyperthermer Chemotherapie, zeigten zudem eine deutlich gesteigerte Proteinexpression unter alleiniger Hyperthermie sowie insbesondere in Kombination mit Zytostatika. Durch die Induktion von HSP27, HSP70 und HSP90 infolge von hyperthermem und zytotoxischem Stress werden in überlebenden Zellen nach hyperthermer Chemotherapie, unerwünschte antiapopotische sowie proliferative Effekte im Sinne von Reparatur- und Zellschutzmechanismen induziert und nehmen negativen Einfluss auf den Therapieerfolg der HIPEC. Schlussfolgernd wäre der Einsatz von HSP-Inhibitoren um die beschriebenen, unerwünschten Zellmechanismen zu verhindern, zu überprüfen. Diese bieten eine interessante Möglichkeit die Effizienz der im klinischen Einsatz gängigen Zytostatika zu steigern und somit einen positiven Einfluss auf den Erfolg der Therapie und die Überlebenszeit von Patienten mit Peritonealkarzinose zu nehmen. Weiterführende Studien der eigenen Arbeitsgruppe mit kombinierten HSP70/HSP90-Inhibitoren zeigten bereits eine signifikant reduzierte Zellviabilität in Kolonkarzinomzellen, die zuvor der hyperthermen Chemotherapie unterzogen wurden. N2 - The combination of cytoreductive surgery followed by hyperthermic intraperitoneal chemoperfusion (HIPEC) emerges as a promising therapeutic strategy in selected patients with peritoneal carcinomatosis, such as colorectal carcinoma. Intraperitoneal chemoperfusion combines local high-dose chemotherapy with hyperthermia. Heat shock proteins (HSPs) play an important role in this process, as they are induced as a result of cellular stress factors such as heat or cytostatic drug-induced chemotoxicity. HSPs induce repair and cell protection mechanisms and thus possibly reduce the desired therapeutic success of HIPEC in individual surviving tumor cells. The aim of this work was to investigate the effects of the external stressors hyperthermia and cytostatic drugs on the expression of heat shock proteins (HSP27, HSP70 and HSP90) in three human colon carcinoma cell lines using an already established in vitro HIPEC model. For this purpose, cell lines HT29, SW480, and SW620 were each exposed to three different temperature levels of 37°C as normothermia, 41°C, and 43°C as hyperthermia for one hour with and without cytostatic drugs (mitomycin C, MMC, and oxaliplatin, OXA). After a regeneration period of 30 min, 24 h, 48 h, and 72 h they were examined by RT-qPCR analysis and Western blots. In addition, following the same procedure, effects of HIPEC on tumor cell proliferation and apoptosis were analyzed using proliferation markers Ki-67, PCNA and MTS assays, and the anti-apoptotic protein Bcl-xL in in vitro tumor cell mounts as well as in ex vivo patient samples before and after HIPEC. Both, one-hour chemotherapy with mitomycin C or oxaliplatin under hyperthermic conditions and isolated hyperthermia treatment resulted in significant overexpression of the HSPs in RTq-PCR analyses of all three colon carcinoma cell lines compared with normothermic control conditions at 37°C. Interestingly, increased HSP gene expression patterns were still observed three days after treatment. Increased protein expression was confirmatory especially for HSP27 and HSP70 under cytostatic treatment with MMC or OXA and resulted in up to a 3-fold increase in expression when cells were exposed to hyperthermic conditions. Tumor cells previously subjected to hyperthermic chemotherapy also interestingly showed proliferative instead of anti-proliferative effects. In MTS assays performed, both hyperthermia alone and additional cytostatic administration resulted in significantly increased cell viability compared to normothermic chemotherapy in the model approach. Consistent with the results of the MTS assays, induction of the proliferation markers PCNA and Ki-67 by hyperthermia and chemotherapy was observed at the gene and protein levels. In the case of PCNA, increased protein expression could be confirmed in ex vivo samples from patients after clinically performed HIPEC. Additional investigations of the anti-apoptotic regulator protein Bcl-xL in in vitro tumor cell preparations as well as in ex vivo samples from patients after hyperthermic chemotherapy, also showed a significantly increased protein expression under hyperthermia alone as well as especially in combination with cytostatic drugs. The induction of HSP27, HSP70 and HSP90 as a result of hyperthermic and cytotoxic stress induces undesired anti-apopotic and proliferative effects in surviving cells after hyperthermic chemotherapy in terms of repair and cell protection mechanisms and has a negative impact on the therapeutic success of HIPEC. In conclusion, the use of HSP inhibitors to prevent the described undesired cellular mechanisms should be investigated. These offer an interesting opportunity to increase the efficiency of cytostatic drugs commonly used in clinical practice and thus have a positive influence on the success of therapy and survival time of patients with peritoneal carcinomatosis. Further studies of the own research group with combined HSP70/HSP90 inhibitors already showed a significantly reduced cell viability in colon carcinoma cells previously subjected to hyperthermic chemotherapy. KW - Dickdarmkrebs KW - Colonkrebs KW - Peritonealkarzinose KW - HIPEC KW - Kolonkarzinom KW - Hitzeschock-Proteine KW - Hypertherme Chemotherapie Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-327101 ER - TY - JOUR A1 - Kelm, Matthias A1 - Kusan, Simon A1 - Surat, Güzin A1 - Anger, Friedrich A1 - Reibetanz, Joachim A1 - Germer, Christoph-Thomas A1 - Schlegel, Nicolas A1 - Flemming, Sven T1 - Disease- and medication-specific differences of the microbial spectrum in perianal fistulizing Crohn’s Disease — relevant aspects for antibiotic therapy JF - Biomedicines N2 - Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future. KW - fistulizing Crohn’s Disease KW - microbial spectrum KW - anorectal abscess KW - perianal fistulas Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290281 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Pelz, Jörg O. W. A1 - Wagner, Johanna A1 - Lichthardt, Sven A1 - Baur, Johannes A1 - Kastner, Caroline A1 - Matthes, Niels A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Laparoscopic right-sided colon resection for colon cancer - has the control group so far been chosen correctly? JF - World Journal of Surgical Oncology N2 - Background: The treatment strategies for colorectal cancer located in the right side of the colon have changed dramatically during the last decade. Due to the introduction of complete mesocolic excision (CME) with central ligation of the vessels and systematic lymph node dissection, the long-term survival of affected patients has increased significantly. It has also been proposed that right-sided colon resection can be performed laparoscopically with the same extent of resection and equal long-term results. Methods: A retrospective evaluation of a prospectively expanded database on right-sided colorectal cancer or adenoma treated at the University Hospital of Wuerzburg between 2009 and 2016 was performed. All patients underwent CME. This data was analyzed alone and in comparison to the published data describing laparoscopic right-sided colon resection for colon cancer. Results: The database contains 279 patients, who underwent right-sided colon resection due to colorectal cancer or colorectal adenoma (255 open; 24 laparoscopic). Operation data (time, length of stay, time on ICU) was equal or superior to laparoscopy, which is comparable to the published results. Surprisingly, the surrogate parameter for correct CME (the number of removed lymph nodes) was significantly higher in the open group. In a subgroup analysis only including patients who were feasible for laparoscopic resection and had been operated with an open procedure by an experienced surgeon, operation time was significantly shorter and the number of removed lymph nodes is significantly higher in the open group. Conclusion: So far, several studies demonstrate that laparoscopic right-sided colon resection is comparable to open resection. Our data suggests that a consequent CME during an open operation leads to significantly more removed lymph nodes than in laparoscopically resected patients and in several so far published data of open control groups from Europe. Further prospective randomized trials comparing the long-term outcome are urgently needed before laparoscopy for right-sided colon resection can be recommended ubiquitously. KW - colon cancer KW - laparoscopic right colectomy KW - lymph nodes Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176186 VL - 16 IS - 117 ER - TY - JOUR A1 - Hankir, Mohammed K. A1 - Rotzinger, Laura A1 - Nordbeck, Arno A1 - Corteville, Caroline A1 - Dischinger, Ulrich A1 - Knop, Juna-Lisa A1 - Hoffmann, Annett A1 - Otto, Christoph A1 - Seyfried, Florian T1 - Leptin receptors are not required for Roux-en-Y gastric bypass surgery to normalize energy and glucose homeostasis in rats JF - Nutrients N2 - Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation. KW - Roux-en-Y gastric bypass surgery KW - energy homeostasis KW - glucose homeostasis KW - fatty liver KW - leptin system KW - Zucker fatty fa/fa rats Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239550 SN - 2072-6643 VL - 13 IS - 5 ER - TY - JOUR A1 - Boelch, Sebastian P. A1 - Gurok, Anna A1 - Gilbert, Fabian A1 - Weißenberger, Manuel A1 - Rudert, Maximilian A1 - Barthel, Thomas A1 - Reppenhagen, Stephan T1 - Why compromise the patella? Five-year follow-up results of medial patellofemoral ligament reconstruction with soft tissue patellar fixation JF - International Orthopaedics N2 - Purpose This study investigates the redislocation rate and functional outcome at a minimum follow-up of five years after medial patellofemoral ligament (MPFL) reconstruction with soft tissue patellar fixation for patella instability. Methods Patients were retrospectively identified and knees were evaluated for trochlea dysplasia according to Dejour, for presence of patella alta and for presence of cartilage lesion at surgery. At a minimum follow-up of five years, information about an incident of redislocation was obtained. Kujala, Lysholm, and Tegner questionnaires as well as range of motion were used to measure functional outcome. Results Eighty-nine knees were included. Follow-up rate for redislocation was 79.8% and for functional outcome 58.4%. After a mean follow-up of 5.8 years, the redislocation rate was 5.6%. There was significant improvement of the Kujala score (68.8 to 88.2, p = 0.000) and of the Lysholm score (71.3 to 88.4, p = 0.000). Range of motion at follow-up was 149.0° (115–165). 77.5% of the knees had patella alta and 52.9% trochlear dysplasia types B, C, or D. Patellar cartilage legions were present in 54.2%. Redislocations occurred in knees with trochlear dysplasia type C in combination with patella alta. Conclusion MPFL reconstruction with soft tissue patellar fixation leads to significant improvement of knee function and low midterm redislocation rate. Patients with high-grade trochlear dysplasia should be considered for additional osseous correction. KW - MPFL KW - medial patellofemoral ligament KW - patella instability KW - patella dislocation KW - trochlear dysplasia KW - patella alta Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235751 SN - 0341-2695 VL - 45 ER - TY - JOUR A1 - Kastner, Carolin A1 - Hendricks, Anne A1 - Deinlein, Hanna A1 - Hankir, Mohammed A1 - Germer, Christoph-Thomas A1 - Schmidt, Stefanie A1 - Wiegering, Armin T1 - Organoid Models for Cancer Research — From Bed to Bench Side and Back JF - Cancers N2 - Simple Summary Despite significant strides in multimodal therapy, cancers still rank within the first three causes of death especially in industrial nations. A lack of individualized approaches and accurate preclinical models are amongst the major barriers that limit the development of novel therapeutic options and drugs. Recently, the 3D culture system of organoids was developed which stably retains the genetic and phenotypic characteristics of the original tissue, healthy as well as diseased. In this review, we summarize current data and evidence on the relevance and reliability of such organoid culture systems in cancer research, focusing on their role in drug investigations (in a personalized manner). Abstract Organoids are a new 3D ex vivo culture system that have been applied in various fields of biomedical research. First isolated from the murine small intestine, they have since been established from a wide range of organs and tissues, both in healthy and diseased states. Organoids genetically, functionally and phenotypically retain the characteristics of their tissue of origin even after multiple passages, making them a valuable tool in studying various physiologic and pathophysiologic processes. The finding that organoids can also be established from tumor tissue or can be engineered to recapitulate tumor tissue has dramatically increased their use in cancer research. In this review, we discuss the potential of organoids to close the gap between preclinical in vitro and in vivo models as well as clinical trials in cancer research focusing on drug investigation and development. KW - cancer KW - tumor disease KW - organoid KW - patient-derived organoid (PDOs) KW - patient-derived tumor organoid (PDTO) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246307 SN - 2072-6694 VL - 13 IS - 19 ER - TY - JOUR A1 - Baur, Johannes A1 - Mathe, Katrin A1 - Gesierich, Anja A1 - Weyandt, Gerhard A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Gasser, Martin A1 - Pelz, Jörg O. W. T1 - Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients JF - World Journal of Surgical Oncology N2 - Background: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. Methods: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. Results: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. Conclusions: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional. KW - malignant melanoma KW - inguinal lymph node dissection KW - regional recurrence KW - V. saphena magna Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157687 VL - 15 IS - 99 ER - TY - JOUR A1 - Kollmann, Cathérine T. A1 - Pretzsch, Elise B. A1 - Kunz, Andreas A1 - Isbert, Christoph A1 - Krajinovic, Katica A1 - Reibetanz, Joachim A1 - Kim, Mia T1 - Anorectal angle at rest predicting successful sacral nerve stimulation in idiopathic fecal incontinence—a cohort analysis JF - International Journal of Colorectal Disease N2 - Purpose Sacral nerve stimulation is an effective treatment for patients suffering from fecal incontinence. However, less is knownabout predictors of success before stimulation. The purpose of this study was to identify predictors of successful sacral nervestimulation in patients with idiopathic fecal incontinence. Methods Consecutive female patients, receiving peripheral nerve evaluation and sacral nerve stimulation between September2008 and October 2014, suffering from idiopathic fecal incontinence were included in this study. Preoperative patient’scharac-teristics, anal manometry, and defecography results were collected prospectively and investigated by retrospective analysis. Mainoutcome measures were independent predictors of treatment success after sacral nerve stimulation. Results From, all in all, 54 patients suffering from idiopathic fecal incontinence receiving peripheral nerve evaluation, favorableoutcome was achieved in 23 of 30 patients after sacral nerve stimulation (per protocol 76.7%; intention to treat 42.6%). From allanalyzed characteristics, wide anorectal angle at rest in preoperative defecography was the only independent predictor offavorable outcome in multivariate analysis (favorable 134.1 ± 13.9° versus unfavorable 118.6 ± 17.1°). Conclusions Anorectal angle at rest in preoperative defecography might present a predictor of outcome after sacral nervestimulation in patients with idiopathic fecal incontinence. KW - sacral nerve stimulation KW - idiopathic fecal incontinence KW - sacral neuromodulation KW - anorectal angl Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232379 SN - 0179-1958 VL - 35 ER - TY - JOUR A1 - Meir, Michael A1 - Maurus, Katja A1 - Kuper, Jochen A1 - Hankir, Mohammed A1 - Wardelmann, Eva A1 - Rosenwald, Andreas A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis, and seminoma development JF - Genes, Chromosomes & Cancer N2 - Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations. KW - germline mutation KW - GIST KW - KIT KW - mastocytosis KW - seminoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257476 VL - 60 IS - 12 ER - TY - JOUR A1 - Madrahimov, Nodir A1 - Mutsenko, Vitalii A1 - Natanov, Ruslan A1 - Radaković, Dejan A1 - Klapproth, André A1 - Hassan, Mohamed A1 - Rosenfeldt, Mathias A1 - Kleefeldt, Florian A1 - Aleksic, Ivan A1 - Ergün, Süleyman A1 - Otto, Christoph A1 - Leyh, Rainer G. A1 - Bening, Constanze T1 - Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model JF - Intensive Care Medicine Experimental N2 - Background Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4–6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an “out-of-hospital” sudden unexpected death with subsequent “in-hospital” cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin–streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V–A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia–reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem. Results BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, − 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice. Conclusions Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma. KW - extracorporeal membrane oxygenation KW - cadaver multiorgan preservation KW - mild hypothermia KW - post-mortem heart recovery Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357381 VL - 11 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Ergün, Süleyman A1 - Peter, Dominik A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Hendel, Robin A1 - Pannenbecker, Pauline A1 - Augustin, Anne Marie A1 - Kunz, Andreas Steven A1 - Feldle, Philipp A1 - Bley, Thorsten Alexander A1 - Grunz, Jan-Peter T1 - Comparison of ultrahigh and standard resolution photon-counting CT angiography of the femoral arteries in a continuously perfused in vitro model JF - European Radiology Experimental N2 - Background With the emergence of photon-counting CT, ultrahigh-resolution (UHR) imaging can be performed without dose penalty. This study aims to directly compare the image quality of UHR and standard resolution (SR) scan mode in femoral artery angiographies. Methods After establishing continuous extracorporeal perfusion in four fresh-frozen cadaveric specimens, photon-counting CT angiographies were performed with a radiation dose of 5 mGy and tube voltage of 120 kV in both SR and UHR mode. Images were reconstructed with dedicated convolution kernels (soft: Body-vascular (Bv)48; sharp: Bv60; ultrasharp: Bv76). Six radiologists evaluated the image quality by means of a pairwise forced-choice comparison tool. Kendall’s concordance coefficient (W) was calculated to quantify interrater agreement. Image quality was further assessed by measuring intraluminal attenuation and image noise as well as by calculating signal-to-noise ratio (SNR) and contrast-to-noise ratios (CNR). Results UHR yielded lower noise than SR for identical reconstructions with kernels ≥ Bv60 (p < 0.001). UHR scans exhibited lower intraluminal attenuation compared to SR (Bv60: 406.4 ± 25.1 versus 418.1 ± 30.1 HU; p < 0.001). Irrespective of scan mode, SNR and CNR decreased while noise increased with sharper kernels but UHR scans were objectively superior to SR nonetheless (Bv60: SNR 25.9 ± 6.4 versus 20.9 ± 5.3; CNR 22.7 ± 5.8 versus 18.4 ± 4.8; p < 0.001). Notably, UHR scans were preferred in subjective assessment when images were reconstructed with the ultrasharp Bv76 kernel, whereas SR was rated superior for Bv60. Interrater agreement was high (W = 0.935). Conclusions Combinations of UHR scan mode and ultrasharp convolution kernel are able to exploit the full image quality potential in photon-counting CT angiography of the femoral arteries. Relevance statement The UHR scan mode offers improved image quality and may increase diagnostic accuracy in CT angiography of the peripheral arterial runoff when optimized reconstruction parameters are chosen. Key points • UHR photon-counting CT improves image quality in combination with ultrasharp convolution kernels. • UHR datasets display lower image noise compared with identically reconstructed standard resolution scans. • Scans in UHR mode show decreased intraluminal attenuation compared with standard resolution imaging. KW - CT angiography KW - femoral arteries KW - photon-counting computed tomography (CT) KW - small pixel effect KW - ultrahigh resolution Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357905 VL - 7 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Hoffmann, Annett A1 - Löst, Margaretha A1 - Anany, Mohamed A. A1 - Zhang, Tengyu A1 - Kucka, Kirstin A1 - Wiegering, Armin A1 - Otto, Christoph A1 - Wajant, Harald T1 - Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity JF - Frontiers in Immunology N2 - Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK. KW - agonistic antibodies KW - cell death KW - FcγR KW - Fn14 KW - NFκB KW - TNF receptor superfamily KW - TWEAK Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323116 VL - 14 ER - TY - JOUR A1 - Döhler, Ida A1 - Röder, Daniel A1 - Schlesinger, Tobias A1 - Nassen, Christian Alexander A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin A1 - Lock, Johan Friso T1 - Risk-adjusted perioperative bridging anticoagulation reduces bleeding complications without increasing thromboembolic events in general and visceral surgery JF - BMC Anesthesiology N2 - Background Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events. Methods We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality. Results A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed. Conclusion It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low. KW - low-molecular heparin KW - atrial fibrillation KW - postoperative bleeding KW - thromboembolism KW - anticoagulation KW - bridging Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357305 VL - 23 ER - TY - JOUR A1 - Kollmann, Catherine A1 - Buerkert, Hannah A1 - Meir, Michael A1 - Richter, Konstantin A1 - Kretzschmar, Kai A1 - Flemming, Sven A1 - Kelm, Matthias A1 - Germer, Christoph-Thomas A1 - Otto, Christoph A1 - Burkard, Natalie A1 - Schlegel, Nicolas T1 - Human organoids are superior to cell culture models for intestinal barrier research JF - Frontiers in Cell and Developmental Biology N2 - Loss of intestinal epithelial barrier function is a hallmark in digestive tract inflammation. The detailed mechanisms remain unclear due to the lack of suitable cell-based models in barrier research. Here we performed a detailed functional characterization of human intestinal organoid cultures under different conditions with the aim to suggest an optimized ex-vivo model to further analyse inflammation-induced intestinal epithelial barrier dysfunction. Differentiated Caco2 cells as a traditional model for intestinal epithelial barrier research displayed mature barrier functions which were reduced after challenge with cytomix (TNFα, IFN-γ, IL-1ß) to mimic inflammatory conditions. Human intestinal organoids grown in culture medium were highly proliferative, displayed high levels of LGR5 with overall low rates of intercellular adhesion and immature barrier function resembling conditions usually found in intestinal crypts. WNT-depletion resulted in the differentiation of intestinal organoids with reduced LGR5 levels and upregulation of markers representing the presence of all cell types present along the crypt-villus axis. This was paralleled by barrier maturation with junctional proteins regularly distributed at the cell borders. Application of cytomix in immature human intestinal organoid cultures resulted in reduced barrier function that was accompanied with cell fragmentation, cell death and overall loss of junctional proteins, demonstrating a high susceptibility of the organoid culture to inflammatory stimuli. In differentiated organoid cultures, cytomix induced a hierarchical sequence of changes beginning with loss of cell adhesion, redistribution of junctional proteins from the cell border, protein degradation which was accompanied by loss of epithelial barrier function. Cell viability was observed to decrease with time but was preserved when initial barrier changes were evident. In summary, differentiated intestinal organoid cultures represent an optimized human ex-vivo model which allows a comprehensive reflection to the situation observed in patients with intestinal inflammation. Our data suggest a hierarchical sequence of inflammation-induced intestinal barrier dysfunction starting with loss of intercellular adhesion, followed by redistribution and loss of junctional proteins resulting in reduced barrier function with consecutive epithelial death. KW - intestinal epithelial barrier KW - Caco2 cells KW - intestinal organoids KW - enteroids KW - gut barrier KW - inflammatory cell model KW - inflammation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357317 SN - 2296-634X VL - 11 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Kleefeldt, Florian A1 - Peter, Dominik A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Grunz, Jan-Peter A1 - Augustin, Anne Marie A1 - Ergün, Süleyman A1 - Bley, Thorsten Alexander A1 - Petritsch, Bernhard T1 - Continuous extracorporeal femoral perfusion model for intravascular ultrasound, computed tomography and digital subtraction angiography JF - PLoS One N2 - Objectives We developed a novel human cadaveric perfusion model with continuous extracorporeal femoral perfusion suitable for performing intra-individual comparison studies, training of interventional procedures and preclinical testing of endovascular devices. Objective of this study was to introduce the techniques and evaluate the feasibility for realistic computed tomography angiography (CTA), digital subtraction angiography (DSA) including vascular interventions, and intravascular ultrasound (IVUS). Methods The establishment of the extracorporeal perfusion was attempted using one formalin-fixed and five fresh-frozen human cadavers. In all specimens, the common femoral and popliteal arteries were prepared, introducer sheaths inserted, and perfusion established by a peristaltic pump. Subsequently, we performed CTA and bilateral DSA in five cadavers and IVUS on both legs of four donors. Examination time without unintentional interruption was measured both with and without non-contrast planning CT. Percutaneous transluminal angioplasty and stenting was performed by two interventional radiologists on nine extremities (five donors) using a broad spectrum of different intravascular devices. Results The perfusion of the upper leg arteries was successfully established in all fresh-frozen but not in the formalin-fixed cadaver. The experimental setup generated a stable circulation in each procedure (ten upper legs) for a period of more than six hours. Images acquired with CT, DSA and IVUS offered a realistic impression and enabled the sufficient visualization of all examined vessel segments. Arterial cannulating, percutaneous transluminal angioplasty as well as stent deployment were feasible in a way that is comparable to a vascular intervention in vivo. The perfusion model allowed for introduction and testing of previously not used devices. Conclusions The continuous femoral perfusion model can be established with moderate effort, works stable, and is utilizable for medical imaging of the peripheral arterial system using CTA, DSA and IVUS. Therefore, it appears suitable for research studies, developing skills in interventional procedures and testing of new or unfamiliar vascular devices. KW - continuous extracorporeal femoral perfusion model KW - novel human cadaveric perfusion model KW - computed tomography angiography (CTA) KW - digital subtraction angiography (DSA) KW - intravascular ultrasound (IVUS) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350136 SN - 1932-6203 VL - 18 IS - 5 ER - TY - JOUR A1 - Plassmeier, Lars A1 - Hankir, Mohammed K. A1 - Seyfried, Florian T1 - Impact of Excess Body Weight on Postsurgical Complications JF - Visceral Medicine N2 - Background: Obesity is considered a risk factor for postoperative complications as it can limit exposure to the operation field, thereby significantly prolonging surgery time. Obesity-associated comorbidities, such as low-grade systemic inflammation, impaired functional status, and type 2 diabetes, are independent risk factors for impaired anastomotic wound healing and nonsurgical site infections. If obesity itself is an independent risk factor for surgical complications remains controversial, but the reason for this is largely unexplored. Summary: A MEDLINE literature search was performed using the terms: “obesity,” “excess body weight,” and “surgical complications.” Out of 65,493 articles 432 meta-analyses were screened, of which 25 meta-analyses were on the subject. The vast majority of complex oncologic procedures in the field of visceral surgery have shown higher complication rates in obese patients. Meta-analyses from the last 10 to 15 years with high numbers of patients enrolled consistently have shown longer operation times, higher blood loss, longer hospital stay for colorectal procedures, oncologic upper gastrointestinal (GI) procedures, and pancreatic surgery. Interestingly, these negative effects seem not to affect the overall survival in oncologic patients, especially in esophageal resections. A selection bias in oncologic upper GI patients may have influenced the results with higher BMI in upper GI cancer to be a predictor for better nutritional and performance status. Key Messages: Contrary to bariatric surgery, only limited evidence indicated that site and type of surgery, the approach to the abdominal cavity (laparoscopic vs. open), institutional factors, and the type of perioperative care such as ERAS protocols may play a role in determining postsurgical complications in obese patients. The initial question remains therefore partially unanswered. Large nationwide register-based studies are necessary to better understand which aspects of obesity and its related comorbidities define it as a risk factor for surgical complications. KW - obesity KW - surgical complications KW - laparoscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244890 SN - 2297-4725 SN - 2297-475X VL - 37 IS - 4 ER - TY - JOUR A1 - Güsgen, C. A1 - Anger, F. A1 - Hauer, T. A1 - Willms, A. A1 - Buhr, H. J. A1 - Germer, C.-T. A1 - Schwab, R. A1 - Lock, J. F. T1 - Fortbildung von Allgemein- und Viszeralchirurgen in der lebensrettenden Notfallchirurgie. Ergebnisse einer Umfrage unter Operationskursteilnehmern JF - Der Chirurg N2 - Hintergrund Die geringe Anzahl operativ zu versorgender Körperhöhlenverletzungen erfordert ein Umdenken in der chirurgischen Aus- und Weiterbildung. Ein entsprechendes Kursformat wird seit 2014 über die DGAV angeboten. Um Berechtigung, Bedarf, Nutzen und Erfolg eines solchen Kursformates zu erheben, erfolgte eine Evaluation durch die bisherigen Kursteilnehmer. Material und Methoden Kursevaluation und zusätzliche Onlinebefragung der bisherigen Kursteilnehmer hinsichtlich Alter, Geschlecht, Ausbildungsstand, Fachrichtung, Versorgungsstufe des Krankenhauses, notfallchirurgischer Erfahrungen, der Häufigkeit chirurgischer Notfallversorgungen, Teilnahme an anderen Kursformaten, Erfahrungen nach der Kursteilnahme, Einschätzung der aktuellen Fort- und Weiterbildungssituation und Finanzierung solcher Kurse. Ergebnisse Insgesamt 142 Kursteilnehmer evaluierten ihre Kursteilnahme, zusätzlich beantworteten 83 den Onlinefragebogen. Über 90 % berichteten von einem nachhaltigen positiven Einfluss des Kurses auf ihr notfallchirurgisches Handeln. Mehr als die Hälfte konnte von konkreten Notfallsituationen berichten, die sie aufgrund der Kursteilnahme besser bewältigen konnten. In der Notfallversorgung erfahrene Chirurgen bewerteten den eigenen Lernerfolg durch die Kursteilnahme signifikant häufiger positiv als ihre weniger erfahrenen Kollegen. Keinen Einfluss auf den Lernerfolg hatten eine Ober- oder Chefarztposition, die Versorgungsstufe des Krankenhauses, das Alter oder Geschlecht der Teilnehmer. Die Mehrheit der antwortenden Chirurgen befürwortet die Integration eines solchen Kursformates in die chirurgische Weiterbildung und fordert hierzu eine finanzielle Unterstützung. Schlussfolgerung Kursformate, in denen notfallchirurgische Strategien und Fähigkeiten vermittelt werden, sind etabliert und werden sehr positiv evaluiert. Die Fort- und Weiterbildung in notfallchirurgischen Fähigkeiten und Kenntnissen liegt im gesellschaftlichen Interesse und zumindest anteilig auch in ihrer Verantwortung. N2 - Background Due to a decreasing number of emergency procedures for body cavity injuries, surgical training is inadequate and current educational concepts must be reconsidered. The German Society for General and Visceral Surgery has set up a surgical training course in 2014 to overcome this shortage. In order to assess the eligibility, needs, benefits and success of such a training format, participants were asked to evaluate the program. Material and methods All participants evaluated the course during participation and were later asked to answer an online survey regarding their age, gender, level of surgical education, surgical discipline, level of care of the hospital, emergency surgical experience and frequency of performing emergency surgery, participation in other programs, experiences after participating in the course, rating of the current training curriculum and funding of such courses. Results Out of 142 participants 83 replied to the online survey. Over 90% reported a lasting positive influence of the course on emergency surgical skills. More than half of the responders remembered a clinical situation which they successfully managed due to the skills they gained during the course. Surgeons experienced in emergency treatment felt significantly more benefit than less experienced colleagues. A consultancy position, the level of care of the hospital, age and sex of the participants did not influence the overall benefits reported. The majority of responding surgeons were in favor of including such a training course in surgical education and stipulated public financial support. Conclusion Course formats that mediate emergency surgery strategies and skills are established and well accepted. Training of surgeons in life-saving emergency surgery is in the public interest and is also partly the responsibility of society. T2 - Advanced training of general and visceral surgeons in life-saving emergency surgery. Results of a survey among participants of a surgery course KW - Damage control surgery KW - Terroranschlagtrauma KW - Abdominaltrauma KW - Messerstichverletzung KW - Schussverletzung KW - damage control surgery KW - terror attack trauma KW - abdominal trauma KW - stab wounds KW - shooting injuries Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235246 SN - 0009-4722 VL - 91 ER - TY - JOUR A1 - Brand, Markus A1 - Reimer, Stanislaus A1 - Reibetanz, Joachim A1 - Flemming, Sven A1 - Kornmann, Marko A1 - Meining, Alexander T1 - Endoscopic full thickness resection vs. transanal endoscopic microsurgery for local treatment of rectal neuroendocrine tumors - a retrospective analysis JF - International Journal of Colorectal Disease N2 - Purpose Local treatment of small well-differentiated rectal neuroendocrine tumors (NETs) is recommended by current guidelines. However, although several endoscopic methods have been established, the highest R0 rate is achieved by transanal endoscopic microsurgery (TEM). Since a recently published study about endoscopic full thickness resection (eFTR) showed a R0 resection rate of 100%, the aim of this study was to evaluate both methods (eFTR vs. TEM). Methods We retrospectively analyzed all patients with rectal NET treated either by TEM (1999–2018) or eFTR (2016–2019) in two tertiary centers (University Hospital Wuerzburg and Ulm). We analyzed clinical, procedural, and histopathological outcomes in both groups. Results Twenty-eight patients with rectal NET received local treatment (TEM: 13; eFTR: 15). Most tumors were at stage T1a and grade G1 or G2 (in the TEM group two G3 NETs were staged T2 after neoadjuvant chemotherapy). In both groups, similar outcomes for en bloc resection rate, R0 resection rate, tumor size, or specimen size were found. No procedural adverse events were noted. Mean procedure time in the TEM group was 48.9 min and 19.2 min in the eFTR group. Conclusion eFTR is a convincing method for local treatment of small rectal NETs combining high safety and efficacy with short interventional time. KW - rectum KW - neuroendocrine tumor (NET) KW - transanal endoscopic microsurgery (TEM) KW - endoscopic full thickness resection (eFTR) KW - full-thickness resection device (FTRD) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234833 SN - 0179-1958 VL - 36 ER - TY - JOUR A1 - Glaser, Kirsten A1 - Kern, David A1 - Speer, Christian P. A1 - Schlegel, Nicolas A1 - Schwab, Michael A1 - Thome, Ulrich H. A1 - Härtel, Christoph A1 - Wright, Clyde J. T1 - Imbalanced inflammatory responses in preterm and term cord blood monocytes and expansion of the CD14\(^+\)CD16\(^+\) subset upon toll-like receptor stimulation JF - International Journal of Molecular Sciences N2 - Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state. KW - neonatal immunology KW - inflammation KW - preterm infants KW - monocytes KW - cord blood KW - monocyte subsets KW - cytokines KW - Toll-like receptor signaling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311056 SN - 1422-0067 VL - 24 IS - 5 ER - TY - JOUR A1 - Griebsch, Nora-Isabell A1 - Kern, Johanna A1 - Hansen, Jonas A1 - Rullmann, Michael A1 - Luthardt, Julia A1 - Helfmeyer, Stephanie A1 - Dekorsy, Franziska J. A1 - Soeder, Marvin A1 - Hankir, Mohammed K. A1 - Zientek, Franziska A1 - Becker, Georg-Alexander A1 - Patt, Marianne A1 - Meyer, Philipp M. A1 - Dietrich, Arne A1 - Blüher, Matthias A1 - Ding, Yu-Shin A1 - Hilbert, Anja A1 - Sabri, Osama A1 - Hesse, Swen T1 - Central serotonin/noradrenaline transporter availability and treatment success in patients with obesity JF - Brain Sciences N2 - Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes. KW - obesity KW - serotonin KW - noradrenaline KW - serotonin transporter KW - noradrenaline transporter KW - Roux-en-Y gastric bypass surgery KW - body mass index (BMI; kg/m\(^2\)) KW - radiotracer KW - PET KW - PET imaging Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290294 SN - 2076-3425 VL - 12 IS - 11 ER - TY - JOUR A1 - Kelm, Matthias A1 - Reibetanz, Joachim A1 - Kim, Mia A1 - Schoettker, Kathrin A1 - Brand, Markus A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Flemming, Sven T1 - Kono-S anastomosis in Crohn’s disease: A retrospective study on postoperative morbidity and disease recurrence in comparison to the conventional side-to-side anastomosis JF - Journal of Clinical Medicine N2 - Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission. KW - Crohn’s disease KW - surgical therapy KW - ileocecal resection KW - Kono-S anastomosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297334 SN - 2077-0383 VL - 11 IS - 23 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Schmitt, Constanze A1 - Herbert, Saskia-Laureen A1 - Feldheim, Jonas A1 - Schlegel, Nicolas A1 - Gosselet, Fabien A1 - Hagemann, Carsten A1 - Roewer, Norbert A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model JF - Fluids and Barriers of the CNS N2 - Background The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13. KW - Metastatic breast cancer KW - Blood–brain barrier KW - In vitro models KW - CX3CL1 KW - CXCL13 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229940 VL - 17 ER - TY - JOUR A1 - Flemming, S. A1 - Hankir, M. A1 - Ernestus, R.-I. A1 - Seyfried, F. A1 - Germer, C.-T. A1 - Meybohm, P. A1 - Wurmb, T. A1 - Vogel, U. A1 - Wiegering, A. T1 - Surgery in times of COVID-19 — recommendations for hospital and patient management JF - Langenbeck's Archives of Surgery N2 - Background The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has escalated rapidly to a global pandemic stretching healthcare systems worldwide to their limits. Surgeonshave had to immediately react to this unprecedented clinical challenge by systematically repurposing surgical wards. Purpose To provide a detailed set of guidelines developed in a surgical ward at University Hospital Wuerzburg to safelyaccommodate the exponentially rising cases of SARS-CoV-2 infected patients without compromising the care of emergencysurgery and oncological patients or jeopardizing the well-being of hospital staff. Conclusions The dynamic prioritization of SARS-CoV-2 infected and surgical patient groups is key to preserving life whilemaintaining high surgical standards. Strictly segregating patient groups in emergency rooms, non-intensive care wards andoperating areas prevents viral spread while adequately training and carefully selecting hospital staff allow them to confidentlyand successfully undertake their respective clinical duties. KW - SARS-CoV-2 KW - COVID-19 KW - Surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231766 SN - 1435-2443 VL - 405 ER - TY - JOUR A1 - Notz, Quirin A1 - Schmalzing, Marc A1 - Wedekink, Florian A1 - Schlesinger, Tobias A1 - Gernert, Michael A1 - Herrmann, Johannes A1 - Sorger, Lena A1 - Weismann, Dirk A1 - Schmid, Benedikt A1 - Sitter, Magdalena A1 - Schlegel, Nicolas A1 - Kranke, Peter A1 - Wischhusen, Jörg A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study JF - Frontiers in Immunology N2 - Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience. KW - Coronavirus Disease 2019 KW - acute respiratory distress syndrome KW - Severe Acute Respiratory Syndrome Coronavirus 2 KW - cytokines KW - inflammation KW - growth differentiation factor 15 KW - immune response Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212815 SN - 1664-3224 VL - 11 ER - TY - THES A1 - Knop, Juna-Lisa T1 - Untersuchungen zur Bedeutung von Spaltprodukten des vaskulär endothelialen (VE-) Cadherin als Auslöser für die Schrankenstörung des Gefäßendothels T1 - Characterisation of the endothelial barrier-disruptive effects of soluble vascular endothelial (sVE-) cadherin N2 - Ein Schlüsselereignis, welches dem prognosebestimmenden Organversagen bei systemi-schen Entzündungsprozessen und Sepsis vorangeht, ist die Entwicklung einer mikrovas-kulären endothelialen Schrankenstörung. Das vaskuläre endotheliale (VE-) Cadherin als mechanischer Stabilisator der Endothelbarriere spielt dabei eine wichtige Rolle. In der Inflammation werden Spaltprodukte von VE-Cadherin (sVE-Cadherin) gebildet. Ge-genstand der vorliegenden Arbeit war die Untersuchung der Hypothese ob diese Spalt-produkte selbst an der Störung der endothelialen Barrierefunktion beteiligt sind. Es wurde hierfür humanes sVE-Cadherin bestehend aus den extrazellulären Domänen EC1-5 (sVE-CadherinEC1-5) generiert. In Messungen des transendothelialen elektrischen Widerstands (TER), mit Immunfluoreszenzfärbungen und Western Blot Analysen wird gezeigt, dass sVE-Cadherin dosisabhängig die Barriere Integrität in primären humanen dermalen Endothelzellen stört. Dies führt zu einer Reduktion von VE-Cadherin und den assoziierten Proteinen α-, γ- und δ-Catenin und ZO-1, die nach der Applikation von sVE-Cadherin an den Zellgrenzen reduziert sind. Die Interaktion zwischen VE-PTP und VE-Cadherin wird durch sVE-CadherinEC1-5 reduziert. Durch pharmakologische Hem-mung der Phosphataseaktivität von VE-PTP mittels AKB9778 wird der durch sVE-CadherinEC1-5-induzierte Verlust der Endothelbarriere aufgehoben. Dagegen zeigt die direkte Aktivierung von Tie-2 mittels Angiopoetin-1 keinen protektiven Effekt auf die durch sVE-CadherinEC1-5 gestörte Endothelbarriere. Weitere Analysen zeigen eine erhöh-te Expression von GEF-H1 durch sVE-CadherinEC1-5. Diese ist ebenfalls durch AKB9778 hemmbar. Zusätzlich zu diesen Untersuchungen wurden die Konstrukte EC1-4 und EC3-5 in ver-schiedene Vektoren kloniert, um zu bestimmen, ob die extrazelluläre Domäne 5 von VE-Cadherin die dominante Rolle bei den sVE-Cadherin-vermittelten Effekten spielt. Zusammenfassend zeigen diese Untersuchungen zum ersten Mal, dass sVE-CadherinEC1-5 unabhängig von proinflammatorischen Auslösern über die Aktivierung des VE-PTP/RhoA-Signalweges den Zusammenbruch der Endothelbarriere mitversursacht. Dies stellt einen neuen pathophysiologischer Mechanismus dar, der zum Gesamtverständnis der entzündungsinduzierten Barriereveränderungen des Endothels beiträgt. N2 - A key prognostic event preceding organ failure in sepsis and systemic inflammatory pro-cesses is dysfunction of the microvascular endothelial barrier. The transmembrane pro-tein vascular endothelial (VE-) cadherin is an important prerequisite to stabilize endothe-lial barrier. VE-cadherin is cleaved under inflammatory conditions which results in the release of soluble VE-cadherin (sVE-cadherin). The main hypothesis of this thesis is to investigate whether sVE-cadherin itself directly disrupts the endothelial barrier in the absence of proinflammatory stimuli. Human sVE-cadherin consisting of extracellular domains EC1-5 (sVE-cadherinEC1-5) was generated and applied onto primary human dermal endothelial cells (HDMECs) for structural and functional analysis. Measurements of transendothelial electrical resistance (TER) and 4 kDa FITC-dectran flux revealed that sVE-cadherinEC1-5 dose-dependently disrupts endothelial barrier integrity. This was confirmed by immunostaining and im-munoblotting analysis which showed that sVE-cadherinEC1-5 treatment reduced overall levels of VE-cadherin and the associated proteins α-, γ- and δ-catenin and ZO-1 as well as their distribution at the cell border of HDMECs. sVE-cadherinEC1-5 treatment reduced the interaction between the phosphatase VE-PTP and VE-cadherin. Accordingly, phar-macological inhibition of VE-PTP using AKB9778 reversed sVE-cadherinEC1-5-induced endothelial barrier loss. Further analysis showed that the increased expression of GEF-H1 by sVE-cadherinEC1-5 is also attenuated by AKB9778. In addition to these studies, the constructs EC1-4 and EC3-5 were cloned into different vectors to determine wheth-er the extracellular domain 5 of VE-cadherin plays the dominant role in sVE-cadherin-mediated effects. In summary, these studies show for the first time that sVE-cadherinEC1-5 actively con-tributes to breakdown of the endothelial barrier independently of proinflammatory stim-uli via activation of the VE-PTP/RhoA signaling pathway. This represents a new patho-physiological mechanism that adds to the understanding of inflammation-induced endo-thelial barrier changes. KW - Endothel KW - Sepsis KW - Cadherine KW - Proteintyrosinphosphatase KW - Rho-Kinasen KW - VE-Cadherin KW - VE-PTP KW - RhoA KW - ve-cadherin Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-344687 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Kleefeldt, Florian A1 - Ergün, Süleyman A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Hendel, Robin A1 - Kunz, Andreas Steven A1 - Pannenbecker, Pauline A1 - Kuhl, Philipp Josef A1 - Augustin, Anne Marie A1 - Bley, Thorsten Alexander A1 - Petritsch, Bernhard A1 - Grunz, Jan-Peter T1 - Standardized assessment of vascular reconstruction kernels in photon-counting CT angiographies of the leg using a continuous extracorporeal perfusion model JF - Scientific Reports N2 - This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability. KW - experimental models of disease KW - preclinical research KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357912 VL - 13 ER - TY - THES A1 - Eichlinger, Robin T1 - Retrospektive monozentrische Analyse des Krankheitsverlaufs und Prognosefaktoren von Patient*innen mit Ileitis terminalis Crohn T1 - Retrospective monocentric analysis of disease progression and prognostic factors in patients with Crohn's ileitis terminalis N2 - Die Erkrankung MC zählt zusammen mit der Colitis Ulcerosa zu den CED. In Deutschland liegt die Prävalenz bei ca. 100-200 Personen pro 100000 Einwohner und steigt stetig. Überwiegend sind Menschen im jungen Erwachsenenalter betroffen, die fest im Berufsleben stehen. Die Erkrankung führt im Verlauf immer wieder zu Arbeitsausfällen und verursacht neben den gesundheitlichen Kosten für Medikamente und Therapie auch wirtschaftliche Ausfälle. Trotz der hohen sozioökonomischen Bedeutung und des Vorliegens gesicherter Erkenntnisse zu Risikofaktoren, anatomischen / histologischen Veränderungen, Symptomkomplexen und zahlreicher Hypothesen bezüglich der Entstehung, ist die Pathogenese nicht gänzlich verstanden. Ebenso komplex wie das Erkrankungsbild selbst ist der Prozess der Diagnosefindung. Ein Goldstandard ist nicht etabliert. Die Diagnose MC ist meist eine klinische, in Zusammenschau mit endoskopischen, histologischen, laborchemischen und radiologischen Befunden. In dieser Arbeit wurde die Versorgungsrealität der MC Erkrankten über die letzten 15 Jahre betrachtet. Es konnte ein Wandel in der chirurgischen Operations- und Anastomosentechnik gezeigt werden. Die Zukunft ist eine minimalinvasive und darmsparende Chirurgie. Im retrospektiven Vergleich der Therapiealgorithmen erfolgte nach damaliger S3-Leitlinie in der Mehrzahl der MC Fälle initial eine medikamentöse Therapie, alle untersuchten Fälle erhielten jedoch eine ICR. In der Subgruppenanalyse wurden Fälle mit isolierter Ileitis terminalis Crohn untersucht. Es konnte die Effektivität der chirurgischen Primärtherapie gegenüber einer medikamentösen Primärtherapie gezeigt werden, was die Daten der aktuellen Literatur stützt. So bestand ein Vorteil hinsichtlich des verringerten Bedarfs an einer medikamentösen Therapie im postoperativen Verlauf von zwei Jahren und bezüglich der rezidiv- und medikamentenfreien Zeit. Die Ergebnisse zeigten zudem, dass eine präventive, postoperative medikamentöse Therapie bei präoperativ vorliegenden Risikofaktoren für ein klinisches Rezidiv nicht zwingend notwendig ist und überdacht werden sollte. Diese Arbeit konnte den Stellenwert der Chirurgie als wichtige Säule der Therapie bei isolierter Ileitis terminalis Crohn untermauern. N2 - Together with ulcerative colitis, MC is a type of IBD. In Germany, the prevalence is around 100-200 people per 100,000 inhabitants and is rising steadily. It predominantly affects people in young adulthood who are firmly established in working life. As the disease progresses, it repeatedly leads to absences from work and causes economic losses in addition to the health costs for medication and therapy. Despite the high socio-economic significance and the availability of reliable findings on risk factors, anatomical/histological changes, symptom complexes and numerous hypotheses regarding the development, the pathogenesis is not fully understood. The process of diagnosis is just as complex as the clinical picture itself. A gold standard has not been established. The diagnosis of MC is usually a clinical one, in conjunction with endoscopic, histological, laboratory and radiological findings. In this study, the reality of care for MC patients over the last 15 years was analysed. A change in surgical operation and anastomosis techniques was demonstrated. The future is minimally invasive and bowel-sparing surgery. In a retrospective comparison of treatment algorithms, the majority of MC cases were initially treated with medication in accordance with the S3 guideline at the time, but all cases analysed received ICR. In the subgroup analysis, cases with isolated Ileitis terminalis Crohn were analysed. The effectiveness of primary surgical therapy compared to primary drug therapy was demonstrated, which supports the data in the current literature. There was an advantage with regard to the reduced need for drug therapy in the postoperative course of two years and with regard to the relapse-free and drug-free period. The results also showed that preventive, postoperative drug therapy is not absolutely necessary in the presence of preoperative risk factors for clinical recurrence and should be reconsidered. This study was able to confirm the importance of surgery as an important pillar of treatment for isolated Crohn's ileitis terminalis. KW - Crohn-Krankheit KW - Chronische Darmentzündung KW - Ileozökalresektion KW - Crohn's disease KW - Morbus Crohn KW - Ileitis terminalis Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352555 ER - TY - JOUR A1 - Baur, Johannes A1 - Ramser, Michaela A1 - Keller, Nicola A1 - Muysoms, Filip A1 - Dörfer, Jörg A1 - Wiegering, Armin A1 - Eisner, Lukas A1 - Dietz, Ulrich A. T1 - Robotische Hernienchirurgie II: Robotische primär ventrale und inzisionale Hernienversorgung (rv-TAPP und r-Rives/r-TARUP). Videobeitrag und Ergebnisse einer Kohortenstudie an 118 Patienten JF - Der Chirurg N2 - Die endoskopische Versorgung von Umbilikal- und Inzisionalhernien hat sich in den vergangenen 30 Jahren an die Limitationen der konventionellen laparoskopischen Instrumente angepasst. Dazu gehört die Entwicklung von Netzen für die intraperitoneale Lage (intraperitoneales Onlay-Mesh, IPOM) mit antiadhäsiven Beschichtungen; allerdings kommt es bei einem beträchtlichen Teil dieser Patienten doch zu Adhäsionen. Minimal-invasive Verfahren führen zu weniger perioperativen Komplikationen, bei einer etwas höheren Rezidivrate. Mit den ergonomischen Ressourcen der Robotik, die abgewinkelte Instrumente anbietet, besteht erstmals die Möglichkeit, Netze minimal-invasiv in unterschiedliche Bauchdeckenschichten zu implantieren und gleichzeitig eine morphologische und funktionelle Rekonstruktion der Bauchdecke zu erreichen. In diesem Videobeitrag wird die Versorgung von Ventral- und Inzisionalhernien mit Netzimplantation in den präperitonealen Raum (robotische ventrale transabdominelle präperitoneale Patchplastik, rv-TAPP) sowie in den retrorektalen Raum (r-Rives bzw. robotische transabdominelle retromuskuläre umbilikale Patchplastik [r-TARUP]) präsentiert. Es werden die Ergebnisse einer Kohortenstudie an 118 konsekutiven Patienten vorgestellt und im Hinblick auf den Mehrwert der robotischen Technik in der Extraperitonealisierung der Netze und in der Weiterbildung diskutiert. KW - retrorektus Netz KW - Umbilikalhernie KW - Inzisionalhernie KW - primär ventrale Hernie KW - minimalinvasiv KW - linea alba Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264912 VL - 92 IS - 9 ER - TY - JOUR A1 - Jurowich, Christian A1 - Lichthardt, Sven A1 - Kastner, Caroline A1 - Haubitz, Imme A1 - Prock, Andre A1 - Filser, Jörg A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Laparoscopic versus open right hemicolectomy in colon carcinoma: A propensity score analysis of the DGAV StuDoQ|ColonCancer registry JF - PLoS ONE N2 - Objective To assess whether laparoscopy has any advantages over open resection for right-sided colon cancer. Summary background data Right hemicolectomy can be performed using either a conventional open or a minimally invasive laparoscopic technique. It is not clear whether these different access routes differ with regard to short-term postoperative outcomes. Methods Patients documented in the German Society for General and Visceral Surgery StuDoQ|ColonCancer registry who underwent right hemicolectomy were analyzed regarding early postoperative complications according to Clavien-Dindo (primary endpoint), operation (OP) time, length of postoperative hospital stay (LOS), MTL30 and number of lymph nodes retrieved (secondary endpoints). Results A total of 4.997 patients were identified as undergoing oncological right hemicolectomy without additional interventions. Of these, 4.062 (81.3%) underwent open, 935 (18.7%) laparoscopic surgery. Propensity score analysis showed a significantly shorter LOS (OR: 0.55 CI 95%0.47-.64) and a significantly longer OP time (OR2.32 CI 1.98–2.71) for the laparoscopic route. Risk factors for postoperative complications, anastomotic insufficiency, ileus, reoperation and positive MTL30 were higher ASA status, higher age and increasing BMI. The surgical access route (open / lap) had no influence on these factors, but the laparoscopic group did have markedly fewer lymph nodes retrieved. Conclusion The present registry-based analysis could detect no relevant advantages for the minimally invasive laparoscopic access route. Further oncological analyses are needed to clarify the extent to which the smaller lymph node harvest in the laparoscopic group is accompanied by a poorer oncological outcome. KW - Laparoscopy KW - Lymph nodes KW - Minimally invasive surgery KW - Surgical oncology KW - Oncology KW - Surgical and invasive medical procedures Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202184 VL - 14 IS - 6 ER - TY - JOUR A1 - Bankoglu, Ezgi Eyluel A1 - Stipp, Franzisca A1 - Gerber, Johanna A1 - Seyfried, Florian A1 - Heidland, August A1 - Bahner, Udo A1 - Stopper, Helga T1 - Effect of cryopreservation on DNA damage and DNA repair activity in human blood samples in the comet assay JF - Archives of Toxicology N2 - The comet assay is a commonly used method to determine DNA damage and repair activity in many types of samples. In recent years, the use of the comet assay in human biomonitoring became highly attractive due to its various modified versions, which may be useful to determine individual susceptibility in blood samples. However, in human biomonitoring studies, working with large sample numbers that are acquired over an extended time period requires some additional considerations. One of the most important issues is the storage of samples and its effect on the outcome of the comet assay. Another important question is the suitability of different blood preparations. In this study, we analysed the effect of cryopreservation on DNA damage and repair activity in human blood samples. In addition, we investigated the suitability of different blood preparations. The alkaline and FPG as well as two different types of repair comet assay and an in vitro hydrogen peroxide challenge were applied. Our results confirmed that cryopreserved blood preparations are suitable for investigating DNA damage in the alkaline and FPG comet assay in whole blood, buffy coat and PBMCs. Ex vivo hydrogen peroxide challenge yielded its optimal effect in isolated PBMCs. The utilised repair comet assay with either UVC or hydrogen peroxide-induced lesions and an aphidicolin block worked well in fresh PBMCs. Cryopreserved PBMCs could not be used immediately after thawing. However, a 16-h recovery with or without mitotic stimulation enabled the application of the repair comet assay, albeit only in a surviving cell fraction. KW - human biomonitoring KW - DNA damage KW - DNA repair KW - comet assay KW - blood samples Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265326 VL - 95 IS - 5 ER - TY - JOUR A1 - Silwedel, Christine A1 - Speer, Christian P. A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Schlegel, Nicolas A1 - Glaser, Kirsten T1 - Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells JF - International Journal of Molecular Science N2 - Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation. KW - Ureaplasma urealyticum KW - Ureaplasma parvum KW - neuroinflammation KW - meningitis KW - blood–brain barrier KW - HBMEC Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201848 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Dischinger, Ulrich A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Corteville, Carolin A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Hankir, Mohamed A1 - Seyfried, Florian Johannes David T1 - Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats JF - Frontiers in Endocrinology N2 - Background Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. Methods High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. Results RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. Conclusions Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB. KW - obesity KW - rygb KW - liraglutide KW - peptide tyrosine tyrosine (PYY) KW - treatment KW - gastric bypass KW - peptide tyrosine tyrosine 3-36 (PYY3-36) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223113 SN - 1664-2392 VL - 11 ER - TY - JOUR A1 - Lehmann, Kai S. A1 - Klinger, Carsten A1 - Diers, Johannes A1 - Buhr, Heinz-Johannes A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Safety of anastomoses in colorectal cancer surgery in octogenarians: a prospective cohort study with propensity score matching JF - BJS Open N2 - Background Up to 20 per cent of all operations for patients with colorectal cancer (CRC) are performed in octogenarians. Anastomotic leakage is a leading cause of morbidity and death after resection for CRC. The aim of this study was to assess the rate of anastomosis creation, the risk of anastomotic leakage and death in surgery for left-sided CRC in elderly patients. Methods This prospective cohort study compared patients less than 80 and 80 or more years with left-sided CRC resection performed between 2013 and 2019. Data were provided from a risk-adjusted surgical quality-assessment system with 219 participating centres in Germany. Outcome measures were the rate of anastomoses, anastomotic leakages, death at 30 days and 2-year overall survival (OS). Propensity score matching was used to control for selection bias and compare subgroups of patients of less than 80 and 80 or more years. Results Out of 18 959 patients, some 3169 (16.7 per cent) were octogenarians. Octogenarians were less likely to receive anastomoses (82.0 versus 92.9 per cent, P < 0.001; odds ratio 0.50 (95 per cent c.i. 0.44 to 0.58), P < 0.001). The rate of anastomotic leakages did not differ between age groups (8.6 versus 9.7 per cent, P = 0.084), but 30-day mortality rate after leakage was significantly higher in octogenarians (15.8 versus 3.5 per cent, P < 0.001). Overall, anastomotic leakage was the strongest predictor for death (odds ratio 4.95 (95 per cent c.i. 3.66 to 6.66), P < 0.001). In the subgroup with no leakage, octogenarians had a lower 2-year OS rate than younger patients (71 versus 87 per cent, P < 0.001), and in the population with anastomotic leakage, the 2-year OS was 80 per cent in younger and 43 per cent in elderly patients (P < 0.001). After propensity score matching, older age remained predictive for not receiving an anastomosis (odds ratio 0.54 (95 per cent c.i. 0.46 to 0.63), P < 0.001) and for death (odds ratio 2.60 (95 per cent c.i. 1.78 to 3.84), P < 0.001), but not for the occurrence of leakages (odds ratio 0.94 (95 per cent c.i. 0.76 to 1.15), P = 0.524). Conclusion Anastomotic leakage is not more common in octogenarians, but an age of 80 years or older is an independent factor for not receiving an anastomosis in surgery for left-sided CRC. The mortality rate in the case of leakage in octogenarians was reported to exceed 15 per cent. KW - colorectal cancer KW - anastomosis KW - surgical KW - prospective studies KW - surgical procedures KW - operative KW - mortality KW - older adult KW - octogenarians Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265044 VL - 5 IS - 6 ER - TY - JOUR A1 - Wiegering, Armin A1 - Matthes, Niels A1 - Mühling, Bettina A1 - Koospal, Monika A1 - Quenzer, Anne A1 - Peter, Stephanie A1 - Germer, Christoph-Thomas A1 - Linnebacher, Michael A1 - Otto, Christoph T1 - Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin JF - Neoplasia N2 - Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC\(_{50}\)< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents. KW - colorectal carcinoma KW - reactivating p53 and inducing tumor apoptosis (RITA) KW - chemotherapy KW - 5-fluorouracil KW - oxaliplatin Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171067 VL - 19 IS - 4 ER - TY - JOUR A1 - Matthes, Niels A1 - Diers, Johannes A1 - Schlegel, Nicolas A1 - Hankir, Mohammed A1 - Haubitz, Imme A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Validation of MTL30 as a quality indicator for colorectal surgery JF - PLoS One N2 - Background Valid indicators are required to measure surgical quality. These ideally should be sensitive and selective while being easy to understand and adjust. We propose here the MTL30 quality indicator which takes into account 30-day mortality, transfer within 30 days, and a length of stay of 30 days as composite markers of an uneventful operative/postoperative course. Methods Patients documented in the StuDoQ|Colon and StuDoQ|Rectal carcinoma register of the German Society for General and Visceral Surgery (DGAV) were analyzed with regard to the effects of patient and tumor-related risk factors as well as postoperative complications on the MTL30. Results In univariate analysis, the MTL30 correlated significantly with patient and tumor-related risk factors such as ASA score (p<0.001), age (p<0.001), or UICC stage (p<0.001). There was a high sensitivity for the postoperative occurrence of complications such as re-operations (p<0.001) or subsequent bleeding (p<0.001), as well as a significant correlation with the CDC classification (p<0.001). In multivariate analysis, patient-related risk factors and postoperative complications significantly increased the odds ratio for a positive MTL30. A negative MTL30 showed a high specify for an uneventful operative and postoperative course. Conclusion The MTL30 is a valid indicator of colorectal surgical quality. KW - surgical care KW - discharge definition KW - definition KW - mortality KW - pancreatectomy KW - complications KW - superior KW - capture Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230530 VL - 15 IS - 8 ER - TY - JOUR A1 - Lock, J. F. A1 - Ungeheuer, L. A1 - Borst, P. A1 - Swol, J. A1 - Löb, S. A1 - Brede, E. M. A1 - Röder, D. A1 - Lengenfelder, B. A1 - Sauer, K. A1 - Gremer, C. - T. T1 - Markedly increased risk of postoperative bleeding complications during perioperative bridging anticoagulation in general and visceral surgery JF - Perioperative Medicine N2 - Background Increasing numbers of patients receiving oral anticoagulants are undergoing elective surgery. Low molecular weight heparin (LMWH) is frequently applied as bridging therapy during perioperative interruption of anticoagulation. The aim of this study was to explore the postoperative bleeding risk of patients receiving surgery under bridging anticoagulation. Methods We performed a monocentric retrospective two-arm matched cohort study. Patients that received perioperative bridging anticoagulation were compared to a matched control group with identical surgical procedure, age, and sex. Emergency and vascular operations were excluded. The primary endpoint was the incidence of major postoperative bleeding. Secondary endpoints were minor postoperative bleeding, thromboembolic events, length of stay, and in-hospital mortality. Multivariate analysis explored risk factors of major postoperative bleeding. Results A total of 263 patients in each study arm were analyzed. The patient cohort included the entire field of general and visceral surgery including a large proportion of major oncological resections. Bridging anticoagulation increased the postoperative incidence of major bleeding events (8% vs. 1%; p < 0.001) as well as minor bleeding events (14% vs. 5%; p < 0.001). Thromboembolic events were equally rare in both groups (1% vs. 2%; p = 0.45). No effect on mortality was observed (1.5% vs. 1.9%). Independent risk factors of major postoperative bleeding were full-therapeutic dose of LMWH, renal insufficiency, and the procedure-specific bleeding risk. Conclusion Perioperative bridging anticoagulation, especially full-therapeutic dose LMWH, markedly increases the risk of postoperative bleeding complications in general and visceral surgery. Surgeons should carefully consider the practice of routine bridging. KW - low molecular heparin KW - atrial fibrillation KW - postoperative bleeding KW - thromboembolism KW - anticoagulation KW - bridging KW - antithrombotic therapy KW - warfarin interruption KW - oral anticoagulants KW - management Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230690 VL - 9 ER - TY - JOUR A1 - Diers, J. A1 - Wagner, J. A1 - Baum, P. A1 - Lichthardt, S. A1 - Kastner, C. A1 - Matthes, N. A1 - Löb, S. A1 - Matthes, H. A1 - Germer, C.-T. A1 - Wiegering, A. T1 - Nationwide in-hospital mortality following colonic cancer resection according to hospital volume in Germany JF - BJS Open N2 - Background: Colonic cancer is the most common cancer of the gastrointestinal tract. The aim of this study was to determine mortality rates following colonic cancer resection and the effect of hospital caseload on in-hospital mortality in Germany. Methods: Patients admitted with a diagnosis of colonic cancer undergoing colonic resection from 2012 to 2015 were identifed from a nationwide registry using procedure codes. The outcome measure was in-hospital mortality. Hospitals were ranked according to their caseload for colonic cancer resection, and patients were categorized into five subgroups on the basis of hospital volume. Results: Some 129 196 colonic cancer resections were reviewed. The overall in-house mortality rate was 5⋅8 per cent, ranging from 6⋅9 per cent (1775 of 25 657 patients) in very low-volume hospitals to 4⋅8 per cent (1239 of 25 825) in very high-volume centres (P < 0⋅001). In multivariable logistic regression analysis the risk-adjusted odds ratio for in-house mortality was 0⋅75 (95 per cent c.i. 0⋅66 to 0⋅84) in very high-volume hospitals performing a mean of 85⋅0 interventions per year, compared with that in very low-volume hospitals performing a mean of only 12⋅7 interventions annually, after adjustment for sex, age, co-morbidity, emergency procedures, prolonged mechanical ventilation and transfusion. Conclusion: In Germany, patients undergoing colonic cancer resections in high-volume hospitals had with improved outcomes compared with patients treated in low-volume hospitals Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204385 VL - 3 IS - 5 ER - TY - JOUR A1 - Schatton, Tobias A1 - Yang, Jun A1 - Kleffel, Sonja A1 - Uehara, Mayuko A1 - Barthel, Steven R. A1 - Schlapbach, Christoph A1 - Zhan, Qian A1 - Dudeney, Stephen A1 - Mueller, Hansgeorg A1 - Lee, Nayoung A1 - de Vries, Juliane C. A1 - Meier, Barbara A1 - Beken, Seppe Vander A1 - Kluth, Mark A. A1 - Ganss, Christoph A1 - Sharpe, Arlene H. A1 - Waaga-Gasser, Ana Maria A1 - Sayegh, Mohamed H. A1 - Abdi, Reza A1 - Scharffetter-Kochanek, Karin A1 - Murphy, George F. A1 - Kupper, Thomas S. A1 - Frank, Natasha Y. A1 - Frank, Markus H. T1 - ABCB5 Identifies Immunoregulatory Dermal Cells JF - Cell Reports N2 - Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5\(^+\) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5\(^+\) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy. KW - mesenchymal stem cells KW - P-glycoprotein KW - regulatory T cells KW - maintain immune homeostasis KW - malignant melanoma KW - in vivo KW - skin KW - generation KW - transplant KW - tolerance Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149989 VL - 12 SP - 1564 EP - 1574 ER - TY - JOUR A1 - Müller, Sophie A1 - Köhler, Franziska A1 - Hendricks, Anne A1 - Kastner, Carolin A1 - Börner, Kevin A1 - Diers, Johannes A1 - Lock, Johan F. A1 - Petritsch, Bernhard A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Brain metastases from colorectal cancer: a systematic review of the literature and meta-analysis to establish a guideline for daily treatment JF - Cancers N2 - Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words “brain”, “metastas*”, “tumor”, “colorectal”, “cancer”, and “malignancy”. In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment. KW - brain metastases KW - cerebral metastases KW - BM KW - colorectal cancer KW - CRC KW - systematic review KW - meta-analysis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228883 SN - 2072-6694 VL - 13 IS - 4 ER - TY - JOUR A1 - Nietzer, Sarah A1 - Baur, Florentin A1 - Sieber, Stefan A1 - Hansmann, Jan A1 - Schwarz, Thomas A1 - Stoffer, Carolin A1 - Häfner, Heide A1 - Gasser, Martin A1 - Waaga-Gasser, Ana Maria A1 - Walles, Heike A1 - Dandekar, Gudrun T1 - Mimicking metastases including tumor stroma: a new technique to generate a three-dimensional colorectal cancer model based on a biological decellularized intestinal scaffold JF - Tissue Engineering Part C-Methods N2 - Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of beta-catenin in a subset of cells. One central drawback of 2D cultures-especially in consideration of drug testing-is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue generation, a bioreactor was constructed for dynamic culture approaches. This induced a close tissue-like association of cultured tumor cells with fibroblasts reflecting tumor biopsies. Therapy with 5-fluorouracil (5-FU) was effective only in 3D coculture. In conclusion, our 3D tumor model reflects human tissue-related tumor characteristics, including lower tumor cell proliferation. It is now available for drug testing in metastatic context-especially for substances targeting tumor-stroma interactions. KW - Multicenter randomized-trial KW - Carcinoma cells KW - Tissue KW - Fluorouracil KW - Matrix KW - 1st-line treatment KW - Beta-catenin KW - Invasion KW - 5-Fluorouracil KW - Fibroblasts Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188202 VL - 22 IS - 7 ER - TY - JOUR A1 - Ramser, Michaela A1 - Baur, Johannes A1 - Keller, Nicola A1 - Kukleta, Jan F. A1 - Dörfer, Jörg A1 - Wiegering, Armin A1 - Eisner, Lukas A1 - Dietz, Ulrich A. T1 - Robotische Hernienchirurgie I: Robotische Leistenhernienversorgung (r‑TAPP). Videobeitrag und Ergebnisse einer Kohortenstudie an 302 operierten Hernien JF - Der Chirurg N2 - Die Versorgung von Leistenhernien mit offenen und minimal-invasiven Verfahren hat in den vergangenen 30 Jahren einen vom Ergebnis her gesehen hohen Standard erreicht. Allerdings besteht noch Bedarf an einer weiteren Reduktion der postoperativen Serome, chronischen Schmerzen und des Rezidivs. In diesem Videobeitrag wird die endoskopische Anatomie der Leiste im Hinblick auf die robotische transabdominelle präperitoneale Patchplastik (r‑TAPP) dargestellt und die Operationsschritte der r‑TAPP als Video illustriert. Es werden die Ergebnisse einer Kohortenstudie an 302 konsekutiven Hernien, die mittels r‑TAPP operiert wurden, vorgestellt und hinsichtlich des Mehrwerts der robotischen Technik – auch in der Weiterbildung – diskutiert. Die r‑TAPP ist die natürliche Weiterentwicklung der konventionellen TAPP und hat das Potenzial, bei zunehmender Geräteverfügbarkeit und Reduktion der Materialkosten zu einem neuen Standard zu werden. Künftige Studien werden den vielseitigen Mehrwert der r‑TAPP auch mit neuen Parametern verfeinern müssen. KW - robotische Leistenhernienversorgung KW - r-TAPP Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264883 VL - 92 IS - 8 ER - TY - JOUR A1 - Anger, Friedrich A1 - Döring, Anna A1 - van Dam, Jacob A1 - Lock, Johann Frisco A1 - Klein, Ingo A1 - Bittrich, Max A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin A1 - Kunzmann, Volker A1 - van Eijck, Casper A1 - Löb, Stefan T1 - Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria JF - Annals of Surgical Oncology N2 - Background International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods Patients’ tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed. Results A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort did not contain BR-C patients. No differences in postoperative complications were detected. Median OS was significantly shorter in BR-A (15 months) and BR-B (12 months) compared with R (20 months) patients (BR-A vs. R: p = 0.09 and BR-B vs. R: p < 0.001). CA19-9, as the determining factor of BR-B patients, turned out to be an independent prognostic risk factor for OS. Conclusions Preoperative staging defining surgical resectability in PDAC according to ICC is crucial for patient survival. Patients with PDAC BR-B should be considered for multimodal neoadjuvant therapy even if considered anatomically resectable. KW - pancreatic head cancer Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235251 SN - 1068-9265 VL - 28 IS - 4 ER -