@article{KollmannBuerkertMeiretal.2023, author = {Kollmann, Catherine and Buerkert, Hannah and Meir, Michael and Richter, Konstantin and Kretzschmar, Kai and Flemming, Sven and Kelm, Matthias and Germer, Christoph-Thomas and Otto, Christoph and Burkard, Natalie and Schlegel, Nicolas}, title = {Human organoids are superior to cell culture models for intestinal barrier research}, series = {Frontiers in Cell and Developmental Biology}, volume = {11}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2023.1223032}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357317}, year = {2023}, abstract = {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.}, language = {en} } @article{DoehlerRoederSchlesingeretal.2023, author = {D{\"o}hler, Ida and R{\"o}der, Daniel and Schlesinger, Tobias and Nassen, Christian Alexander and Germer, Christoph-Thomas and Wiegering, Armin and Lock, Johan Friso}, title = {Risk-adjusted perioperative bridging anticoagulation reduces bleeding complications without increasing thromboembolic events in general and visceral surgery}, series = {BMC Anesthesiology}, volume = {23}, journal = {BMC Anesthesiology}, doi = {10.1186/s12871-023-02017-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357305}, year = {2023}, abstract = {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.}, language = {en} } @article{LenschowWennmannHendricksetal.2022, author = {Lenschow, Christina and Wennmann, Andreas and Hendricks, Anne and Germer, Christoph-Thomas and Fassnacht, Martin and Buck, Andreas and Werner, Rudolf A. and Plassmeier, Lars and Schlegel, Nicolas}, title = {Questionable value of [\(^{99m}\)Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {8}, doi = {10.1007/s00423-022-02648-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323926}, pages = {3661-3669}, year = {2022}, abstract = {Purpose A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. Methods A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. Results From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71\% were female. Neck ultrasound was carried out in 91.7\% and localized a PA in 76.6\%. In 23.4\% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4\% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4\% of patients (OR 13.23; 95\% CI 5.24-33.56). Conclusion [\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.}, language = {en} } @article{HeringDoerriesFlemmingetal.2022, author = {Hering, Ilona and D{\"o}rries, Luise and Flemming, Sven and Krietenstein, Laura and Koschker, Ann-Kathrin and Fassnacht, Martin and Germer, Christoph-Thomas and Hankir, Mohammed K. and Seyfried, Florian}, title = {Impact of preoperative weight loss achieved by gastric balloon on peri- and postoperative outcomes of bariatric surgery in super-obese patients: a retrospective matched-pair analysis}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {5}, doi = {10.1007/s00423-022-02472-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323909}, pages = {1873-1879}, year = {2022}, abstract = {Background An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied. Methods In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls. Results Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0\% vs. 32.2\%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53\% vs 23.78 ± 9.89\% after 1 year, p < 0.05 and 32.13 ± 10.5\% vs 22.21 ± 10.9\% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up. Conclusion A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients' expectations.}, language = {en} } @article{ReimerSeyfriedFlemmingetal.2022, author = {Reimer, Stanislaus and Seyfried, Florian and Flemming, Sven and Brand, Markus and Weich, Alexander and Widder, Anna and Plaßmeier, Lars and Kraus, Peter and D{\"o}ring, Anna and Hering, Ilona and Hankir, Mohammed K. and Meining, Alexander and Germer, Christoph-Thomas and Lock, Johan F. and Groneberg, Kaja}, title = {Evolution of endoscopic vacuum therapy for upper gastrointestinal leakage over a 10-year period: a quality improvement study}, series = {Surgical Endoscopy}, volume = {36}, journal = {Surgical Endoscopy}, number = {12}, doi = {10.1007/s00464-022-09400-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323953}, pages = {9169-9178}, year = {2022}, abstract = {Background Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients' outcome. Methods All patients treated by EVT at our center during 2012-2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge. Results A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0\% (P = .006). EVT efficacy increased from 80 to 91\% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9\% (P = .013) and reoperations became less frequent (38.0\% vs.15.6\%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9\% vs. 84.4\%, P = .043). Conclusions Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome.}, language = {en} } @article{ReibetanzKelmUttingeretal.2022, author = {Reibetanz, Joachim and Kelm, Matthias and Uttinger, Konstantin L. and Reuter, Miriam and Schlegel, Nicolas and Hankir, Mohamed and Wiegering, Verena and Germer, Christoph-Thomas and Fassnacht, Martin and Lock, Johan Friso and Wiegering, Armin}, title = {Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {6}, doi = {10.1007/s00423-022-02568-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323947}, pages = {2481-2488}, year = {2022}, abstract = {Purpose In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. Methods We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. Results Of 83 patients with adrenalectomy for hypercortisolism (65.1\% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2\%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7\% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0\% vs. 33\%; p < 0.001) and delayed recovery (median: 10.2\% vs. 79.2\%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2\% vs. 25.0\% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0\% vs. 8.3\%; p = 0.081). Conclusion While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10\%.}, language = {en} } @article{KoehlerReeseHendricksetal.2022, author = {K{\"o}hler, Franziska and Reese, Lena and Hendricks, Anne and Kastner, Carolin and M{\"u}ller, Sophie and Lock, Johan F. and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Low-grade mucinous neoplasms (LAMN) of the appendix in Germany between 2011 and 2018: a nationwide analysis based on data provided by the German Center for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI)}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {8}, doi = {10.1007/s00423-022-02639-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323919}, pages = {3615-3622}, year = {2022}, abstract = {Introduction Low-grade appendiceal mucinous neoplasms (LAMN) are semi-malignant tumors of the appendix which are incidentally found in up to 1\% of appendectomy specimen. To this day, no valid descriptive analysis on LAMN is available for the German population. Methods Data of LAMN (ICD-10: D37.3) were collected from the population-based cancer registries in Germany, provided by the German Center for Cancer Registry Data (Zentrum f{\"u}r Krebsregisterdaten—ZfKD). Data was anonymized and included gender, age at diagnosis, tumor staging according to the TNM-classification, state of residence, information on the performed therapy, and survival data. Results A total of 612 cases were reported to the ZfKD between 2011 and 2018. A total of 63.07\% were female and 36.93\% were male. Great inhomogeneity in reporting cases was seen in the federal states of Germany including the fact that some federal states did not report any cases at all. Age distribution showed a mean age of 62.03 years (SD 16.15) at diagnosis. However, data on tumor stage was only available in 24.86\% of cases (n = 152). A total of 49.34\% of these patients presented with a T4-stage. Likewise, information regarding performed therapy was available in the minority of patients: 269 patients received surgery, 22 did not and for 312 cases no information was available. Twenty-four patients received chemotherapy, 188 did not, and for 400 cases, no information was available. Overall 5-year survival was estimated at 79.52\%. Patients below the age of 55 years at time of diagnosis had a significantly higher 5-year survival rate compared to patients above the age of 55 years (85.77\% vs. 73.27\%). Discussion In this study, we observed an incidence of LAMN in 0.13\% of all appendectomy specimen in 2018. It seems likely that not all cases were reported to the ZfKD; therefore, case numbers may be considered underestimated. Age and gender distribution goes in line with international studies with females being predominantly affected. Especially regarding tumor stage and therapy in depth information cannot be provided through the ZfKD-database. This data analysis emphasizes the need for further studies and the need for setting up a specialized registry for this unique tumor entity to develop guidelines for the appropriate treatment and follow-up.}, language = {en} } @article{AngerLockKleinetal.2022, author = {Anger, Friedrich and Lock, Johan Friso and Klein, Ingo and Hartlapp, Ingo and Wiegering, Armin and Germer, Christoph-Thomas and Kunzmann, Volker and L{\"o}b, Stefan}, title = {Does concurrent cholestasis alter the prognostic value of preoperatively elevated CA19-9 serum levels in patients with pancreatic head adenocarcinoma?}, series = {Annals of Surgical Oncology}, volume = {29}, journal = {Annals of Surgical Oncology}, number = {13}, doi = {10.1245/s10434-022-12460-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323854}, pages = {8523-8533}, year = {2022}, abstract = {Background Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. Methods Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. Results Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 \%) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 \% of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. Conclusions In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.}, language = {en} } @article{KelmKusanSuratetal.2022, author = {Kelm, Matthias and Kusan, Simon and Surat, G{\"u}zin and Anger, Friedrich and Reibetanz, Joachim and Germer, Christoph-Thomas and Schlegel, Nicolas and Flemming, Sven}, title = {Disease- and medication-specific differences of the microbial spectrum in perianal fistulizing Crohn's Disease — relevant aspects for antibiotic therapy}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {11}, issn = {2227-9059}, doi = {10.3390/biomedicines10112682}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290281}, year = {2022}, abstract = {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.}, language = {en} } @article{SuratMeyerSautterRueschetal.2022, author = {Surat, G{\"u}zin and Meyer-Sautter, Pascal and R{\"u}sch, Jan and Braun-Feldweg, Johannes and Markus, Christian Karl and Germer, Christoph-Thomas and Lock, Johan Friso}, title = {Cefazolin might be adequate for perioperative antibiotic prophylaxis in intra-abdominal infections without sepsis: a quality improvement study}, series = {Antibiotics}, volume = {11}, journal = {Antibiotics}, number = {4}, issn = {2079-6382}, doi = {10.3390/antibiotics11040501}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270816}, year = {2022}, abstract = {Background: The adequate choice of perioperative antibiotic prophylaxis (PAP) could influence the risk of surgical site infections (SSIs) in general surgery. A new local PAP guideline was implemented in May 2017 and set the first-generation cefazolin (CFZ) instead the second-generation cefuroxime (CXM) as the new standard prophylactic antibiotic. The aim of this study was to compare the risk of SSIs after this implementation in intra-abdominal infections (IAIs) without sepsis. Methods: We performed a single center-quality improvement study at a 1500 bed sized university hospital in Germany analyzing patients after emergency surgery during 2016 to 2019 (n = 985), of which patients receiving CXM or CFZ were selected (n = 587). Propensity score matching was performed to ensure a comparable risk of SSIs in both groups. None-inferiority margin for SSIs was defined as 8\% vs. 4\%. Results: Two matched cohorts with respectively 196 patients were compared. The rate of SSIs was higher in the CFZ group (7.1\% vs. 3.6\%, p = 0.117) below the non-inferiority margin. The rate of other postoperative infections was significantly higher in the CFZ group (2.0\% vs. 8.7\%, p = 0.004). No other differences including postoperative morbidity, mortality or length-of-stay were observed. Conclusion: Perioperative antibiotic prophylaxis might be safely maintained by CFZ even in the treatment of intra-abdominal infections.}, language = {en} }