Impact of acoustic radiation force impulse imaging in clinical practice of patients after orthotopic liver transplantation - Wildner, Dane; Strobel, Deike; Konturek, Peter C.; Görtz, Rüdiger; Croner, Roland S.; Neurath, Markus; Zopf, Steffen (Medical Science Monitor, 2014)
Acoustic radiation force impulse (ARFI) elastography is a reliable diagnostic device for quantitative non-invasive assessment of liver fibrosis in patients with chronic liver disease. The aim of our prospective study was to evaluate the impact of ARFI in patients after orthotopic liver transplantation (OLT). Therefore, we compared ARFI shear wave velocities with clinical features, non-invasive markers, and the histology of patients following OLT.Post-transplant patients underwent a clinical examination and blood samples were taken. B-mode and Doppler ultrasound (US) of the portal vein and the hepatic artery were performed. Subsequently, a minimum of 10 valid ARFI values were measured in the left and right liver lobe. Liver biopsy was performed if indicated.Between May 2012 and May 2014, 58 Patients after OLT were included in the prospective study. Laboratory markers and aspartate aminotransferase-to-platelet ratio index (APRI) correlated with ARFI values (r=0.44, p<0.001). The histological (n=22) fibrosis score (Ludwig) was significantly correlated with the ARFI of the biopsy site (r=0.55, p=0.008). The mean shear-wave velocities were significantly increased in advanced fibrosis (F<=2 1.57±0.57 m/s; F>=3 2.85±0.66 m/s; p<0.001), obstructive cholestasis and active viral hepatitis. The area under the receiver operating characteristic (AUROC) curves for the accuracy of ARFI were 74% (F>=1), 73% (F>=2), 93% (F>=3), and 80% (=F4).ARFI elastography correlates well with laboratory values and with noninvasive and invasive markers of fibrosis in patients after OLT. In this regard, elevated ARFI-velocities should be interpreted with caution in the context of obstructive cholestasis and active viral disease.
EVALuna2:1855

Impact of a digital surgical workflow including Digital Device Briefing Tool on morbidity and mortality in a patient population undergoing primary stapled colorectal anastomosis for benign or malignant colorectal disease: protocol for a multicentre prospective cohort study - Lauscher, Johannes; Beyer, Katharina; Hellinger, Achim; Croner, Roland S.; Ridwelski, Karsten; Krautz, Christian; Lim, Christine; Coplan, Paul M.; Kurepkat, Marc; Ribaric, Goran (BMJ Open, 2023)
INTRODUCTION: With growing emphasis on surgical safety, it appears fundamental to assess the safety of colorectal resection involving primary stapled anastomosis. Surgical stapling devices can considerably foster patient safety in colorectal surgery, but their misuse or malfunction encompass a unique risk of postoperative complications. The Digital Device Briefing Tool (DDBT) is a digital cognitive aid developed to enhance safe use of the Ethicon circular stapling device during colorectal resection. The purpose of this study is to evaluate how a digital operative workflow, including DDBT, compared with routine surgical care, affects morbidity and mortality in patients undergoing left-sided colorectal resection with primary stapled colorectal anastomosis for colorectal cancer or benign disease. METHODS AND ANALYSIS: A multicentre, prospective cohort study will be conducted at five certified academic colorectal centres in Germany. It compares a non-digital with a Johnson & Johnson digital solution (Surgical Process Institute Deutschland (SPI))-guided operative workflow in patients undergoing left hemicolectomy, sigmoidectomy, anterior rectal resection and Hartmann reversal procedure. The sample size is set at 528 cases in total, divided into 3 groups (a non-digital and two SPI-guided workflow cohorts, with and without DDBT) in a ratio of 1:1:1, with 176 patients each. The primary endpoint is a composite outcome comprising the overall rate of surgical complications, including death, during hospitalisation and within the first 30 days after colorectal resection. Secondary endpoints include operating time, length of hospital stay and 30-day hospital readmission rate. ETHICS AND DISSEMINATION: This study will be performed in line with the Declaration of Helsinki. The ethics committee of the Charité-University Medicine Berlin, Germany, approved the study (No: 22-0277-EA2/060/22). Study Investigators will obtain written informed consent from each patient before a patient may participate in this study. The study results will be submitted to an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00029682.
CRIS-Team Scopus Importer:2023-04-07
Keywords: Colorectal surgery; Health & safety; Protocols & guidelines

Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial - Hofheinz, R. -D.; Arnold, D.; Fokas, E.; Kaufmann, M.; Hothorn, T.; Folprecht, G.; Fietkau, Rainer; Hohenberger, Werner; Ghadimi, M.; Liersch, T.; Grabenbauer, G. G.; Sauer, Rolf; et al. (Annals of Oncology, 2018)
Background: The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial. Patients and methods: We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3-4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60-70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis. Results: A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P < 0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged <60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P = 0.013) and systemic recurrences (P = 0.023), DFS (P = 0.011), and even overall survival (OS; P = 0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40-70 years compared with elderly patients treated with oxaliplatin. Conclusion: The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit. Clinical Trials Number: NCT00349076.
EVALuna2:36460

Impact of Aspirin Intake on Postoperative Survival after Primary Pancreatic Resection of Pancreatic Ductal Adenocarcinoma—A Single-Center Evaluation - Hackner, Danilo; Hobbs, Mirianna; Merkel, Susanne; Krautz, Christian; Weber, Georg; Grützmann, Robert; Brunner, Maximilian (Biomedicines, 2023)
(1) Background: The intake of aspirin (ASS) has been demonstrated to have a relevant impact on the pathogenesis, incidence and outcome in different solid gastrointestinal tumors. However, data on the effect of ASS on the short-term outcome and the long-term survival in patients with pancreatic carcinoma are still limited. (2) Methods: A total of 213 patients who underwent primary resection of PDAC at the University Hospital of Erlangen from January 2000 to December 2018 were included in this retrospective single-center study in total. Patients were stratified according to the aspirin intake into three groups: continuous aspirin intake (cASS), perioperatively interrupted aspirin intake (iASS) and no aspirin intake (no ASS) at the timepoint of surgery. The postoperative outcome as well as long-term survival were compared between the groups. (3) Results: There were no differences regarding postoperative morbidity (iASS: 54% vs. cASS: 53% vs. no ASS: 64%, p = 0.448) and in-hospital mortality (iASS: 4% vs. cASS: 10% vs. no ASS: 3%, p = 0.198) between the groups. The overall survival (OS) and disease-free survival (DFS) did not differ in the groups when comparing the ASS-intake status (OS: iASS 17.8 months vs. cASS 19.6 months vs. no ASS 21.6 months, p = 0.489; DFS: iASS 14.0 months vs. cASS 18.3 months vs. no ASS 14.7 months, p = 0.957). Multivariate analysis revealed that age (hazard ratio (HR) 2.2, p < 0.001), lymph node-positive status (HR 2.0, p < 0.001), R status 1 or 2 (HR 2.8, p < 0.001) and differentiation with a grading of 3 (HR 1.7, p = 0.005) were significant independent prognostic factors regarding the OS. Moreover, age (HR 1.5, p = 0.040), lymph node-positive status (HR 1.8, p = 0.002) and high-grade (G3) carcinomas (HR 1.5, p = 0.037) could be identified as independent prognostic parameters for DFS. (4) Conclusions: In patients undergoing primary surgery for curative resection of pancreatic carcinoma, the perioperative intake of ASS had no significant impact on postoperative outcome, overall and disease-free survival.
CRIS-Team Scopus Importer:2023-06-09
Keywords: aspirin intake; disease-free survival; overall survival; pancreatic ductal adenocarcinoma; pancreatic resection

Impact of collection programs for the generation of monocyte apheresis products on product quality and composition as starting material for the generation of cellular therapeutics - Pfeiffer, Hella; Gary, Regina; Mackensen, Andreas; Achenbach, Susanne; Strasser, Erwin; Aigner, Michael; Völkl, Simon (Transfusion, 2018)
BACKGROUND: With the discontinuation of the last generation of apheresis machines, new options for monocyte apheresis became available. As apheresis products play a crucial role in the generation of new cellular therapeutics (e.g., generation of dendritic cells [DCs] or precursor for T-cell experiments) we sought to compare two different collection programs for potential benefits or disadvantages due to different composition of the cellular products. STUDY DESIGN AND METHODS: Composition of discontinuously and continuously collected monocyte products from the same 13 donors was analyzed. For further evaluation as starting material for manufacturing of cellular therapeutics typically used steps such as Ficoll Isopaque, cryoconservation and monocyte isolation, with subsequent generation of mature DCs (mDCs) and assessment of T-cell function, were performed on seven of these apheresis pairs. RESULTS: Yield of total cells, monocytes, and mDCs was equal with both methods. T-cell composition did not differ significantly in content of CD3+, CD4+, and CD8+ cells. Differentiation status and cytokine production of CD8+ T cells upon stimulation with cytomegalovirus pp65 antigen was not significantly different. CONCLUSION: Both methods seem comparably suited for the generation of cellular products. If the intended use is "fresh" (without cryoconservation), continuously harvested cells show better cell numbers, while discontinuously harvested cells show better recovery after cryoconservation.
EVALuna2:34646

Impact of CRISPR/Cas9-Mediated CD73 Knockout in Pancreatic Cancer - Zhang, Jinping; Zhang, Shuman; Dörflein, Isabella; Ren, Xiaofan; Pfeffer, Sina; Britzen-Laurent, Nathalie; Grützmann, Robert; Duan, Xianglong; Pilarsky, Christian (Cancers, 2023)
Pancreatic cancer is among the cancers with the highest mortality rates. Most of the patients are found to have advanced cancer, losing the chance of surgical treatment, and there is an urgent need to find new treatment methods. Targeted therapy for specific genes that play a key role in cancer is now an important means to improve the survival rate of patients. We determined that CD73 is highly expressed in pancreatic cancer by flow cytometry and qRT-PCR assays combined with bioinformatics techniques. Application of CRISPR/Cas9 technology to knockout CD73 in human and murine cell lines, respectively, revealed that CD73 inactivation inhibited cell growth and migration and induced G1 cell cycle arrest. We also found that CD73 deletion inhibited the ERK/STAT3 pathway and activated the E-cadherin pathway. In addition, a CRISPR/Cas9 protein kinase library screen was performed and identified Pbk, Fastk, Cdk19, Adck5, Trim28, and Pfkp as possible genes regulating CD73.
CRIS-Team Scopus Importer:2023-10-20
Keywords: CD73; CRISPR/Cas9; deep sequencing; pancreatic cancer

Impact of Patient Age on Postoperative Short-Term and Long-Term Outcome after Pancreatic Resection of Pancreatic Ductal Adenocarcinoma - Hackner, Danilo; Hobbs, Mirianna; Merkel, Susanne; Siepmann, Timo; Krautz, Christian; Weber, Georg; Grützmann, Robert; Brunner, Maximilian (Cancers, 2022)
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is frequently seen in elderly patients. The aim of our retrospective study was to evaluate the impact of age on postoperative short-term and long-term outcomes in patients undergoing curative pancreatic resection for PDAC. Our data confirm that pancreatic resections can be performed with equal short-term outcomes even in older age. However, patient age significantly influenced the overall and disease-free survival of patients with PDAC undergoing primary resection in curative intent. Therefore, the choice of the optimal therapy concept for each patient should be individualized taking into account the patient's age. (1) Purpose: to evaluate the impact of age on postoperative short-term and long-term outcomes in patients undergoing curative pancreatic resection for PDAC. (2) Methods: This retrospective single-center study comprised 213 patients who had undergone primary resection of PDAC from January 2000 to December 2018 at the University Hospital of Erlangen, Germany. Patients were stratified according the age into two groups: younger (<= 70 years) and older (>70 years) patients. Postoperative outcome and long-term survival were compared between the groups. (3) Results: There were no significant differences regarding inhospital morbidity (58% vs. 67%, p = 0.255) or inhospital mortality (2% vs. 7%, p = 0.073) between the two groups. The median overall survival (OS) and disease-free survival (DFS) were significantly shorter in elderly patients (OS: 29.2 vs. 17.1 months, p < 0.001, respectively; DFS: 14.9 vs. 10.4 months, p = 0.034). Multivariate analysis revealed that age was a significant independent prognostic predictor for OS and DFS (HR 2.23, 95% CI 1.58-3.15; p < 0.001 for OS and HR 1.62, 95% CI 1.17-2.24; p = 0.004 for DFS). (4) Conclusion: patient age significantly influenced overall and disease-free survival in patients with PDAC undergoing primary resection in curative intent.
CRIS-Team WoS Importer:2022-09-09

Impact of resection margin status on survival in advanced N stage pancreatic cancer – a multi-institutional analysis - Teske, Christian; Stimpel, Richard; Distler, Marius; Merkel, Susanne; Grützmann, Robert; Bolm, Louisa; Wellner, Ulrich; Keck, Tobias; Aust, Daniela; Weitz, Juergen; Welsch, Thilo (Langenbecks Archives of Surgery, 2021)
Background: The present study aimed to examine the impact of microscopically tumour-infiltrated resection margins (R1) in pancreatic ductal adenocarcinoma (PDAC) patients with advanced lymphonodular metastasis (pN1–pN2) on overall survival (OS). Methods: This retrospective, multi-institutional analysis included patients undergoing surgical resection for PDAC at three tertiary university centres between 2005 and 2018. Subcohorts of patients with lymph node status pN0–N2 were stratified according to the histopathological resection status using Kaplan-Meier survival analysis. Results: The OS of the entire cohort (n = 620) correlated inversely with the pN status (26 [pN0], 18 [pN1], 11.8 [pN2] months, P < 0.001) and R status (21.7 [R0], 12.5 [R1] months, P < 0.001). However, there was no statistically significant OS difference between R0 versus R1 in cases with advanced lymphonodular metastases: 19.6 months (95% CI: 17.4–20.9) versus 13.6 months (95% CI: 10.7–18.0) for pN1 stage and 13.7 months (95% CI: 10.7–18.9) versus 10.1 months (95% CI: 7.9–19.1) for pN2, respectively. Accordingly, N stage–dependent Cox regression analysis revealed that R status was a prognostic factor in pN0 cases only. Furthermore, there was no significant survival disadvantage for patients with R0 resection but circumferential resection margin invasion (≤ 1 mm; CRM+; 10.7 months) versus CRM-negative (13.7 months) cases in pN2 stages (P = 0.5). Conclusions: An R1 resection is not associated with worse OS in pN2 cases. If there is evidence of advanced lymph node metastasis and a re-resection due to an R1 situation (e.g. at venous or arterial vessels) may substantially increase the perioperative risk, margin clearance in order to reach local control might be avoided with respect to the OS.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Lymph node; Pancreatectomy; PDAC; Resection status; Survival

Impact of selective anti-BMP9 treatment on tumor cells and tumor angiogenesis - Brand, Verena; Lehmann, Christian; Umkehrer, Christian; Bissinger, Stefan; Thier, Martina; De Wouters, Mariana; Raemsch, Romi; Jucknischke, Ute; Haas, Alexander; Breuer, Sebastian; Birzele, Fabian; Racek, Tomas; et al. (Molecular Oncology, 2016)
The role of bone morphogenic protein 9 (BMP9) signaling in angiogenesis has been controversial, with a number of studies showing that it acts either as a pro-angiogenic or, conversely, as an anti-angiogenic factor in a context-dependent manner. Notably, BMP9 was also reported to function in both pro- or anti-tumorigenic roles during tumor progression. It has therefore remained unclear, whether selective BMP9 inhibition is a useful target for antibody therapy of cancer. To shed light on these questions, we characterized BMP9 expression in plasma of patients with different cancer indications and found elevated levels of pro-domains and precursor BMP9 with a strong response in renal cell carcinoma (RCC). These studies prompted us to evaluate the potential of selective anti-BMP9 cancer therapy in RCC. We generated a novel monoclonal therapeutic antibody candidate, mAb BMP9-0093, that selectively targets all different BMP9 variants but does not bind to the closest homolog BMP10. In vitro, mAb BMP9-0093 treatment inhibited signaling, endothelin-1 (ET-1) production and spreading of endothelial cells and restored BMP9-induced decrease in pericyte migration and attachment. Furthermore, BMP9-mediated epithelial-mesenchymal transition of renal cell carcinoma cells was reversed by mAb BMP9-0093 treatment in vitro. In vivo, mAb BMP9-0093 showed significant anti-tumor activity that was associated with an increase in apoptosis as well as a decrease in tumor cell proliferation and ET-1 release. Furthermore, mAb BMP9-0093 induced mural cell coverage of endothelial cells, which was corroborated by a reduction in vascular permeability, demonstrated by a diminished penetration of omalizumab-Alexa 647 into tumor tissue. Our findings provide new evidence for a better understanding of BMP9 contribution in tumor progression and angiogenesis that may result in the development of effective targeted therapeutic interventions.
EVALuna2:15267

Impact of Selective Quality of Life Analysis in Patients with Local Hyperhidrosis after Sympathicus Clipping [Bedeutung der selektiven Lebensqualitätsanalyse nach Sympathikus-Clipping bei Patienten mit lokaler Hyperhidrose] - Schreiner, Waldemar; Mykoliuk, Iurii; Dudek, Wojciech; Sirbu, Horia (Zentralblatt für Chirurgie, 2019)
Introduction Hyperhidrosis (HH) is associated with physical and psychological restrictions. The treatment includes both conservative and surgical methods and aims to permanently improve the quality of life (QoL) of those affected. Endoscopic sympathetic blockade (ESB) is an established surgical therapeutic method and is considered effective when conservative treatment options fail. The aim of our study was to comprehensively analyse the QoL alteration and patient satisfaction after ESB and to identify the corresponding influencing factors. Methods From July 2008 to April 2016, 105 patients were operated for treatment-refractory HH. In all cases, an ESB was performed according to the HH form and the STS expert consensus (STS: Society of Thoracic Surgeons). QoL and hyperhidrosis status were selectively analysed pre- and postoperatively and evaluated using detailed questionnaires (a self-developed questionnaire, SF36, DLQI, Hyperhidrosis LQ (HidroQoL)). Statistical processing was performed with SPSS Statistics version 21.0.0.2 for Windows (Armonk, NY: IBM Corp.). Descriptive statistical analysis and nonparametric tests were used. Results 105 patients who underwent bilateral ESB between July 2008 and April 2016 were evaluated: 73 women (69.5%) and 31 men (29.5%) with median age of 26 years (range: 16-64 years). Of the 105 patients who underwent bilateral ESB, 12 patients had focal Hyperhidrosis palmar and axillar (12.4%), 20 had Hyperhidrosis palmo-plantar (19.0%), 47 had Hyperhidrosis palmoplantar and axillar (44.8%), 11 had Hyperhidrosis axillar (10.5%), and 14 had Hyperhidrosis facial (13.3%). HydroQoL scores showed improvement in all forms of HH. All patient groups demonstrated improvement in DLQI, while the LQ analysis of SF36 showed an improvement in social functioning and mental well-being in all forms of HH other than HA. 86.7% of patients (n = 91) were satisfied with their postoperative outcome. Compensatory sweating (CS) was observed in 76.2% of cases (n = 80), without a clear LQ impact. No significant correlation between CS and the hyperhidrosis form was found. Conclusions ESB is associated with a long-time improvement in social functioning, psychological well-being, and high patient satisfaction. The onset of CS has no clear correlation to QoL and patient satisfaction.
CRIS-Team Scopus Importer:2019-05-02
Keywords: DLQI; ESB; hyperhidrosis; quality of life; SF36; sympathetic trunk

Impact of surface coating and systemic anticoagulants on hemostasis and inflammation in a human whole blood model - Spiegelburg, Doreen Tabea; Mannes, Marco; Schultze, Anke; Scheibenberger, Frieder; Müller, Frederik; Klitzing, Amadeo; Messerer, David Alexander Christian; Ekdahl, Kristina Nilsson; Nilsson, Bo; Huber-Lang, Markus; Braun, Christian Karl (PLoS ONE, 2023)
Background Surface compatibility with blood is critical both for scientific investigations on hemostasis and clinical applications. Regarding in vitro and ex vivo investigations, minimal alteration in physiological hemostasis is of particular importance to draw reliable conclusions on the human coagulation system. At the same time, artificial coagulation activation must be avoided, which is relevant for the patient, for example to prevent stent graft occlusion. The aim was to evaluate the advantages and disadvantages of antithrombotic and antifouling surface coatings in the context of their suitability for ex vivo incubation and the study of coagulation properties. Methods We investigated the impact of different protocols for surface coating of synthetic material and different anticoagulants on hemostasis and platelet activation in ex vivo human whole blood. Blood samples from healthy donors were incubated in coated microtubes on a rotating wheel at 37∘C. Two protocols for surface coating were analyzed for hemostatic parameters and metabolic status, a heparin-based coating (CHC, Corline Heparin Conjugate) without further anticoagulation and a passivating coating (MPC, 2-methacryloyloxethyl phosphorylcholine) with added anticoagulants (enoxaparin, ENOX; or fondaparinux, FPX). Employing the MPC-based coating, the anticoagulants enoxaparin and fondaparinux were compared regarding their differential effects on plasmatic coagulation by thrombelastometry and on platelet activation by flowcytometry and platelet function assays. Results Using the CHC coating, significant coagulation cascade activation was observed, whereas parameters remained mostly unchanged with MPC-based protocols. Extended incubation caused significantly elevated levels of the soluble membrane attack complex. Neither ENOX nor FPX caused a relevant impairment of platelet function or activation capacity and thrombelastometric parameters remained unchanged with both protocols. For translational purposes, we additionally modeled endotoxemia with the MPC-based protocols by incubating with lipopolysaccharide plus/minus thrombin. While coagulation parameters remained unchanged, elevated Interleukin 8 and Matrix Metalloproteinase 9 demonstrated preserved immune cell responsiveness. Conclusions The MPC-based protocols demonstrated better hemocompatibility compared to CHC, and ENOX and FPX proved useful for additional anticoagulation. Furthermore, this simple-to-use whole blood model may be useful for experimental analyses of the early coagulatory and immunological response without decalcification.
CRIS-Team Scopus Importer:2023-01-20

Impaired T-bet-pSTAT1? and perforin-mediated immune responses in the tumoral region of lung adenocarcinoma - Andreev, Katerina; Trufa, Denis; Siegemund, Raphaela; Rieker, Ralf; Hartmann, Arndt; Schmidt, Joachim; Sirbu, Horia; Finotto, Susetta (British Journal of Cancer, 2015)
In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients.We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay.We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-?-dependent pSTAT1? isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1? levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity.These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.
EVALuna2:6728

Implementation of Current ENETS Guidelines for Surgery of Small (2cm) Pancreatic Neuroendocrine Neoplasms in the German Surgical Community: An Analysis of the Prospective DGAV StuDoQ|Pancreas Registry - Mintziras, Ioannis; Keck, Tobias; Werner, Jens; Fichtner-Feigl, Stefan; Wittel, Uwe; Senninger, Norbert; Vowinkel, Thorsten; Koeninger, Joerg; Anthuber, Matthias; Geissler, Bernd; Bartsch, Detlef Klaus; Ghadimi, Michael; et al. (World Journal of Surgery, 2019)
BackgroundENETS guidelines recommend parenchyma-sparing procedures without formal lymphadenectomy, ideally with a minimally invasive laparoscopic approach for sporadic small pNENs (2cm). Non-functioning (NF) small pNENs can also be observed. The aim of the study was to evaluate how these recommendations are implemented in the German surgical community.MethodsData from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery were analyzed regarding patient's demographics, tumor characteristics, surgical procedures, histology and perioperative outcomes.ResultsEighty-four (29.2%) of 287 patients had sporadic pNENs 2cm. Forty-three (51.2%) patients were male, and the mean age at diagnosis was 58.815.6years. Twenty-five (29.8%) pNENs were located in the pancreatic head. The diagnosis pNEN was preoperatively established in 53 (65%) of 84 patients. Sixty-two (73.8%) patients had formal pancreatic resections, including partial pancreaticoduodenectomy or total pancreatectomy (21.4%). Only 22 (26.2%) patients underwent parenchyma-sparing resections and 23 (27.4%) patients had minimally invasive procedures. A lymphadenectomy was performed in 63 (75.4%) patients, and lymph node metastases were diagnosed in 6 (7.2%) patients. Eighty-two (97.7%) patients had an R0 resection. Sixty (72%) tumors were classified G1, 24 (28%) tumors G2. Twenty-seven (32.2%) of 84 patients had postoperative relevant Clavien-Dindo grade 3 complications. Thirty- and 90-day mortalities were 2.4% and 3.6%.ConclusionsENETS guidelines for surgery of small pNENs are yet not well accepted in the German surgical community, since the rate of formal resections with standard lymphadenectomy is high and the minimally invasive approach is underused. The attitude to operate small NF tumors seems to be rather aggressive.
CRIS-Team WoS Importer:2020-02-21

Implementing complete mesocolic excision for colon cancer - mission completed? - Croner, Roland S.; Ptok, Henry; Merkel, Susanne; Hohenberger, Werner (Innovative Surgical Science, 2018)
The definition of complete mesocolic excision (CME) for colon carcinomas revolutionized the way of colon surgery. This technique conquered the world starting from Erlangen. Nevertheless, currently new developments especially in minimally invasive surgery challenge CME to become settled as a standard of care. To understand the evolution of CME, anatomical details occurring during embryogenesis and their variations have to be considered. This knowledge is indispensable to transfer CME from an open to a minimally invasive setting. Conventional surgery for colon cancer (non-CME) has a morbidity of 12.1-28.5% and a 3.7% mortality risk vs. 12-36.4% morbidity and 2.1-3% mortality for open CME. The morbidity of laparoscopic CME is between 4 and 31% with a mortality of 0.5-0.9%. In robotic assisted surgery, morbidity between 10 and 25% with a mortality of 1% was published. The cancer-related survival after 3 and 5 years for open CME is respectively 91.3-95% and 90% vs. 87% and 74% for non-CME. For laparoscopic CME the 3- and 5-year cancer-related survival is 87.8-97% and 79.5-80.2%. In stage UICC III the 3- and 5-year cancer-related survival is 83.9% and 80.8% in the Erlangen data of open technique vs. 75.4% and 65.5-71.7% for laparoscopic surgery. For stage UICC III the 3- and 5-year local tumor recurrence is 3.8%. The published data and the results from Erlangen demonstrate that CME is safe in experienced hands with no increased morbidity. It offers an obvious survival benefit for the patients which can be achieved solely by surgery. Teaching programs are needed for minimally invasive CME to facilitate this technique in the same quality compared to open surgery. Passing these challenges CME will become the standard of care for patients with colon carcinomas offering all benefits of minimally invasive surgery and oncological outcome.
EVALuna2:212690

Implementing complete mesocolic excision for colon cancer - Mission completed? - Croner, Roland S.; Ptok, Henry; Merkel, Susanne; Hohenberger, Werner (Innovative Surgical Science, 2020)
The definition of complete mesocolic excision (CME) for colon carcinomas revolutionized the way of colon surgery. This technique conquered the world starting from Erlangen. Nevertheless, currently new developments especially in minimally invasive surgery challenge CME to become settled as a standard of care. To understand the evolution of CME, anatomical details occurring during embryogenesis and their variations have to be considered. This knowledge is indispensable to transfer CME from an open to a minimally invasive setting. Conventional surgery for colon cancer (non-CME) has a morbidity of 12.1-28.5% and a 3.7% mortality risk vs. 12-36.4% morbidity and 2.1-3% mortality for open CME. The morbidity of laparoscopic CME is between 4 and 31% with a mortality of 0.5-0.9%. In robotic assisted surgery, morbidity between 10 and 25% with a mortality of 1% was published. The cancer-related survival after 3 and 5 years for open CME is respectively 91.3-95% and 90% vs. 87% and 74% for non-CME. For laparoscopic CME the 3- and 5-year cancer-related survival is 87.8-97% and 79.5-80.2%. In stage UICC III the 3- and 5-year cancer-related survival is 83.9% and 80.8% in the Erlangen data of open technique vs. 75.4% and 65.5-71.7% for laparoscopic surgery. For stage UICC III the 3- and 5-year local tumor recurrence is 3.8%. The published data and the results from Erlangen demonstrate that CME is safe in experienced hands with no increased morbidity. It offers an obvious survival benefit for the patients which can be achieved solely by surgery. Teaching programs are needed for minimally invasive CME to facilitate this technique in the same quality compared to open surgery. Passing these challenges CME will become the standard of care for patients with colon carcinomas offering all benefits of minimally invasive surgery and oncological outcome.
CRIS-Team Scopus Importer:2020-02-04
Keywords: colon cancer; colorectal cancer; complete mesocolic excision; minimally invasive surgery; robotic

Improved survival after an educational project on colon cancer management in the county of Stockholm - A population based cohort study - Bernhoff, Richard; Martling, A.; Sjovall, A.; Granath, F.; Hohenberger, Werner; Holm, T. (Ejso, 2015)
Outcomes in rectal cancer have improved dramatically after the introduction of total mesorectal excision (TME). Recently, the TME concept has been transformed into that of complete mesocolic excision (CME) in an attempt to improve prognosis for patients with colon cancer.Multidisciplinary team (MDT) workshops including the CME concept were held annually between 2004 and 2008 at the Karolinska University Hospital. The workshops focused on preoperative staging, surgery and histopathology and included lectures and live surgery sessions. To compare survival before and after the "Stockholm Colon Cancer Project" all patients diagnosed with a right sided colon cancer between January 1, 2001 and December 31, 2003 (Group 1) and from January 1, 2006 until December 31, 2008 (Group 2) in Stockholm were identified from the Swedish ColoRectal Cancer Registry (SCRCR).The proportion of patients having a tumour resection and the proportion having emergency surgery was higher in Group 1. There were more early tumours and more R0 resections in Group 2. Overall survival in all diagnosed patients and disease free survival after tumour resection was improved in the second time period.Surgical teaching programmes may have an impact on the management and outcome in colon cancer. The exact impact from the "Stockholm Colon Cancer Project" cannot be established, however it is likely that it contributed to the improved survival.
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Improving the Quality of Care for Cancer Patients through Oncological Second Opinions in a Comprehensive Cancer Center: Feasibility of Patient-Initiated Second Opinions through a Health-Insurance Service Point - Schulmeyer, Carla; Beckmann, Matthias; Fasching, Peter; Häberle, Lothar; Golcher, Henriette; Kunath, Frank; Wullich, Bernd; Emons, Julius (Diagnostics, 2023)
Background: To improve the quality and cost-effectiveness of care, cancer patients can obtain a second medical opinion on their treatment. Validation of the diagnostic procedure (e.g., imaging), diagnosis, and treatment recommendation allows oncological therapy to be applied in a more targeted way, optimizing interdisciplinary care. This study describes patients who received second opinions at the Comprehensive Cancer Center for Erlangen–Nuremberg metropolitan area in Germany over a 6-year period, as well as the amount of time spent on second-opinion counseling. Methods: This prospective, descriptive, single-center observational study included 584 male and female cancer patients undergoing gynecological, urologic, or general surgery who sought a second medical opinion. The extent to which the first opinion complied with standard guidelines was assessed solely descriptively. Results: The first opinion was in accordance with the guidelines and complete in 54.5% of the patients, and guideline compliant but incomplete in 13.2%. The median time taken to form a second opinion was 225 min, and the cancer information service was contacted by patients an average of eight times. Conclusions: The initial opinion was guideline compliant and complete in every second case. Without a second opinion, the remaining patients would have been denied a guideline-compliant treatment recommendation. Obtaining a second opinion gives patients an opportunity to receive a guideline-compliant treatment recommendation and enables them to benefit from newer, individualized therapeutic approaches in clinical trials. Establishing patient-initiated second opinions via central contact points appears to be a feasible option for improving guideline compliance.
CRIS-Team Scopus Importer:2023-11-24
Keywords: gastrointestinal cancer; gynecologic cancer; sarcoma; second medical opinion; urologic cancer

Inaccuracies - Nimptsch, Ulrike; Krautz, Christian (Deutsches Ärzteblatt international, 2020)
CRIS-Team WoS Importer:2020-07-24

Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss - Lin, Neng-Yu; Chen, Chih-Wei; Kagwiria, Rosebeth; Liang, Ruifang; Beyer, Christian; Distler, Alfiya; Luther, Julia; Engelke, Klaus; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor ? B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy.Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.
EVALuna2:10103

Incarcerated recurrent inguinal hernia containing an acute appendicitis (Amyand hernia): an extremely rare surgical situation - Velimezis, Georgios; Vassos, Nikolaos; Kapogiannatos, Georgios; Koronakisi, Dimitrios; Perrakis, Evangelos; Perrakis, Aristotelis (Archives of Medical Science, 2017)
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Incisional hernia after liver transplantation: mesh-based repair and what else? - Perrakis, Aristotelis; Knüttel, Dagmar; Rahimli, Mirhasan; Andric, Mihailo; Croner, Roland S.; Vassos, Nikolaos (Surgery Today, 2020)
Purpose: Incisional hernia (IH) is not uncommon after liver transplantation (LT). We investigated the long-term outcome of mesh-based hernia repair using an inlay-onlay technique. Methods: Our analysis was based on a prospective collected database of all LT recipients from our hospital over a period of 15 years. We analyzed clinical data including the period between LT and hernia development, the size and localization of the hernia, the length of in-hospital stay, immunosuppression, and postoperative morbidity, as well as follow-up data. The median follow-up period was 120 (range 12–200) months. Results: Among a total of 220 patients who underwent a collective 239 LTs, 29 (13%) were found to have an IH after a median period of 27.5 months (range 3–96 months). There were 12 (41%) men and 17 (59%) women, with a median age of 51 years. The median size of the IH was 13 cm (range 2–30 cm) and the median in-hospital stay was 6 days. Mild postoperative complications developed in seven patients, including two onlay mesh infections. One patient (3.4%) suffered recurrence. Conclusion: Mesh-based hernia repair using the inlay/onlay technique represents an effective and safe method for patients with an IH after LT, without additional risk from continuous immunosuppression.
CRIS-Team Scopus Importer:2020-10-23
Keywords: Incisional hernia; Liver transplantation; Mesh

Increased expression of guanylate binding protein-1 in lesional skin of patients with cutaneous lupus erythematosus - Naschberger, Elisabeth; Wenzel, Joerg; Kretz, Cosima C.; Herrmann, Martin; Stürzl, Michael; Kuhn, Annegret (Experimental Dermatology, 2011)
The large GTPase human guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation and is induced by interferon (IFN)-α and IFN-γ in endothelial cells (ECs). The aim of this study was to investigate whether GBP-1 is a marker of skin lesions in patients with cutaneous lupus erythematosus (CLE). Western blotting revealed that GBP-1 was in vitro induced by IFN-α and -γ in primary keratinocytes obtained from healthy controls. Moreover, we found that this protein was expressed by keratinocytes and ECs in primary and ultraviolet (UV)-induced skin lesions from patients with various subtypes of CLE, when compared to non-lesional skin. No GBP-1 expression was noted in skin biopsy specimens 24 or 72h after UV irradiation prior to lesion formation in patients with CLE or in healthy control specimens with or without UV irradiation. Initial findings suggest that GBP-1 is not expressed in other skin diseases with different inflammatory aetiology, such as atopic dermatitis. We conclude that GBP-1 expression is closely associated with skin lesions in patients with CLE, suggesting a contribution of GBP-1 in the pathogenesis of this disease. © 2011 John Wiley & Sons A/S.
Created from Fastlane, Scopus look-up
Keywords: Guanylate binding protein; Inflammation; Interferon; Lupus erythematosus; Skin; UV light

Increased expression of OLFM4 and lysozyme during necrotizing enterocolitis in neonates: an observational research study - Diez, Sonja; Renner, Marcus; Bahlinger, Veronika; Hartmann, Arndt; Besendörfer, Manuel; Müller, Hanna (BMC Pediatrics, 2022)
Background: In neonatal patients with necrotizing enterocolitis (NEC) the inflammatory response is mediated by a plurality of different proteins. The proteins olfactomedin 4 (OLFM4) and lysozyme (LYZ) are part of the intestinal mucosal defense and especially OLFM4 has rarely been evaluated in neonatal gastrointestinal diseases. The aim of this study was to analyze whether expression levels of both proteins of innate immunity, OLFM4 and lysozyme, were increased during NEC in neonates. Methods: Intestinal tissues of patients with NEC were examined with immunohistochemical staining of formalin-fixed and paraffin-embedded sections of resected tissue using antibodies against OLFM4 and lysozyme. Staining-positive tissues were semi-quantitatively scored from 0 (no staining), 1 (weak staining), 2 (moderate staining) to 3 (highly intense staining) by two individual investigators. Intestinal tissue of infants with volvulus was used as a control as other intestinal tissue without major inflammation was not available. Results: Both applied antibodies against OLFM4 showed different staining patterns with higher staining intensity of the antibody OLFM4 (D1E4M). OLFM4 (median score of the antibody OLFM4 (D1E4M): 3.0) and lysozyme (median score: 3.0) are highly expressed in intestinal and immune cells during NEC. Expression of OLFM4 and lysozyme in the control samples with volvulus was observable but significantly lower (median score of the antibody OLFM4 (D1E4M): 1.25; median score of the antibody against LYZ: 2.0; p = 0.033 and p = 0.037, respectively). Conclusions: Both proteins, OLFM4 and lysozyme, may play a role in the pathogenesis of NEC in neonatal patients, but the exact mechanisms of OLFM4 and lysozyme function and their role in immunological responses have not yet been resolved in detail. These observations add new insights as basis for further large-scale population research.
CRIS-Team Scopus Importer:2022-04-22
Keywords: Inflammation; Lysozyme; Necrotizing enterocolitis; Neonatal gastrointestinal diseases; OLFM4

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer - Heim, Lisanne; Kachler, Katerina; Siegmund, Raphaela; Trufa, Denis; Mittler, Susanne; Geppert, Carol-Immanuel; Friedrich, Juliane; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (British Journal of Cancer, 2019)
Background: The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. Methods: Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. Results: Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35 + Foxp-3 + cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68 + macrophages were induced and correlated with IL-35 + cells. Finally, IL-35 positively correlated with TTF-1 + PD-L1 + cells in the TU region of NSCLC patients. Conclusions: Induced IL-35 + Foxp3 + cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1 + PD-L1 + cells. In the tumour-free CTR area, IL-35 correlated with CD68 + macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.
CRIS-Team Scopus Importer:2019-05-10

Increased expression of the Th17-IL-6R/pSTAT3/BATF/Ror?T-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung - Balabko, Liubov; Andreev, Katerina; Burmann, Nadine; Schubert, Melanie; Mathews, Martina; Trufa, Denis; Reppert, Sarah; Rau, Tilmann; Schicht, Martin; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta (Scientific Reports, 2014)
Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (ROR?T), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.
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Increased Incidence of Perforated Appendicitis in Children During COVID-19 Pandemic in a Bavarian Multi-Center Study - Schafer, Frank-Mattias; Meyer, Johannes; Kellnar, Stephan; Warmbrunn, Jakob; Schuster, Tobias; Simon, Stefanie; Meyer, Thomas; Platzer, Julia; Hubertus, Jochen; Seitz, Sigurd; Knorr, Christian; Stehr, Maximilian (Frontiers in Pediatrics, 2021)
Introduction: Since early 2020 the COVID-19 pandemic and statutory preventive reorganization of treatment capacities with cancellation of elective surgery as well as curfew regulations led to vastly decreased utilization of primary health care.
CRIS-Team WoS Importer:2021-05-28

Independent Validation and Assay Standardization of Improved Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis - Mahajan, Ujjwal M.; Oehrle, Bettina; Sirtl, Simon; Alnatsha, Ahmed; Goni, Elisabetta; Regel, Ivonne; Beyer, Georg; Vornhülz, Marlies; Vielhauer, Jakob; Chromik, Ansgar; Bahra, Markus; Klein, Fritz; et al. (Gastroenterology, 2022)
Background & Aims: Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature. Methods: We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography–tandem mass spectrometry platform. A machine learning–aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance. Results: The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-9 >2 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-9 <37 U/mL, 39.7%, 94.1%, and 76.3%, respectively. Conclusions: The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.
CRIS-Team Scopus Importer:2022-11-04
Keywords: CA19-9; Chronic Pancreatitis; Diagnostic Signature; Metabolic Signature; Pancreatic Cancer

Indications for resection and perioperative outcomes of surgery for pancreatic neuroendocrine neoplasms in Germany: an analysis of the prospective DGAV StuDoQ vertical bar Pancreas registry - Mintziras, Ioannis; Keck, Tobias; Werner, Jens; Fichtner-Feigl, Stefan; Wittel, Uwe; Senninger, Norbert; Vowinkel, Thorsten; Koeninger, Joerg; Anthuber, Matthias; Geissler, Bernd; Bartsch, Detlef Klaus; Ghadimi, Michael; et al. (Surgery Today, 2019)
Purpose Pancreatic neuroendocrine neoplasms (pNENs) are rare, and their surgical management is complex. This study evaluated the current practice of pNEN surgery across Germany, including its adherence with guidelines and its perioperative outcomes.
CRIS-Team WoS Importer:2020-02-14

Indications for Surgical Therapy in Chronic Pancreatitis Operationsindikationen bei der chronischen Pankreatitis - Müller-Debus, Charlotte Friederieke; Wellner, Ulrich Friedrich; Bösch, Florian; Belyaev, Orlin; Brunner, Maximilian; Radulova-Mauersberger, Olga; Grützmann, Robert; Uhl, Waldemar; Witzigmann, Helmut; Werner, Jens; Keck, Tobias (Zentralblatt für Chirurgie, 2020)
Chronic pancreatitis is a recurrent disease with repeating exacerbations of inflammation of the pancreatic gland - associated with belt-like back pain. Without treatment, recurrent chronic pancreatitis leads to development of opioid-dependent pain. The chronic pancreatitis leads to recurrent hospital stays for the affected patient and socioeconomic challenges. In progress it can lead to local complications of chronic pancreatitis, such as formation of pseudocysts, biliary duct obstruction, duodenal obstruction or portal hypertension. The aim of this article is a detailed description of the indication for surgical therapy in chronic pancreatitis. The underlying analysis was a systematic literature research and evaluation, the formulation of key questions according to the PICO system and the evaluation of indications and key statements and questions, as implemented in a three level Delphi process among the members of the pancreas research group and the indications for the surgery group of the German Society of General and Visceral Surgery (DGAV). Surgical resection of the inflammatory pancreatic head pseudotumour, after initial conservative therapy, is a highly efficient therapy for the control of pain and the avoidance of complications in chronic pancreatitis. For this purpose, well evaluated surgical strategies are available. Delay in surgical therapy can lead to chronic pain, kachexia and malnutrition and increase complications of surgical therapy.
CRIS-Team Scopus Importer:2020-08-14
Keywords: chronic pancreatitis; indication; pancreas; PICO; surgery

Indications for the surgical management of pancreatic neoplasms - Brunner, Maximilian; Belyaev, Orlin; Boesch, Florian; Keck, Tobias; Witzigmann, Helmut; Grützmann, Robert; Uhl, Waldemar; Werner, Jens (Zeitschrift für Gastroenterologie, 2021)
Due to its rising incidence, pancreatic neoplasia, which mainly include adenocarcinomas, neuroendocrine and cystic neoplasia of the pancreas, is becoming increasingly relevant in everyday clinical practice.
CRIS-Team WoS Importer:2021-12-10

Indikationen zur chirurgischen und interventionellen Behandlung der akuten Pankreatitis - Radulova-Mauersberger, Olga; Belyaev, Orlin; Birgin, Emrullah; Bösch, Florian; Brunner, Maximilian; Müller-Debus, Charlotte Friederieke; Wellner, Ulrich Friedrich; Grützmann, Robert; Keck, Tobias; Werner, Jens; Uhl, Waldemar; Witzigmann, Helmut (Zentralblatt für Chirurgie, 2020)
BACKGROUND: 15 to 20% of patients with acute pancreatitis develop necrosis of the pancreatic parenchyma or extrapancreatic tissue. The disease is associated with a mortality rate of up to 20%. The mainstays of treatment consist of intensive medical care and surgical and interventional therapy. METHODS: A systematic literature search focused on indications for surgical and interventional therapy of necrotising pancreatitis. 85 articles were analysed for this review. By using the Delphi method, the results were presented to the quality committee for pancreas diseases of the German Society for General and Visceral Surgery and to expert pancreatologists in an interactive conference using plenary voting during the visceral medicine congress 2019 in Wiesbaden. For the finalised recommendations, an agreement of 84% of participants was achieved. RESULTS: Documented or clinical suspicion of infected, necrotising pancreatitis are indications for surgical and interventional therapy (recommendation grade: strong; evidence grade; low). Sterile necrosis is a less common indication for intervention due to late complications or persistent severe pancreatitis. Invasive interventions should be delayed when possible until four weeks after onset of pancreatitis. Optimal treatment strategy consists of a "step-up approach" (evidence grade: high; recommendation grade: strong). The first step is catheter drainage, followed, if necessary, by minimally invasive surgical or interventional necrosectomy. If minimally invasive techniques do not result in clinical improvement, open necrosectomy is necessary. 35 to 50% of patients are successfully treated with drainage alone. Indications for emergency intervention are bowel perforation, bowel ischemia and bleeding. Surgical decompression of abdominal compartment syndrome is indicated if the patient is refractory to medical treatment and percutaneous drainage. Abscesses and symptomatic pseudocysts are indications for interventional drainage. Early cholecystectomy during index admission is recommended for patients with mild biliary pancreatitis. Cholecystectomy should be delayed after severe, biliary pancreatitis. CONCLUSION: The recommendations for surgical an interventional therapy of necrotising pancreatitis address the basis of current indications in literature. They should serve in daily practice as a reference standard for decision making in multidisciplinary teams.
CRIS-Team Scopus Importer:2020-06-30

Indikationen zur invasiven Koronardiagnostik und Revaskularisation - Achenbach, Susanne; Naber, C.; Levenson, B.; Böning, A.; Schächinger, V. (Der Kardiologe, 2017)
Invasive diagnostic coronary procedures – which in addition to invasive angiography also include intracoronary imaging and measurement of the fractional flow reserve (FFR) – as well as interventional and surgical coronary revascularization are effective measures for the diagnostic workup and treatment of patients with coronary artery disease. Nevertheless, they are invasive procedures with corresponding cost and effort, and a nonnegligible complication rate. Hence, the indication to perform invasive coronary diagnostic procedures and revascularization must be made under careful consideration of the patient’s clinical situation, the results of noninvasive testing, and comorbidities, particularly in patients with known or suspected stable coronary artery disease, rather than unstable patients or those with acute coronary syndromes. In this position statement, clinical indications for invasive diagnostic coronary procedures and for coronary revascularization are summarized, taking into account, wherever possible, respective Clinical Practice Guidelines published by the European Society of Cardiology and endorsed by the German Cardiac Society.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Coronary angiography; Coronary artery disease; Guidelines; Indications; Revascularization

Indikatoren der Ergebnisqualität für die multimodale invasive Behandlung der peripheren arteriellen Verschlusskrankheit (PAVK) - Uhl, C.; Rümenapf, G.; Görtz, H.; Böckler, D.; Behrendt, C. A.; Pleye, J.; Rother, Ulrich (Gefässchirurgie, 2020)
Background: Evaluation of quality indicators in medical treatment strategies is becoming increasingly important, e.g., in the treatment of peripheral artery disease (PAD). Therefore, this study aimed to demonstrate the range of published data of outcome quality depending on different revascularization methods and to define indicators of quality in the treatment of patients with PAD. Methods: Between 1 June 2019 and 25 February 2020, literature regarding open and endovascular revascularization procedures in the treatment of PAD was analyzed by the commission “PAD and diabetic foot” from the DGG e. V. Several outcome quality indicators were defined. A narrative literature search was conducted in order to collect data (mean, range) for the specific indicators. Results: Data regarding outcome quality was assessed. 8 Indicators for outcome quality could be defined for endovascular and open surgical treatment (Claudicatio intermittens [CI]: Early results [30 days]: early graft failure, access side complications; long-term results [5 years]: primary patency, worsening of the Rutherford stadium; chronic critical limb ischemia [CLI]: early results [30 days]: early graft failure, 30 days major amputation; long-term results [1 year]: primary patency, limb salvage). Conclusion: The findings of this study demonstrate the wide range of the published outcome quality after the treatment of peripheral arterial disease (PAD). The Commission “PAD and diabetic foot” from the DGG e. V. defined indicators to report outcome quality. Based on these findings, future registries investigating the outcome of the treatment of PAD are encouraged to use these indicators to generate comparative data.
CRIS-Team Scopus Importer:2020-08-14
Keywords: Amputation; Bypass; Cardiovascular diseases; Diabetes mellitus; Quality indicators

Indocyanine green angiography and the old question of vascular autonomy - Long term changes of microcirculation in microsurgically transplanted free flaps - Ludolph, Ingo; Arkudas, Andreas; Lang, Werner; Rother, Ulrich; Horch, Raymund E.; Cai, Aijia (Clinical Hemorheology and Microcirculation, 2019)
BACKGROUND: Free tissue transfer has become a routine procedure with low failure. In case of a compromised vascular pedicle, flap survival is time dependantly possible due to flap autonomization. However it remains unknown at what time and to which degree different factors influence flap autonomization.
CRIS-Team WoS Importer:2019-10-15

INDOCYANINE-GREEN FOR INTRAOPERATIVE LASER FLUORESCENCE ANGIOGRAPHY IN KIDNEY TRANSPLANTATION: PRELIMINARY EXPERIENCE AND DOSE FINDING - Rother, Ulrich; Gerken, A.; Lang, Werner; Nowak, K. (2016)
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Induction of apoptosis in circulating angiogenic cells by microparticles. - Distler, Jörg; Akhmetshina, Alfiya; Dees, Clara; Juengel, Astrid; Stürzl, Michael; Gay, Steffen; Pisetsky, David S.; Schett, Georg; Distler, Oliver (Arthritis & Rheumatism-Arthritis Care & Research, 2011)
Systemic sclerosis (SSc) is an autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers of circulating angiogenic cells (CACs). The aim of this study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with reduced numbers of CACs. Apoptosis was quantified by staining for annexin V and measurement of caspase 3 activity. The uptake of microparticles by CACs was determined by fluorescence-activated cell sorting and by fluorescence microscopy. Tritiated arachidonic acid and phosphatidylinositol 3,5-bisphosphate were used to demonstrate the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticle-induced apoptosis of endothelial progenitor cells. Microparticles derived from activated or apoptotic ECs, the expression of which is strongly increased in the blood of patients with SSc, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs, and purified arachidonic acid mimics the proapoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase, and inhibition of acid sphingomyelinase prevents microparticle-induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs, and impaired formation of new vessels in SSc. OBJECTIVE METHODS RESULTS CONCLUSION

Infection with human immunodeficiency virus-1 increases expression of vascular endothelial cell growth factor in T cells: implications for acquired immunodeficiency syndrome-associated vasculopathy. - Ascherl, Gudrun; Hohenadl, Christine; Schatz, Octavian; Shumay, Elena; Bogner, J.; Tschachler, Erwin; Monini, Paolo; Ensoli, Barbara; Stürzl, Michael; et al. (Blood, 1999)
Alterations in the vascular system and the onset of angioproliferative lesions such as Kaposi's sarcoma (KS) are common traits of human immunodeficiency virus-1 (HIV-1)-infected patients. To investigate possible factors involved in acquired immunodeficiency syndrome (AIDS)-associated vasculopathy and vascular malfunction, expression of vascular endothelial cell growth factor-A (VEGF-A) was analyzed in HUT 78 T lymphocytes upon infection with HIV-1. VEGF-A was found to be increased in supernatants from infected cells as compared with uninfected cells. In addition, VEGF-A mRNA expression and protein secretion were significantly increased in HUT 78 cells incubated with conditioned medium (CM) derived from HIV-1 chronically infected HUT 78 cells (HIV-TCM) as compared with CM from uninfected cells (TCM). Increase of VEGF-A production in T cells was promoted by inflammatory cytokines (IC) present in HIV-TCM, including tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin-1beta (IL-1beta), and IL-6. These IC that have been shown to be increased in sera of HIV-1-infected patients and to be increased by HIV-1 infection or cell activation in these individuals as well as HIV-TCM also increased VEGF-A expression in primary T lymphocytes. Consistent with this, VEGF-A concentrations were found to be higher in sera of HIV-1-infected patients with (mean, 357.1 +/- 197.9 pg/mL) and without KS (mean, 256.7 +/- 137.5 pg/mL) as compared with uninfected individuals (mean, 188.6 +/- 91.7 pg/mL). These data suggest that increased secretion of VEGF-A by T lymphocytes of HIV-1-infected individuals may induce vascular leakage and stimulate proliferation of vascular endothelial cells, which are hallmarks of AIDS-associated vasculopathy and especially of KS development.

Inflammatory bowel diseases : Crohn's disease and ulcerative colitis - Fischer, Sören; Rath, T.; Neurath, Markus (Internist, 2018)
Inflammatory bowel diseases (IBD) are complex diseases. Epidemiological studies suggest rising incidences in industrialized countries. The article is based on a literature search in PubMed and is oriented on the current guidelines published by the European Crohn's and Colitis Organisation. IBD are characterized by chronic diarrhoea, abdominal pain and peranal haemorrhage. Extraintestinal manifestations commonly affect joints, skin, eyes and bile tracts. Early diagnosis and therapeutic intervention determine individual patient outcome. Medical treatment currently includes aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors and biologicals. IBDs require anti-inflammatory and if necessary immunosuppressive therapy. Due to extraintestinal complications and the possible need for surgical intervention, an interdisciplinary approach is important.
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Inflammatory cytokines synergize with the HIV-1 Tat protein to promote angiogenesis and Kaposi's sarcoma via induction of basic fibroblast growth factor and the alpha v beta 3 integrin. - Barillari, Giovanni; Sgadari, Cecilia; Palladino, Clelia; Gendelman, R; Caputo, Antonella; Morris, C B; Nair, B. C.; Markham, P; Nel, A; Stürzl, Michael; Ensoli, Barbara (Journal of Immunology, 1999)
The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi's sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1 beta, TNF-alpha, and IFN-gamma, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the alpha v beta 3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat. In contrast, no correlation is observed with the expression of alpha v beta 5, which is promoted by VEGF and binds Tat basic region. Finally, KS lesion formation induced by bFGF and Tat in nude mice is blocked by antagonists of RGD-binding integrins. Because alpha v beta 3 is an RGD-binding integrin that is highly expressed in primary KS lesions, where it colocalizes with extracellular Tat on vessels and spindle cells, these results suggest that alpha v beta 3 competitors may represent a new strategy for the treatment of AIDS-KS.

Influence of body mass index on long-term outcome in patients with rectal cancer-a single centre experience - Kalb, Maximilian; Langheinrich, Melanie C.; Merkel, Susanne; Krautz, Christian; Brunner, Maximilian; Bénard, Alan; Weber, Klaus; Pilarsky, Christian; Grützmann, Robert; Weber, Georg (Cancers, 2019)
Background: Excess bodyweight is known to influence the risk of colorectal cancer; however, little evidence exists for the influence of the body mass index (BMI) on the long-term outcome of patients with rectal cancer. Methods: We assessed the impact of the BMI on the risk of local recurrence, distant metastasis and overall-survival in 612 patients between 2003 and 2010 after rectal cancer diagnosis and treatment at the University Hospital Erlangen. A Cox-regression model was used to estimate the hazard ratio and multivariate risk of mortality and distant-metastasis. Median follow up-time was 58 months. Results: Patients with obesity class II or higher (BMI ≥ 35 kg/m2, n = 25) and patients with underweight (BMI < 18.5 kg/m2, n = 5) had reduced overall survival (hazard ratio (HR) = 1.6; 95% confidence interval (CI) 0.9-2.7) as well as higher rates of distant metastases (hazard ratio HR = 1.7; 95% CI 0.9-3.3) as compared to patients with normal bodyweight (18.5 ≤ BMI < 25 kg/m2, n = 209), overweight (25 ≤ BMI <30 kg/m2, n = 257) or obesity class I (30 ≤ BMI >35 kg/m2, n = 102). There were no significant differences for local recurrence. Conclusions: Underweight and excess bodyweight are associated with lower overall survival and higher rates of distant metastasis in patients with rectal cancer.
CRIS-Team Scopus Importer:2019-06-21
Keywords: Body mass index; Distant metastasis; Overall survival; Rectal cancer

Influence of Duration and Temperature of Transport and Storage Prior to Processing on Cell Quality of Cord Blood Units - A German Experience - Strobel, Joachim; Brenner, Lukas; Zimmermann, Robert; Weiss, Dominik; Zingsem, Jürgen; Eckstein, Reinhold; Weisbach, Volker Günter (Clinical Laboratory, 2015)
In Germany, cord blood needs to be transported to the processing facility to be processed and cryopreserved within 48 hours after collection according to national guidelines. During that time, a temperature of 22 ± 4 degrees C must be maintained. The purpose of this study was to analyse the influence of temperature during transport and storage prior to processing and cryopreservation on stem cells in 2460 both autologous and allogeneic umbilical cord blood samples.Total and viable CD45+ cells, total and viable CD34+ cells, and mononuclear cells (MNC) of cord blood and resulting leucocyte concentrate both before and after freezing were analysed by flow cytometry. Transport protocols and the records of temperature measuring chips used in transport were evaluated in order to analyse how long each unit was exposed to which temperature ranges.On average, the cord blood preparations were delivered within 16.4 ± 6.3 hours. No cord blood was delivered and processed later than 48 hours after donation. Temperature of transport and storage before processing had minor but sometimes significant effects on cell viability. A temperature range of 20 - 24 degrees C showed best survival rates for CD34+ cells and highest colony forming potential.The temperature prior to processing has little yet sometimes significant effects on cell viability in stem cell concentrates prepared from cord blood. However, the absolute differences in cell viabilities are quite small. Therefore, the effect is clinically negligible in a range from 4 degrees C to 28 degrees C if cryopreservation is done within 48 hours.
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Influence of early irradiation on in vitro red blood cell (RBC) storage variables of leucoreduced RBCs in additive solution SAG-M - Hauck-Dlimi, Barbara; Braun, Timm; Eckstein, Reinhold; Strobel, Joachim; Zimmermann, Rüdiger (Vox Sanguinis, 2016)
The only accepted way to avoid transfusion-associated graft-versus-host disease is irradiation of blood components. With respect to irradiation and associated storage time, different recommendations exist. We examined early irradiated (day +3) leucoreduced red blood cell units for irradiation-associated damages during storage.We studied 80 leucoreduced units from two manufacturers. All RBCs were stored in the additive solution saline-adenine-glucose-mannitol (SAG-M) and leucoreduced on collection day. Forty components were irradiated on day +3 with 30 Gy, 40 served as non-irradiated controls. Samples were drawn and analysed from these 80 units on days +3, +7, +14, +21, +28, +35 and +42.From day +14, there was a significant difference in the in vitro haemolysis rate between the non-irradiated and the irradiated components. Two of the irradiated units showed a haemolysis rate over the recommended limit of 0·8% on day +42. Potassium and lactate dehydrogenase activity increased faster in irradiated groups during storage.Our findings show that leucoreduced RBCs which are irradiated early after collection show an obvious radiation damage over storage period. Interestingly, on days +28, +35 and +42 the quality of RBCs which were irradiated on day +3 was nearly identical to the quality of RBCs which were irradiated on day +14 in a former series. Early irradiation does not cause more damage of RBCs during subsequent storage than irradiation on day +14. The maximum storage period of irradiated RBCs should remain restricted to 28 days from collection, however independently from the day of irradiation within this period.
EVALuna2:15994

Influence of end-stage renal disease on long-term survival after major amputation - Meyer, Alexander; Griesbach, Colin; Maudanz, Nils; Lang, Werner; Almási-Sperling, Veronika; Rother, Ulrich (Vasa-Journal of Vascular Diseases, 2020)
Background: To analyze long-term outcomes and possible influencing factors in patients with endstage renal disease (ESRD) and critical limb ischemia (CLI) after major amputation compared to patients with normal renal function and non-dialysis-dependent chronic kidney disease. Patients and methods: Abstraction of single-center medical records of patients undergoing above knee (AKA) and below knee (BKA) amputation over a 10 years period (n = 436; 2009-2018). Excluded were amputations due to trauma or tumor. Patients were subdivided according to renal function in three categories: ESRD patients (n = 98), non-dialysis dependent chronic kidney disease (CKD, n = 98) and normal renal function (NF, n = 240). Predefined endpoints were survival and postoperative complications. Cox-regression models were built to analyze independent risk factors for outcome parameters. Results: In total, 298 AKA, 133 BKA and 5 knee joint exarticulations were performed. ESRD patients showed inferior in-hospital results as to death (ESRD 36.7 % vs. CKD 19.4 % and NF 20.0 %, P = .002). Similarly, long-term survival rates (6 months: ESRD 55.0 % vs. CKD 69.4 %, NF 67.9 % 1 year: ESRD 48.6 %, CKD 60.2 %, NF 60.8 % 5 years: ESRD 9.9 %, CKD 31.8 %, NF 37.1 %, P < .001) were significantly decreased for ESRD patients. Median postoperative survival was 10 months in ERSD, and 22 months in CKD and NF, respectively. Analysis of postoperative surgical complications revealed no differences between groups (ESRD 19.4 %, CKD 17.3 %, NF 17.0 %; P = 0.433). Cox regression analysis indicated that dialysis (HR 1.63; 95 % CI 1.22-2.16; P = .001), hypertension (HR 1.59; 95 % CI 0.99-2.54) and smoking (HR 1.22; 95% CI 1.03-1.44; P = .022) was associated with increased risk of death during follow-up. Conclusions: Mortality after limb amputation in ERSD patients remains high. Survival of ERSD patients is lower in relation to chronic kidney disease and patients with normal renal function. Due to poor in hospital outcomes and absent long-term survival, benefit of primary amputation in ERSD seems scarce.
CRIS-Team Scopus Importer:2020-07-10
Keywords: amputation; critical limb ischemia; dialysis; outcome; Vascular

Influence of Eversion Endarterectomy and Patch Reconstruction on Postoperative Blood Pressure After Carotid Surgery - Meyer, Alexander; Gall, Christine; Verdenhalven, Julia; Lang, Werner; Almási-Sperling, Veronika; Behrendt, Christian Alexander; Günther, Josefine; Rother, Ulrich (Annals of Vascular Surgery, 2022)
Background: Post carotid blood pressure fluctuation and hypertension (PEH) are associated with increased risk for adverse outcome; there is limited evidence on the impact of eversion endarterectomy (E-CEA) versus conventional endarterectomy with patch closure (C-CEA) on postoperative blood pressure course. Patients and Methods: In this retrospective observational study, 859 consecutive carotid endarterectomy procedures between 2004 and 2014 (C-CEA n = 585 vs. E-CEA n = 274), were evaluated. Pre- and postoperative blood pressure values were recorded from recovery room until third postoperative day and compared between both techniques; influences on the dichotomous target variable “at least one postoperative blood pressure peak”, that is need for postoperative vasodilators, were analyzed by a logistic regression model. Influences on postoperative systolic blood pressure were evaluated by a linear mixed effects regression model. Results: Preoperative baseline blood pressure was not different between both comparison groups. During postoperative course, significantly increased mean systolic blood pressure values in the E-CEA group from recovery room to second postoperative day (recovery room C-CEA: 129.2 mm Hg vs. E-CEA: 136.5 mm Hg; P < 0.001; first postoperative day C-CEA: 132.4 mm Hg vs. E-CEA: 139.3 mm Hg; P = 0.0002; second postoperative day C-CEA: 138.6 mm Hg vs. E-CEA: 143.1 mm Hg; P = 0.023) were observed. No hyperperfusion syndrome was detected as wells as no difference in postoperative complication rate. Frequency of antihypertensive interventions was also elevated in E-CEA group (C-CEA 22.1 % vs. E-CEA 31.8 %; P = 0.003). E-CEA (OR 1.591, 95% CI [1.146; 2.202]; P = 0.005) and presence of preoperatively elevated systolic readings (OR 1.015, 95%CI [1.006;1.024]; P < 0.001) was also associated with increased need for antihypertensive interventions. Conclusion: E-CEA was associated with significantly elevated postoperative blood pressure, compared to C-CEA. C-CEA was associated with postoperative blood pressure decrease; however, no difference as to neurologic and surgical complications was detected between both surgical techniques in clinical practice.
CRIS-Team Scopus Importer:2021-12-24
Keywords: Blood pressure; Carotid artery disease; Endarterectomy; Postcarotid hypertension

Influence of gender on coronary atherosclerosis and inflammatory biomarker profile: a CT angiographic study - Bittner, Daniel O.; Rösner, Caroline; Göller, Markus; Raaz-Schrauder, Dorette; Dey, D.; Kilian, Tobias; Achenbach, Susanne; Marwan, Mohamed (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Influence of Hospital Volume Effects and Minimum Caseload Requirements on Quality of Care in Pancreatic Surgery in Germany - Krautz, Christian; Denz, Axel; Grützmann, Robert; Weber, Georg (Visceral Medicine, 2017)
Numerous international studies have identified hospital volume as significant independent variable of death following pancreatic surgery. Most of these studies were limited to regions of countries or portions of a national population and did not include data on volume-outcome effects in Germany.The Medline database was systematically searched to identify studies that analyzed volume-outcome relationships and effects of minimum caseload requirements on outcomes of pancreatic surgery in Germany.Recent observational studies utilizing German hospital discharge data confirmed that patients undergoing pancreatic surgery in Germany also have better outcomes when treated in facilities with high annual caseloads. Besides a decreased risk of in-hospital mortality, there is also a reduced risk of 1-year mortality in high-volume hospitals. In addition, there is evidence that adherence to already existing minimum caseload requirements reduces morbidity and mortality of pancreatic surgery in Germany. As a result of an insufficient centralization in the recent past, however, a large proportion of hospitals that perform pancreatic surgery still do not meet minimum caseload requirements.Specific measures (i.e. sanctions for failure to achieve minimum volumes) that initiate a sufficient centralization process without threatening patient access to surgical care are needed.
EVALuna2:15293

Influence of interrupted versus continuous suture technique on intestinal anastomotic leakage rate in patients with Crohn’s disease — a propensity score matched analysis - Mittelstädt, Anke; von Löffelholz, Tobias; Weber, Klaus; Denz, Axel; Krautz, Christian; Grützmann, Robert; Weber, Georg; Brunner, Maximilian (International Journal of Colorectal Disease, 2022)
Purpose: Intestinal anastomosis is a crucial step in most intestinal resections, as anastomotic leakage is often associated with severe consequences for affected patients. There are especially two different techniques for hand-sewn intestinal anastomosis: the interrupted suture technique (IST) and the continuous suture technique (CST). This study investigated whether one of these two suture techniques is associated with a lower rate of anastomotic leakage. Methods: A retrospective review of 332 patients with Crohn’s disease who received at least one hand-sewn colonic anastomosis at our institution from 2010 to 2020 was performed. Using propensity score matching 183 patients with IST were compared to 96 patients with CST in regard to the impact of the anastomotic technique on patient outcomes. Results: Overall anastomotic leakage rate was 5%. Leakage rate did not differ between the suture technique groups (IST: 6% vs. CST: 3%, p = 0.393). Multivariate analysis revealed the ASA score as only independent risk factor for anastomotic leakage (OR 5.3 (95% CI = 1.2–23.2), p = 0.026). Suture technique also showed no significant influence on morbidity and the re-surgery rate in multivariate analysis. Conclusion: Our data suggest that the chosen suture technique (interrupted vs. continuous) has no influence on postoperative outcome, especially on anastomotic leakage rate. This finding should be confirmed by a randomized controlled trial.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Anastomotic leakage; Continuous suture technique; Crohn’s disease; Interrupted suture technique; Intestinal anastomosis

Influence of Irradiation on Leukodepleted Small Unit Red Blood Cell (RBC) Bags for Infant Transfusion in Additive Solution SAG-M - Hauck-Dlimi, Barbara; Schiffer, Katharina; Eckstein, Reinhold; Strobel, Joachim; Zimmermann, Robert (Clinical Laboratory, 2016)
BACKGROUND: To reduce transfusion-associated graft-versus-host disease irradiation of blood products is widely accepted. There is little data about the effect of gamma-irradiation on leukoreduced RBCs stored in SAG-M that are subdivided for use in transfusion to preterm infants and small children. METHODS: We studied 30 leukoreduced SAG-M preserved RBC bags. All RBCs were leukoreduced on the collection day. The 30 units were divided into two groups. Every unit was divided into three bags. One of these bags served as nonirradiated control (group 1A, group 2A), the other two were gamma-irradiated at different times. In vitro evaluation of irradiated and nonirradiated units was performed on the days +3, +7, +14, +21, and +28 from the day of collection. RESULTS: Gamma irradiation induced a higher increase of extracellular hemoglobin, LDH, and potassium than non-irradiated storage over the time. No irradiated or non-irradiated unit showed a hemolysis rate over the recommended limit of 0.8% over the 28 day period. CONCLUSIONS: Our findings show that subdivision of RBCs does not have an appreciable influence on the storage of leukoreduced, irradiated RBCs in AS SAG-M. Our "worst case scenario" was irradiation on day +3 after donation and subsequent storage until day +28. Especially for infant use, it is important to have the possibility to irradiate even late after donation, because this procedure offers the possibility to use one RBC bag over a longer period of time and to reduce the donor exposure for infants. Therefore, subdivided leukoreduced RBCs can be safely irradiated until day +14 and subsequently stored until day +28 after donation.
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Influence of sex on results and consequences of coronary fractional flow reserve in clinical practice: results of a prospective large-scale multicenter registry - Tröbs, Monique; Marwan, Mohamed; Gaede, Luise; Moellmann, H.; Giesler, T.; Rittger, H.; Rudolph, T.; Pauschinger, M.; Moshage, W.; Brueck, M.; Achenbach, Susanne (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein - Wu, Jian-Jun; Li, Wenwei; Shao, Yaming; Avey, Denis; Fu, Bishi; Gillen, Joseph; Hand, Travis; Ma, Siming; Liu, Xia; Miley, Wendell; Konrad, Andreas; Neipel, Frank; et al. (Cell Host & Microbe, 2015)
Invading viral DNA can be recognized by the host cytosolic DNA sensor, cyclic GMP-AMP (cGAMP) synthase (cGAS), resulting in production of the second messenger cGAMP, which directs the adaptor protein STING to stimulate production of type I interferons (IFNs). Although several DNA viruses are sensed by cGAS, viral strategies targeting cGAS are virtually unknown. We report here that Kaposi's sarcoma-associated herpesvirus (KSHV) ORF52, an abundant gammaherpesvirus-specific tegument protein, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity through a mechanism involving both cGAS binding and DNA binding. Moreover, ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA, suggesting conserved inhibitory mechanisms. Furthermore, KSHV infection evokes cGAS-dependent responses that can limit the infection, and an ORF52 null mutant exhibits increased cGAS signaling. Our findings reveal a mechanism through which gammaherpesviruses antagonize host cGAS DNA sensing.
EVALuna2:8258

Inhibition of Hedgehog Acyltransferase Alleviates the Profibrotic Effects of Transforming Growth Factor beta in Systemic Sclerosis - Liang, Ruifang; Kagwiria, Rosebeth; Dees, Clara; Zhang, Yun; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
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Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer - Busenhart, Philipp; Montalban-Arques, Ana; Katkeviciute, Egle; Morsy, Yasser; Van Passen, Chiara; Hering, Larissa; Atrott, Kirstin; Lang, Silvia; Garzon, Jesus Francisco Glaus; Naschberger, Elisabeth; Hartmann, Arndt; Rogler, Gerhard; et al. (Journal for ImmunoTherapy of Cancer, 2022)
Background Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer. Methods Using orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD). Results We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy. Conclusions These findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy.
CRIS-Team Scopus Importer:2022-02-25
Keywords: CD8-positive T-lymphocytes; cytotoxicity; drug evaluation; immunologic; immunotherapy; preclinical; tumor microenvironment

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages - Maier, Christiane; Bergmann, Christina; Weinkam, Rita; Kittan, Nicolai; Schett, Georg; Distler, Jörg; Beyer, Christian; Ramming, Andreas (Annals of the Rheumatic Diseases, 2017)
To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
EVALuna2:13394

In-hospital mortality and failure to rescue following hepatobiliary surgery in Germany - a nationwide analysis - Krautz, Christian; Gall, Christine; Gefeller, Olaf; Nimptsch, Ulrike; Mansky, Thomas; Brunner, Maximilian; Grützmann, Robert; Kersting, Stephan; Weber, Georg (BMC Surgery, 2020)
BACKGROUND: Recent observational studies on volume-outcome associations in hepatobiliary surgery were not designed to account for the varying extent of hepatobiliary resections and the consequential risk of perioperative morbidity and mortality. Therefore, this study aimed to determine the risk-adjusted in-hospital mortality for minor and major hepatobiliary resections at the national level in Germany and to examine the effect of hospital volume on in-hospital mortality, and failure to rescue. METHODS: All inpatient cases of hepatobiliary surgery (n = 31,114) in Germany from 2009 to 2015 were studied using national hospital discharge data. After ranking hospitals according to increasing hospital volumes, five volume categories were established based on all hepatobiliary resections. The association between hospital volume and in-hospital mortality following minor and major hepatobiliary resections was evaluated by multivariable regression methods. RESULTS: Minor hepatobiliary resections were associated with an overall mortality rate of 3.9% and showed no significant volume-outcome associations. In contrast, overall mortality rate of major hepatobiliary resections was 10.3%. In this cohort, risk-adjusted in-hospital mortality following major resections varied widely across hospital volume categories, from 11.4% (95% CI 10.4-12.5) in very low volume hospitals to 7.4% (95% CI 6.6-8.2) in very high volume hospitals (risk-adjusted OR 0.59, 95% CI 0.41-0.54). Moreover, rates of failure to rescue decreased from 29.38% (95% CI 26.7-32.2) in very low volume hospitals to 21.38% (95% CI 19.2-23.8) in very high volume hospitals. CONCLUSIONS: In Germany, patients who are undergoing major hepatobiliary resections have improved outcomes, if they are admitted to higher volume hospitals. However, such associations are not evident following minor hepatobiliary resections. Following major hepatobiliary resections, 70-80% of the excess mortality in very low volume hospitals was estimated to be attributable to failure to rescue.
CRIS-Team Scopus Importer:2020-08-07

In-hospital outcomes in patients with critical limb ischemia and end-stage renal disease after revascularization - Meyer, Alexander; Lang, Werner; Borowski, Matthias; Torsello, Giovanni; Bisdas, Theodosios (Journal of Vascular Surgery, 2016)
Analysis of in-hospital outcomes in patients treated for critical limb ischemia (CLI) and end-stage renal disease (ESRD) compared to CLI patients with normal renal function.A subgroup analysis of the German CRITISCH registry, a prospective multicenter registry, assessing the first-line treatment strategies in CLI patients in 27 vascular centers in Germany was performed. The study cohort was divided into ESRD patients (n = 102) and patients with normal renal function (n = 674; glomerular filtration rate >60/mL/min/1.73 m(2)). The following first-line treatment strategies were assessed: endovascular therapy (EVT), bypass surgery, patch plasty, and no vascular intervention (conservative treatment, primary amputation). Uni- and multivariate analyses were performed to identify differences between groups as to six end points: amputation or death (composite end point), amputation, death, hemodynamic failure, major adverse cardiac and cerebrovascular events, and reintervention.Differences between the ESRD and non-ESRD group were found regarding the applied first-line therapy (P = .016): The first-line treatment strategies in ESRD patients were EVT in 64% (n = 65), bypass surgery in 13% (n = 13), patch plasty in 11% (n = 11), and no vascular intervention in 13% (n = 13). In non-ESRD patients, EVT was applied in 48% (n = 326), bypass surgery in 27% (n = 185), patch plasty in 13% (n = 86), and no vascular intervention in 11% (n = 77). For ESRD patients, a noticeably increased risk of the composite end point (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.19-5.79; P = .017), amputation (OR, 3.14; 95% CI, 1.35-7.31; P = .008), and hemodynamic failure (OR, 2.19; 95% CI, 1.19-4.04; P = .012) was observed.CLI patients on dialysis represent a challenging cohort prone to in-hospital death, amputation, and hemodynamic failure. Two-thirds of these high-risk patients are treated with EVT. Present data suggest that this modality is generally considered as the most favorable treatment option in this patient subgroup.
EVALuna2:15273

In-hospital outcomes of patients with non-iatrogenic civilian vascular trauma - Meyer, Alexander; Hübner, Viola; Lang, Werner; Almási-Sperling, Veronika; Rother, Ulrich (Vasa-Journal of Vascular Diseases, 2020)
Background: Morbidity, lesion pattern, management and short-term outcomes of civilian vascular trauma are rarely evaluated. Therefore, analysis of in hospital results in patients with nor-iatrogenic vascular trauma in a tertiary referral hospital was performed. Patients and methods: Retrospective evaluation of patients with vascular trauma from 2007-2017 was done. 48 patients (34 male, 14 females, mean age 56 years) were included. Excluded were patients with iatrogenic vascular complications. Major cause of vascular trauma were traffic accidents in 43.8 %, fall from great heights in 27.1 %, sport and home related injuries in 16.8 %, suicidal injuries in 4.2 % and gunshot wounds in 2.1 % (other 6.3 %). 60.4 % of patients presented with blunt, 39.6 % of patients with penetrating vascular trauma. More than half of the cases included polytraumatized patients (544 %). Results: Most commonly affected were the popliteal (25.0 %) and the axillar artery (18.8 %). Aortic injuries were present in 14.6 % of cases, whereas the femoral and subclavian artery were involved in 12.6 % and 10.4 %. Vascular reconstruction was performed by interposition graft in 45.9 %, direct suture in 18.8 %, patchplasty in 10.4 %, ligation in 124 %, and implantation of stentgraft in 12.5 %. Postoperative complication rate was 54.2 %. Rate of in-hospital major amputation was 14.6 % and in-hospital mortality was 14.6 % as well. Comparison between blunt and penetrating trauma as to postoperative complication (p = 0.322), blood transfusion (p = 0.452) and amputation (p = 0.304) showed no significant differences, whereas lethality in blunt trauma was 20.6 % vs. 5.2 % in penetrating trauma. Injury severity score (ISS) was significantly elevated for blunt trauma patients (mean ISS Score blunt 32 vs 21 penetrating, p = 0.043). Conclusions: The majority of vascular lesions is caused by blunt trauma. Blunt lesions do also show a severe injury pattern, compared to penetrating trauma, and the complication rate remains high. However, by means of vascular reconstruction, limb salvage is feasible in a high percentage of cases.
CRIS-Team WoS Importer:2020-05-15

Initiating a Robotic Program for Abdominal Surgery - Experiences from a Centre in Germany - Brunner, Maximilian; Matzel, Klaus; Aladashvili, Archil; Krautz, Christian; Grützmann, Robert; Croner, Roland (Zentralblatt für Chirurgie, 2018)
PURPOSE: Robotic systems are becoming increasingly important in abdominal surgery. We describe the implementation of a robotic program at a German centre for abdominal surgery, with focus on feasibility, safety, patient selection, learning curves, financial aspects and the lessons learned. METHODS: This retrospective analysis covered data on patient demographics, intra- and postoperative parameters, oncological results and costs of all robotic-assisted abdominal operations performed at our institution between August 2012 to December 2016. It was also evaluated how possible factors for preoperative patient selection might influence intra- or postoperative outcome and learning parameters. RESULTS: 81 operations were performed - mostly colorectal resections (n = 35), ventral mesh rectopexy (n = 23) and liver resections (n = 18). The conversion rate was 7%. All oncological patients underwent R0 resection. Mean postoperative hospitalisation was 8.8 days; mean morbidity was 24%, with major complications (Clavien-Dindo > II) in 7%; mortality was 0%. BMI above 33.5 kg/m2 was associated with significantly higher morbidity (p = 0.024) and rate of major complications (p = 0.046), as well as a significantly longer hospitalisation (p = 0.009). Patients older than 65 years had significantly higher morbidity (p = 0.025). With increasing numbers of operations, time of surgery decreased (p = 0.001). The average cost of a robot-assisted operation, including hospital stay, was 15,221 €. The costs of robotic sigmoid resections or liver resections were higher (compared to the open approach: 106.8 and 62.8% higher, respectively, compared to the laparoscopic approach 93.5 and 66.5% higher, respectively). CONCLUSIONS: Robotic surgery is a safe approach. A crucial factor in the successful and safe performance of robotic assisted operations is proper patient selection, especially during the implementation period. The inevitable learning curve and the higher costs compared to open and laparocopic surgery must be respected and specialisation of the whole team is necessary.
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Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity - Schwartz, Christian; Schmidt, Viviane; Deinzer, Andrea; Hawerkamp, H. C.; Hams, E.; Bayerlein, Jasmin; Roeger, O.; Bailer, Moritz; Krautz, Christian; El Gendy, Amr; Elshafei, Moustafa; Heneghan, H. M.; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity - Schwartz, Christian; Schmidt, Viviane; Deinzer, Andrea; Hawerkamp, Heike C.; Hams, Emily; Bayerlein, Jasmin; Roeger, Ole; Bailer, Moritz; Krautz, Christian; Elgendy, Amr; Elshafei, Moustafa; Heneghan, Helen M.; et al. (Science Translational Medicine, 2022)
Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.
CRIS-Team Scopus Importer:2022-03-25

Innate PD-L1 limits T cell mediated adipose tissue inflammation - Schwartz, Christian; Schmidt, Viviane; Deinzer, Andrea; Hawerkamp, Heike C.; Hams, Emily; Bayerlein, Jasmin; Roeger, Ole; Bailer, Moritz; Krautz, Christian; El Gendy, Amr; Elshafei, Moustafa; Hogan, Andrew E.; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.<br
CRIS-Team WoS Importer:2022-03-11

In Reply - Raptis, Dimitrios; Schneider, Ignaz Hans Friedrich; Matzel, Klaus E.; Hohenberger, Werner; Ott, Oliver; Fietkau, Rainer (Deutsches Ärzteblatt international, 2015)
EVALuna2:15209

In silico analysis of the transportome in human pancreatic ductal adenocarcinoma - Zaccagnino, A.; Pilarsky, Christian; Tawfik, D.; Sebens, Susanne; Trauzold, A.; Novak, Ivana; Schwab, A.; Kalthoff, H. (European Biophysics Journal, 2016)
The altered expression and/or activity of ion channels and transporters (transportome) have been associated with malignant behavior of cancer cells and were proposed to be a hallmark of cancer. However, the impact of altered transportome in epithelial cancers, such as pancreatic ductal adenocarcinoma (PDAC), as well as its pathophysiological consequences, still remains unclear. Here, we report the in silico analysis of 840 transportome genes in PDAC patients' tissues. Our study was focused on the transportome changes and their correlation with functional and behavioral responses in PDAC tumor and stromal compartments. The dysregulated gene expression datasets were filtered using a cut-off of fold-change values <=-2 or >=2 (adjusted p value <=0.05). The dysregulated transportome genes were clearly associated with impaired physiological secretory mechanisms and/or pH regulation, control of cell volume, and cell polarity. Additionally, some down-regulated transportome genes were found to be closely linked to epithelial cell differentiation. Furthermore, the observed decrease in genes coding for calcium and chloride transport might be a mechanism for evasion of apoptosis. In conclusion, the current work provides a comprehensive overview of the altered transportome expression and its association with predicted PDAC malignancy with special focus on the epithelial compartment.
EVALuna2:15285

Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis - Min, Jouha; Nothing, Maria Grazia; Coble, Ben; Zheng, Hui; Park, Jongmin; Im, Hyungsoon; Castro, Cesar M.; Swirski, Filip K.; Weissleder, Ralph; Lee, Hakho; Weber, Georg (ACS nano, 2018)
Sepsis is an often fatal condition that arises when the immune response to an infection causes widespread systemic organ injury. A critical unmet need in combating sepsis is the lack of accurate early biomarkers that produce actionable results in busy clinical settings. Here, we report the development of a point-of-care platform for rapid sepsis detection. Termed IBS (integrated biosensor for sepsis), our approach leverages (i) the pathophysiological role of cytokine interleukin-3 (IL-3) in early sepsis and (ii) a hybrid magneto-electrochemical sensor for IL-3 detection. The developed platform produces test results within 1 h from native blood samples and detects IL-3 at a sensitivity of <10 pg/mL; this performance is >5-times faster and >10-times more sensitive than conventional enzyme-linked immunoadsorbent assays, the current gold standard. Using clinical samples, we show that elevated plasma IL-3 levels are associated with high organ failure rate and thus greater risk of mortality, confirming the potential of IL-3 as a sepsis diagnostic biomarker. With further system development ( e. g., full automation, data security measures) and rigorous validation studies, the compact and fast IBS could be a practical clinical tool for timely diagnosis and proactive treatment of sepsis.
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Interdisciplinary Surgical Approaches in Vaginal and Perineal Reconstruction of Advanced Rectal and Anal Female Cancer Patients - Horch, Raymund E.; Ludolph, Ingo; Weber, Klaus; Grützmann, Robert; Arkudas, Andreas; Cai, Aijia (Frontiers in Oncology, 2020)
Relapsing or far advanced rectal and anal cancers remain difficult to treat and require interdisciplinary approaches. Due to modern standard protocols all patients receive irradiation and neoadjuvant chemotherapy—and in case of a relapse a second irradiation—rendering the surgical site prone to surgical site infections and oftentimes long lasting sinus and septic complications after exenteration in the pelvis. Despite an improved overall survival rate in these patients the downside of radical tumor surgery in the pelvis is a major loss of quality of life, especially in women when parts of the vagina need to be resected. Derived from our experince with over 300 patients receiving pelvic and perineal reconstruciton with a transpelvic vertical rectus abdominis myocutaneous (tpVRAM) flap we studied the impact of this surgical technique on the outcomes of female patients with or without vaginal reconstruction following pelvic exenteration. We found out that the tpVRAM flap is reliably perfused and helps to reduce long term wound healing desasters in the irradiated perineal/vaginal/gluteal region.
CRIS-Team Scopus Importer:2020-06-02
Keywords: anal cancer; rectal cancer; transpelvic vertical rectus abdominis myocutaneous flap; vaginal reconstruction; VRAM

Interdisciplinary Surgical Therapy of Extremity Soft-Tissue Sarcomas: A Personalized Resection and Reconstruction Algorithm - Osterloh, Justus; Ludolph, Ingo; Grützmann, Robert; Meyer, Alexander; Lang, Werner; Horch, Raymund E.; Fechner, Katja; Arkudas, Andreas (Journal of Personalized Medicine, 2023)
Soft-tissue sarcomas (STS) are rare, but potentially life-threatening malignancies. STS can occur anywhere in the human body with the limbs being the most common site. Referral to a specialized sarcoma center is crucial to guarantee prompt and appropriate treatment. STS treatment strategies should be discussed in an interdisciplinary tumor board to involve expertise from all available resources, including an experienced reconstructive surgeon for an optimal outcome. In many cases, extensive resection is needed to achieve R0 resection, resulting in large defects after surgery. Hence, an evaluation of whether plastic reconstruction might be required is mandatory to avoid complications due to insufficient primary wound closure. In this retrospective observational study, we present data of patients with extremity STS treated at the Sarcoma Center, University Hospital Erlangen, in 2021. We found that complications were more frequent in patients who received secondary flap reconstruction after insufficient primary wound closure compared to patients who received primary flap reconstruction. Additionally, we propose an algorithm for an interdisciplinary surgical therapy of soft-tissue sarcomas regarding resection and reconstruction and present two problematic cases to emphasize the complexity of surgical sarcoma therapy.
CRIS-Team Scopus Importer:2023-03-10
Keywords: extremity soft-tissue sarcomas; reconstructive surgery; surgical resection

Interdisciplinary treatment of extensive chest wall defects due to irradiation - Schmitz, Marweh; Sirbu, Horia; Horch, Raymund E. (Chirurg, 2015)
EVALuna2:15589

Interesting image. Tc-99m sestamibi SPECT/CT as a new tool for monitoring perfusion and viability of buried perforator based free flaps in breast reconstruction after breast cancer. - Dragu, Adrian; Linke, Rainer; Kuwert, Torsten; Unglaub, Frank; Kneser, Ulrich; Stürzl, Michael; Horch, Raymund E.; Bach, Alexander D. (Clinical Nuclear Medicine, 2010)

Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation. - Pammer, Johannes; Reinisch, Christine; Birner, Peter; Pogoda, Kristin; Stürzl, Michael; Tschachler, Erwin (Laboratory Investigation, 2006)
Although the antiangiogenic activity of type I interferons (IFN) is well known, the mechanism by which it occurs is unclear. In the present study, we have investigated effects of short-term and long-term IFN-alpha exposure on different types of endothelial cells (EC). Short-term IFN-alpha treatment resulted in a distinct reduction of apoptosis of serum and growth factor starved HUVEC and HDMEC. This was accompanied by a strong upregulation of the IFN inducible guanylate binding protein-1 (GBP-1) whereas no consistent regulation of several known antiapoptotic proteins was evident. Stable transfection of HUVEC with an expression vector for GBP-1 mimicked the protective effect of IFN-alpha, suggesting that GBP-1 may contribute to the inhibition of apoptosis. When IFN-alpha, together with serum and EC growth factors, was present continuously a decrease of population doublings by more than 40% was observed in both HDMEC and HCAEC. In addition, the cells displayed a senescent phenotype significantly earlier than control cells and showed an increased adherence for monocytes. Our findings suggest that the antiangiogenic effect of IFN-alpha is mediated by inducing EC senescence rather than EC apoptosis. Furthermore IFN-alpha released in chronic inflammatory conditions might contribute via its prosenescent activity to the pathogenesis of atherosclerosis.

Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice - Haep, Lisa; Britzen-Laurent, Nathalie; Weber, Thomas G.; Naschberger, Elisabeth; Schäfer, Amrei; Kremmer, Elisabeth; Försch, Sebastian; Scheuer, Werner; Wirtz, Stefan; Waldner, Maximilian; Stürzl, Michael; Vieth, Michael (Inflammatory Bowel Diseases, 2015)
Interferon (IFN)-? is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-? in IBD have been predominantly investigated. Based on previous studies showing that IFN-? acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-? on the vascular system in IBD.Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-? were more strongly upregulated in colitis tissues. IFN-? exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-?-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-? in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.The dissection of the pleiotropic activities of IFN-? in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.
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Interferon-gamma triggers an anti-tumorigenic chain reaction in the tumor vessels of colorectal carcinoma - Stürzl, Michael; Langer, Victoria; Regensburger, Daniela; Tenkerian, Clara; Klingler, Annika; Waldner, Maximilian; Becker, Christoph; Meniel, Valerie; Grützmann, Robert; Geppert, Carol-Immanuel; Britzen-Laurent, Nathalie; Naschberger, Elisabeth (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Interferon-α counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer - Persano, Luca; Moserle, Lidia; Esposito, Giovanni; Bronte, Vincenzo; Barbieri, Vito; Iafrate, Massimo; Gardiman, Marina P.; Larghero, Patrizia; Pfeffer, Ulrich; Naschberger, Elisabeth; Stürzl, Michael; Indraccolo, Stefano; et al. (Carcinogenesis, 2009)
Interferon (IFN)-α is a cytokine with marked therapeutic activity in transplantable tumor models, that is in part due to angiogenesis inhibition. Aim of this study was to investigate the effects of IFN-α during the early phases of tumor development in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. To provide sustained IFN-α production, TRAMP mice were injected intraperitoneally with lentiviral vectors. IFN-α administration resulted in rapid and protracted upregulation of IFN-α-regulated genes associated with antiangiogenic and antiproliferative functions in the prostate of TRAMP mice, including guanylate-binding protein 1 (GBP-1), IFI204 and CXCL10-11. These transcriptional changes were accompanied by effects on the tumor vasculature, including significant reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, without induction of tumor necrosis. Intriguingly, GBP-1 and myxovirus resistance A, two IFN-regulated proteins, were found expressed in ∼40% of human prostate cancer samples analyzed, suggesting expression of endogenous IFN-α. Overall, these findings demonstrate that IFN-α is able to counteract the angiogenic switch and impairs tumor cell proliferation in preinvasive lesions. Since the angiogenic switch also marks progression of human prostatic cancer, these results highlight the potential of angiogenesis inhibitors for the development of chemoprevention strategies in high-risk individuals. © The Author 2009. Published by Oxford University Press. All rights reserved.
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Interferon γ-Induced human guanylate binding protein 1 inhibits mammary tumor growth in mice - Lipnik, Karoline; Naschberger, Elisabeth; Britzen-Laurent, Nathalie; Kodajova, Petra; Petznek, Helga; Rungaldier, Stefanie; Astigiano, Simonetta; Ferrini, Silvano; Stürzl, Michael; Hohenadl, Christine (Molecular Medicine, 2010)
Interferon γ (IFN-γ) has recently been implicated in cancer immunosurveillance. Among the most abundant proteins induced by IFN-γ are guanylate binding proteins (GBPs), which belong to the superfamily of large GTPases and are widely expressed in various species. Here, we investigated whether the well-known human GBP-1 (hGBP-1), which has been shown to exert antiangio-genic activities and was described as a prognostic marker in colorectal carcinomas, may contribute to an IFN-γ-mediated tumor defense. To this end, an IFN-independent, inducible hGBP-1 expression system was established in murine mammary carcinoma (TS/A) cells, which were then transplanted into syngeneic immune-competent Balb/c mice. Animals carrying TS/A cells that had been given doxycycline for induction of hGBP-1 expression revealed a significantly reduced tumor growth compared with mock-treated mice. Immunohistochemical analysis of the respective tumors demonstrated a tightly regulated, high-level expression of hGBP-1. No signs of an enhanced immunosurveillance were observed by investigating the number of infiltrating B and T cells. However, hemoglobin levels as well as the number of proliferating tumor cells were shown to be significantly reduced in hGBP-1-expressing tumors. This finding corresponded to reduced amounts of vascular endothelial growth factor A (VEGF-A) released by hGBP-1-expressing TS/A cells in vitro and reduced VEGF-A protein levels in the corresponding mammary tumors in vivo. The results suggest that hGBP-1 may contribute to IFN-γ-mediated antitumorigenic activities by inhibiting paracrine effects of tumor cells on angiogenesis. Consequently, owing to these activities GBPs might be considered as potent members in an innate, IFN-γ-induced antitumoral defense system. © 2010 The Feinstein Institute for Medical Research.
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Interleukin-10-regulated tumour tolerance in non-small cell lung cancer - Vahl, Julius Malte; Friedrich, Juliane; Mittler, Susanne; Trump, Sonja; Heim, Lisanne; Kachler, Katerina; Balabko, Liubov; Fuhrich, Nicole; Geppert, Carol-Immanuel; Trufa, Denis; Sopel, Nina; Rieker, Ralf; et al. (British Journal of Cancer, 2017)
Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3(+) T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.These new findings suggest that IL-10 counteracts IFN-? effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.British Journal of Cancer advance online publication 10 October 2017 doi:10.1038/bjc.2017.336 www.bjcancer.com.
EVALuna2:6915

Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis - Chousterman, B. G.; He, S.; Fenn, A. M.; Nairz, M.; Anzai, A.; Brenner, T.; Uhle, F.; Iwamoto, Y.; Robbins, C. S.; Noiret, L.; Maier, S. L.; Znnchen, T.; et al. (2016)
EVALuna2:15268

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections - Bénard, Alan; Jacobsen, Anne; Brunner, Maximilian; Krautz, Christian; Klösch, Bettina; Swierzy, Izabela; Naschberger, Elisabeth; Podolska, Malgorzata; Kouhestani, Dina; David, Paul; Birkholz, Torsten; Castellanos, Ixchel; et al. (Nature Communications, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
CRIS-Team Scopus Importer:2021-03-05

Interleukin-3 protects against secondary viral infections in sepsis - Benard, A.; Weber, Georg (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming - Benard, Alan; Hansen, Frederik; Uhle, Florian; Klösch, Bettina; Czubayko, Franziska; Mittelstädt, Anke; Jacobsen, Anne; David, Paul; Podolska, Malgorzata; Anthuber, Anna; Swierzy, Izabela; Schaack, Dominik; et al. (Frontiers in Immunology, 2023)
Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.
CRIS-Team Scopus Importer:2023-03-24
Keywords: interleukin-3; plasmacytoid dendritic cells; sepsis; T cell priming; viral pneumonia

Intermittent negative pressure therapy in patients with no-option chronic limb-threatening ischemia - Yagshyyev, Shatlyk; Hausmann, Philipp; Li, Yi; Kempf, Julius; Zetzmann, Katharina; Dessi, Katia; Moosmann, Oxana; Almási-Sperling, Veronika; Meyer, Alexander; Gerken, Andreas L.H.; Lang, Werner; Rother, Ulrich (Vasa-Journal of Vascular Diseases, 2023)
Background: Aim of this study was to assess the influence of intermitted negative pressure (INP) therapy on the foot microcirculation in patients with no-option CLTI. Patients and methods: CLTI patients defined as no option for revascularization on the basis of an interdisciplinary vascular board decision (interventional radiology, vascular surgery) were included in this study. INP therapy was performed at home. Therapy regime was: 1 hour twice daily. Follow-up was after 6 weeks and 3 months. Microcirculation measurement was performed by laser Doppler flowmetry and white light spectrometry (oxygen to see, O2CTM). Following parameters were evaluated: oxygen saturation (sO2 in%), relative hemoglobin (rHb) and flow (in arbitrary units A.U.). Additionally the clinical outcome of the patients was assessed. Results: From September 2020 to June 2022, 228 patients were screened. In total 19 patients (13 men, 6 women, mean age was 73.95 years) were included. 6 weeks after INP therapy the microcirculation showed a significant improvement for the parameter sO2 (%) (p=0.004). After 3 months a non-significant decrease compared to 6 weeks follow-up was seen for the parameter sO2; however, the perfusion was still improved compared to baseline measurement. With regard to the microperfusion values flow (AU) and hemoglobin (AU), the changes were not significant. Clinically, the patients reported a significant reduction of rest pain after therapy (p=0.005). Conclusions: INP therapy in no-option CLTI patients showed a significant improvement of the skin perfusion after 6 weeks. Therefore, INP therapy might have therapeutic potential in these critical ill patients.
CRIS-Team Scopus Importer:2023-11-17
Keywords: chronic limb-threating ischemia; FlowOx; intermittent negative pressure; microperfusion; no-option patients; oxygen to see (O2C)

International Continence Society best practice statement for use of sacral neuromodulation. - Goldman, Howard B.; Lloyd, Jessica C.; Noblett, Karen L.; Carey, Marcus P.; Castano Botero, Juan Carlos; Gajewski, Jerzy B.; Lehur, Paul A.; Hassouna, Magdy M.; Matzel, Klaus; Paquette, Ian M.; De Wachter, Stefan; Ehlert, Michael J.; et al. (Neurourology and Urodynamics, 2018)
AIMS: Sacral neuromodulation (SNM) is an accepted therapy for a variety of conditions. However, despite over 20 years of experience, it remains a specialized procedure with a number of subtleties. Here we present the recommendations issued from the International Continence Society (ICS) SNM Consensus Panel. METHODS: Under the auspices of the ICS, eight urologists, three colorectal surgeons and two urogynecologists, covering a wide breadth of geographic and specialty interest representation, met in January 2017 to discuss best practices for neuromodulation. Suggestions for statements were submitted in advance and specific topics were assigned to committee members, who prepared and presented supporting data to the group, at which time each topic was discussed in depth. Best practice statements were formulated based on available data. This document was then circulated to multiple external reviewers after which final edits were made and approved by the group. RESULTS: The present recommendations, based on the most relevant data available in the literature, as well as expert opinion, address a variety of specific and at times problematic issues associated with SNM. These include the use of SNM for a variety of underlying conditions, need for pre-procedural testing, use of staged versus single-stage procedures, screening for success during the trial phase, ideal anesthesia, device implantation, post-procedural management, trouble-shooting loss of device function, and future directions for research. CONCLUSIONS: These guidelines undoubtedly constitute a reference document, which will help urologists, gynecologists, and colorectal surgeons optimize their use of SNM for refractory urinary urgency and frequency, UUI, NOR, and FI.
EVALuna2:34497

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study - Pages, Franck; Mlecnik, Bernhard; Marliot, Florence; Bindea, Gabriela; Ou, Fang-Shu; Bifulco, Carlo; Lugli, Alessandro; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Borger, Elisa; et al. (Lancet, 2018)
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
EVALuna2:34256

International validation of the low anterior resection syndrome score - Juul, Therese; Ahlberg, Madelene; Biondo, Sebastiano; Emmertsen, Katrine Jossing; Espin, Eloy; Jimenez, Luis Miguel; Matzel, Klaus; Palmer, Gabriella; Sauermann, Anna Catherin; Trenti, Loris; Zhang, Wei; Laurberg, Soren; et al. (Annals of Surgery, 2014)
The aims of this study were to investigate the convergent and discriminative validity and reliability of the low anterior resection syndrome (LARS) score in an international setting.The LARS score is a simple self-administered questionnaire measuring bowel dysfunction after rectal cancer surgery. The score is intended to be commonly used in international research and clinical practice in the future. Therefore, a thorough validation in an international setting is of utmost importance.The LARS score was translated using methods in keeping with current international recommendations. A total of 801 patients operated for rectal cancer in Sweden, Spain, Germany, and Denmark completed the LARS score questionnaire, including an anchor question assessing the impact of bowel function on quality of life. A subgroup of 218 patients completed the LARS score twice. Data were analyzed per country.The LARS score has demonstrated a high convergent validity in terms of a high correlation between LARS score and quality of life (P < 0.001). Sensitivity ranged from 67.7% to 88.3% and specificity from 58.1% to 86.3%. The LARS score was able to discriminate between groups of patients differing with regard to radiotherapy, surgery, and age (P < 0.05). The score also demonstrated high reliability at test-retest with narrow limits of agreement and no statistically significant difference between scores at the first and second test.The Swedish, Spanish, German, and Danish versions of the LARS score have proven to be valid and reliable tools for measuring LARS in European rectal cancer patients.
EVALuna2:15141

Interobserver variability of CT angiography for evaluation of aortic annulus dimensions prior to transcatheter aortic valve implantation (TAVI) - Schmidkonz, Christian; Marwan, M.; Klinghammer, Lutz; Mitschke, M.; Schuhbaeck, A.; Lell, Michael; Achenbach, Susanne; Pflederer, T.; Arnold, Martin (European Journal of Radiology, 2014)
Assessment of aortic annulus dimensions prior to transcatheter aortic valve implantation (TAVI) is crucial for accurate prosthesis sizing in order to avoid prosthesis-annulus-mismatch possibly resulting in complications like valve dislodgement, paravalvular regurgitation or annulus rupture. Contrast-enhanced multidetector computed tomography allows 3-dimensional assessment of aortic annulus dimensions. Only limited data exist about its interobserver variability.In 100 consecutive patients with symptomatic severe aortic stenosis (51 male, BMI 27±5kg/m(2), age 81±7 years, heart rate 72±15bpm, Logistic Euroscore 31±14%, STS-Score 7±4%), pre-interventional aortic annulus assessment was performed by dual source computed tomography (collimation 2×128×0.6mm, high pitch spiral data acquisition mode, 40-60ml contrast agents, radiation dose 3.5±0.9mSv). The following aortic annulus characteristics were determined by three independent observers: aortic annulus maximum, minimum and mean diameters (Dmax, Dmin, Dmean), eccentricity index (EI), effective aortic annulus diameter according to its circumference (Dcirc), effective aortic annulus diameter according to its area (Darea), distance from the aortic annulus plane to the left (LCA) and right coronary artery (RCA) ostia, maximum (DmaxAR) and minimum aortic root diameter (DminAR), maximum (DmaxSTJ) and minimum diameter of the sinotubular junction (DminSTJ). Subsequently, interobserver variabilities were assessed.Correlation between the three observers showed moderate to close agreement (between r=0.67 and r=0.97, all p<0.001). Mean differences (SE) between the three observers ranged from 0.07 (0.06)mm to 0.24 (0.07)mm for assessing the mean AA diameter (Dmean), from 0.28 (0.04)mm to 0.60 (0.06)mm for determining the effective AA diameter derived from the annulus area (Darea) and from 0.03 (0.07)mm to 0.07 (0.11)mm derived from the AA perimeter (Dcirc). For measurements of LCA and RCA distances to the AA level, mean interobserver differences (SE) ranged from 0.36 (0.07)mm to 0.76 (0.09)mm and from 0.15 (0.06)mm to 0.45 (0.11)mm.Computed tomography provides reproducible measurements of the aortic annulus and root geometry in patients scheduled for TAVI. The perimeter-derived aortic annulus diameter shows the lowest interobserver differences. Interobserver variabilities in prosthesis size recommendation were further reduced, if all three sizing methods were considered and stated as a "consensus result".
EVALuna2:11956

Interplay of GTPases and Cytoskeleton in Cellular Barrier Defects during Gut Inflammation - Lopez Posadas, Rocío; Stürzl, Michael; Atreya, Imke; Neurath, Markus; Britzen-Laurent, Nathalie (Frontiers in Immunology, 2017)
An essential role of the intestine is to build and maintain a barrier preventing the luminal gut microbiota from invading the host. This involves two coordinated physical and immunological barriers formed by single layers of intestinal epithelial and endothelial cells, which avoid the activation of local immune responses or the systemic dissemination of microbial agents, and preserve tissue homeostasis. Accordingly, alterations of epithelial and endothelial barrier functions have been associated with gut inflammation, for example during inflammatory bowel disease (IBD). The discriminative control of nutriment uptake and sealing toward potentially pathological microorganisms requires a profound regulation of para- and transcellular permeability. On the subcellular level, the cytoskeleton exerts key regulatory functions in the maintenance of cellular barriers. Increased epithelial/endothelial permeability occurs primarily as a result of a reorganization of cytoskeletal-junctional complexes. Pro-inflammatory mediators such as cytokines can induce cytoskeletal rearrangements, causing inflammation-dependent defects in gut barrier function. In this context, small GTPases of the Rho family and large GTPases from the Dynamin superfamily appear as major cellular switches regulating the interaction between intercellular junctions and actomyosin complexes, and in turn cytoskeleton plasticity. Strikingly, some of these proteins, such as RhoA or guanylate-binding protein-1 (GBP-1) have been associated with gut inflammation and IBD. In this review, we will summarize the role of small and large GTPases for cytoskeleton plasticity and epithelial/endothelial barrier in the context of gut inflammation.
EVALuna2:15286

Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results - Gryc, Thomas; Ott, Oliver; Putz, Florian; Knippen, Stefan; Raptis, Dimitrios; Fietkau, Rainer; Strnad, Vratislav (Brachytherapy, 2016)
To analyze the efficacy of a protocol-based brachytherapy (BT) boost after external beam radiation therapy (EBRT) with simultaneous chemotherapy in patients with anal carcinoma.About 190 patients have been analyzed. Around 143 patients were identified with a good clinical response at the end of EBRT. Another 47 patients received an additional BT boost to the residual tumor at 6 weeks after end of chemoradiation.The 5-year incidence of local recurrence was 24% in patients with BT boost and 19% in patients without BT boost (p = 0.238). The 5-year disease-free survival rate, overall survival rate, and colostomy-free survival rate were 64% and 75% and 76.1% in the BT group and 69% (p = 0.212), 72% (p = 0.924), and 82.7% (p = 0.488) in the non-BT group. We found no differences in late toxicity between the groups.For patients with anal cancer with not a good response to 50-59 Gy EBRT with simultaneous chemotherapy, the further dose escalation using the BT boost up to a mean of 67.5 Gy seems to improve the clinical outcome to the same level as observed in patients with a good response to ERBT, without an increase in late side effects.
EVALuna2:15265

Intestinal graft-versus-host disease is driven by BATF-dependent IL-7R(hi)GM-CSF+ T cells - Ullrich, Evelyn; Abendroth, Benjamin; Rothamer, Johanna; Huber, Carina; Buettner-Herold, Maike; Kitowski, Vera; Vogler, Tina; Longerich, Thomas; Zundler, Sebastian; Völkl, Simon; Beilhack, Andreas; Rose-John, Stefan; et al. (2018)
EVALuna2:207769

Intra-abdominal localized hyaline-vascular Castleman disease: imaging characteristics and management of a rare condition. - Vassos, Nikolaos; Raptis, Dimitrios; Lell, Michael; Klein, Peter; Perrakis, Aristotelis; Köhler, Jens; Croner, Roland S.; Hohenberger, Werner; Agaimy, Abbas (Archives of Medical Science, 2016)
EVALuna2:6759

Intra- and Postoperative Blood Flow Monitoring in a Sheep Model of Uterus Transplantation - Kengelbach-Weigand, Annika; Lotz, Laura; Schmid, Rafael; Lang, Werner; Beckmann, Matthias; Hoffmann, Inge; Horch, Raymund E.; Renner, Stefan; Dittrich, Ralf; Boos, Anja; Hildebrandt, Thomas (In Vivo, 2019)
Background: The introduction of the opportunity to transplant a viable uterus into women for fulfilling their desire to have a child has awakened high expectations worldwide. Materials and Methods: A sheep model was used to evaluate tools for optimizing measurement of blood flow in uterine transplantation. Intraoperatively, blood flow was measured using unidirectional Doppler and indocyanine green (ICG) fluorescence imaging. Postoperatively, an implantable Doppler probe served as a tool for clinical monitoring the patency of anastomosed vessels. Results: ICG imaging showed complete vascularization of the uterus before and in short-term evaluation after surgery. The implantable Doppler probe proved to be highly suitable for assessing patency of vessels in a non-invasive way. Results of histology, and real-time polymerase chain reaction demonstrated viability of the transplanted uterus. Conclusion: Different methods to monitor vasculature patency have proven to be advantageous in supporting both surgeons and researchers in ensuring successful implementation of uterine transplantation.
CRIS-Team WoS Importer:2019-03-08

Intracellular localization map of human herpesvirus 8 proteins. - Sander, Gaby; Konrad, Andreas; Thurau, Mathias; Wies, Effi; Leubert, Rene; Kremmer, Elisabeth; Dinkel, Holger; Schulz, Thomas; Neipel, Frank; Stürzl, Michael (Journal of Virology, 2008)
Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma. We present a localization map of 85 HHV-8-encoded proteins in mammalian cells. Viral open reading frames were cloned with a Myc tag in expression plasmids, confirmed by full-length sequencing, and expressed in HeLa cells. Protein localizations were analyzed by immunofluorescence microscopy. Fifty-one percent of all proteins were localized in the cytoplasm, 22% were in the nucleus, and 27% were found in both compartments. Surprisingly, we detected viral FLIP (v-FLIP) in the nucleus and in the cytoplasm, whereas cellular FLIPs are generally localized exclusively in the cytoplasm. This suggested that v-FLIP may exert additional or alternative functions compared to cellular FLIPs. In addition, it has been shown recently that the K10 protein can bind to at least 15 different HHV-8 proteins. We noticed that K10 and only five of its 15 putative binding factors were localized in the nucleus when the proteins were expressed in HeLa cells individually. Interestingly, in coexpression experiments K10 colocalized with 87% (13 of 15) of its putative binding partners. Colocalization was induced by translocation of either K10 alone or both proteins. These results indicate active intracellular translocation processes in virus-infected cells. Specifically in this framework, the localization map may provide a useful reference to further elucidate the function of HHV-8-encoded genes in human diseases.

Intracellular Quantification and Localization of Label-Free Iron Oxide Nanoparticles by Holotomographic Microscopy - Friedrich, Ralf P.; Schreiber, Eveline; Tietze, Rainer; Yang, Hai; Pilarsky, Christian; Alexiou, Christoph (Nanotechnology, Science and Applications, 2020)
Background: The limitations of optical microscopy to determine the cellular localization of label-free nanoparticles prevent a solid prediction of the cellular effect of particles intended for medical applications. To avoid the strong physicochemical changes associated with fluorescent labelling, which often result in differences in cellular uptake, efficiency and toxicity of particles, novel detection techniques are required.
CRIS-Team WoS Importer:2021-01-29

Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner - Britzen-Laurent, Nathalie; Bauer, Michael; Berton, Valeria; Fischer, Nicole; Syguda, Adrian; Reipschlaeger, Simone; Naschberger, Elisabeth; Herrmann, Christian; Stürzl, Michael (PLoS ONE, 2010)
Guanylate-binding proteins (GBPs) belong to the dynamin family of large GTPases and represent the major IFN-c-induced proteins. Here we systematically investigated the mechanisms regulating the subcellular localization of GBPs. Three GBPs (GBP-1, GBP-2 and GBP-5) carry a C-terminal CaaX-prenylation signal, which is typical for small GTPases of the Ras family, and increases the membrane affinity of proteins. In this study, we demonstrated that GBP-1, GBP-2 and GBP-5 are prenylated in vivo and that prenylation is required for the membrane association of GBP-1, GBP-2 and GBP-5. Using coimmunoprecipitation, yeast-two-hybrid analysis and fluorescence complementation assays, we showed for the first time that GBPs are able to homodimerize in vivo and that the membrane association of GBPs is regulated by dimerization similarly to dynamin. Interestingly, GBPs could also heterodimerize. This resulted in hierarchical positioning effects on the intracellular localization of the proteins. Specifically, GBP-1 recruited GBP-5 and GBP-2 into its own cellular compartment and GBP-5 repositioned GBP-2. In addition, GBP-1, GBP-2 and GBP-5 were able to redirect non-prenylated GBPs to their compartment in a prenylation-dependent manner. Overall, these findings prove in vivo the ability of GBPs to dimerize, indicate that heterodimerization regulates sub-cellular localization of GBPs and underscore putative membrane-associated functions of this family of proteins. © 2010 Britzen-Laurent et al.
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Intraoperative Blood Flow Analysis of Free Flaps with Arteriovenous Loops for Autologous Microsurgical Reconstruction - Geierlehner, Alexander; Horch, Raymund E.; Ludolph, Ingo; Lang, Werner; Rother, Ulrich; Meyer, Alexander; Arkudas, Andreas (Journal of Clinical Medicine, 2023)
Background: Arteriovenous (AV) loops help to overcome absent or poor-quality recipient vessels in highly complex microvascular free flap reconstruction cases. There are no studies on blood flow and perfusion patterns. The purpose of this study was to evaluate and compare intraoperative hemodynamic characteristics of AV loops followed by free tissue transfer for thoracic wall and lower extremity reconstruction. Methods: this prospective clinical study combined Transit-Time Flowmetry and microvascular Indocyanine Green Angiography for the assessment of blood flow volume, arterial vascular resistance and intrinsic transit time at the time of AV loop construction and on the day of free flap transfer. Results: A total of 11 patients underwent AV loop creation, of whom five required chest wall reconstruction and six required reconstruction of the lower extremities. In seven of these cases, the latissimus dorsi flap and in four cases the vertical rectus abdominis myocutaneous (VRAM) flap was used as a free flap. At the time of loop construction, the blood flow volume of AV loops was 466 ± 180 mL/min, which increased to 698 ± 464 mL/min on the day of free tissue transfer (p > 0.1). After free flap anastomosis, the blood flow volume significantly decreased to 18.5 ± 8.3 mL/min (p < 0.001). There was no significant difference in blood flow volume or arterial vascular resistance between latissimus dorsi and VRAM flaps, nor between thoracic wall and lower extremity reconstruction. However, a significant correlation between the flap weight and the blood flow volume, as well as to the arterial vascular resistance, was found (p < 0.05). Conclusion: This is the first study to perform intraoperative blood flow and hemodynamic measurements of AV loops followed by free tissue transfer. Our results show hemodynamic differences and contribute to deeper understanding of the properties of AV loops for free flap reconstruction.
CRIS-Team Scopus Importer:2023-12-22
Keywords: ICG fluoroscopy; interdisciplinary plastic surgery; microsurgery; plastic surgery; reconstructive surgery; surgical innovation

Intraoperative robotic-assisted low anterior rectal resection performance assessment using procedure-specific binary metrics and a global rating scale - Gomez Ruiz, Marcos; Tou, Samson; Gallagher, Anthony G.; Cagigas Fernandez, Carmen; Cristobal Poch, Lidia; Matzel, Klaus (BJS Open, 2022)
In this prospective, multicentre study, we objectively assessed the performance of experienced and novice colorectal surgeons performing robotic-assisted low anterior rectal resection (for rectal cancer surgery) with two assessment methods: proficient-based progressive (PBP), and GEARS. Both assessment methods discriminated between group performances, but PBP binary metrics seem to be a more useful tool in this study. PBP binary metrics revealed that some experienced surgeons performed poorly.
CRIS-Team WoS Importer:2022-05-20

Introduction of complete mesocolic excision with central vascular ligation as standardized surgical treatment for colon cancer in Greece. Results of a pilot study and bi-institutional cooperation - Perrakis, Aristotelis; Vassos, Nikolaos; Weber, Klaus; Matzel, Klaus E.; Papadopoulos, Konstantinos; Koukis, Georgios; Perrakis, Evangelos; Croner, Roland S.; Hohenberger, Werner (Archives of Medical Science, 2019)
Introduction: Complete mesocolic excision (CME) is generally accepted as state of the art in colon cancer surgery. However, the long-term impact of CME has not been systematically examined. Therefore cohort studies might be a possible way to clarify any differences between conventional resections and CME. Following bilateral cooperation between the Department of Surgery/University Hospital of Erlangen and the 1st Surgical Department of the General Hospital of Nikaia/Piraeus, including teaching activities for introduction of CME, a cohort study was performed, considering surgical quality criteria and clinical outcome.
CRIS-Team WoS Importer:2019-09-27

Inverse relation of Fas-ligand and tumor-infiltrating lymphocytes in angiosarcoma: indications of apoptotic tumor counterattack. - Zietz, Christian; Rumpler, Ulrich; Stürzl, Michael; Löhrs, Udo (American Journal of Pathology, 2001)
Fas and Fas-L regulate immune responses through the induction of cell death. Fas-L is commonly expressed in activated immune cells and in the endothelium. In the latter it contributes to the inhibition of transvascular cell migration by the induction of apoptosis in Fas-bearing lymphocytes. Here we investigated whether the Fas/Fas-L system may regulate lymphocyte invasion into angiosarcomas. Fas and Fas-L expression was quantitatively determined in different grade angiosarcomas (n = 40) and related to the number of extravasated tumor-infiltrating lymphocytes (TILs). Fas expression was detected in < 50% of the cases. In positive tumors both the number of Fas-positive cells and the staining intensity were highly variable and did not correlate with the number of TILs, the mean time of survival, and the histopathological tumor grade. By contrast, Fas-L expression was detected in >70% of the cases and the relative numbers of Fas-L-positive cells correlated inversely with the numbers of CD3- and CD8-positive TILs (P < or = 0.004). The survival times of patients with high Fas-L-expressing angiosarcomas were significantly reduced as compared to patients with low Fas-L-expressing tumors. Our results show that angiosarcomas with low Fas-L expression are characterized by numerous TILs, whereas sarcomas with high Fas-L expression show significantly reduced numbers of TILs. These results suggest that the Fas/Fas-L system may repress TIL invasion into angiosarcoma and by this may contribute to the evasion of the anti-tumor immune surveillance of angiosarcoma in the course of an apoptotic tumor counterattack mechanism.

Investigating Intestinal Barrier Breakdown in Living Organoids - Bardenbacher, Marco; Ruder, Barbara; Britzen-Laurent, Nathalie; Naschberger, Elisabeth; Becker, Christoph; Palmisano, Ralf; Stürzl, Michael; Tripal, Philipp (Journal of Visualized Experiments, 2020)
Organoids and three-dimensional (3D) cell cultures allow the investigation of complex biological mechanisms and regulations in vitro, which previously was not possible in classical cell culture monolayers. Moreover, monolayer cell cultures are good in vitro model systems but do not represent the complex cellular differentiation processes and functions that rely on 3D structure. This has so far only been possible in animal experiments, which are laborious, time consuming, and hard to assess by optical techniques. Here we describe an assay to quantitatively determine the barrier integrity over time in living small intestinal mouse organoids. To validate our model, we applied interferon gamma (IFN-gamma) as a positive control for barrier destruction and organoids derived from IFN-gamma receptor 2 knock out mice as a negative control. The assay allowed us to determine the impact of IFN-gamma on the intestinal barrier integrity and the IFN-gamma induced degradation of the tight junction proteins claudin-2, -7, and -15. This assay could also be used to investigate the impact of chemical compounds, proteins, toxins, bacteria, or patient-derived probes on the intestinal barrier integrity.
CRIS-Team WoS Importer:2020-04-17

Investigation of Different Methods of Intraoperative Graft Perfusion Assessment during Kidney Transplantation for the Prediction of Delayed Graft Function: A Prospective Pilot Trial - Gerken, Andreas L.H.; Keese, Michael; Weiss, Christel; Krücken, Hanna Sophie; Pecher, Katarina A.P.; Ministro, Augusto; Rahbari, Nuh N.; Reissfelder, Christoph; Rother, Ulrich; Yazdani, Babak; Kälsch, Anna Isabelle; Krämer, Bernhard K.; et al. (Journal of Personalized Medicine, 2022)
Delayed graft function (DGF) after renal transplantation is a relevant clinical problem affecting long-term organ function. The early detection of patients at risk is crucial for postoperative monitoring and treatment algorithms. In this prospective cohort study, allograft perfusion was evaluated intraoperatively in 26 kidney recipients by visual and formal perfusion assessment, duplex sonography, and quantitative microperfusion assessment using O2C spectrometry and ICG fluorescence angiography. The O2C tissue spectrometry device provides a quantitative method of microperfusion assessment that can be employed during kidney transplantation as an easy-to-use and highly sensitive alternative to ICG fluorescence angiography. Intraoperative microvascular flow and velocity in the allograft cortex after reperfusion predicted DGF with a sensitivity of 100% and a specificity of 82%. Threshold values of 57 A.U. for microvascular flow and 13 A.U. for microvascular velocity were identified by an ROC analysis. This study, therefore, confirmed that impairment of microperfusion of the allograft cortex directly after reperfusion was a key indicator for the occurrence of DGF after kidney transplantation. Our results support the combined use of intraoperative duplex sonography, for macrovascular quality control, and quantitative microperfusion assessment, such as O2C spectrometry, for individual risk stratification to guide subsequent postoperative management.
CRIS-Team Scopus Importer:2022-11-04
Keywords: indocyanine green; laser Doppler; near-infrared fluorescence; renal allograft; tissue oxygenation; transplant function

In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease - Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; et al. (Nature Medicine, 2014)
As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.
EVALuna2:1838

IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3 - Kesselring, Rebecca; Glaesner, Joachim; Hiergeist, Andreas; Naschberger, Elisabeth; Neumann, Helmut; Brunner, Stefan M.; Wege, Anja K.; Seebauer, Caroline; Koehl, Gudrun; Merkl, Susanne; Croner, Roland S.; Hackl, Christina; et al. (Cancer Cell, 2016)
Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.
EVALuna2:2089

Iron Store of Repeat Plasma and Platelet Apheresis Donors - Pfeiffer, Hella; Hechler, Johannes; Zimmermann, Robert; Hackstein, Holger; Achenbach, Susanne (Clinical Laboratory, 2021)
Background: Repeat apheresis donation causes a noticeable loss of whole blood: through routine blood tests with every donation as well as through residual blood left within the used apheresis set. While the effect of blood loss on donor iron stores has been widely researched for whole blood donations, fewer and especially contradictory results exist for apheresis donors. Methods: A retrospective analysis of the donor blood samples (Department of Transfusion Medicine, University Hospital Erlangen) of the past 11 years (n = 52.976) was performed. Serum ferritin and hemoglobin were used to detect iron deficiency. Values at admission were compared to values measured at the donations. To investigate the impact of the donation frequency, this frequency was calculated for every single donor (for the whole duration of 11 years as well as for each individual year). Correlation and regression analyses between frequency and iron parameters were performed. A special group were long-time repeat donors, whose changes in ferritin values were analyzed in comparison to the first-ever ferritin value before the first donation. Results: All donor groups show significantly lower mean ferritin and hemoglobin values after repeated donations than at admission. Interestingly, there are much more iron-depleted females in the control group than there are iron-depleted males. The correlation and regression analysis showed a significant relationship between donation frequency and iron-deficiency in males, but not in females. The analysis of the long-time repeat donors showed that the relative ferritin value dropped more in males than in females. When comparing iron-depleted long-time donors, females tend to be iron-depleted much more often even before the first donation. Conclusions: Repeat apheresis donation has a noticeable effect on the iron store of the blood donor, leading to a high percentage of iron-deficient donors, especially in women. The very small correlation between donation frequency and iron depletion for females is most likely due to the fact that women tend to be iron-deficient even before the first donation. Because of the natural variation of inter-donation-intervals, the calculated donation frequency might not be that exact. As a result, the correlation between donation frequency and iron stores might be higher than suggested by this work.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Apheresis; Blood donation; Blood donor; Iron; Iron deficiency

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology: Results from a prospective three-phased multicentre trial - Klenske, Entcho; Zopf, Steffen; Neufert, Clemens; Naegel, Andreas; Gschossmann, Juergen; Muehldorfer, Steffen; Pfeifer, Lukas; Fischer, Sören; Vitali, Francesco; Iacucci, Marietta; Ghosh, Subrata; Rath, Michelle G.; et al. (PLoS ONE, 2018)
BACKGROUND AND AIMS: Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS: In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS: The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION: The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.
EVALuna2:35169

Isolated testicular pain mimicking ruptured abdominal aortic aneurysm in a nonagenarian - Regus, Susanne; Apel, Hendrik; Dankerl, Peter; Lang, Werner (American Journal of Emergency Medicine, 2015)
Ruptured abdominal aortic aneurysm commonly presents as acute abdominal or lower back pain and hemodynamic instability. We discuss the case of a 90-year-old patient who presented to the emergency unit with a 3-day history of left testicular pain. Ultrasound scan demonstrated and a computed tomography scan confirmed a 6 cm in diameter ruptured abdominal aortic aneurysm with enlargement and hematoma of the left psoas muscle causing the symptoms. This atypical presentation highlights the need for clinical vigilance and emergency physician-performed ultrasound scan in the older patients with seemingly benign testicular symptoms.
EVALuna2:14469

Isolation of Endothelial Cells from Human Tumors - Naschberger, Elisabeth; Schellerer, Vera; Rau, Tilman T.; Croner, Roland S.; Stürzl, Michael (Cancer Cell Culture, 2011)
Antiangiogenic drugs have been used successfully for the treatment of colorectal cancer (CRC) and several other tumor types. Until recently, viable tumor endothelial cells (TEC) and normal endothelial cells of uninvolved colon tissue (NEC) from the same patient have not been available to optimize treatment strategies in vitro. Here, we describe a protocol for the isolation of TEC and NEC. These cells were isolated at a very high purity via magnetic cell sorting of tissue samples obtained from surgical specimens of patients suffering from CRC. Isolated TEC and NEC expressed CD31, CD105, VE-cadherin, VCAM-1, ICAM-1, and E-selectin, formed capillaries in basal membrane extract, and were able to take up acetylated LDL. They were negative for podoplanin, CD45, CD68, and CK-20, indicating blood vessel endothelial lineage. Expression of vWF was more pronounced in NEC cultures, whereas vWF was absent or only slightly expressed in all TEC cultures in vitro. Lower intracellular concentrations of vWF were also detected in TEC as compared to NEC at the tissue level. The latter finding demonstrated that differential features of TEC and NEC in vivo arc stably perpetuated in culture. The isolated endothelial cell cultures may provide a useful in vitro model system to elucidate epigenetic effects on angiogenesis in cancer and to optimize antiangiogenic therapy.
Created from Fastlane, WoS look-up

Isolation of Enterococcus faecium and determination of its mechanism for promoting the growth and development of Drosophila - Li, Yujuan; Pan, Lei; Li, Pengcheng; Gao, Fuguo; Wang, Lei; Chen, Jian; Li, Zhichao; Gao, Yongheng; Gong, Yumei; Jin, Faguang (Scientific Reports, 2023)
Intestinal symbiotic microorganisms have a strong capacity to regulate the physiological functions of their host, and Drosophila serves as a useful model. Enterococcus faecium (E. faecium) is a member of the normal intestinal flora of animals. Lactic acid bacteria (LAB) such as E. faecium can promote the growth and development of Drosophila, but the mechanism of regulation of Drosophila is poorly understood. In this study, we found that E. faecium used a carbon source to produce probiotic acids. E. faecium is a symbiotic bacterium for Drosophila, and adult flies passed on parental flora to offspring. E. faecium promoted the growth and development of Drosophila, especially under poor nutritional conditions. E. faecium shortened the developmental process for Drosophila and accelerated the transformation from larva to pupa. Finally, E. faecium promoted the growth and development of Drosophila through TOR and insulin signalling pathways.
CRIS-Team Scopus Importer:2023-11-17

Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol - Naschberger, Elisabeth; Regensburger, Daniela; Tenkerian, Clara; Langheinrich, Melanie; Engel, Felix; Geppert, Carol-Immanuel; Hartmann, Arndt; Grützmann, Robert; Schellerer, Vera; Stürzl, Michael (Journal of Visualized Experiments, 2018)
Primary cells isolated from human carcinomas are valuable tools to identify pathogenic mechanisms contributing to disease development and progression. In particular, endothelial cells (EC) constituting the inner surface of vessels, directly participate in oxygen delivery, nutrient supply, and removal of waste products to and from tumors, and are thereby prominently involved in the constitution of the tumor microenvironment (TME). Tumor endothelial cells (TECs) can be used as cellular biosensors of the intratumoral microenvironment established by communication between tumor and stromal cells. TECs also serve as targets of therapy. Accordingly, in culture these cells allow studies on mechanisms of response or resistance to anti-angiogenic treatment. Recently, it was found that TECs isolated from human colorectal carcinoma (CRC) exhibit memory-like effects based on the specific TME they were derived from. Moreover, these TECs actively contribute to the establishment of a specific TME by the secretion of different factors. For example, TECs in a prognostically favorable Th1-TME secrete the anti-angiogenic tumor-suppressive factor secreted protein, acidic and rich in cysteine-like 1 (SPARCL1). SPARCL1 regulates vessel homeostasis and inhibits tumor cell proliferation and migration. Hence, cultures of pure, viable TECs isolated from human solid tumors are a valuable tool for functional studies on the role of the vascular system in tumorigenesis. Here, a new up-to-date protocol for the isolation of primary EC from the normal colon as well as CRC is described. The technique is based on mechanical and enzymatic tissue digestion, immunolabeling, and fluorescence activated cell sorting (FACS)-sorting of triple-positive cells (CD31, VE-cadherin, CD105). With this protocol, viable TEC or normal endothelial cell (NEC) cultures could be isolated from colon tissues with a success rate of 62.12% when subjected to FACS-sorting (41 pure EC cultures from 66 tissue samples). Accordingly, this protocol provides a robust approach to isolate human EC cultures from normal colon and CRC.
EVALuna2:34267

Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival? - Schreiner, Waldemar; Dudek, Wojciech; Sirbu, Horia (Interactive Cardiovascular and Thoracic Surgery, 2015)
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether salvage pulmonary resection is possible and worthwhile for patients with recurrence of non-small-cell lung cancer (NSCLC) after prior definitive non-operative therapy. A total of nine reports were identified using the reported search, of which four represented the best available evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All studies were retrospective. In total, 48 pulmonary salvage resections were performed in 47 patients after prior definitive radiation, chemoradiation or stereotactic body radiation therapy, of which 28 were lobectomies (including 1 sleeve lobectomy), 12 pneumonectomies, 4 bilobectomies and 4 sublobar resections (2 segmentectomies and 2 wedge resections). Postoperative complications ranged from 0 to 58% (mean from four studies 42.5%). Only one study reported any mortality (4%), the other three had zero mortality. Median postoperative survival was reported in two studies and ranged from 9 to 30 months. Experience with salvage lung resection for locally recurrent NSCLC, after prior definitive non-surgical treatment, remains limited. Therefore, this analysis was based on only 48 resections in 47 patients from four retrospective studies. Nevertheless, the published data suggest that salvage lung surgery for recurrent, previously non-operatively managed non-small-cell lung cancer is a worthwhile treatment option with good survival, acceptable morbidity and low mortality.
EVALuna2:25168

IT infrastructure components to support clinical care and translational research projects in a comprehensive cancer center - Prokosch, Hans-Ulrich; Ries, Markus; Beyer, Alexander; Schwenk, Martin; Seggewies, Christof; Köpcke, Felix; Mate, Sebastian; Martin, Marcus; Bärthlein, Barbara; Beckmann, Matthias; Stürzl, Michael; Croner, Roland; et al. (User Centred Networked Health Care, 2011)
This paper presents the concept of an integrated IT infrastructure framework established at the comprehensive cancer center at the University Hospital Erlangen. The framework is based on the single source concept where data from the electronic medical record are reused for clinical and translational research projects. The applicability of the approach is illustrated by two case studies from colon cancer and prostate cancer research projects. © 2011 European Federation for Medical Informatics. All rights reserved.
UnivIS-Import:2015-04-14:Pub.2011.tech.IMMD.infome.itinfr
Keywords: Cancer documentation; Center; Comprehensive cancer; IT infrastructure framework; Single source concept; Translational research

IVOPAK II Study: Morbidity Following Secondary Resection of Colorectal Liver Metastases - Schellerer, Vera; Merkel, Susanne; Grützmann, Robert; Kersting, Stephan; Wein, Axel (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment - Zhang, Yun; Liang, Ruifang; Chen, Chih-Wei; Mallano, Tatjana; Dees, Clara; Distler, Alfiya; Reich, Adam; Bergmann, Christina; Ramming, Andreas; Gelse, Kolja; Mielenz, Dirk; Distler, Oliver; et al. (Annals of the Rheumatic Diseases, 2017)
Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-?. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.
EVALuna2:13270

Jugular venous congestion in acute pulmonary embolism - Schlundt, Christian; Bietau, Christian; Achenbach, Susanne (Herz, 2014)
EVALuna2:11994

Jumonji Domain Containing Protein 3 (JMJD3) As a Novel Epigenetic Mechanism of Fibroblast Activation By Regulation of Fra-2 - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Lin, Neng-Yu; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kam, Pui-See; Distler, Oliver; Schett, Georg; Distler, Jörg (2016)
EVALuna2:35056

Kaposi's sarcoma: a review of gene expression and ultrastructure of KS spindle cells in vivo. - Stürzl, Michael; Brandstetter, Heinz; Roth, W K (Aids Research and Human Retroviruses, 1992)
The ultrastructural features and the gene expression pattern of Kaposi's sarcoma (KS) spindle cells in vivo suggest that KS is a tumor of the mixed cell type. The expression pattern of cytokines and cytokine receptors in the tumor lesion, together with the results obtained from in vitro characterization of KS-derived cells, provide evidence that paracrine mechanisms of growth factor action are important for the maintenance of KS. The reports on virus infection of KS cells suggest an indirect role of virus infection in the induction of KS, most likely mediated by immunostimulation and subsequent production of cytokines.

Kaposi's sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. - Hahn, Alexander; Birkmann, Alexander; Wies, Effi; Dorer, Dominik; Mahr, Kerstin; Stürzl, Michael; Titgemeyer, Fritz; Neipel, Frank (Journal of Virology, 2009)
The attachment, entry, and fusion of Kaposi's sarcoma-associated herpesvirus (KSHV) with target cells are mediated by complex machinery containing, among others, viral glycoprotein H (gH) and its alleged chaperone, gL. We observed that KSHV gH, in contrast to its homologues in several other herpesviruses, is transported to the cytoplasm membrane independently from gL, but not vice versa. Mutational analysis revealed that the N terminus of gH is sufficient for gL interaction. However, the entire extracellular part of gH is required for efficient gL secretion. The soluble ectodomain of gH was sufficient to interact with the surfaces of potential target cells in a heparin-dependent manner, and binding was further enhanced by coexpression of gL. Surface plasmon resonance revealed a remarkably high affinity of gH for glycosaminoglycans. Heparan sulfate (HS) proteoglycans of the syndecan family act as cellular receptors for the gH/gL complex. They promoted KSHV infection, and expression of gH/gL on target cells inhibited subsequent KSHV infection. Whereas gH alone was able to bind to HS, we observed that only the gH/gL complex adhered to heparan sulfate-negative cells at lamellipodium-like structures.

Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays. - Schatz, Octavian; Monini, Paolo; Bugarini, Roberto; Neipel, Frank; Schulz, Thomas F.; Andreoni, Massimo; Erb, Peter; Eggers, Maren; Haas, Jürgen; Buttò, Stefano; Lukwiya, Matthew; Bogner, Johannes R.; et al. (Journal of Medical Virology, 2001)
A multicentre study was undertaken to define novel assays with increased inter-assay concordance, sensitivity, specificity and predictive value for serological diagnosis of human herpesvirus type 8 (HHV-8) infection. A total of 562 sera from European and Ugandan human immunodeficiency virus (HIV)-infected or uninfected individuals with or without Kaposi's sarcoma (KS) and blood donors were examined under code by 18 different assays in seven European laboratories. Sera from KS patients and all non-KS sera found positive by at least 70%, 80%, or 90% of the assays were considered "true positive." The validity of the assays was then evaluated by univariate logistic regression analysis. Two immunofluorescence assays (IFA) for detection of antibodies against HHV-8 lytic (Rlyt) or latent (LLANA) antigens and two enzyme-linked-immunosorbent assays (ELISA) (M2, EK8.1) for detection of antibodies against HHV-8 structural proteins were found to be highly concordant, specific, and sensitive, with odds ratios that indicated a high predictive value. When used together, the two IFA (Rlyt-LLANA) showed the best combination of sensitivity (89.1%) and specificity (94.9%). The performance of these assays indicate that they may be used for the clinical management of individuals at risk of developing HHV-8 associated tumours such as allograft recipients.

Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity - Full, Florian; Jungnickl, Doris; Reuter, Nina; Bogner, Elke; Brulois, Kevin; Scholz, Brigitte; Stürzl, Michael; Myoung, Jinjong; Jung, Jae U.; Stamminger, Thomas; Enßer, Armin (PLoS Pathogens, 2014)
Nuclear domain 10 (ND10) components are restriction factors that inhibit herpesviral replication. Effector proteins of different herpesviruses can antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. We investigated the interplay of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) infection and cellular defense by nuclear domain 10 (ND10) components. Knock-down experiments in primary human cells show that KSHV-infection is restricted by the ND10 components PML and Sp100, but not by ATRX. After KSHV infection, ATRX is efficiently depleted and Daxx is dispersed from ND10, indicating that these two ND10 components can be antagonized by KSHV. We then identified the ORF75 tegument protein of KSHV as the viral factor that induces the disappearance of ATRX and relocalization of Daxx. ORF75 belongs to a viral protein family (viral FGARATs) that has homologous proteins in all gamma-herpesviruses. Isolated expression of ORF75 in primary cells induces a relocalization of PML and dispersal of Sp100, indicating that this viral effector protein is able to influence multiple ND10 components. Moreover, by constructing a KSHV mutant harboring a stop codon at the beginning of ORF75, we could demonstrate that ORF75 is absolutely essential for viral replication and the initiation of viral immediate-early gene expression. Using recombinant viruses either carrying Flag- or YFP-tagged variants of ORF75, we could further corroborate the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity, and show that it is independent of the PML antagonist vIRF3. Members of the viral FGARAT family target different ND10 components, suggesting that the ND10 targets of viral FGARAT proteins have diversified during evolution. We assume that overcoming ND10 intrinsic defense constitutes a critical event in the replication of all herpesviruses; on the other hand, restriction of herpesviral replication by ND10 components may also promote latency as the default outcome of infection.
EVALuna2:8222

Kaposi's sarcoma-derived cell line SLK is not of endothelial origin, but is a contaminant from a known renal carcinoma cell line. - Stürzl, Michael; Gaus, Dominika; Dirks, Wilhelm G.; Ganem, Don; Jochmann, Ramona (International Journal of Cancer, 2013)
Kaposi's sarcoma (KS) is an endothelial cell-derived tumor. Investigations of the molecular mechanisms of KS pathogenesis and the identification of drugs for treatment of KS depend critically on valid cell-culture models. Two major immortalized cell lines are available for KS research. Recently, the KS cell line KS Y-1 has been shown to be cross-contaminated with the T24 urinary bladder cancer cell line (ATCC HTB-4). Here, we show by short tandem repeat profiling that the second KS cell line, SLK, is indistinguishable from the clear-cell renal-cell carcinoma cell line Caki-1. Immunocytochemical detection of cytokeratin expression confirmed the epithelial-cell origin of SLK cells. Our findings indicate that SLK cells are not of endothelial origin and should not be used in future studies as a model for KS-derived endothelial tumor cells. We suggest that in the future, more attention needs to be paid to the authenticity of cells in lines derived from human tissues.

Ketos: Clinical decision support and machine learning as a service – A training and deployment platform based on Docker, OMOP-CDM, and FHIR Web Services - Gründner, Julian; Schwachhofer, Thorsten; Sippl, Phillip; Wolf, Nicolas; Erpenbeck, Marcel; Gulden, Christian; Kapsner, Lorenz A.; Zierk, Jakob; Mate, Sebastian; Stürzl, Michael; Croner, Roland; Prokosch, Hans-Ulrich; et al. (PLoS ONE, 2019)
Background and objective To take full advantage of decision support, machine learning, and patient-level prediction models, it is important that models are not only created, but also deployed in a clinical setting. The KETOS platform demonstrated in this work implements a tool for researchers allowing them to perform statistical analyses and deploy resulting models in a secure environment. Methods The proposed system uses Docker virtualization to provide researchers with reproducible data analysis and development environments, accessible via Jupyter Notebook, to perform statistical analysis and develop, train and deploy models based on standardized input data. The platform is built in a modular fashion and interfaces with web services using the Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR) standard to access patient data. In our prototypical implementation we use an OMOP common data model (OMOP-CDM) database. The architecture supports the entire research lifecycle from creating a data analysis environment, retrieving data, and training to final deployment in a hospital setting. Results We evaluated the platform by establishing and deploying an analysis and end user application for hemoglobin reference intervals within the University Hospital Erlangen. To demonstrate the potential of the system to deploy arbitrary models, we loaded a colorectal cancer dataset into an OMOP database and built machine learning models to predict patient outcomes and made them available via a web service. We demonstrated both the integration with FHIR as well as an example end user application. Finally, we integrated the platform with the open source DataSHIELD architecture to allow for distributed privacy preserving data analysis and training across networks of hospitals. Conclusion The KETOS platform takes a novel approach to data analysis, training and deploying decision support models in a hospital or healthcare setting. It does so in a secure and privacy-preserving manner, combining the flexibility of Docker virtualization with the advantages of standardized vocabularies, a widely applied database schema (OMOP-CDM), and a standardized way to exchange medical data (FHIR).
CRIS-Team Scopus Importer:2019-10-11

Klassifikation der Präparatequalität nach kompletter mesokolischer Exzision für rechtsseitige Kolonkarzinome - Hohenberger, Werner (Coloproctology, 2019)
CRIS-Team Scopus Importer:2019-09-03

Kommentar zu den 2013 Leitlinien der Europäischen Gesellschaft für Kardiologie (ESC) zum Management der stabilen koronaren Herzkrankheit (KHK) - Sechtem, U.; Achenbach, Susanne; Gitt, A. K.; Marx, N.; Kelm, M.; Schächinger, V. (Der Kardiologe, 2015)
The 2013 guidelines of the European Society of Cardiology (ESC) on the management of stable coronary artery disease (CAD) give practical recommendations for the use of diagnostic tools to identify hemodynamically relevant coronary artery stenoses. Furthermore, they give advice for the management of previously symptomatic patients with known obstructive or non-obstructive CAD, who have become asymptomatic with treatment and need regular follow-up. The selection of appropriate diagnostic tests is based on the tabulated pretest probability of the patient, which plays a central role in the diagnostic algorithm. An invasive approach is recommended only for patients who either have severe angina or who are judged to be at high risk for adverse events based on clinical evidence or the results of diagnostic tests. The optimal use of preventive and antianginal medications is shown in a scheme which includes the new antianginal drugs. The guidelines recommend a percutaneous coronary intervention (PCI) as an alternative to bypass surgery in patients with multivessel disease or left main stem stenosis if the SYNTAX score is low.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Diagnostics; Follow-up; Indications; Recommendation; Therapy

Kommentar zum 2016 Positionspapier der Europäischen Gesellschaft für Kardiologie (ESC) zu kardiovaskulären Komplikationen onkologischer Therapien - Pfister, R.; Achenbach, Susanne; Boenner, F.; Mueller, O. J.; Hallek, Michael; Kochanek, M.; Bokemeyer, C.; Weissinger, F.; Lueftner, D.; Baldus, S.; Kelm, M. (Der Kardiologe, 2018)
Resulting from advances in oncological treatment, cancer patients frequently experience cardiovascular complications of the cancer treatment. Furthermore, many of the recently developed new drugs in oncology are potentially associated with cardiovascular side effects. Given this increased complexity in the field of cardio-oncology, the European Society of Cardiology published a position paper on cancer treatment and cardiovascular toxicity in August 2016. This position paper for the first time systematically reviewed the pathophysiology and clinical manifestations of cardiovascular disease entities during and after cancer treatment and provided suggestions for screening, diagnosis, monitoring, prevention and treatment. The following comments of the German Society of Cardiology in cooperation with the German Society of Hematology and Medical Oncology briefly summarizes and critically reviews the important aspects of the position paper.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Cardio-oncology; Cardiotoxicity; Chemotherapy; Left-ventricular dysfunction; Radiation

Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo. - Venalis, Paulius; Maurer, Britta; Akhmetshina, Alfiya; Busch, Nicole; Dees, Clara; Stürzl, Michael; Zwerina, Jochen; Juengel, Astrid; Gay, Steffen; Schett, Georg; Distler, Oliver; Distler, Jörg (Journal of Cellular and Molecular Medicine, 2009)
Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

Laparoscopic right hemicolectomy with CME: standardization using the "critical view" concept - Strey, Christoph Werner; Wullstein, Christoph; Adamina, Michel; Agha, Ayman; Aselmann, Heiko; Becker, Thomas; Grützmann, Robert; Kneist, Werner; Maak, Matthias; Mann, Benno; Moesta, Kurt Thomas; Runkel, Norbert; et al. (Surgical Endoscopy, 2018)
BACKGROUND: Complete mesocolic excision is gradually becoming an established oncologic surgical principle for right hemicolectomy. However, the procedure is technically demanding and carries the risk of serious complications, especially when performed laparoscopically. A standardized procedure that minimizes technical hazards and facilitates teaching is, therefore, highly desirable. METHODS: An expert group of surgeons and one anatomist met three times. The initial aim was to achieve consensus about the surgical anatomy before agreeing on a sequence for dissection in laparoscopic CME. This proposal was evaluated and discussed in an anatomy workshop using post-mortem body donors along with videos of process-informed procedures, leading to a definite consensus. RESULTS: In order to provide a clear picture of the surgical anatomy, the "open book" model was developed, consisting of symbolic pages representing the corresponding dissection planes (retroperitoneal, ileocolic, transverse mesocolic, and mesogastric), vascular relations, and radicality criteria. The description of the procedure is based on eight preparative milestones, which all serve as critical views of safety. The chosen sequence of the milestones was designed to maximize control during central vascular dissection. Failure to reach any of the critical views should alert the surgeon to a possible incorrect dissection and to consider converting to an open procedure. CONCLUSION: Combining the open-book anatomical model with a clearly structured dissection sequence, using critical views as safety checkpoints, may provide a safe and efficient platform for teaching laparoscopic right hemicolectomy with CME.
EVALuna2:210704

Laparoscopic Right Hemicolectomy with Complete Mesocolic Excision (CME) Laparoskopische Hemikolektomie rechts mit kompletter mesokolischer Exzision (CME) - Brunner, Maximilian; Wiesmüller, Felix; Weber, Klaus; Maak, Matthias; Kersting, Stephan; Grützmann, Robert; Krautz, Christian; Weber, Georg (Zentralblatt für Chirurgie, 2020)
CRIS-Team Scopus Importer:2020-03-17

Laparoscopic surgery for colon cancer: quality requirements for (extended) right hemicolectomy - Lux, Philipp; Weber, K.; Hohenberger, Werner (Chirurg, 2014)
The current S3 guidelines on the surgical treatment of colorectal cancer note that with a suitable patient selection and expertise of the surgeon the same oncological results can be achieved laparoscopically as with the open procedure. This requires that the same quality requirements have to be provided for both methods. The most important quality parameters of right sided (extended) hemicolectomy are central ligation of the supplying arteries (ileocolic artery, right branch of the middle colic artery and middle colic artery) flush to the central origin of the vessel (superior mesenteric artery or middle colic artery) and the sharp dissection of the mesocolon without any preparation tears. The photographic documentation of the fresh surgical specimens for categorizing the preparation quality as well as to determine the pedicle of the vessel can capture this quality well and is also currently the best surrogate parameter to evaluate the oncological quality of the operation. At present, there are still considerable widespread deficits not only with the laparoscopic approach but also in open surgery which must be urgently fixed.
EVALuna2:15170

Laparoscopic surgery for rectal cancer reveals comparable oncological outcome even in context of worse short-term results—long-term analysis of nearly 500 patients from two high-volume centers - Zimmermann, Markus; Merkel, Susanne; Weber, Klaus; Bruch, Hans Peter; Hohenberger, Werner; Keck, Tobias; Grützmann, Robert (International Journal of Colorectal Disease, 2019)
Purpose: Large randomized controlled trials have investigated the oncological value of the laparoscopic approach to colorectal cancer. Mainly, non-inferiority for the laparoscopic approach regarding long-term survival could be shown. Nevertheless, some recent trials revealed inferiority especially due to histopathological quality of specimen or location of the tumor in the rectum. The main objective of this study was to compare two historical patient collectives of specialized centers for either the laparoscopic or the open resection approach, regarding long-term survival and disease progression of rectal cancer according to tumor localization in a retrospective propensity score–matched analysis. Methods: A retrospective analysis, based on two prospectively maintained institutional colorectal cancer databases, was performed. The database of the reference center in Erlangen maintained almost exclusively open operations whereas the database in Lübeck maintained to a vast majority laparoscopic operations. To adjust risk profiles, a 1:1 propensity score matching was performed. Results: Seven hundred fifty-five patients of both centers (Erlangen, n = 507, Lübeck n = 248) were included. Propensity score matching resulted in two equalized groups with 248 patients. Regarding the postoperative complications, advantages for the open approach were seen. Analyzing the survival data, no differences in disease-free as well as overall survival were shown. Also, no differences in the overall loco-regional recurrence and distant metastasis rate were detected. Conclusion: In centers with adequate expertise, open and laparoscopic procedures result in equivalent oncologic long-term outcomes. Advantages for the open resected group concerning short-term results and complications were detected, due to remarkably low rates of anastomotic leakage.
CRIS-Team Scopus Importer:2019-07-23
Keywords: Laparoscopic surgery; Open surgery; Propensity score; Rectal cancer; Recurrence; Survival

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study - Balduzzi, A.; van Hilst, J.; Korrel, M.; Lof, S.; Al-Sarireh, B.; Alseidi, A.; Berrevoet, F.; Björnsson, B.; van den Boezem, P.; Boggi, U.; Busch, O. R.; Butturini, G.; et al. (Surgical Endoscopy, 2021)
Background: A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. Methods: An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007–2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. Results: Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien–Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. Conclusion: The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.
CRIS-Team Scopus Importer:2021-01-15
Keywords: ERLP; Extended resection; Left pancreatectomy; PDAC

Laryngeal morbidity after intubation with or without neuromuscular block in thyroid surgery using recurrent laryngeal nerve monitoring - Birkholz, Torsten; Irouschek, Andrea; Saalfrank-Schardt, Christina; Klein, Peter; Schmidt, Joachim (Auris Nasus Larynx, 2012)
The avoidance of neuromuscular blocking agents (NMBA) for endotracheal intubation is associated with a higher incidence of laryngeal discomfort and lesions, but could impair effectiveness of intra operative recurrent laryngeal nerve monitoring (IONM).In a retrospective quality assessment study over a period of 30 months, a collective that had been intubated without NMBA was compared with a group, which had received NMBA. Endolaryngeal EMG was accomplished with a MagStim(®)-EMG-electrode.Out of the 127 patients with 224 nerves at risk (NAR; NMBA 102 NAR, no NMBA 122 NAR), more than 90% received a total intravenous anaesthesia with propofol, and 88% had remifentanil. Laryngeal side effects and damage scores did not differ significantly.In this special setting of IONM and thyroid surgery, avoidance of NMBA for endotracheal intubation seems not to increase the incidence of laryngeal side effects and lesions. If endotracheal intubation without NMBA is required, the authors suggest a standardized approach using induction agents as propofol and remifentanil.
EVALuna2:15058

Late Breaking Abstract - Induction of the transcriptional repressor B lymphocytes-induced maturation protein-1 (Blimp-1) in lung cancer - Neurath, Laura; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (EUROPEAN RESPIRATORY JOURNAL, 2020)
CRIS-Team WoS Importer:2021-02-12

Late-Onset Aspergillus Fumigatus Infection of an Aortic Stent Graft in an Immunocompetent Patient - Ballazhi, Fatos; Weyand, Michael; Lang, Werner; Schoerner, Christoph; Seitz, Tatjana (Thoracic and Cardiovascular Surgeon Reports, 2015)
Aspergillus fumigatus as a clinical entity is difficult to diagnose. We present a case, which could facilitate diagnosis and management of the aforementioned disease. A 60-year-old man with stent graft implantation in the descending aorta (6 years ago) presented with fever, night sweats, and weight loss over 5 months. Leukocytosis and elevated C-reactive protein were constantly spiking. Blood cultures were negative. Notably, the serum immunoglobulin E (IgE) level was strongly elevated (> 1,000 U/mL). Anamnestically, the patient suffered from a mild form of atopic dermatitis and bronchial asthma. The pulmonary status showed no abnormalities in the computed tomography image. Nonetheless, a chest scan revealed a suspected abscess around the stent graft of the descending aorta. Extra-anatomic ascending to descending aortic bypass (Gelsoft 22 mm, Vascutek, Juchinnan, Scotland, United Kingdom) was performed. Intraoperative samples revealed A. fumigatus. These findings were confirmed by polymerase chain reaction analysis. Infection by A. fumigatus represents a diagnostic challenge because blood cultures are usually negative, but expeditious treatment is required to prevent occurrence of irreversible complications. A late graft infection, possibly caused by A. fumigatus should be suspected in patients with implanted grafts, who suffer from unexplained, blood culture-negative fever that does not respond to antibiotics and who have a history of dermatitis or bronchial asthma with elevated IgE antibodies.
EVALuna2:7685

Left-sided Gallbladder in the Era of Laparoscopic Cholecystectomy: A Single-center Experience - Velimezis, Georgios; Vassos, Nikolaos; Kapogiannatos, Georgios; Koronakis, Dimitrios; Salpiggidis, Christos; Perrakis, Evangelos; Perrakis, Aristotelis (American Surgeon, 2015)
The malposition of gallbladder under the liver segment III, defined as left-sided gallbladder (LSG), is an unexpected situation for the laparoscopic surgeon. The purpose of this study is to present our experience in treating patients with cholecystitis and LSG discovered incidentally during laparoscopic surgical procedure. Between 1993 and 2009, 5569 patients underwent laparoscopic cholecystectomy in our surgical department. Their records were reviewed and seven patients revealed having LSG (0.12%). Analysis parameters included demographic data, diagnostic methods, mode of surgery, and postoperative outcome. Mean follow-up was 140 months. Of the seven patients, five were women. Mean patient age was 56.7 years. All patients were referred to our department with clinical symptoms of classic cholelithiasis and the diagnosis was established in all of them during surgery. Laparoscopic cholecystectomy was successful in five patients, while in two patients, a conversion to open procedure was needed. A postoperative complication, i.e., biliary leakage was registered in one patient, which was treated successfully. Laparoscopic cholecystectomy is safe even in LSG, but the surgeon must consider the possibility for more anatomical anomalies, adjust the technique of dissection, and must not hesitate, if in doubt, to strive for conversion to open procedure to avoid serious complications.
EVALuna2:15182

Lehrfilm Facharztweiterbildung: Hemithyreoidektomie mit Neuromonitoring des N. laryngeus recurrens - Brunner, Maximilian; Bleichroth, Hannah; Linke, Katja; Krautz, Christian; Grützmann, Robert; Kersting, Stephan; Weber, Georg (Zentralblatt für Chirurgie, 2019)
INTRODUCTION: The mean prevalence of thyroid nodules in adults is about 20% and increases with age. Most of the thyroid nodules are benign, and are rarely malignant. However, malignancy can often only be conclusively determined after resection. Therefore, it is essential that the surgical technique should be free of complications. Despite all published minimally invasive techniques, the open procedure via a Kocher incision is still standard and commonly used in a teaching setting. This standardised technique is presented step-by-step in the video. INDICATION: Sonographic and MIBI-scintigraphic possibly malignant solitary node in the right thyroid lobe. PROCEDURE: Hemithyreoidectomy with neuromonitoring of recurrent laryngeal nerve. CONCLUSION: Hemithyroidectomy is an adequate primary therapy for a solitary possibly malignant thyroid nodule. Intraoperative neuromonitoring to identify and protect the recurrent laryngeal nerve, visualisation and protection of the parathyroid glands without compromising blood circulation and careful hemostasis are the main pillars of low risk surgery of the thyroid.
CRIS-Team Scopus Importer:2019-12-24

Leitliniengerechte Therapie des Morbus Crohn: Aktuelle Handlungsempfehlungen - Fischer, Sören; Neurath, Markus (Gastroenterologe, 2019)
Background: Crohn’s disease is a complex condition with rising incidence worldwide. The approval of multiple new therapeutic options results in growing challenges for physicians and guidelines. Objectives: The aim of this paper is to describe a plausible algorithm for the treatment of Crohn’s disease based on the current scientific knowledge. Materials and methods: We refer to the current guidelines of the German Gastroenterology Organization (DGVS), the European Crohn’s and Colitis Organization (ECCO), the American College of Gastroenterology (ACG) as well as the drug professional information. Results: The therapy of Crohn’s disease depends on the affected tract regions, severity of inflammation, individual patient characteristics, previous therapies, and the patient’s preferences. Conclusions: The therapeutic options in Crohn’s disease are constantly evolving. The prediction of therapy response is a continued challenge for medical science. In the principle of participatory medicine, shared decision-making of patient and physician leads to better adherence to the therapy.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Biologicals; Colorectal surgery; Drug therapy; Glucocorticoids; Inflammatory bowel diseases

Leitlinie zum Einrichten und Betreiben von Herzkatheterlaboren und Hybridoperationssälen/Hybridlaboren: 3. Auflage 2015 - Schächinger, V.; Nef, H.; Achenbach, Susanne; Butter, C.; Deisenhofer, I.; Eckardt, L.; Eggebrecht, H.; Kuon, E.; Levenson, B.; Linke, A.; Madlener, K.; Mudra, H.; et al. (Der Kardiologe, 2015)
Besides diagnostic heart catheterization and coronary interventions, numerous additional procedures are now performed in catheterization laboratories with special requirements for equipment and sequence of operations. The current third edition of the guidelines to establish and operate catheterization laboratories, hybrid operating rooms (OR) and hybrid laboratories gives recommendations with respect to these procedures, including invasive electrophysiology, implantation of rhythm devices and also with respect to catheter-based valve therapy, especially transcather aortic valve implantation (TAVI). Special aspects of hygiene and structural conditions, which are required for hybrid ORs and hybrid laboratories, are discussed. The guidelines provide recommendations for planning a catheterization laboratory and hybrid OR as well as for operational aspects, which include legal regulations, hygiene requirements, structural architectural aspects and radiation safety. Furthermore, aspects of technical equipment, integration of modern three-dimensional imaging modalities, data management and workforce, including cardiac analgesia, are provided.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Cardiac catheterization; Coronary intervention; Electrophysiology; Hybrid operating room; Transcatheter aortic valve implantation

Length of Variable Numbers of Tandem Repeats in the Carboxyl Ester Lipase (CEL) Gene May Confer Susceptibility to Alcoholic Liver Cirrhosis but Not Alcoholic Chronic Pancreatitis - Fjeld, Karianne; Beer, Sebastian; Johnstone, Marianne; Zimmer, Constantin; Moessner, Joachim; Ruffert, Claudia; Krehan, Mario; Zapf, Christian; Njolstad, Pal Rasmus; Johansson, Stefan; Bugert, Peter; Miyajima, Fabio; et al. (PLoS ONE, 2016)
Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.
EVALuna2:15257

Leukocytosis and Neutrophilia as independent prognostic Biomarkers for clinical Outcome in the randomized Phase III CAO/ARO/AIO-04 Rectal Cancer Study - Diefenhardt, M.; Hofheinz, R-D; Martin, D.; Beissbarth, T.; Arnold, D.; Hartmann, Arndt; Von Der Grun, J.; Grützmann, Robert; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Rieger, M.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial - Diefenhardt, Markus; Hofheinz, Ralf Dieter; Martin, Daniel; Beißbarth, Tim; Arnold, Dirk; Hartmann, Arndt; von der Grün, Jens; Grützmann, Robert; Liersch, Torsten; Ströbel, Philipp; Grabenbauer, Gerhard G.; Rieger, Michael; et al. (International Journal of Cancer, 2019)
Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5-FU-based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO-04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow-up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease-free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment-induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5-FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high-level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.
CRIS-Team Scopus Importer:2019-05-07
Keywords: clinical radiotherapeutic studies; clinical trials; colorectal cancer; molecular markers of metastasis and progression; radiochemotherapy

Leveraging medical imaging for medical education - A cinematic rendering-featured lecture - Binder, Johannes; Krautz, Christian; Engel, Klaus; Grützmann, Robert; Fellner, Franz A.; Burger, Pascal H.M.; Scholz, Michael (Annals of Anatomy-Anatomischer Anzeiger, 2018)
BACKGROUND: The integration of medical imaging into anatomical education offers advantages in understanding and learning. However, spatial orientation with conventional (2D) imaging data is challenging, and the students' ability to imagine structures in three dimensions is individual. In addition, the quality of current volume rendering methods is limited. OBJECTIVE: We tested Cinematic Rendering (CR), a novel visualization technique that provides photorealistic volume rendering, in the setting of an interactive anatomy lecture with first-year undergraduate medical and dental students. Our goal was to estimate the acceptance and positive effects CR adds to the subjects. METHODS: A total of 120 students were surveyed with specifically designed self-assessment questionnaires on the use of CR as a tool in anatomical education. RESULTS: Of 120 participating students (87 medical and 33 dental) a large majority of 95.9% (Q3) experienced CR as helpful to understand anatomy better. Overall a large majority of the students experienced CR as helpful for learning and understanding, 85% saw an improvement in anatomical education through the integration of CR (Q3-6) and could also imagine using CR as a self-study tool on an electronic device. CONCLUSION: Our undergraduate medical and dental students experienced CR as a beneficial tool for anatomical education in the chosen setting (lecture) and see further opportunities for the sensible use of this technique. Future research on the topic should include other application possibilities as well.
EVALuna2:35343

Lipomatous Solitary Fibrous Tumors Harbor Rare NAB2-STAT6 Fusion Variants and Show Up-Regulation of the Gene PPARG, Encoding for a Regulator of Adipocyte Differentiation - Haller, Florian; Schlieben, Lea D.; Ferrazzi, Fulvia; Michal, Michael; Stöhr, Robert; Moskalev, Evgeny; Bieg, Matthias; Bovée, Judith V.M.G.; Ströbel, Philip; Ishaque, Naveed; Grützmann, Robert; Meidenbauer, Norbert; et al. (American Journal of Pathology, 2021)
Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture–based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4–STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.
CRIS-Team Scopus Importer:2021-06-04

Liposomal doxorubicin in the treatment of AIDS-associated Kaposi's sarcoma: clinical, histological and cell biological evaluation. - Stürzl, Michael; Zietz, Christian; Eisenburg, B; Goebel, F D; Gillitzer, R; Hofschneider, Peter Hans; Bogner, J. R. (RES VIROLOGY, 1994)
AIDS-associated Kaposi's sarcoma (KS) in eight patients was treated with the systemic application of liposomal doxorubicin (20 mg/m2 per cycle). After six cycles of treatment a significant regression of KS was observed in all patients. Tumour volume was reduced from 556 +/- 635 mm3 before therapy to 42 +/- 134 mm3 after therapy as determined by ultrasonography of selected tumours. Histological examination revealed a reduction of tumour-like structures and the absence of KS spindle cells in involved areas after therapy. In vitro experiments with KS-derived cell cultures, which most likely represent the KS spindle cells, suggested that liposomal doxorubicin may cause regression of KS via two different mechanisms: (i) by highly specific inhibition of KS spindle cell proliferation and (ii) by induction of monocyte chemoattractant protein-1 expression in KS spindle cells, which may result in increased recruitment of phagocytic cells (monocytes/macrophages) into the lesions. A cooperative action of both mechanisms may explain the high efficacy of liposomal doxorubicin in the treatment of AIDS-KS.
Keywords: AIDS; Kaposi's sarcoma; Doxorubicin; Liposome Therapy; Spindle cells; Monocyte chemoattractant protein-1

Liver Transplant Due to Flupirtine-Induced Acute Liver Failure - Dondorf, Felix; Croner, Roland S.; Tautenhahn, Hans Michael; Felgendreff, Philipp; Ardelt, Michael; Settmacher, Utz; Rauchfuss, Falk (Experimental and Clinical Transplantation, 2020)
Objectives: Acute drug-induced liver failure is a rare indication for liver transplant. There is only one case of flupirtine-induced liver failure requiring transplant in the literature. In February 2018, the European Medicines Agency issued a withdrawal of approval for flupirtine medication in European countries as a result of the risk of acute liver failure.
CRIS-Team WoS Importer:2020-08-21

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer - Penter, Livius; Dietze, Kerstin; Ritter, Julia; Cobo, Maria Fernanda Lammoglia; Garmshausen, Josefin; Aigner, Felix; Bullinger, Lars; Hackstein, Holger; Wienzek-Lischka, Sandra; Blankenstein, Thomas; Hummel, Michael; Dornmair, Klaus; et al. (OncoImmunology, 2019)
The degree and type of T cell infiltration influence rectal cancer prognosis regardless of classical tumor staging. We asked whether clonal expansion and tumor infiltration are restricted to selected-phenotype T cells; which clones are accessible in peripheral blood; and what the spatial distribution of their target antigens is. From five rectal cancer patients, we isolated paired tumor-infiltrating T cells (TILs) and T cells from unaffected rectum mucosa (T-UM) using 13-parameter FACS single cell index sorting. TCR alpha beta sequences, cytokine, and transcription factor expression were determined with single cell sequencing. TILs and T-UM occupied distinct phenotype compartments and clonal expansion predominantly occurred within CD8(+) T cells. Expanded TIL clones identified by paired TCR alpha beta sequencing and exclusively detectable in the tumor showed characteristic PD-1 and TIM-3 expression. TCR beta repertoire sequencing identified 49 out of 149 expanded TIL clones circulating in peripheral blood and 41 (84%) of these were PD-1(-) TIM-3(-). To determine whether clonal expansion of predominantly tumor-infiltrating T cell clones was driven by antigens uniquely presented in tumor tissue, selected TCRs were reconstructed and incubated with cells isolated from corresponding tumor or unaffected mucosa. The majority of clones exclusively detected in the tumor recognized antigen at both sites. In summary, rectal cancer is infiltrated with expanded distinct-phenotype T cell clones that either i) predominantly infiltrate the tumor, ii) predominantly infiltrate the unaffected mucosa, or iii) overlap between tumor, unaffected mucosa, and peripheral blood. However, the target antigens of predominantly tumor-infiltrating TIL clones do not appear to be restricted to tumor tissue.
CRIS-Team WoS Importer:2019-04-16

Local therapy for cancer: Also an important pillar of precision medicine in oncology Lokale Tumortherapie: Auch eine wichtige Säule der Präzisionsmedizin in der Onkologie - Guckenberger, Matthias; Grützmann, Robert; Ricke, Jens; Schmidberger, H. (Onkologe, 2020)
CRIS-Team Scopus Importer:2020-09-04

Local therapy for oligometastasized colorectal carcinoma Lokale Therapieverfahren beim oligometastasierten kolorektalen Karzinom - Kersting, Stephan; Grützmann, Robert (Onkologe, 2020)
Colorectal cancer (CRC) is one of the most common malignant diseases. In recent years, the clinical outcome of patients with metastatic CRC has greatly improved. This is due to a higher proportion of resections through improved surgical techniques, improved chemotherapeutic agents, the increased use of ablative techniques, and especially more intensive management of the cancer itself. This is reflected in the increasing number of patients treated in a multidisciplinary team environment and in specialized cancer centers. Further improvements can be found in imaging techniques, but also in prognostic and predictive molecular markers. Treatment decisions for patients with metastatic CRC should be based on evidence. For this purpose, the entire “toolbox” of local therapeutic procedures must be known and available and must be discussed again and again in an interdisciplinary setting.
CRIS-Team Scopus Importer:2020-08-14
Keywords: Ablation techniques; Combined modality therapy; Individualized therapy; Liver surgery; Neoplasm metastasis/liver

LOGIST - A local observational GIST registry: A non-interventional registry to observe patients with gastrointestinal stromal tumors (GIST) after R0/R1 resection - with or without adjuvant therapy with imatinib (CSTI571BDE77) - an interim analysis with 5 - Reichardt, P.; Quietzsch, D.; Stuebs, P.; Cameron, S.; Gellert, K.; Wilhelm, M.; Killing, B.; Croner, R.; Kopp, H. -G; Will, U.; Wardelmann, E.; Krajinovic, K. (2016)
EVALuna2:15240

Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis - Fischer, Sören; Rath, Timo; Geppert, Carol-Immanuel; Manger, Bernhard; Schett, Georg; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2017)
EVALuna2:6885

Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: A case report - Semrau, S.; Agaimy, Abbas; Pavel, Marianne Ellen; Lubgan, Dorota; Schmidt, Daniela; Golcher, H.; Grützmann, Robert; Fietkau, Rainer; Cavallaro, Alexander Josef (Journal of Medical Case Reports, 2019)
Background: Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation. Case presentation: A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years. Conclusions: Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Chemoradiation; MANEC; Rectum; SBRT

Long-term efficacy of NASHA Dx injection therapy for treatment of fecal incontinence - Mellgren, A.; Matzel, Klaus; Pollack, J.; Hull, T.; Bernstein, M.; Graf, W. (Neurogastroenterology and Motility, 2014)
Injectable bulking treatment for fecal incontinence (FI) is intended to expand tissue in the anal canal and prevent fecal leakage. Use of injectable bulking agents is increasing because it can be performed in an outpatient setting and with low risk for morbidity. This study evaluated the long-term (36-month) clinical effectiveness and safety of injection of non-animal stabilized hyaluronic acid/dextranomer (NASHA Dx) on FI symptoms.In a prospective multicenter trial, 136 patients with FI received the NASHA Dx bulking agent. Treatment success defined as a reduction in number of FI episodes by 50% or more compared with baseline (Responder50 ). Change from baseline in Cleveland Clinic Florida Fecal Incontinence Score (CCFIS) and Fecal Incontinence Quality of Life Scale (FIQL), and adverse events were also evaluated.Successful decrease in symptoms was achieved in 52% of patients at 6 months and this was sustained at 12 months (57%) and 36 months (52%). Mean CCFIS decreased from 14 at baseline to 11 at 36 months (p < 0.001). Quality-of-life scores for all four domains improved significantly between baseline and 36 months of follow-up. Severe adverse events were rare and most adverse events were transient and pertained to minor bleeding and pain or discomfort.Submucosal injection of NASHA Dx provided a significant improvement of FI symptoms in a majority of patients and this effect was stable during the course of the follow-up and maintained for 3 years.
EVALuna2:15171

Long-Term Experience of Arterio-Venous Fistula Surgery in Children on Hemodialysis - Almási-Sperling, Veronika; Gall, Christine; Haney, Briain; Latzel, Nina; Knieling, Ferdinand; Hilger, Alina; Regensburger, Adrian; Meyer, Alexander; Lang, Werner; Rother, Ulrich (Journal of Clinical Medicine, 2024)
Background: Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods: This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients’ demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results: Fifty-seven patients were analyzed with a median age of 15 years (range, 7–18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0–23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions: AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.
CRIS-Team Scopus Importer:2024-07-12
Keywords: arterio-venous fistula; children; long term; primary patency; secondary patency

Long‐term follow‐up of patients receiving neoadjuvant treatment modalties for soft tissue sarcomas of the extremities - Rauch, Miriam; Agaimy, Abbas; Semrau, Sabine; Willner, Alexander; Ott, Oliver; Fietkau, Rainer; Hohenberger, Werner; Croner, Roland S.; Grützmann, Robert; Fechner, Katja; Vassos, Nikolaos (Cancers, 2021)
Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long‐term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15‐year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m2/d, d1–5, q28) and doxorubicine (50 mg/m2/d, d3, q28). We investigated the clinical, (post)‐operative and histopathological data and the oncological follow‐up as well. The median follow‐up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range; 21–93) was observed. Seventy‐four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high‐risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5‐year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%; whereas the 5‐year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusion: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high‐risk STS had a significantly better MFS when receiving NT than patients with low‐risk STS. NT was associated with a higher probability of postoperative but well‐manageable complications.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Extremity; Neoadjuvant therapy; Radiation; Radiochemotherapy; Soft tissue sarcoma

Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease - Krauss, Ekaterina; Agaimy, Abbas; Gottfried, Angelina; Maiss, Juergen; Weidinger, Thomas; Albrecht, Heinz; Hartmann, Arndt; Hohenberger, Werner; Neurath, Markus; Kessler, Hermann; Mudter, Jonas (International Journal of Clinical and Experimental Pathology, 2014)
Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital.In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations.53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon.Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.
EVALuna2:1853

Long-term Outcome of Incisional Hernia Repairs Using the Erlangen Inlay Onlay Mesh (EIOM) Technique - Ayik, Nizameddin; Klein, Peter; Grützmann, Robert; Demir, Resit (Journal of Surgical Research, 2019)
Background: The objective of this study was to investigate the long-term outcome of incisional hernias treated with the Erlangen Inlay Onlay Mesh (EIOM) repair technique, taking into account recurrence, complications, and patient satisfaction. Methods: A total of 163 patients treated in the surgical department of Erlangen university hospital with the EIOM repair between the years 1996 and 2009 were evaluated retrospectively. Results: The collected data revealed a mean follow-up period of 70 (18-190) months. Incisional hernia recurrence after EIOM repair was observed in 6 (3.7%) patients after a mean observation period of 70 mo (18-190) postoperatively. The recurrence rate increased significantly when the body mass index (BMI) was higher than 32 kg/m2. Here, a recurrence rate of 10.5% for BMI> 32 versus 1.7% with BMI ≤32 was reported. There were no significant differences in hernia recurrence if haven been operated by an assistant under supervision or by a consultant. In regard to patient satisfaction, 91% of patients included in this study were satisfied with the surgical outcome. Conclusions: The EIOM procedure is a safe surgical technique that can be used for the treatment of all, also for giant incisional abdominal wall hernias regardless of the size, BMI, or position of the incisional hernia.
CRIS-Team Scopus Importer:2019-06-04
Keywords: Abdominal incisional hernia; Inlay onlay; Long-term; Open mesh repair; Sublay Erlangen

Long-term outcome of sacral neuromodulation for chronic refractory constipation - Maeda, Yasuko; Kamm, Michael A.; Vaizey, Carolynne J.; Matzel, Klaus; Johansson, Claes; Rosen, Harald; Baeten, Cornelius G.; Laurberg, Soren (Techniques in Coloproctology, 2017)
Sacral neuromodulation has been reported as a treatment for severe idiopathic constipation. This study aimed to evaluate the long-term effects of sacral neuromodulation by following patients who participated in a prospective, open-label, multicentre study up to 5 years.Patients were followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months. Symptoms and quality of life were assessed using bowel diary, the Cleveland Clinic constipation score and the Short Form-36 quality-of-life scale.Sixty-two patients (7 male, median age 40 years) underwent test stimulation, and 45 proceeded to permanent implantation. Twenty-seven patients exited the study (7 withdrawn consent, 7 loss of efficacy, 6 site-specific reasons, 4 withdrew other reasons, 2 lost to follow-up, 1 prior to follow-up). Eighteen patients (29%) attended 60-month follow-up. In 10 patients who submitted bowel diary, their improvement of symptoms was sustained: the number of defecations per week (4.1 ± 3.7 vs 8.1 ± 3.4, mean ± standard deviation, p < 0.001, baseline vs 60 months) and sensation of incomplete emptying (0.8 ± 0.3 vs 0.2 ± 0.1, p = 0.002). In 14 patients (23%) with Cleveland Clinic constipation score, improvement was sustained at 60 months [17.9 ± 4.4 (baseline) to 10.4 ± 4.1, p < 0.001]. Some 103 device-related adverse events were reported in 27 (61%).Benefit from sacral neuromodulation in the long-term was observed in a small minority of patients with intractable constipation. The results should be interpreted with caution given the high dropout and complication rate during the follow-up period.
EVALuna2:15316

Long-Term Outcomes of Extra-Anatomic Femoro-Tibial Bypass Reconstructions in Chronic Limb-Threating Ischemia - Meyer, Alexander; Boxberger, Evgenia; Behrendt, Christian Alexander; Yagshyyev, Shatlyk; Welk, Irina; Lang, Werner; Rother, Ulrich (Journal of Clinical Medicine, 2022)
(1) Background: While tibial bypass surgery still plays a role in the treatment of patients with chronic limb-threatening ischemia and diabetic foot syndrome; only a few centers have recorded considerable numbers of these conditions. The current study aimed to determine contemporary practice with special focus on the performance of extra-anatomic grafting to the infrapopliteal arteries. (2) Methods: A retrospective, single-center study included patients with tibial bypass grafts from 1 January 2008 to 31 December 2019. Primary endpoints were complication rate, graft patency, amputation, overall survival, and major adverse cardiac (MACE) or limb event (MALE). The cohort was stratified by extra-anatomic vs. anatomic position. (3) Results: A total of 455 patients (31% female) with Rutherford stage 4 (12.5%) and 5/6 (69.5%) were included (thereof, 19.5% had high amputation risk according to the Wound Ischemia Foot Infection score). Autologous reconstruction was performed in 316 cases, and prosthetic reconstruction in 131 cases, with a total of 51 (11.2%) extra-anatomic grafts. Early occlusion rate was 9.0% with an in-hospital overall mortality of 2.8%. The in-hospital rate of MACE was 2.4% and of MALE, 1.5%. After one, three and five years, the primary patency of venous bypasses was 74.5%, 68.6% and 61.7%, respectively. For prosthetic grafts, this was 55.1%, 46.0%, and 38.3%, respectively (p < 0.001). The patency of extra-anatomic prosthetic grafts performed significantly better compared with anatomically positioned prosthetic grafts (log-rank p = 0.008). In multivariate analyses, diabetes (hazard ratio, HR 1.314, CI 1.023–1.688, p = 0.032), coronary artery disease (HR 1.343, CI 1.041–1.732, p = 0.023), and dialysis dependency (HR 2.678, CI 1.687–4.250, p < 0.001) were associated with lower odds of survival (4) Conclusion: In this large, single-center cohort, tibial bypass surgery demonstrated satisfactory results with overall low perioperative complication rates and long-term patency rates of 60% and 38%, respectively. Extra-anatomic bypasses represent a feasible alternative to venous grafts in terms of patency. A tailored, patient-centered approach considering predictors such as diabetes, dialysis dependency, and coronary artery disease along with prediction models may further improve the long-term results in the future.
CRIS-Team Scopus Importer:2022-03-04
Keywords: CLTI; Extra-anatomic bypass reconstruction; Prosthetic bypass grafts; Tibial bypass surgery

Long-term outcomes of sacral nerve stimulation for faecal incontinence - Altomare, D. F.; Giuratrabocchetta, S.; Knowles, C. H.; Munoz Duyos, A.; Robert-Yap, J.; Matzel, Klaus (British Journal of Surgery, 2015)
Sacral nerve stimulation (SNS) has proven short- to medium-term effectiveness for the treatment of faecal incontinence (FI); fewer long-term outcomes have been presented and usually in small series. Here, the long-term effectiveness of SNS was evaluated in a large European cohort of patients with a minimum of 5 years' follow-up.Prospectively registered data from patients with FI who had received SNS for at least 5 years from ten European centres were collated by survey. Daily stool diaries, and Cleveland Clinic and St Mark's incontinence scores were evaluated at baseline, after implantation and at the last follow-up. SNS was considered successful when at least 50 per cent symptom improvement was maintained at last follow-up.A total of 407 patients underwent temporary stimulation, of whom 272 (66·8 per cent) had an impulse generator implanted; 228 (56·0 per cent) were available for long-term follow-up at a median of 84 (i.q.r. 70-113) months. Significant reductions in the number of FI episodes per week (from median 7 to 0·25) and summative symptom scores (median Cleveland Clinic score from 16 to 7, St Mark's score from 19 to 6) were recorded after implantation (all P < 0·001) and maintained in long-term follow-up. In per-protocol analysis, long-term success was maintained in 71·3 per cent of patients and full continence was achieved in 50·0 per cent; respective values based on intention-to-treat analysis were 47·7 and 33·4 per cent. Predictive analyses determined no significant association between pretreatment variables and successful outcomes. Risk of long-term failure correlated with minor symptom score improvement during the temporary test phase.SNS remains an effective treatment for FI in the long term for approximately half of the patients starting therapy.
EVALuna2:15198

Long-term prognostic impact of surgical complications in the German Rectal Cancer Trial CAO/ARO/AIO-94 - Sprenger, T.; Beissbarth, T.; Sauer, Rolf; Tschmelitsch, J.; Fietkau, Rainer; Liersch, T.; Hohenberger, Werner; Staib, L.; Gaedcke, J.; Raab, H. -R.; Roedel, C.; Ghadimi, M. (British Journal of Surgery, 2018)
BACKGROUND: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. METHODS: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long-term follow-up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. RESULTS: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10-year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10-year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis-free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. CONCLUSION: Surgical complications were associated with adverse oncological outcomes in this trial.
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Long-Term Survival after Salvage Surgery for Local Failure after Definitive Chemoradiation Therapy for Locally Advanced Non-small Cell Lung Cancer - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Thoracic and Cardiovascular Surgeon, 2018)
BACKGROUND: The incidence of local failure and residual tumor after definitive chemoradiation therapy (dCRT) for locally advanced non-small-cell lung cancer remains high, irrespective of applied radiation dose (>59 Gy). So-called salvage surgery has been suggested as a feasible treatment option after failure of definitive chemoradiation for locally advanced non-small cell lung cancer (NSCLC). Experience with salvage lung surgery (SLS) is limited, and long-term survival is rarely reported. Patient selection criteria for surgical lung salvage are not defined. The aim of this study was to assess postoperative survival and perioperative morbidity/mortality to identify prognostic factors and to define patient selection criteria. PATIENTS AND METHODS: Records of 13 consecutive patients with locally advanced NSCLC, who underwent SLS at a single institution between March 2011 and November 2016, were reviewed. Descriptive statistics were applied for patient characteristics and surgical and oncological outcome. Survival rates were calculated using the Kaplan-Meier method and were compared with the long-rank test. RESULTS: All patients initially received curative-intent definitive chemoradiation with median radiation doses of 66 Gy (range 59.4-72) and concurrent platinum-based chemotherapy. Clinical tumor stage before definitive chemoradiation was IIIA in 9, IIIB in 3, IV in 1 patients. Median interval between definitive chemoradiation and salvage surgery was 6.7 months. Perioperative morbidity and 30-days-mortality was 38% and 7.7%, respectively. The median postoperative survival and estimated 5-year survival rate were 29.7 months and 46%, respectively. CONCLUSION: SLS in patients with locally advanced non-small cell lung surgery following dCRT is feasible, prolongs long-term survival and allows local tumor control. Selection criteria remain undefined and patients should be considered surgical candidates during multidisciplinary team conference.
EVALuna2:35734

Long-term tumor-free survival in a metastatic pancreatic carcinoma patient with FOLFIRINOX/Mitomycin, high-dose, fever inducing Viscum album extracts and subsequent R0 resection: A case report - Werthmann, Paul Georg; Inter, Pia; Welsch, Thilo; Sturm, Anne-Kathrin; Grützmann, Robert; Debus, Markus; Sterner, Martin-Guenther; Kienle, Gunver Sophia (Medicine, 2018)
RATIONALE: Metastatic pancreatic cancer has a dismal prognosis. Many patients seek integrative care as an add-on to their conventional cancer treatment. Viscum album extracts (VAE)-widely used as an adjunct to cancer treatment-have cytotoxic, apoptogenic, and immune stimulatory properties. A statistically significant survival benefit has been demonstrated for VAE in advanced pancreatic cancer. PATIENT CONCERNS AND DIAGNOSIS: A 28-year old patient presented with painless jaundice and was subsequently diagnosed as pancreatic adenocarcinoma with liver metastases. INTERVENTIONS: He was treated with FOLFIRINOX/Mitomycin, hyperthermia and fever-inducing VAE. OUTCOMES: Subsequently, the liver metastases regressed. Surgical intervention involved successful R0-resection of the primary tumor, as well as an atypical liver resection. A relapse was again treated with FOLFIRINOX/Mitomycin and hyperthermia. As of publication of this report, 49 months after initial diagnosis, the patient exhibits good condition, and is unrestricted in quality of life (till publication). LESSONS: This case demonstrates the favorable outcome of a patient with metastatic pancreatic cancer following treatment with chemotherapy, integrative medicine, and surgical excision. As other positive outcomes in pancreatic cancer patients are related to inflammatory events, we presume the immunologic effects of VAE to have contributed to the favorable outcome here. Based on this case, and the other positive results of VAE use in pancreatic cancer, further investigations seem highly worthwhile.
EVALuna2:210703

Loss of enhancer of zeste homologue 2 (EZH2) at tumor invasion front is correlated with higher aggressiveness in colorectal cancer cells - Böhm, Julian; Muenzner, Julienne Kathrin; Caliskan, Aylin; Ndreshkjana, Benardina; Erlenbach-Wünsch, Katharina; Merkel, Susanne; Croner, Roland; Rau, Tilman; Geppert, Carol-Immanuel; Hartmann, Arndt; Roehe, Adriana Vial; Schneider-Stock, Regine (Journal of Cancer Research and Clinical Oncology, 2019)
Purpose: Enhancer of zeste homolog 2 (EZH2) is associated with epigenetic gene silencing and aggressiveness in many tumor types. However, the prognostic impact of high EZH2 expression is controversially discussed for colorectal cancer. For this reason, we immunohistochemically analyzed EZH2 expression in 105 specimens from colon cancer patients separately for tumor center and invasion front. Methods: All sections from tissue microarrays were evaluated manually and digitally using Definiens Tissue Studio software (TSS). To mirror-image the EZH2 status at the tumor invasion front, we treated HCT116 colon cancer cells with the EZH2 inhibitor 3-Deazaneplanocin A (DZNep) and studied the growth of in ovo xenografts in the chorioallantoic membrane (CAM) assay. Results: We showed a significant decrease in EZH2 expression and the repressive H3K27me3 code at the tumor invasion front as supported by the TSS-constructed heatmaps. Loss of EZH2 at tumor invasion front, but not in tumor center was correlated with unfavorable prognosis and more advanced tumor stages. The observed cell cycle arrest in vitro and in vivo was associated with higher tumor aggressiveness. Xenografts formed by DZNep-treated HCT116 cells showed loosely packed tumor masses, infiltrative growth into the CAM, and high vessel density. Conclusion: The differences in EZH2 expression between tumor center and invasion front as well as different scoring and cutoff values can most likely explain controversial literature data concerning the prognostic value of EZH2. Epigenetic therapies using EZH2 inhibitors have to be carefully evaluated for each specific tumor type, since alterations in cell differentiation might lead to unfavorable results.
CRIS-Team Scopus Importer:2019-07-23
Keywords: CAM assay; Colorectal cancer; EZH2; EZH2 inhibition; Tumor invasion front; Worse prognosis

Loss of EZH2 at tumor invasive front is correlated with higher aggressiveness - Böhm, Julian; Muenzner, Julienne K.; Caliskan, Aylin; Ndreshkjana, Benardina; Erlenbach-Wunsch, Katharina; Merkel, Susanne; Croner, Roland S.; Rau, Tilman T.; Geppert, Carol-Immanuel; Hartmann, Arndt; Vial-Roehe, Adriana; Schneider-Stock, Regine (2018)
EVALuna2:205467

Loss of IFN-gamma pathway gene expression in tumor cells as mechanism of immune escape of colorectal carcinoma - Britzen-Laurent, Nathalie; Straube, Julia; Waldner, Maximilian; Becker, Christoph; Croner, Roland; Pilarsky, Christian; Merkel, Susanne; Stürzl, Michael (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Low anterior resection syndrome and quality of life: an international multicenter study - Juul, Therese; Ahlberg, Madelene; Biondo, Sebastiano; Espin, Eloy; Jimenez, Luis Miguel; Matzel, Klaus; Palmer, Gabriella Jansson; Sauermann, Anna Catherin; Trenti, Loris; Zhang, Wei; Laurberg, Soren; Christensen, Peter (Diseases of the colon & rectum, 2014)
An increasing number of patients are surviving a diagnosis of rectal cancer. The majority of the patients are treated with the sphincter-sparing surgical procedure low anterior resection, and 50% to 90% of these patients experience bowel dysfunction, known as the low anterior resection syndrome. No previous studies have investigated the association between the low anterior resection syndrome and quality of life in an international setting with the use of a validated instrument for the classification of the low anterior resection syndrome.The aim of this study was to investigate the association between quality of life and the low anterior resection syndrome in European patients who have had rectal cancer.The study was designed as an international cross-sectional study involving 5 centers in 4 European countries.All patients had undergone low anterior resection for rectal cancer, had no stoma, had no dissemination or recurrence at the time of the study, and were at least 16 months past surgery.The patients received by mail the Low Anterior Resection Syndrome Score and the quality-of-life questionnaire EORTC QLQ-C30.Eight subscales were selected to be the focus of this study: global quality of life; physical, role, emotional, and social functioning; fatigue; constipation; and diarrhea.A total of 796 patients were included, which corresponds to a response rate of 75.0%. In comparison with patients without low anterior resection syndrome, patients with major low anterior resection syndrome fared substantially worse in all selected subscales (difference >= 10 points, p < 0.01), with the exception of constipation.The cross-sectional design prevents an evaluation of causality.The quality of life of patients who have had rectal cancer is closely associated with the severity of the low anterior resection syndrome. Therefore, it is important that clinicians and researchers focus on this syndrome to improve the prevention and the treatment of bowel dysfunction and the information given to patients.
EVALuna2:15166

Low-Dose CT Fluoroscopy-Guided Drainage of Deep Pelvic Fluid Collections after Colorectal Cancer Surgery: Technical Success, Clinical Outcome and Safety in 40 Patients - Stahl, Robert; Seidensticker, Max; De Figueiredo, Giovanna Negrao; Pedersen, Vera; Crispin, Alexander; Forbrig, Robert; Ozpeynirci, Yigit; Liebig, Thomas; D'Anastasi, Melvin; Hackner, Danilo; Trumm, Christoph G. (Diagnostics, 2023)
Purpose: To assess the technical (TS) and clinical success (CS) of CT fluoroscopy-guided drainage (CTD) in patients with symptomatic deep pelvic fluid collections following colorectal surgery. Methods: A retrospective analysis (years 2005 to 2020) comprised 43 drain placements in 40 patients undergoing low-dose (10–20 mA tube current) quick-check CTD using a percutaneous transgluteal (n = 39) or transperineal (n = 1) access. TS was defined as sufficient drainage of the fluid collection by ≥50% and the absence of complications according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE). CS comprised the marked reduction of elevated laboratory inflammation parameters by ≥50% under minimally invasive combination therapy (i.v. broad-spectrum antibiotics, drainage) within 30 days after intervention and no surgical revision related to the intervention required. Results: TS was gained in 93.0%. CS was obtained in 83.3% for C-reactive Protein and in 78.6% for Leukocytes. In five patients (12.5%), a reoperation due to an unfavorable clinical outcome was necessary. Total dose length product (DLP) tended to be lower in the second half of the observation period (median: years 2013 to 2020: 544.0 mGy*cm vs. years 2005 to 2012: 735.5 mGy*cm) and was significantly lower for the CT fluoroscopy part (median: years 2013 to 2020: 47.0 mGy*cm vs. years 2005 to 2012: 85.0 mGy*cm). Conclusions: Given a minor proportion of patients requiring surgical revision due to anastomotic leakage, the CTD of deep pelvic fluid collections is safe and provides an excellent technical and clinical outcome. The reduction of radiation exposition over time can be achieved by both the ongoing development of CT technology and the increased level of interventional radiology (IR) expertise.
CRIS-Team Scopus Importer:2023-03-10
Keywords: clinical outcome; colorectal surgery; CT-guided drainage; pelvic fluid collection; technical outcome

Low-Milliampere CT Fluoroscopy-Guided Percutaneous Drainage Placement after Pancreatic Surgery: Technical and Clinical Outcome in 133 Consecutive Patients during a 14-Year Period - Trumm, Christoph G.; Hackner, Danilo; Badmann, Katharina; Crispin, Alexander; Forbrig, Robert; Ozpeynirci, Yigit; Kuppinger, David; Pedersen, Vera; Liebig, Thomas; Stahl, Robert (Diagnostics, 2022)
(1) Purpose: To retrospectively assess the technical and clinical outcome of patients with symptomatic postoperative fluid collections after pancreatic surgery, treated with CT-guided drainage (CTD). (2) Methods: 133 eligible patients between 2004 and 2017 were included. We defined technical success as the sufficient drainage of the fluid collection(s) and the absence of peri-interventional complications (minor or major according to SIR criteria). Per definition, clinical success was characterized by normalization of specific blood parameters within 30 days after the intervention or a decrease by at least 50% without requiring additional surgical revision. C-reactive protein (CRP), Leukocytes, Interleukin-6, and Dose length product (DLP) for parts of the intervention were determined. (3) Results: 97.0% of 167 interventions were technically successful. Clinical success was achieved in 87.5% of CRP, in 78.4% of Leukocytes, and in 87.5% of Interleukin-6 assessments. The median of successful decrease was 6 days for CRP, 5 days for Leukocytes, and 2 days for Interleukin-6. No surgical revision was necessary in 93.2%. DLP was significantly lower in the second half of the observation period (total DLP: median 621.5 mGy*cm between 2011-2017 vs. median 944.5 mGy*cm between 2004-2010). (4) Conclusions: Technical success rate of CTD was very high and the clinical success rate was fair to good. Given an elderly and multimorbid patient cohort, CTD can have a temporizing effect in the postoperative period after pancreatic surgery. Reducing the radiation dose over time might reflect developments in CT technology and increased experience of interventional radiologists.
CRIS-Team WoS Importer:2022-09-30

Lung Contusion in Polytrauma: An Analysis of the TraumaRegister DGU - Schulz-Drost, Stefan; Finkbeiner, Rebekka; Lefering, Rolf; Grosso, Marco; Krinner, Sebastian; Langenbach, Andreas (Thoracic and Cardiovascular Surgeon, 2021)
Background Thorax trauma frequently occurs in which injuries to the bony chest, lung contusions (LCs), and others are diagnosed. The significance of this violation is described very differently and is mostly based on monocentric data. Methods A retrospective analysis of the TraumaRegister DGU ®(TR-DGU) dataset (Project 2014-062) was performed between 2009 and 2014 (injury severity score [ISS] ≥ 16, primary admission to a trauma center, no isolated traumatic brain injury). Patients with LC (Abbreviated Injury Scale [AIS] 3 + 4) were compared with the control group, and an analysis of different age groups was performed. Results A total of 49,567 patients were included, thereunder 14,521 (29.3%) without relevant thoracic trauma (TT); 95.9% blunt traumas. 18,892 patients (38.1%) had LC and 14,008 (28.3%) had severe LC with AIS 3 + 4; thereunder 72.7% males. For severe LC, the average age was the lowest (44.7 ± 19.7 years) and ISS the highest (30.4 ± 12.1 points). Intubation, intensive care, (multi-) organ failure, sepsis, and extrathoracic injuries were most common in severe LC. Shock, chest tubes, further thoracic injuries, and patient death occurred most frequently in TT without LC.Younger patients showed a higher incidence of LC than the older ones; however, high patient age was a highly significant risk factor for the development of complications and poor outcome. Conclusion Since LC was present in almost 40% of the severely injured and was related to higher morbidity, LC should be detected and managed at the earliest possible time. Proper follow-ups employing chest X-rays and computed tomography (CT) scans are recommended.
CRIS-Team Scopus Importer:2021-12-24
Keywords: chest trauma; lung contusion; Polytrauma; pulmonary contusion; TraumaRegister

Lung Resection after Definitive and Neo-Adjuvant Chemoradiation for Stage IIIA/B Locally Advanced Non-Small Cell Lung Cancer: a Retrospective Analysis - Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Lettmaier, Sebastian; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2018)
BACKGROUND: The outcomes of so called "salvage" resections after definitive chemoradiation vs. curative resections after neoadjuvant chemoradiation therapy (IT-resection) in patients with stage IIIA/B locally advanced non-small cell lung cancer have rarely been compared. The aim of our study was to compare perioperative results, postoperative and recurrence-free survival and to identify relevant prognostic survival factors for both therapy strategies. PATIENTS AND METHODS: Between June 2008 and May 2017, 43 patients underwent pulmonary resection following induction therapy (group 1) and 14 patients underwent salvage resection after definitive chemoradiation (group 2). Retrospective analysis was performed of demographic factors, tumour stage and location, initial therapy, preoperative regression status, perioperative morbidity and mortality, postoperative and recurrence-free survival. RESULTS: In group 2, significantly higher radiation dose was applied (p < 0.001) and the interval between chemoradiation and lung resection was significantly longer (p = 0.02). In addition, significantly higher perioperative blood loss and more frequent blood transfusions were noted (p = 0.003 and 0.005, respectively). Perioperative morbidity and mortality were statistically comparable in the two groups (p = 0.72 and 0.395, respectively). Postoperative 5 year survival in group 1 was 55%, in group 2 48% (log-rank p = 0.353). Five year recurrence-free survival in group 1 was 53%, in group 2 42% (log-rank p = 0.180). Diffuse metastasis occurred mostly in group 2, whereas in group 1 oligometastasis was more frequently noted. CONCLUSION: Postoperative outcome after salvage resection seems statistically comparable to results following curative resection after induction therapy. Diffuse distant metastasis is frequently noted. Careful patient selection is required.
EVALuna2:35732

Lung tumor immune evasion mechanism in Non-small cell lung cancer (NSCLC) targets pSTAT5 in CD4+CD25+FoxP3-T effector cells - Tausche, Patrick; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Lymph node dissection after primary surgery and neoadjuvant radiochemotherapy of rectal cancer : Interim analysis of a multicenter prospective observational study (OCUM) - Kreis, M. E.; Maurer, C. A.; Ruppert, R.; Ptok, H.; Strassburg, J.; Junginger, T.; Merkel, Susanne; Hermanek, Peter (Chirurg, 2015)
The OCUM trial (NCT01325649) aims to clarify whether low rates of local recurrence are also achieved when the indications for neoadjuvant radiochemotherapy are not based on the clinical TNM staging but on preoperative magnetic resonance imaging with measurement of the tumor distance to the circumferential resection margin. In this interim analysis the lymph node status in OCUM patients was investigated as a surrogate parameter for quality of surgery and histopathological work-up.Until now a total of 560 patients have been included in this study. Total mesorectal excision (TME) without pretreatment was undertaken in 338 patients (60.4 %) and neoadjuvant radiochemotherapy was administered in 222 (39.6 %) patients. The histological work-up was performed according to the guidelines of the German Association of Pathologists. Data are given as median values and ranges in brackets.The lymph node yield was 24 (7-79) in 338 patients undergoing primary TME surgery without pretreatment, while 20 (3-56) lymph nodes were identified in patients after neoadjuvant radiochemotherapy (p = 0.001). A minimum of 12 lymph nodes were analyzed in 335 out of 338 patients (99.1 %) and in 209 out of 222 patients (94.1 %) following neoadjuvant radiochemotherapy (p = 0.001). Lymph node metastasis was identified (p = 0.362) in 116 out of 338 patients without pretreatment (34.3 %) and in 71 out of 222 patients after neoadjuvant radiochemotherapy (32.0 %). Patient age did not influence the number of identified lymph nodes or rate of lymph node metastasis.In this trial the number of identified lymph nodes suggests that the quality of surgery and histopathological work-up were adequate compared to the standards defined by national guidelines. Neoadjuvant radiochemotherapy led to a reduced lymph node yield compared to surgery without pretreatment; however, this did not influence the rate of lymph node metastasis.
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Lymph node metastasis of carcinomas of transverse colon including flexures. Consideration of the extramesocolic lymph node stations - Perrakis, Aristotelis; Weber, Klaus; Merkel, Susanne; Matzel, Klaus; Agaimy, Abbas; Gebbert, Carol; Hohenberger, Werner (International Journal of Colorectal Disease, 2014)
Complete mesocolic excision (CME) is nowadays state of the art in the treatment of colon cancer. In cases of carcinoma of transverse colon and of both flexures an extramesocolic lymph node metastasis can be found in the infrapancreatic lymph node region (ILR) and across the gastroepiploic arcade (GLR). These direct metastatic routes were not previously systematically considered. In order to validate our hypothesis of these direct metastatic pathways and to obtain evidence of our approach of including dissection of these areas as part of CME, we initiated a prospective study evaluating these lymph node regions during surgery.Forty-five consecutive patients with primary tumour manifestation in transverse colon and both flexures between May 2010 and January 2013 were prospectively analyzed. Patients were followed up for at least 6 months. Mode of surgery, histopathology, morbidity and mortality were evaluated.Twenty-six patients had a carcinoma of transverse colon, 16 patients one of hepatic flexure and four patients one of splenic flexure. The median lymph node yield was 40. Occurrence of lymph node metastasis in ILR was registered in five patients and in GLR in four patients. The mean lymph node ratio was 0.085. Postoperative complications occurred in nine patients, and postoperative mortality was 2 %.We were able to demonstrate this novel metastatic route of carcinomas of the transverse colon and of both flexures in ILR and GLR. These could be considered as regional lymph node regions and have to be included into surgery for cancer of the transverse colon including both flexures.
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Machine Learning-Supported Diagnosis of Small Blue Round Cell Sarcomas Using Targeted RNA Sequencing. - Schlieben, Lea D.; Carta, Maria Giulia; Moskalev, Evgeny; Stöhr, Robert; Metzler, Markus; Besendörfer, Manuel; Meidenbauer, Norbert; Semrau, Sabine; Janka, Rolf Matthias; Grützmann, Robert; Wiemann, Stefan; Hartmann, Arndt; et al. (Journal of Molecular Diagnostics, 2024)
Small blue round cell sarcomas (SBRCSs) are a heterogeneous group of tumors with overlapping morphologic features but markedly varying prognosis. They are characterized by distinct chromosomal alterations, particularly rearrangements leading to gene fusions, whose detection currently represents the most reliable diagnostic marker. Ewing sarcomas are the most common SBRCSs, defined by gene fusions involving EWSR1 and transcription factors of the ETS family, and the most frequent non-EWSR1-rearranged SBRCSs harbor a CIC rearrangement. Unfortunately, currently the identification of CIC::DUX4 translocation events, the most common CIC rearrangement, is challenging. Here, we present a machine-learning approach to support SBRCS diagnosis that relies on gene expression profiles measured via targeted sequencing. The analyses on a curated cohort of 69 soft-tissue tumors showed markedly distinct expression patterns for SBRCS subgroups. A random forest classifier trained on Ewing sarcoma and CIC-rearranged cases predicted probabilities of being CIC-rearranged >0.9 for CIC-rearranged-like sarcomas and <0.6 for other SBRCSs. Testing on a retrospective cohort of 1335 routine diagnostic cases identified 15 candidate CIC-rearranged tumors with a probability >0.75, all of which were supported by expert histopathologic reassessment. Furthermore, the multigene random forest classifier appeared advantageous over using high ETV4 expression alone, previously proposed as a surrogate to identify CIC rearrangement. Taken together, the expression-based classifier can offer valuable support for SBRCS pathologic diagnosis.
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Magnetic nanoparticles for cancer therapy - Dürr, Stephan; Janko, Christina; Lyer, Stefan; Tripal, Philipp; Schwarz, Marc; Zaloga, Jan; Tietze, Rainer; Alexiou, Christoph (Nanotechnology Reviews, 2013)
Cancer is one of the biggest challenges facing the medical research in our time. The goals are to improve not only the therapeutic outcome, even in the cases of advanced and metastatic cancer, but also the methods of treatment, which often have considerable adverse effects. In addition, the current developments, such as demographic change, population growth, and increasing healthcare costs, have to be taken into consideration. In all likelihood, nanotechnology and, in particular, the use of magnetic nanoparticles consisting of the elements nickel, cobalt, and iron can make a significant contribution. The greatest potential can be ascribed to the drug delivery systems: magnetic nanoparticles are functionalized by binding them to various substances, including chemotherapeutic agents, radionuclides, nucleic acids, and antibodies. They can then be guided and accumulated using a magnetic field. Hyperthermia can be induced with an alternating magnetic field, providing another therapeutic option. Magnetic nanoparticles may be useful in overcoming cancer drug resistance. They also contribute to realizing a combination of diagnostic investigation and therapy in the field of " theranostics ". The multifaceted and promising results of research in the recent years offer the prospect of a real advance in cancer therapy in the near future.
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Keywords: Cancer drug resistance; Cancer therapy; Drug delivery; Hyperthermia; Magnetic nanoparticles

Magnification endoscopy with optical chromoendoscopy for in vivo assessment of histological inflammation in patients with inflammatory bowel disease - Klenske, E.; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iacucci, M.; Neurath, Markus; Rath, Timo (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Magnification endoscopy with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with inflammatory bowel disease - Klenske, Entcho; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iaccuci, Marietta; Neurath, Markus; Rath, Timo (Endoscopy International Open, 2019)
Background and study aims Apart from mucosal healing as an established treatment goal in inflammatory bowel diseases (IBD), recent evidence suggests that histologic healing may become another key prognostic parameter in IBD patients. We aimed to evaluate whether magnification endoscopy with optical chromoendoscopy can accurately assess histologic inflammation in IBD patients.
CRIS-Team WoS Importer:2019-09-13

Major and minor complications after anterior rectal resection for deeply infiltrating endometriosis - Renner, Stefan; Kessler, Hermann; Topal, Nalan; Proske, Kim; Adler, Werner; Burghaus, Stefanie; Haupt, Werner; Beckmann, Matthias; Lermann, Johannes (Archives of Gynecology and Obstetrics, 2017)
The aim of the present study was to analyze major and minor complications-including long-term impairment of intestinal, bladder, and sexual function-following surgery for deeply infiltrating endometriosis using anterior rectal resection.Patients who had undergone anterior rectal resection due to endometriosis between 2001 and 2011 were included (n = 113). Clinical and surgical data, as well as minor and major complications, were recorded. A questionnaire was sent to the patients and also to a healthy control group (n = 100).Major complications occurred in 15.9% of cases and minor complications in 15%. Patients with postoperative ileostomies (n = 8) initially had ultralow anastomoses significantly more often. The questionnaire response rate was 77%, with a mean follow-up period of 85.9 months. Weak urinary flow was reported by 22.4% of the patients: a feeling of residual urine by 18.4%; more than one bowel movement/day by 57.5%; and insufficient lubrication during intercourse by 36.5%. These results differed significantly from the control group. Subgroup analysis showed no statistical associations between questionnaire responses and major or minor complications, ultralow anastomoses, bilateral dissection of the sacrouterine ligaments, or dissection of the vagina and rectovaginal space.The major complication rate was consistent with the literature, but there were fewer minor complications. Patients with bowel anastomoses below 6 cm (ultralow) should receive information postoperatively about the high risk of insufficiency and should be closely monitored. The high rate of bladder, bowel, and sexual function impairment, and inadequate data make further prospective studies on this topic necessary.
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Major Pathologic Response after Induction Therapy Has a Long-Term Impact on Survival and Tumor Recurrence in Stage IIIA/B Locally Advanced NSCLC - Schreiner, Waldemar; Dudek, Wojciech; Rieker, Ralf; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Thoracic and Cardiovascular Surgeon, 2019)
BACKGROUND: Major pathologic response (MPR) determines favorable outcome in locally advanced non-small cell lung cancer after induction therapy (IT) followed by lung resection. The aim of this retrospective study was to identify the prognostic relevance of MPR in long-term interval. METHODS: In 55 patients, the survival rate according to MPR and non-MPR was estimated by Kaplan-Meier method and compared using log-rank, Breslow, and Tarone-Ware tests. RESULTS: The IT included chemoradiation with 50.4 Gy (range: 45-56.4 Gy) combined with platinum-based chemotherapy in 52 patients (94.5%) and platinum-based chemotherapy in 3 patients (5.5%). Perioperative morbidity and 30-day mortality were 36 and 3.6%, respectively. The estimated 5-year postoperative and progressive-free survivals were statistically significantly improved in MPR versus non-MPR with 53.5 versus 18% and 49.4 versus 18.5%, respectively. According to the log-rank, Breslow, and Tarone-Ware tests, the MPR demonstrates prognostic significance in early, long-term, and whole postoperative interval. CONCLUSION: MPR is associated with a robust correlation to long-term postoperative and recurrence-free survival improvement, and can potentially simplify the multidisciplinary debate and allow further stratification of adjuvant treatment in multimodality therapy.
EVALuna2:207414

Major vascular complications after transfemoral arterial closure system implantation: a single-center study - Chatzigeorgiadis, Pavlos; Hellwig, Konstantin; Almási-Sperling, Veronika; Meyer, Alexander; Lang, Werner; Rother, Ulrich (International Angiology, 2020)
BACKGROUND: During the past decades, the use of vascular closure devices (VCDs) has been established due to the increasing number of interventions. Of particular concern is the perceived risk of VCDs for development of implant-induced vascular major complications. Therefore, the aim of this analysis was to report the variety of vascular access side complications after the use of VCDs, and to analyze the referred risk factors. METHODS: All cases of vascular complications associated with VCD use requiring surgical repair from 2010 to 2016 were retrospectively analyzed in a single center trial. Systemic and local complications, risk factors as pre-existing diseases and their influence on the surgical outcome were evaluated. RESULTS: A total of 46 individuals were included in this study (male/female: 16/30). The total number of interventions in the involved departments of the study center during the same period was 9754 Therefore the complication rate after VCD implantation was 0.47%. The detected complications ranged from symptomatic claudication (N.=24) to acute leg ischemia (N.=19) and major bleeding (N.=3). Surgical reconstruction was performed by direct suture (N.=4), transverse arteriotomy with thrombectomy (N.=2), endarterectomy with patchplasty (N.=35), inguinal graft interposition or bypass (N.=3) and primary major amputation (N.=2). In regard to the risk factors, the study has concluded that atherosclerosis, female gender and diabetes mellitus are correlated with major vascular complications (bleeding and limb ischemia). However, in cases with therapeutic anticoagulation the rate of major bleeding was significantly elevated (P=0.028). CONCLUSIONS: Reported complication rates associated with femoral VCD implantation are low. However, in some cases VCD implantation may account for severe complications including limb losses. Therefore, an adequate patient selection is necessary to detect those cases at higher risk for complications.
CRIS-Team Scopus Importer:2020-04-14

Malignant epithelioid peripheral nerve sheath tumor with prominent reticular/microcystic pattern in a child: a low-grade neoplasm with 18-years follow-up - Agaimy, Abbas; Stachel, Daniel; Jüngert, Jörg; Radkow, Tanja; Carbon, Roman; Metzler, Markus; Holter, Wolfgang (Applied Immunohistochemistry & Molecular Morphology, 2014)
Malignant peripheral nerve sheath tumors (MPNSTs) constitute <2% of soft tissue neoplasms in children and display a wide histologic spectrum including low-grade and epithelioid variants, although most are high-grade spindle cell sarcomas. Here, we describe an unusual case of a large retroperitoneal epithelioid MPNST diagnosed in a 7-year-old girl without family history or clinical features of neurofibromatosis type 1. The patient was treated by repeated surgical interventions, polychemotherapy, autologous stem cell transplantation, and irradiation therapy. Over the years, she developed multiple disseminated abdominal recurrences but is currently alive with very slowly progressing disseminated intra-abdominal disease 18 years from initial diagnosis. Histologically, the tumor was composed of medium-sized polygonal and ovoid-to-spindled cells set within a copious myxoid matrix with a prominent reticular and microcystic pattern reminiscent of the recently described reticular/microcystic schwannoma. Immunohistochemistry revealed strong and diffuse expression of S100, CD56, CD57, collagen IV, and neuron-specific enolase, with negativity for perineurial cell markers (claudin-1, epithelial membrane antigen, and glucose transporter-1) and other lineage-specific mesenchymal and epithelial antigens. This unusual variant of low-grade MPNST must be differentiated from a variety of other entities, in particular benign perineurioma, myxoid neurofibroma, and benign reticular/microcystic schwannoma. Confinement of the recurrent disease to the abdominal cavity emphasizes the necessity of primary curative wide excision of this highly recurring but nonmetastasizing low-grade neoplasm.
EVALuna2:6527

Malignant progression of invasive tumour cells seen in hypoxia present an accumulation of β-catenin in the nucleus at the tumour front - Demir, Resit; Dimmler, Arno; Naschberger, Elisabeth; Demir, Ilknur; Papadopoulos, Thomas; Melling, Nathaniel; Stürzl, Michael; Hohenberger, Werner (Experimental and Molecular Pathology, 2009)
Of all processes involved in tumour progression, local invasion and formation of metastases are the clinically most relevant but the scientifically least well understood at their molecular level. The loss of cell adhesion, then tumour cell migration with changes in the cytoskeleton, invasion and metastatic dissemination are the steps of the "metastatic cascade". The E-cadherin-catenin complex plays a key role in cell adhesion thus building the first step in malignant progression. In many epithelial cancers, E-cadherin is lost concomitantly with tumour progression. Thus β-catenin dissociates in the cytoplasm and accumulates in the nucleus as a transcription factor. Recent experimental progress has identified that tumour hypoxia not only induces tumour angiogenesis, but also modulates malignant progression to initiate tumour invasion and metastasis. It was hypothesised that hypoxia within tumours causes dysfunction of the E-cadherin-catenin complex with an accumulation of β-catenin in the nucleus and produces an invasive phenotype of tumour cells. For this purpose fertilized chicken eggs were incubated for ten days in normoxic conditions. Subsequently colon carcinoma cells (SW-480) were placed on the chorioallantoic membrane. During the following six days the eggs were incubated either in normoxic conditions or in stepwise decreasing hypoxic conditions. SW-480 colon carcinoma cells did not invade the epithelial layer in normoxic conditions. β-catenin was membrane bound or in the cytoplasm. The nuclei were regularly omitted. In contrast, an invasion through the epithelial layer into the mesoderm was already seen after three days when incubated in hypoxic conditions. β-catenin was membrane bound in non-invasive regions of the tumour nodule but there was an accumulation of β-catenin in the nucleus in the invasive tumour front. Hypoxia seems to be responsible for accumulation of β-catenin in the nucleus which is accompanied by a more invasive phenotype of tumour cells at the tumour front. © 2009 Elsevier Inc. All rights reserved.
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Keywords: Beta-Catenin; Chorioallantoic membrane; Hypoxia; Malignant progression

Management of clinically relevant postpancreatectomy hemorrhage (PPH) over two decades - A comparative study of 1 450 consecutive patients undergoing pancreatic resection - Wolk, Steffen; Grützmann, Robert; Rahbari, Nuh N.; Hoffmann, Ralf T.; Plodeck, Verena; Weitz, Juergen; Welsch, Thilo; Distler, Marius (Pancreatology, 2017)
PPH is the main cause of mortality (up to 50%) after pancreatic resection. Due to differences in time of onset, localization and clinical impairment, there is no consistent management algorithm.Between 1994 and 2014 the occurrence of PPH in 115 out of 1 450 patients from a prospectively collected database was analyzed. The cohort was divided into two time periods: 1994-2009 and 2010-2014. The differences between the two groups were analyzed.The overall incidence of PPH was 7.9%. The main causes of hemorrhage were the pancreatic anastomosis (31.1%) and the splanchnic arteries (23.5%). In the first period, there were more anastomotic hemorrhages (40.0% vs. 20.4%, p = 0.02), while in the second period more hemorrhages from the splanchnic arteries occurred (12.3% vs. 37%, p = 0.002). Bleeding control was achieved by relaparotomy (45.7%), noninterventionally (22.8%), endoscopically (19.7%) and angiographically (13.4%). In the second period, the relevance of interventional angiography significantly increased (24.6% vs. 4.3%, p = 0.001), whereas endoscopy lost importance (7% vs. 30%, p = 0.001). The in-hospital case fatality rate after PPH was 27.4%, with higher case fatality rate following extraluminal hemorrhage (23.9% vs. 3.4%, p < 0.001).A shift in the management of PPH could be seen over the two periods. Interventional angiography has gained more importance in the treatment of severe extraluminal hemorrhage of the splanchnic arteries. Adequate treatment of PPH is crucial to improve the outcome.
EVALuna2:15302

Management of Complications of Pancreatic Anastomoses - Schmid, Axel; Uder, Michael; Grützmann, Robert; Weber, Georg (Zentralblatt für Chirurgie, 2017)
Background The pancreatic anastomosis may be the Achilles heel in pancreatic surgery. When a postoperative pancreatic fistula develops, be it mild or severe, in some cases life-threatening, POPF-associated complications can occur. Objectives Possibilities for the prophylaxis, diagnosis and therapy of POPF and POPF-associated complications in an interdisciplinary setting. Results Differentiated diagnostic and therapeutic management of POPF grade A - C is supported by recent studies to reduce morbidity and mortality. Depending on time and severity of POPF and POPF-associated complications, a conservative/interventional or surgical approach is indicated. Conclusion With the precise classification of POPF and POPF-associated complications, interdisciplinary diagnostic and therapeutic management can reduce morbidity and mortality after pancreatic surgery.
EVALuna2:15303

Management of liver metastases of gastrointestinal stromal tumors (GIST) - Vassos, Nikolaos; Agaimy, Abbas; Hohenberger, Werner; Croner, Roland S. (Annals of Hepatology, 2015)
Liver metastases (LM) are crucial prognostic manifestation of gastrointestinal stromal tumors (GIST). With the advent of tyrosine kinase inhibitors (TKI), management of metastatic GIST has radically changed. Long clinical follow-up provides an increased proportion of GIST patients with LM who are candidates for potentially curative therapy.Patients who underwent treatment for liver metastases of GIST between 2000-2009 in our department were included in the study. Mean follow-up was 84 months (range 40-145) months. In retrospective analysis we investigated clinical, macro-/microscopic and immunohistochemical criteria, surgical, interventional and TKI therapy as well.In 87 GIST-patients we identified 25 (29%) patients with metastatic disease. Of these, 12 patients (14%) suffered from LM with a mean age of 60.5 (range, 35-75) years. Primary GIST were located at stomach (n = 4, 33%) or small intestine (n = 8, 67%); all of them expressed CD117 and/or CD34. LM were multiple (83%), distributed in both lobes (67%). They were detected synchronously with primary tumor in 33% and metachronously in 77%. All patients with liver involvement were considered to treatment with TKI. LM were resected (R0) in 4 patients (33%). In recurrent (2/4) and TKI resistant cases, interventional treatment (radiofrequency ablation) and TKI escalation were carried out. During a median follow-up of 84 months (range 30-152), 2 patients died (16.5%) for progressive disease and one patient for other reasons. Nine patients (75%) were alive.Treatment of LM from GIST needs a multimodal approach. TKI-therapy is required at any case. In case of respectability, surgery must be carried out. In unresectable cases or recurrent/progressive disease, interventional treatment or TKI escalation should be considered. Therefore, these patients need to be treated in experienced centres, where multimodal approaches are established.
EVALuna2:6694

Management of Pregnancy in Inherited Dysfibrinogenemia after Recurrent Miscarriage - Zimmermann, Robert; Peisl, Julia; Geisen, Christoph; Koerber, Stephanie; Achenbach, Susanne; Hackstein, Holger (Transfusionsmedizin, 2019)
Dysfibrinogenemia can lead to bleeding or thrombosis as well as to obstetric complications. The latter include early pregnancy loss, hemorrhage, placental abruption, and thrombosis. There are only a few case reports with treatment recommendations for pregnancy in affected women. We report on a meanwhile 34-year-old woman who had four consecutive early abortions between 2013 and 2015. At the presentation in our outpatient clinic, the patient reported a tendency to bruising, but no other bleeding and no thromboembolic events. Laboratory examinations showed a reduced Quick value, a prolonged thrombin time, a largely prolonged reptilase time, and fibrinogen concentrations of 0.67 g/l (Clauss method) and 3.87 g/l (immunoturbidimetry). The patient was diagnosed with dysfibrinogenemia. The molecular biological examination revealed the mutation c.103C>T. (p.Arg35Cys) in Exon 2 of the FGA gene (synonym A alpha 16Arg -> Cys substitution). During the fifth and sixth pregnancy, the patient was treated with a low-molecular heparin using the recommended prophylaxis dose for increased risk of thrombosis. At the same time, the patient received fibrinogen concentrate three times a week (3 x 2 g per week). Both pregnancies were uneventful. Poor pregnancy outcomes were reported in many cases if functionally active fibrinogen levels were less than 0.6 g/l (Clauss method). After the diagnosis of dysfibrinogenemia in a woman without an obvious tendency to bleed and without thromboembolic events in her history, it seems to us to be the best procedure to substitute fibrinogen and to applicate low-molecular-weight heparins at the same time to prevent bleeding, thrombosis, and pregnancy loss as well.
CRIS-Team WoS Importer:2019-04-12

Management of true visceral artery aneurysms in 31 cases - Regus, Susanne; Lang, Werner (Journal of Visceral Surgery, 2016)
True visceral artery aneurysms (VAA) should be treated under elective conditions in dependency on maximum diameter. In this respect, the traditional accepted threshold is 2cm, whereas VAA sizing less than 2cm should conservatively be observed without invasive treatment. The aim of this study was to review differences in the treatment outcome over three decades.This was a retrospective review of all treated VAAs at one institution from 1985 to 2015. Patients demographics, aneurysm characteristics, management and outcome were recorded with special regard to differences in the course of time.Thirty-one true VAA in 29 patients (74% female) were repaired (5 ruptured, 26 intact). Mean diameter was 30.27±11mm for intact and 38.0±8.5mm for ruptured VAA (rVAA) (P=NS). Most patients were asymptomatic (67.8% asymptomatic, 16.1% symptomatic without rupture and 16.1% with rupture). There was a vice-versa situation in chosen treatment techniques between the first (1985-2000) and the second (2001-2015) time period [first period: 75% open repair (OR) and 25% endovascular repair (ER); second period: 27% OR and 73% ER; P=0.009]. OR included aneurysm ligation and resection with (end-to-end-anastomosis, graft interposition or without blood flow reconstruction), while ER was exclusively coil embolization with sacrifice of all parent afferent and efferent arteries. Immediate technical success was 81% for all procedures. There was a trend toward higher technical success rate of VAA being treated in second time period, but we found no significant differences (69% in the first, 93% in the second; P=0.101). Conversion to OR due to technical failures was necessary after 3 endovascular repairs (20%). The overall 30-day-mortality rate decreases in the course of time (25% in the first and 0% in the second period; P=0.038). Furthermore, there was a lower 30-day mortaliy rate after ER of all VAA (elective and urgent repair) (20% after OR, 0% after ER; P=0.038). There was no decrease in 30-day mortality rate of rVAA (100% in the first and 20% in the second period; P=NS).In the fact of medical progress and a growing number of endovascular procedures, this study presents a decrease in mortality rate after elective aneurysm repair over three decades. This might become an argument to reduce the 2-cm threshold in highly selected individuals.
EVALuna2:15276

Management of vesicoenteric fistulas arising from perforated Meckel’s diverticulum: a report of a case and review of the literature - Diamantidis, Dimitrios; Papatheodorou, Nikolaos; Kostoglou, Panagiotis; Tsakaldimis, Georgios; Botaitis, Sotirios (Oxford Medical Case Reports, 2024)
Vesicoenteric fistulas are rare, with an incidence of 0.1%–0.2% in the general population, and Meckel’s diverticulum is a rare cause, accounting for less than 5% of cases with challenging diagnosis due to atypical symptoms at the admission. This article presents a case of a vesicoenteric fistula formation between Meckel’s diverticulum perforated by a foreign body and urinary bladder in a 38-years-old Caucasian male admitted to emergency department due to colicky abdominal pain located in the lower abdomen. An extensive review of the literature was conducted referring all the cases of vesicoenteric fistula incorporating Meckel’s diverticulum to elucidate the clinical characteristics, explore the diagnostic yield, and to summarize the therapeutic approach.
CRIS-Team Scopus Importer:2024-06-14

Managing One-Lung Ventilation in Tracheostomized Patients: A 6-Year Retrospective Analysis - Golditz, Tobias; Schmidt, Joachim; Ackermann, Andreas; Danzl, Anja; Birkholz, Torsten; Sirbu, Horia; Irouschek, Andrea (Thoracic and Cardiovascular Surgeon, 2024)
Background To ensure safe and optimal surgical conditions in thoracic surgery, one-lung ventilation is crucial. Various techniques exist to achieve one-lung ventilation. Tracheotomized patients who require one-lung ventilation represent a unique and rare subgroup that demands specialized knowledge and skills. The very limited literature has discussed alternative methods, no randomized controlled trials have addressed this issue yet. Methods We performed a retrospective analysis of patients who underwent one-lung ventilation in the Department of Thoracic Surgery of a German University Hospital between 2016 and 2021. The study assessed patient demographics, airway management techniques, ventilation parameters, and adverse events. Results In 3,197 anesthesia procedures during the observation period, 152 patients had an existing tracheostomy, of which 56 required one-lung ventilation. Among others in 42 cases, a tracheostomy tube was combined with a bronchial blocker, and in 10 cases, a double-lumen tracheostomy tube was used. There were no severe complications. Intraoperative dislocations that required repositioning of the device occurred in six patients (13.3%) with bronchial blockers and one patient with double-lumen tracheostomy tube (10%). Conclusion The management of one-lung ventilation in tracheotomized patients presents unique challenges. While double-lumen tracheostomy tubes have specific advantages, we recommend considering their use carefully. For most tracheotomized patients, bronchial blockers in conjunction with a tracheostomy tube are used, which offers safety and practicality, irrespective of the tracheostomy's age or type. Further research and randomized controlled trials are warranted to establish best practices for one-lung ventilation in this unique patient population.
CRIS-Team Scopus Importer:2024-05-03
Keywords: airway; anesthesia; guidelines; practice; trachea; ventilation

Massive intoxication with rivaroxaban, phenprocoumon, and diclofenac: A case report - Pfeiffer, Hella; Herbst, Larissa; Schwarze, Bernd; Eckstein, Reinhold; Weisbach, Volker Günter (Medicine, 2016)
RATIONALE: Oral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional) overdose. We report the case of a patient with a massive mixed anticoagulant intoxication. PATIENT CONCERNS: The patient had ingested 1960 mg rivaroxaban, 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole in suicidal intention. DIAGNOSES: Massive mixed anticoagulant overdose. INTERVENTIONS: The patient was closely monitored. The phenprocoumon overdose was treated by the administration of vitamin K and PCC. OUTCOMES: Despite the massive inhibition of the coagulation system, the patient did not experience bleeding apart from a slight gross hematuria. LESSONS: Despite the ingestion of a massive amount of rivaroxaban, the plasma levels were not as high as feared, due to the ceiling effect of rivaroxaban absorption. Elimination occurred according to the half-life of rivaroxaban and was not unduly prolonged by the ingested quantity.
EVALuna2:32778

Maternal HIV type 1 infection suppresses MMP-1 expression in endothelial cells of uninfected newborns: Non viral vertical transmission of HIV type 1-related effects - Naschberger, Elisabeth; Stürzl, Michael; et al. (Aids Research and Human Retroviruses, 2005)
HIV-1 infection is associated with vascular alterations. This is accompanied by an increased risk of cardiovascular diseases and Kaposi's sarcoma, an endothelial cell-derived tumor. We investigated the impact of maternal HIV-1 infection on phenotype and gene expression of endothelial cells in newborns. For this reason endothelial precursor cells and differentiated endothelial cells were isolated from cord blood as well as from umbilical veins and arteries of noninfected infants born to HIV-1-infected (H-group) and noninfected (N-group) mothers. No apparent differences in proliferation, capillary formation, and expression of endothelial cell markers were detected in these cells. Interestingly, the expression of matrix metalloproteinase was repressed significantly (χ2 analysis, p < 0.002) and consistently at the RNA, the protein, and the secretory levels in the H-group as compared to the N-group. Neither treatment with zidovudine (AZT), mutations in the matrix metalloproteinase-1 (MMP-1) promoter, nor epigenetic changes in the promoter methylation pattern were responsible for the repression of MMP-1 expression in H-group endothelial cells. The reduced MMP-1 expression may contribute to the impaired cardiac function that has been observed in children of HIV-1-infected women. Most interestingly, our findings indicate that HIV-1-related effects can be transferred from mother to child in the absence of HIV-1 transmission. © Mary Ann Liebert, Inc.
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Matricellular Protein SPARCL1 Regulates Blood Vessel Integrity and Antagonizes Inflammatory Bowel Disease - Regensburger, Daniela; Tenkerian, Clara; Pürzer, Victoria; Schmid, Benjamin; Wohlfahrt, Thomas; Stolzer, Iris; Lopez Posadas, Rocío; Günther, Claudia; Waldner, Maximilian; Becker, Christoph; Sticht, Heinrich; Petter, Katja; et al. (Inflammatory Bowel Diseases, 2021)
Background The understanding of vascular plasticity is key to defining the role of blood vessels in physiologic and pathogenic processes. In the present study, the impact of the vascular quiescence marker SPARCL1 on angiogenesis, capillary morphogenesis, and vessel integrity was evaluated. Methods Angiogenesis was studied using the metatarsal test, an ex vivo model of sprouting angiogenesis. In addition, acute and chronic dextran sodium sulfate colitis models with SPARCL1 knockout mice were applied. Results This approach indicated that SPARCL1 inhibits angiogenesis and supports vessel morphogenesis and integrity. Evidence was provided that SPARCL1-mediated stabilization of vessel integrity counteracts vessel permeability and inflammation in acute and chronic dextran sodium sulfate colitis models. Structure-function analyses of purified SPARCL1 identified the acidic domain of the protein necessary for its anti-angiogenic activity. Conclusions Our findings inaugurate SPARCL1 as a blood vessel–derived anti-angiogenic molecule required for vessel morphogenesis and integrity. SPARCL1 opens new perspectives as a vascular marker of susceptibility to colitis and as a therapeutic molecule to support blood vessel stability in this disease. <br
Keywords: angiogenesis; blood vessel; DSS colitis; endothelial cell; inflammatory bowel disease; permeability; SPARCL1

Matricellular protein SPARCL1 regulates tumor microenvironment-dependent endothelial cell heterogeneity in colorectal carcinoma - Naschberger, Elisabeth; Liebl, Andrea; Schellerer, Vera; Schütz, Manuela; Britzen-Laurent, Nathalie; Kölbel, Patrick; Schaal, Ute; Haep, Lisa; Regensburger, Daniela; Wittmann, Thomas; Klein-Hitpass, Ludger; Rau, Tilman; et al. (Journal of Clinical Investigation, 2016)
Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. The gene encoding the matricellular protein SPARCL1 was most strongly upregulated in Th1-TME TECs. It was also highly expressed in ECs in healthy colon tissues and Th1-TME CRCs but low in control-TME CRCs. In vitro, SPARCL1 expression was induced in confluent, quiescent ECs and functionally contributed to EC quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown increased sprouting. In human CRC tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent ECs inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels. Together, these findings demonstrate TME-dependent intertumoral TEC heterogeneity in CRC. They further indicate that TEC heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-TME CRCs.
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Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation - May, Stephanie; Owen, Heather; Phesse, Toby J.; Greenow, Kirsty R.; Jones, Gareth-Rhys; Blackwood, Adam; Cook, Peter C.; Towers, Christopher; Gallimore, Awen M.; Williams, Geraint T.; Stürzl, Michael; Britzen-Laurent, Nathalie; et al. (Journal of Pathology, 2018)
Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2-/- mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non-epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non-epithelial roles of Mbd2 are key in preventing the transition from acute to tumour-promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2-/- immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour-enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti- or pro-tumourigenic and this makes it a useful new epigenetic model for inflammation-associated carcinogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Measurement of immature platelets with Abbott CD-Sapphire and Sysmex XE-5000 in haematology and oncology patients - Meintker, Lisa; Haimerl, Maria; Ringwald, Juergen; Krause, Stefan (Clinical Chemistry and Laboratory Medicine, 2013)
Background: Measurement of immature platelets was introduced into routine diagnostics by Sysmex as immature platelet fraction (IPF) some years ago and recently by Abbott as reticulated platelet fraction (rPT). Here, we compare both methods. Methods: We evaluated the precision and agreement of these parameters between Sysmex XE-5000 and Abbott CD-Sapphire in three distinct thrombocytopaenic cohorts: 30 patients with beginning thrombocytopaenia and 64 patients with recovering platelets (PLT) after chemotherapy, 16 patients with immune thrombocytopaenia (ITP) or heparin-induced thrombocytopaenia type 2 (HIT) and 110 additional normal controls. Furthermore, we analysed, how IPF/rPT differed between these thrombocytopaenic cohorts and controls. Results: Both analysers demonstrated acceptable overall precision (repeatability) of IPF/rPT with lower precision at low PLT counts. IPF/rPT artificially increased during storage of blood samples overnight. Inter-instrument comparison showed a moderate correlation (Pearson rÂ0.38) and a systematic bias of 1.04 towards higher IPF-values with the XE-5000. IPF/rPT was highest in recovering thrombopoesis after chemotherapy and moderately increased in ITP/HIT. The normal range deduced from control samples was much narrower with CD-Sapphire (1.0%-3.8%, established here for the first time) in comparison to XE-5000 (0.8%-7.9%) leading to a smaller overlap of samples with increased PLT turnover and normal controls. Conclusions: IPF and rPT both give useful information on PLT turnover, although the two analysers only show a moderate inter-instrument correlation and have different reference ranges. A better separation of patient groups with high PLT turnover like ITP/HIT from normal controls is obtained by CD-Sapphire. © 2013 by Walter de Gruyter Berlin Boston.
Created from Fastlane, Scopus look-up
Keywords: heparin-induced thrombocytopaenia type 2 (HIT); immature platelet; immature platelet fraction (IPF); immune thrombocytopaenia (ITP); reticulated platelet; thrombocytopaenia

Measurements of immature platelets with haematology analysers are of limited value to separate immune thrombocytopenia from bone marrow failure - Cybulska, Annalina; Meintker, Lisa; Ringwald, Juergen; Krause, Stefan (British Journal of Haematology, 2017)
Detection of immature platelets in the circulation may help to dissect thrombocytopenia due to platelet destruction from bone marrow failure (BMF). We prospectively tested the predictive value of immature platelets, measured as immature platelet fraction (IPF) on the XE-5000 (Sysmex, Kobe, Japan) or percentage of reticulated platelets (rPT) on the CD Sapphire (Abbott Diagnostics, Santa Clara, CA, USA) to separate immune thrombocytopenia (ITP) from BMF (leukaemia, myelodysplastic syndrome, aplastic anaemia). We analysed 58 samples of patients with BMF, 47 samples of patients with ITP and 97 controls. Median rPT (CD Sapphire) was increased to 9·0% in ITP and to 10·9% in BMF, compared to 1·9% in controls. Median IPF (XE-5000) was 16·2% in ITP, 10·2% in BMF and 2·5% in controls. We found an inverse correlation between high fractions of immature platelets and low platelet counts in thrombocytopenic samples regardless of the diagnosis. In conclusion, we observed a broad overlap of immature platelets between ITP and BMF, which may be caused by an accelerated release of immature platelets in any thrombocytopenic state and decreased production in many patients with ITP. Despite this, IPF (XE-5000) had some power to discriminate ITP from BMF, whereas rPT (CD Sapphire) was of no predictive value.
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Measuring Lymphocyte Proliferation in Response to Specific Antigen and Mitogen Stimuli Using Flow Cytometry - Heider, Stefan; Strobel, Joachim; Mempel, Wolfgang; Eckstein, Reinhold; Weisbach, Volker Günter (Clinical Laboratory, 2016)
BACKGROUND: We present a multivariate test system using flow cytometry after in-vitro lymphocyte stimulation using 5 mitogens and 7 antigens to describe in-vitro immunofunction. METHODS: The present work is a crucial step towards establishing a simple, CFSE-based, multivariate test system that can describe the dynamics of stimulus-induced lymphocyte proliferation with considerably more precision than is possible with the radionucleotide method using 3H-thymidine. Using multicolour flow cytometry, our method allows additional phenotyping of the proliferating cells and quantifies the proliferation behaviour by precisely resolving daughter generations and determining the precursor frequency. CONCLUSIONS: Taking the calculated apoptosis parameters into account not only provides additional information about the stimulus-specific response behaviour but also improves the validity of the commonly used proliferation indices. Not only can we confirm previous findings that healthy people have marked differences in a multivariate test system in terms of the individual in-vitro reactivity to various stimuli but also substantiate that the response pattern of an individual is remarkably constant. In follow-up studies we can show for the first time that the results of immunofunctional testing do not change over a period of at least 6 months and appear to be an inherent characteristic of the individual and thus possibly have a genetic basis.
EVALuna2:32777

Mechanism of GTPase-activity-induced self-assembly of human guanylate binding protein 1. - Voepel, Tobias; Syguda, Adrian; Britzen-Laurent, Nathalie; Kunzelmann, Simone; Luedemann, Maik-Borris; Dovengerds, Christine; Stürzl, Michael; Herrmann, Christian (Journal of Molecular Biology, 2010)
Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of large GTPases (LGs). In the course of GTP hydrolysis, the protein undergoes structural changes leading to self-assembly of the protein, which is a characteristic property of all family members. For self-assembly, the protein employs two distinct interaction sites, one of which is located within the LG domain of the protein located at the N-terminus, and the second is located in the C-terminal alpha-helical domain. Here, we identify intramolecular contacts between the LG domain and the helical part of hGBP1, which relay nucleotide-dependent structural changes from the N-terminus to the C-terminus and thereby mediate tetramer formation of the protein through a second contact site at the C-terminus. Furthermore, we demonstrate the impact of this intramolecular communication on the enzymatic activity of hGBP1 and on its cellular localization.

Mechanism of paclitaxel activity in Kaposi's sarcoma. - Sgadari, Cecilia; Toschi, Elena; Palladino, Clelia; Barillari, Giovanni; Carlei, Davide; Cereseto, Anna; Ciccolella, Cristiana; Yarchoan, Robert; Monini, Paolo; Stürzl, Michael; Ensoli, Barbara (Journal of Immunology, 2000)
Kaposi's sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-shaped cells predominantly of endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. At least in early stage, KS behaves as a reactive lesion sustained by the action of inflammatory cytokines and growth factors, has a polyclonal nature, and can regress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increased expression of antiapoptotic oncogenes. We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spindle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatment of certain neoplasms, has recently been found to be active also in patients with advanced HIV-associated KS. In this report we investigated the mechanism(s) of paclitaxel activity in KS. By using a model of experimental KS induced by the inoculation of KS-derived spindle cells in nude mice and primary cultures of KS spindle cells, we found that paclitaxel promotes regression of KS lesions in vivo and that it blocks the growth, migration, and invasion of KS cells in vitro. Furthermore, paclitaxel treatment promoted apoptosis and down-regulated Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. Our results suggest that paclitaxel interferes with KS by down-regulating Bcl-2 antiapoptotic effect.

Medial injuries of the clavicle: more prevalent than expected? A big data analysis of incidence, age, and gender distribution based on nationwide routine data - Bakir, Mustafa Sinan; Unterkofler, Jan; Haralambiev, Lyubomir; Kim, Simon; Carbon, Roman; Ekkernkamp, Axel; Schulz-Drost, Stefan (European Journal of Trauma and Emergency Surgery, 2020)
Purpose: Although shoulder-girdle injuries occur frequently, injuries of the medial part remain widely unexplored. This study overviews these rare injuries with a focus on incidence, age, and sex distribution in Germany. Methods: The data are based on diagnoses according to ICD-10 in all German hospitals provided by the German Federal Statistical Office. ICD-10 codes S42.01 (medial clavicle fracture, MCF) and S43.2 (sternoclavicular joint dislocation, SCJD) were evaluated in detail between 2012 and 2014. Results: We identified 14,264 cases with medial clavicle injuries (MCIs). MCFs occurred more often (11.6% of all clavicle-related shoulder-girdle injuries vs. 0.6% for SCJD). Mean ages of MCI were significantly different between males (43.7 years) and females (57.1 years) (p < 0.01). Age demonstrated a bimodal distribution with peaks at 20 and 50 years, which were predominantly associated with males. Females showed more injuries at age beyond 70 years. This applies to both SCJD and MCF. The incidence rate of these shoulder-girdle injuries was 47.0 per 100,000 person-years, for MCIs overall 5.9 (4.1 for men, 1.8 for women). This indicates disparity with a significant predominance of male patients over females as for all shoulder-girdle injuries (p < 0.01). Among children (< 16 years old), the incidence rate showed no significant difference in gender ratio. Conclusion: MCIs appear more frequently than estimated so far and are distinguished from other clavicle fractures in that they occur more at higher age and peaking around 50 years. Further work on possible prevention strategies should focus on the most frequently affected groups of men around 20 and 50 years old.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Age distribution; Gender; Incidence; Medial clavicle fracture; Shoulder-girdle; Sternoclavicular joint dislocation

Medikamentenfreisetzende Koronarstents/-scaffolds und medikamentenbeschichtete Ballonkatheter - Nef, H. M.; Abdel-Wahab, M.; Achenbach, Susanne; Joner, M.; Levenson, B.; Mehilli, J.; Moellmann, H.; Thiele, Holger; Zahn, R.; Zeus, T.; Elsaesser, A. (Der Kardiologe, 2018)
The rapid development of stent technologies since the introduction of percutaneous catheter interventions (PCI) 40 years ago requires a continuous further education of interventional cardiologists in everyday clinical practice. Careful selection of the stent products, taking into account the study results, is one of the daily tasks. At the same time, the individually different clinical situations of patients must be considered and incorporated into the decision-making algorithm. This present positional paper is intended to provide an overview of currently available drug-eluting stents/scaffolds and drug-coated balloon catheters in Germany. In addition to the study results of the last few years, the clinical indications are taken into consideration and discussed in detail. Finally, the article deals with the various aspects within the framework of antithrombotic therapy after PCI.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Bare metal stents; Drug coated balloons; Drug eluting stents

Medium supplementation with human, but not fetal calf serum facilitates endocytosis of PLGA nanoparticles by human primary B-lymphocytes via complement opsonization - Pusch, Lennart; Brox, Regine; Cunningham, Sarah; Fischer, Dagmar; Hackstein, Holger (Biochemical and Biophysical Research Communications, 2023)
The “biological identity” of nanoparticles (NPs) is governed by a shell consisting of various biomolecules that is formed upon exposure to biological media, the so-called biomolecule corona. Consequently, supplementation of cell culture media with e.g. different sera is likely to affect interactions between cells and NPs ex-vivo, especially endocytosis. We aimed to investigate the differential impact of human and fetal-bovine serum on the endocytosis of poly (lactic-co-glycolic acid) NPs by human peripheral blood mononuclear cells via flow cytometry. Furthermore, we employed different methods to inhibit endocytosis, providing mechanistic insights. The resulting biomolecule corona was characterized via denaturing gel electrophoresis. We found profound differences between human and fetal bovine serum regarding the endocytosis of fluorescently labeled PLGA nanoparticles by different classes of human leukocytes. Uptake by B-lymphocytes was particularly sensitive. We further present evidence, that these effects are mediated by a biomolecule corona. We demonstrate to our knowledge for the first time that the complement is an important contributor to the endocytosis of non-surface-engineered PLGA-nanoparticles prepared via emulsion solvent evaporation by human immune cells. Our data demonstrates that results obtained with xenogeneic culture supplements such as fetal bovine serum may have to be interpreted with caution.
CRIS-Team Scopus Importer:2023-03-24
Keywords: Biomolecule corona; Complement; Culture medium; Nanoparticles; PLGA

Meeting Medical Need - Development of a High-Throughput Assay Using Pancreatic Cancer Patient Derived Organoids as a Tool for Personalized Medicine - Sankarasubramanian, Sushmitha; Niethard, Maya; Pilarsky, Christian; Regenbrecht, Christian; Wedeken, Lena (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Melanocytes as an emerging key player in niche regulation of limbal stem cells - Schlötzer-Schrehardt, Ursula; Polisetti, Naresh; Zenkel, Matthias; Naschberger, Elisabeth; Heger, Lukas; Dudziak, Diana; Stürzl, Michael; Kruse, Friedrich (2018)
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Melanocytes as emerging key players in niche regulation of limbal epithelial stem cells - Polisetti, Naresh; Gießl, Andreas; Zenkel, Matthias; Heger, Lukas; Dudziak, Diana; Naschberger, Elisabeth; Stich, Lena; Steinkasserer, Alexander; Kruse, Friedrich; Schlötzer-Schrehardt, Ursula (Ocular Surface, 2021)
Purpose: Limbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis. Methods: Human corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays. Results: LMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation. Conclusion: These findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.
CRIS-Team Scopus Importer:2021-09-03
Keywords: Angiostasis; Immune regulation; Inflammation; Limbal niche; Limbal stem cells; Melanocytes; Wound healing

Membranous septum length as predictor for permanent pacemaker implantation after TAVI - Jung, Susan; Ammon, Fabian; Smolka, Silvia; Moshage, Maximilian; Marwan, Mohamed; Achenbach, Susanne (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03