Mesentery - a 'New' organ - Coffey, J. Calvin; Walsh, Dara; Byrnes, Kevin G.; Hohenberger, Werner; Heald, Richard J. (Emerging Topics in Life Sciences, 2020)
The mesentery is the organ in which all abdominal digestive organs develop, and which maintains these in systemic continuity in adulthood. Interest in the mesentery was rekindled by advancements of Heald and Hohenberger in colorectal surgery. Conventional descriptions hold there are multiple mesenteries centrally connected to the posterior midline. Recent advances first demonstrated that, distal to the duodenojejunal flexure, the mesentery is a continuous collection of tissues. This observation explained how the small and large intestines are centrally connected, and the anatomy of the associated peritoneal landscape. In turn it prompted recategorisation of the mesentery as an organ. Subsequent work demonstrated the mesentery remains continuous throughout development, and that abdominal digestive organs (i.e. liver, spleen, intestine and pancreas) develop either on, or in it. This relationship is retained into adulthood when abdominal digestive organs are directly connected to the mesentery (i.e. they are 'mesenteric' in embryological origin and anatomical position). Recognition of mesenteric continuity identified the mesenteric model of abdominal anatomy according to which all abdominal abdomino-pelvic organs are organised into either a mesenteric or a non-mesenteric domain. This model explains the positional anatomy of all abdominal digestive organs, and associated vasculature. Moreover, it explains the peritoneal landscape and enables differentiation of peritoneum from the mesentery. Increased scientific focus on the mesentery has identified multiple vital or specialised functions. These vary across time and in anatomical location. The following review demonstrates how recent advances related to the mesentery are re-orientating the study of human biology in general and, by extension, clinical practice.
CRIS-Team WoS Importer:2020-09-25

Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis - Mayerle, Julia; Kalthoff, Holger; Reszka, Regina; Kamlage, Beate; Peter, Erik; Schniewind, Bodo; Maldonado, Sandra González; Pilarsky, Christian; Heidecke, Claus Dieter; Schatz, Philipp; Distler, Marius; Scheiber, Jonas A.; et al. (Gut, 2017)
Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose.For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry.A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature.In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.
EVALuna2:15284

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting - Parma, Beatrice; Ramesh, Vignesh; Gollavilli, Paradesi Naidu; Siddiqui, Aarif; Pinna, Luisa; Schwab, Annemarie; Marschall, Sabine; Zhang, Shuman; Pilarsky, Christian; Napoli, Francesca; Volante, Marco; Urbanczyk, Sophia; et al. (Journal of Experimental & Clinical Cancer Research, 2021)
Background The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures. Methods Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9. Results We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients' prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B. Conclusions These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.
CRIS-Team WoS Importer:2021-08-20

Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study - Nagata, Naoyoshi; Nishijima, Suguru; Kojima, Yasushi; Hisada, Yuya; Imbe, Koh; Miyoshi-Akiyama, Tohru; Suda, Wataru; Kimura, Moto; Aoki, Ryo; Sekine, Katsunori; Ohsugi, Mitsuru; Miki, Kuniko; et al. (Gastroenterology, 2022)
Background & Aims: To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts. Methods: We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets. Results: Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified. Conclusions: Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.
CRIS-Team Scopus Importer:2022-06-03
Keywords: Bacteriophage; Biomarker; Microbiome; Pancreatic cancer; Shotgun metagenomics

Met amplification in non‐small cell lung cancer (Nsclc)— a consecutive evaluation using next‐generation sequencing (ngs) in a real‐world setting - Schubart, Christoph; Stöhr, Robert; Tögel, Lars; Fuchs, Florian; Sirbu, Horia; Seitz, Gerhard; Seggewiss‐bernhardt, Ruth; Leistner, Rumo; Sterlacci, William; Seidl, Christoph; Mugler, Michael; Kapp, Markus; et al. (Cancers, 2021)
In non‐small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next‐generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high‐level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN >10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon‐based NGS assessment of the MET GCN detects high‐level MET amplified cases harboring a MET GCN >10 but fails to detect the various facets of MET gene amplification in the context of a therapy‐induced resistance mechanism.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Amplification; Fluorescence in situ hybridization; MET; MET inhibitor; Next‐generation sequencing; NSCLC; Precision medicine; Resistance mechanism

Metastatic adenocarcinomas of the stomach or esophagogastric junction (UICC stage IV) are not always a palliative situation: a retrospective analysis - Schildberg, Claus W.; Weidinger, Thomas; Hohenberger, Werner; Wein, Axel; Langheinrich, Melanie; Neurath, Markus; Boxberger, Frank (World Journal of Surgery, 2014)
Gastric cancer is one of the most common cancers. Unfortunately, it is often diagnosed at the advanced stage International Union Against Cancer stage IV. This induced us to carry out an interdisciplinary analysis of this patient group with the Department of Internal Medicine 1. Our aim was to discuss cancers classified initially as unresectable in a meeting of the interdisciplinary tumor board after palliative chemotherapy, and to refer selected patients for surgery after establishing resectability. The outcome of the chemotherapy, operation method, complication rate, and long-term survival were analyzed.From 1999 to 2008, 76 patients with metastatic gastric cancer or carcinoma of the esophagogastric junction were discussed by the interdisciplinary tumor board of the University of Erlangen and classified initially as unresectable. The patients then received palliative chemotherapy according to the AIO regimen (weekly high-dose 5-fluorouracil/folinic acid [FU/FA] in a 24 h infusion), plus irinotecan. If the tumor was subsequently classified as resectable, the patient underwent either gastric resection or gastrectomy with DII-III dissection. Metastases were resected depending on their location (liver). Peritoneal carcinomatosis was treated additionally by HIPEC. Statistical analysis was with SPSSS version 20.Surgical and general complications and hospital mortality were acceptable. There were no cases of anastomotic leak, but one patient died of fulminant pneumonia. The R0 resection rate was 69 %, and four patients had long-term survival of more than 60 months. There were significant survival advantages.Metastatic gastric cancer or carcinoma of the esophagogastric junction can become resectable after downsizing the tumor with palliative chemotherapy. Long-term survival is achieved in some cases. Therefore, every patient with this type of cancer should be discussed by the interdisciplinary tumour board after palliative chemotherapy to provide him with a chance of cure after re-evaluation.
EVALuna2:1716

Microbiome Patterns in Matched Bile, Duodenal, Pancreatic Tumor Tissue, Drainage, and Stool Samples: Association with Preoperative Stenting and Postoperative Pancreatic Fistula Development - Langheinrich, Melanie; Wirtz, Stefan; Kneis, Barbara; Gittler, Matthias M.; Tyc, Olaf; Schierwagen, Robert; Brunner, Maximilian; Krautz, Christian; Pilarsky, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; et al. (Journal of Clinical Medicine, 2020)
Postoperative complications after pancreatic surgery are still a significant problem in clinical practice. The aim of this study was to characterize and compare the microbiomes of different body compartments (bile duct, duodenal mucosa, pancreatic tumor lesion, postoperative drainage fluid, and stool samples; preoperative and postoperative) in patients undergoing pancreatic surgery for suspected pancreatic cancer, and their association with relevant clinical factors (stent placement, pancreatic fistula, and gland texture). For this, solid (duodenal mucosa, pancreatic tumor tissue, stool) and liquid (bile, drainage fluid) biopsy samples of 10 patients were analyzed using 16s rRNA gene next-generation sequencing. Our analysis revealed: (i) a distinct microbiome in the different compartments, (ii) markedly higher abundance of Enterococcus in patients undergoing preoperative stent placement in the common bile duct, (iii) significant differences in the beta diversity between patients who developed a postoperative pancreatic fistula (POPF B/C), (iv) patients with POPF B/C were more likely to have bacteria belonging to the genus Enterococcus, and (v) differences in microbiome composition with regard to the pancreatic gland texture. The structure of the microbiome is distinctive in different compartments, and can be associated with the development of a postoperative pancreatic fistula.
CRIS-Team WoS Importer:2020-11-06

Microcirculation Evaluated by Intraoperative Fluorescence Angiography after Tibial Bypass Surgery - Rother, Ulrich; Lang, Werner; Horch, Raymund E.; Ludolph, Ingo; Meyer, Alexander; Regus, Susanne (Annals of Vascular Surgery, 2017)
Intact microperfusion of the foot in the critical ischemic limb remains a crucial condition for ulcer healing. Aim of this clinical study was to evaluate the immediate effect of tibial bypass surgery on the microcirculation by usage of fluorescence angiography.Prospective analysis of 33 patients presenting with critical limb ischemia (Rutherford IV-VI) undergoing tibial bypass surgery was performed. Macroperfusion was investigated by measurement of ankle-brachial index. For assessment of microperfusion, intraoperative fluorescence angiography (SPY Elite, NOVADAQ) was undertaken during general anesthesia immediately before and after operation. For each investigation, a fluorescence dye (Indocyanine green) with an amount of 0.1 mg/kg was administered intravenously. Follow-up investigations were performed to assess the clinical outcome.The mean follow-up time was 8.28 (±4.46) months. The parameters Ingress (IN) and Ingress rate (InR) of the fluorescence dye representing the microcirculation showed a significant improvement to preoperative values and correlated with the ankle-brachial index significantly. Furthermore, a significant difference between the individual improvement of the microcirculation parameters (preoperative-postoperative) between patients with postoperative clinical improvement (wound healing, absence of rest pain) and those without could be demonstrated (InR: P = 0.039, IN: P = 0.036).The parameters IN and InR significantly reproduced the postoperative improvement of the microcirculation. An increased ankle-brachial index significantly correlated with increased microcirculation parameters. A better clinical outcome was found in those patients who had a higher relative improvement of microcirculation postoperatively.
EVALuna2:15278

Microcirculatory assessment of vascular diseases - Marcoccia, Antonella; Klein-Weigel, Peter F.; Gschwandtner, Michael E.; Wautrecht, Jean-Claude; Matuska, Jiri; Rother, Ulrich; Houben, Alfons J. H. M. (Vasa-Journal of Vascular Diseases, 2020)
The term "microcirculation" refers to the terminal vascular network of the body, which includes arterioles, capillaries, venules as well as initial lymphatic vessels. Additionally, it insinuates to their unique function in thermoregulatior, fluid balance, maintenance of cellular exchange, and metabolism. Disturbances of microvascular function were identified to precede macrovascular involvement in the presence of cardiovascular risk factors and is the hallmark of terminal disease stages like critical limb or acral ischemia. Nevertheless, despite its obvious significance in vascular medicine assessment of microvascular function became increasingly neglected in the clinical institutions during the last decades and seems to play a subordinary role in medical education. We therefore provide an overview over relevant and clinically practicable methods to assess microcirculation in vascular medicine with critical estimations of their pros and cons and their perspectives in the future.
CRIS-Team WoS Importer:2020-05-15

Microfluidics applications for high-throughput single cell sequencing - Zhou, Wen-Min; Yan, Yan-Yan; Guo, Qiao-Ru; Ji, Hong; Wang, Hui; Xu, Tian-Tian; Makabel, Bolat; Pilarsky, Christian; He, Gen; Yu, Xi-Yong; Zhang, Jian-Ye (Journal of Nanobiotechnology, 2021)
The inherent heterogeneity of individual cells in cell populations plays significant roles in disease development and progression, which is critical for disease diagnosis and treatment. Substantial evidences show that the majority of traditional gene profiling methods mask the difference of individual cells. Single cell sequencing can provide data to characterize the inherent heterogeneity of individual cells, and reveal complex and rare cell populations. Different microfluidic technologies have emerged for single cell researches and become the frontiers and hot topics over the past decade. In this review article, we introduce the processes of single cell sequencing, and review the principles of microfluidics for single cell analysis. Also, we discuss the common high-throughput single cell sequencing technologies along with their advantages and disadvantages. Lastly, microfluidics applications in single cell sequencing technology for the diagnosis of cancers and immune system diseases are briefly illustrated. [Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2021-10-29
Keywords: Biomedical applications; Droplets; High-throughput; Microfluidic; Single cell RNA sequencing (scRNA-seq); Single cell separation

Microfluidic Technology for the Isolation and Analysis of Exosomes - Wu, Yusong; Wang, Yuqing; Lu, Yanjun; Luo, Xiaomei; Huang, Yinghong; Xie, Ting; Pilarsky, Christian; Dang, Yuanye; Zhang, Jianye (Micromachines, 2022)
Exosomes are lipid-bilayer enclosed vesicles with diameters of 30–150 nm, which play a pivotal role in cell communication by transporting their cargoes such as proteins, lipids, and genetic materials. In recent years, exosomes have been under intense investigation, as they show great promise in numerous areas, especially as bio-markers in liquid biopsies. However, due to the high heterogeneity and the nano size of exosomes, the separation of exosomes is not easy. This review will deliver an outline of the conventional methods and the microfluidic-based technologies for exosome separation. Particular attention is devoted to microfluidic devices, highlighting the efficiency of exosome isolation by these methods. Additionally, this review will introduce advances made in the integrated microfluidics technologies that enable the separation and analysis of exosomes.
CRIS-Team Scopus Importer:2022-11-11
Keywords: detection; exosomes; extra-cellular vesicle; isolation; microfluidics

Minimalinvasive Resektion zystischer Pankreasneoplasien - Brunner, Maximilian; Krautz, Christian; Grützmann, Robert; Weber, Georg (Zentralblatt für Chirurgie, 2023)
CRIS-Team Scopus Importer:2023-12-01
Keywords: Enukleation; minimalinvasive Pankreaschirurgie; Pankreasschwanzresektion; Pankreassegmentresektion; roboterassistierte Pankreaschirurgie; zystische Pankreasneoplasien

Minimum case volumes from the perspective of university providers - Krautz, Christian; Grützmann, Robert (Chirurg, 2022)
The association between patient volume and treatment quality has been sufficiently proven for certain surgical interventions (e.g., resections of the esophagus and pancreas). International experience shows that centralization of patient care in these fields leads to an improvement in outcome quality. If properly enforced, minimum caseload requirements can induce centralization effects in the hospital market. Overcapacities in the German hospital market and high nationwide in-hospital mortality rates (e.g., nationwide postoperative hospital mortality after esophageal and pancreatic resections) justify the current changes in the minimum caseload requirement regulation. Nevertheless, still open questions on volume-outcome relationships (e.g., additive volume effects of associated organ systems) have yet to be answered by scientific studies. In addition, the special role of university medical centers in the German healthcare system needs to be considered in the minimum caseload requirement regulation in order not to jeopardize the importance of university clinics in science, education and patient care through self-regulatory processes in the hospital market induced by minimum caseload requirements.
CRIS-Team WoS Importer:2022-03-25

MiR-122, the regulator of the immune privileged liver - Gefen, Maytal; Layani, Shanny; Klahr, Emma; Hindi, Mor; Rosenberg, Nofar; Abramovitch, Rinat; Nachmansson, Nathalie; Yehezkel, Adi; Peled, Amnon; Rachmilewitz, Jacob; Abraham, Michal; Berger, Michael; et al. (JOURNAL OF HEPATOLOGY, 2022)
CRIS-Team WoS Importer:2022-08-12

MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling - Mziaut, Hassan; Henniger, Georg; Ganss, Katharina; Hempel, Sebastian; Wolk, Steffen; McChord, Johanna; Chowdhury, Kamal; Ravassard, Philippe; Knoch, Klaus Peter; Krautz, Christian; Weitz, Jürgen; Grützmann, Robert; et al. (Molecular Metabolism, 2020)
Objective: MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice. Methods: RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132−/− and control mice. Results: Partial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212−/− mice than the control littermates. Conclusions: This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.
CRIS-Team Scopus Importer:2019-12-24
Keywords: Apoptosis; miR-132; Pancreatectomy; Pten/Akt/Foxo3a; β cell regeneration

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma - Feiersinger, Fabian; Nolte, Elke; Wach, Sven; Rau, Tilman; Vassos, Nikolaos; Geppert, Carol-Immanuel; Konrad, Andreas; Merkel, Susanne; Taubert, Helge; Stürzl, Michael; Croner, Roland S. (PLoS ONE, 2016)
Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01).In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.
EVALuna2:6831

Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids - Dinter, Jonas; Friedrich, Ralf P.; Yang, Hai; Pilarsky, Christian; Mangge, Harald; Pöttler, Marina; Janko, Christina; Alexiou, Christoph; Lyer, Stefan (Materials, 2023)
Pancreatic ductal adenocarcinoma is a hard-to-treat, deadly malignancy. Traditional treatments, such as surgery, radiation and chemotherapy, unfortunately are still not able to significantly improve long-term survival. Three-dimensional (3D) cell cultures might be a platform to study new drug types in a highly reproducible, resource-saving model within a relevant pathophysiological cellular microenvironment. We used a 3D culture of human pancreatic ductal adenocarcinoma cell lines to investigate a potential new treatment approach using superparamagnetic iron oxide nanoparticles (SPIONs) as a drug delivery system for mitoxantrone (MTO), a chemotherapeutic agent. We established a PaCa DD183 cell line and generated PANC-1SMAD4 (−/−) cells by using the CRISPR-Cas9 system, differing in a prognostically relevant mutation in the TGF-β pathway. Afterwards, we formed spheroids using PaCa DD183, PANC-1 and PANC-1SMAD4 (−/−) cells, and analyzed the uptake and cytotoxic effect of free MTO and MTO-loaded SPIONs by microscopy and flow cytometry. MTO and SPION–MTO-induced cell death in all tumor spheroids in a dose-dependent manner. Interestingly, spheroids with a SMAD4 mutation showed an increased uptake of MTO and SPION–MTO, while at the same time being more resistant to the cytotoxic effects of the chemotherapeutic agents. MTO-loaded SPIONs, with their ability for magnetic drug targeting, could be a future approach for treating pancreatic ductal adenocarcinomas.
CRIS-Team Scopus Importer:2023-04-28
Keywords: 3D cell culture; magnetic drug targeting; nanomedicine; pancreatic ductal adenocarcinoma; superparamagnetic iron oxide nanoparticles

Model-based roentgen stereophotogrammetric analysis using elementary geometrical shape models: 10 years results of an uncemented acetabular cup component - Jacobsen, Anne; Seehaus, Frank; Hong, Yutong; Cao, Han; Schuh, Alexander; Forst, Raimund; Sesselmann, Stefan (BMC Musculoskeletal Disorders, 2018)
BACKGROUND: Non-cemented acetabular cup components demonstrated different clinical performance depending on their surface texture or bearing couple. However, clinical osseointegration needs to be proved for each total joint arthroplasty (TJA) design. Aim of this study was to detect the in vivo migration pattern of a non-cemented cup design, using model-based roentgen stereophotogrammetric analysis with elementary geometrical shape models (EGS-RSA) to calculate early cup migration. METHODS: Interchangeable applicability of the model-based EGS-RSA method next to gold standard marker-based RSA method was assessed by clinical radiographs. Afterwards, in vivo acetabular cup migration for 39 patients in a maximum follow up of 120 months (10 years) was calculated using model-based EGS-RSA. RESULTS: For the axes with the best predictive capability for acetabular cup loosening, mean (±SD) values were calculated for migration and rotation of the cup. The cup migrated 0.16 (±0.22) mm along the cranio-caudal axis after 24 months and 0.36 (±0.72) mm after 120 months, respectively. It rotated - 0.61 (±0.57) deg. about the medio-lateral axis after 24 months and - 0.53 (±0.67) deg. after 120 months, respectively. CONCLUSIONS: Interchangeable applicability of model-based EGS-RSA next to gold standard marker-based RSA method could be shown. Model-based EGS-RSA enables an in vivo migration measurement without the necessity of TJA specific surface models. Migration of the investigated acetabular cup component indicates significant migration values along all the three axes. However, migration values after the second postoperative year were within the thresholds reported in literature, indicating no risk for later aseptic component loosening of this TJA design.
EVALuna2:36353

Modeling Exit Strategies from COVID-19 Lockdown with a Focus on Antibody Tests - German, Reinhard; Djanatliev, Anatoli; Maile, Lisa; Bazan, Peter; Hackstein, Holger (2020)
This paper presents two epidemiological models that have been developed in order to study the disease dynamics of the COVID-19 pandemic and exit strategies from the lockdown which has been imposed on many countries world-wide. A strategy is needed such that both the health system is not overloaded letting people die in an uncontrolled way and also such that the majority of people can get back their social contacts as soon as possible. We investigate the potential effects of a combination of measures such as continuation of hygienic constraints after leaving lockdown, isolation of infectious persons, repeated and adaptive short-term contact reductions and also large-scale use of antibody tests in order to know who can be assumed to be immune and participate at public life without constraints. We apply two commonly used modeling approaches: extended SEIR models formulated both as System Dynamics and Agent-Based Simulation, in order to get insight into the disease dynamics of a complete country like Germany and also into more detailed behavior of smaller regions. We confirm the findings of other models that without intervention the consequences of the pandemic can be catastrophic and we extend such findings with effective strategies to overcome the challenge. Based on the modeling assumptions it can be expected that repeated short-term contact reductions will be necessary in the next years to avoid overload of the health system and that on the other side herd immunity can be achieved and antibody tests are an effective way to mitigate the contact reductions for many.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialThis is a simulation studyFunding StatementNo external funding was received for this researchAuthor DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is given in the paper directly

Modern Strategies for the Treatment of Fecal Incontinence Moderne Therapiestrategien bei Stuhlinkontinenz - Brunner, Maximilian; Bittorf, Birgit; Matzel, Klaus (Zentralblatt für Chirurgie, 2019)
Background Fecal incontinence (FI) is often associated with significant suffering for affected patients and reduction of their quality of life. Fecal incontinence has an underestimated prevalence and will gain in importance in the future due to demographic change in Germany. During the last several years, new technologies have been developed and new evidence has been gathered for existing methods. The aim of this work is to highlight current developments and new treatment options for fecal incontinence. Methods and Results A review of recent literature on the treatment of fecal incontinence was conducted. For conservative therapy, the combination of various treatment options has been proven to be particularly effective. For surgical therapy, long term efficacy of sacral nerve stimulation has been confirmed. Sacral nerve stimulation is now considered first line therapy. Sphincteroplasty remains a valid treatment option in patients with FI due to a sphincter gap. Long term efficacy is low. Bulking agents are an alternative - predominantly in passive FI, although the evidence is limited due to the use of different substances and techniques, lack of long-term results and suboptimal study designs. For the treatment of FI in the context of a masked defecation disorder, ventral mesh rectopexy has become established. Conclusion The spectrum of therapeutic options for the treatment of FI is continuously evolving. There is consensus that conservative treatment should be the initial therapy. Currently only a limited number of established surgical options are available. Development and evaluation of new treatment options and further improved evidence of efficacy of the existing treatment modalities are desirable.
CRIS-Team Scopus Importer:2019-05-02
Keywords: conservative therapy; fecal incontinence; modern treatment strategies; sacral nerve stimulation; sphincteroplasty; surgery

Modulation of Neutrophil Activity by Soluble Complement Cleavage Products—An In-Depth Analysis - Wohlgemuth, Lisa; Stratmann, Alexander Elias Paul; Muennich, Frederik; Bernhard, Stefan; Thomass, Bertram Dietrich; Munnich, Finn; Mohamed, Adam Omar Khalaf; Mannes, Marco; Schmidt, Christoph Quirin; Ekdahl, Kristina Nilsson; Nilsson, Bo; Fauler, Michael; et al. (Cells, 2022)
The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity was monitored by flow cytometry regarding cellular (electro-)physiology, cellular activity, and changes in the surface expression of activation markers. The study revealed no major effects induced by C3a or C4a on neutrophil functions. By contrast, exposure to C5a or C5a des-Arg stimulated neutrophil activity as reflected in changes in membrane potential, intracellular pH, glucose uptake, and cellular size. Similarly, C5a and C5a des-Arg but no other monitored complement cleavage product enhanced phagocytosis and reactive oxygen species generation. C5a and C5a des-Arg also altered the neutrophil surface expression of several complement receptors and neutrophil activation markers, including C5aR1, CD62L, CD10, and CD11b, among others. In addition, a detailed characterization of the C5a-induced effects was performed with a time resolution of seconds. The multiparametric response of neutrophils was further analyzed by a principal component analysis, revealing CD11b, CD10, and CD16 to be key surrogates of the C5a-induced effects. Overall, we provide a comprehensive insight into the very early interactions of neutrophil granulocytes with activated complement split products and the resulting neutrophil activity. The results provide a basis for a better and, importantly, time-resolved and multiparametric understanding of neutrophil-related (patho-)physiologies.
CRIS-Team Scopus Importer:2022-11-04
Keywords: anaphylatoxins; complement system; inflammation; innate immunity; neutrophils

Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure - Bittel, Miriam; Kremer, Andreas; Stürzl, Michael; Wirtz, Stefan; Stolzer, Iris; Neurath, Markus; Ballon, Gianna; Günther, Claudia (Cell Death & Disease, 2019)
During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.
CRIS-Team Scopus Importer:2019-12-03

Molecular characterization of peripheral arterial disease in proximal extremity arteries - Croner, Roland S.; Balzer, Klaus; Schellerer, Vera; Mueller, Volker; Schlabrakowsi, Anne; Stürzl, Michael; Naschberger, Elisabeth; Lang, Werner (Journal of Surgical Research, 2012)
Purpose: Although risk factors for atherosclerosis in peripheral arterial disease (PAD) are well defined, the underlying mechanisms are poorly understood and no medication exists for causal therapy. Molecular pathways that could be targeted have not been identified so far. To address this issue, we compared the molecular profiles of healthy versus PAD proximal femoral arteries. Methods: Gene expression profiles from proximal femoral arteries of patients with PAD (Fontaine stage IIb-IV; n = 20) and femoral arteries from healthy controls (CO) (n = 3) were compared by microarray technology. We evaluated all samples by histopathology and performed microdissection on the CO tissue before molecular analysis. We analyzed genes regarding their cellular localization, molecular function, and risk factors such as hypercholesterolemia, smoking, and diabetes. We used a selected panel of genes for polymerase chain reaction validation of microarray results and compared the data with previously published studies. Results: Most genes overexpressed in PAD versus CO were located in the cytoplasm, membrane, and nucleus. Functionally, they had binding activity to nucleotides, cytoskeletal proteins, and transcription factors. They were mainly involved in immune regulation (e.g., interleukin-8, chemokine ligand 18, and allograft-inflammatory factor-1) (P < 0.01). Down-regulated genes in PAD versus CO were located in the extracellular region. They had transporter and G-protein receptor activity. They were associated with signaling, cell growth, and tissue formation (e.g., myosin VB, marker for differentiated aortic smooth muscle, myosin 11) (P < 0.01). Polymerase chain reaction successfully validated the expression of the differences among 10 selected genes (e.g., chemokine ligand 18, common leukocyte antigen, killer cell lectin-like receptor subfamily B, member 1, and interleukin-8). Conclusions: Genes enrolled in immune regulation and inflammatory response were identified as key players in PAD. Various membrane-bound molecules with binding activity are hereunder. Identification of such molecules may elucidate relevant players that act as candidates for therapeutic targets or prognostic markers in the future. © 2012 Elsevier Inc. All rights reserved.
Created from Fastlane, Scopus look-up
Keywords: Artheriosclerosis; Microarray; Molecular marker; Peripheral arterial disease

Molecularly characterised xenograft tumour mouse models: valuable tools for evaluation of new therapeutic strategies for secondary liver cancers. - Mischek, Daniela; Steinborn, Ralf; Petznek, Helga; Bichler, Christoph; Zatloukal, Kurt; Stürzl, Michael; Guenzburg, Walter H.; Hohenadl, Christine (Journal of Biomedicine and Biotechnology, 2009)
To develop and evaluate new therapeutic strategies for the treatment of human cancers, well-characterised preclinical model systems are a prerequisite. To this aim, we have established xenotransplantation mouse models and corresponding cell cultures from surgically obtained secondary human liver tumours. Established xenograft tumours were patho- and immunohistologically characterised, and expression levels of cancer-relevant genes were quantified in paired original and xenograft tumours and the derivative cell cultures applying RT-PCR-based array technology. Most of the characteristic morphological and immunohistochemical features of the original tumours were shown to be maintained. No differences were found concerning expression of genes involved in cell cycle regulation and oncogenesis. Interestingly, cytokine and matrix metalloproteinase encoding genes appeared to be expressed differentially. Thus, the established models are closely reflecting pathohistological and molecular characteristics of the selected human tumours and may therefore provide useful tools for preclinical analyses of new antitumour strategies in vivo.

Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract. - Langheinrich, Melanie; Schellerer, Vera; Perrakis, Aristotelis; Lohmüller, Clemens; Schildberg, Claus; Naschberger, Elisabeth; Stürzl, Michael; Hohenberger, Werner; Croner, Roland S. (International Journal of Clinical and Experimental Pathology, 2012)
Tumor cell dissemination from the primary tumor site to distant organs is one of the characteristic properties of malignant tumors and represents a crucial step in the progression of disease. Although the pattern of spread may vary in different types of carcinomas, dissemination via the lymphatic system represents a common event in metastasis. The extent of lymph node metastasis is one of the major determinants for the prognosis of patients with gastrointestinal carcinomas and guides the therapeutically management. During the last decades, significant attention has been given to the molecular mechanisms that control lymphatic metastasis. The process of lymphangiogenesis has come into the focus. Lymphangiogenesis, the formation of newly lymphatics, comprises a series of complex cellular events and is controlled by a balance between pro- and anti-lymphangiogenic signals. This article will briefly describe the lymphatic system and then provide an overview of the molecular players involved in tumor lymphangiogenesis.

Molecular signature for lymphatic metastasis in colorectal carcinomas. - Croner, Roland S.; Förtsch, Thomas; Brueckl, Wolfgang M.; Roedel, Franz; Roedel, Claus; Papadopoulos, Thomas; Brabletz, Thomas; Kirchner, Thomas; Sachs, Martin; Behrens, Jürgen; Klein-Hitpass, Ludger; Stürzl, Michael; et al. (Annals of Surgery, 2008)
Fifty differently expressed genes between stage UICC I, II versus III CRC were identified respecting the selection criteria by allowing for multiple testing. The data validation by the independent clinical study confirmed our results. In comparison to MC, the genes were over- or underexpressed. They belong to various functional groups such as cellular adhesion, transporters, signaling, metabolism, protein synthesis, gene control, and immune system. Forty tumor samples of stage UICC I, II CRC, 40 samples of stage III CRC, and 25 biopsies of healthy mucosa (MC) were shock frozen in liquid nitrogen and underwent cryotomy after manual dissection for tumor tissue or MC enrichment. Isolated RNA was hybridized to GeneChips (HG-U133A, Affymetrix). Preprocessing of the microarray results was done by the robust multichip average method, and differentially expressed genes were selected by the maximum Wilcoxon statistic over 22,215 probe sets. The results were validated at an independent clinical study. Our large patient cohort and the data validation on an independent study identified 50 differentially expressed genes between CRC of different histopathologic stages. These findings indicate that molecular staging of CRC may be possible, which could help to guide individual CRC treatment before surgery. TNM-staging of colorectal carcinomas (CRC) relies on the histopathologic workup of the surgically removed specimen. If valid preoperative staging methods existed, patients could be selected for adequate individual therapy before surgery. Microarray techniques provide a promising tool to identify stage-specific molecular signatures on primary tumor biopsies. RESULTS MATERIAL AND METHODS CONCLUSION PURPOSE

Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study - Croner, R. S.; Geppert, Carol-Immanuel; Bader, F. G.; Nitsche, U.; Spaeth, C.; Rosenberg, R.; Zettl, A.; Matias-Guiu, Xavier; Tarragona, J.; Gueller, U.; Stürzl, Michael; Zuber, M. (British Journal of Cancer, 2014)
Background:Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in 20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA.Methods:Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations.Results:In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes.Conclusions:OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.
EVALuna2:6584

Monitoring spinal muscular atrophy with three-dimensional optoacoustic imaging - Nedoschill, Emmanuel; Wagner, Alexandra L.; Danko, Vera; Bühler, Adrian; Raming, Roman; Jüngert, Jörg M.; Neurath, Markus; Waldner, Maximilian; Rother, Ulrich; Wölfle, Joachim; Trollmann, Regina; Knieling, Ferdinand; et al. (Med, 2024)
Background: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. Methods: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). Findings: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. Conclusions: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. Funding: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.
CRIS-Team Scopus Importer:2024-05-03
Keywords: gene therapy; non-invasive imaging; optoacoustic imaging; pediatric spinal muscular atrophy; photoacoustic imaging; spinal muscular atrophy; Translation to patients

Monopolar and bipolar combination injuries of the clavicle: Retrospective incidence analysis and proposal of a new classification system - Bakir, M. Sinan; Carbon, Roman; Ekkernkamp, Axel; Schulz-Drost, Stefan (Journal of Clinical Medicine, 2021)
Clavicle injuries are common, but only few case reports describe combined clavicular injuries (CCI). CCI include combinations between clavicular fractures and acromioclavicular/sternoclavicular joint dislocations (SCJD). We present the first general therapeutic recommendations for CCI based on a new classification and their distribution. A retrospective, epidemiological, big data analysis was based on ICD-10 diagnoses from 2012 to 2014 provided by the German Federal Statistical Office. CCI represent 0.7% of all clavicle-related injuries (n = 814 out of 114,003). SCJD show by far the highest proportion of combination injuries (13.2% of all SCJD were part of CCI) while the proportion of CCI in relation to the other injury entities was significantly less (p < 0.023). CCIs were classified depending on (1) the polarity (monopolar type I, 92.2% versus bipolar type II, 7.8%). Monopolar type I was further differentiated depending on (2) the positional relationship between the combined injuries: Ia two injuries directly at the respective pole versus Ib with an injury at one end plus an additional midshaft clavicle fracture. Type II was further differentiated depending on (3) the injured structures: IIa ligamento-osseous, type IIb purely ligamentous (rarest with 0.6%). According to our classification, the CCI severity increases from type Ia to IIb. CCI are more important than previously believed and seen as an indication for surgery. The exclusion of further, contra-polar injuries in the event of a clavicle injury is clinically relevant and should be focused.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Acromioclavicular joint dislocation; Big data analysis; Classification system; Clavicle fracture; Clavicular combination injury; Floating clavicle; Routine data; Sternoclavicular joint dislocation

Moonlighting chromatin: when DNA escapes nuclear control - Singh, Jeeshan; Boettcher, Michael; Dölling, Maximilian; Heuer, Annika; Hohberger, Bettina; Leppkes, Moritz; Naschberger, Elisabeth; Schapher, Mirco; Schauer, Christine; Schoen, Janina; Stürzl, Michael; Vitkov, Ljubomir; et al. (Cell Death and Differentiation, 2023)
Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable. [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2023-02-17

Morphologic HIV demonstration in formalin embedded material–techniques, problems, results - Zietz, Christian; Speiser, B; Hell, W; Stürzl, Michael; Wolf, H; Roth, W K (Verhandlungen der Deutschen Gesellschaft für Pathologie, 1991)
Formalin-fixed, paraffin-embedded material of archival specimens is suitable for a morphological HIV-detection: Infected cells with HIV in the proliferative phase can be demonstrated with reliable results on tissue sections by immunohistological technics using new antibodies. In situ nucleic acid hybridisation technics can also show HIV in the expression phase on paraffin-embedded material, but often fail in demonstrating latently HIV-infected cells. The DNA-Polymerase chain reaction can detect latent Provirus in morphologically defined areas of paraffin sections even in autopsy material, i.e. lymphnodes and even eyes of patients with HIV-Infection, but requires precaution and control with respect to contamination.

MRI-Based Treatment of Rectal Cancer: Is Prognostication of the Recurrence Risk Solid Enough to Render Radiation Redundant? - Sautter-Bihl, Marie-Luise; Hohenberger, Werner; Fietkau, Rainer; Roedel, Claus; Schmidberger, Heinz; Sauer, Rolf (Annals of Surgical Oncology, 2014)
Most current guidelines recommend neoadjuvant short course radiotherapy (sRT) or radio-chemotherapy (nRCT) for rectal cancer stage II and III. After the introduction of total mesorectal excision (TME) and magnetic resonance imaging (MRI), this proceeding has been questioned and omission of neoadjuvant treatment according to preoperative MRI-criteria has been propagated. Aim of the present paper is to review the state of evidence regarding MRI-based treatment decision depending on the predicted width of the circumferential resection margin (CRM).A comprehensive survey of the literature was performed using the search terms "rectal cancer", "radiotherapy", "radio-chemotherapy", "MRI-based therapy", "circumferential resection margin". Data from lately published observational studies were compared to results from randomized trials and outcome analyses of the Norwegian national cancer registry.Only one observational study using MRI-based treatment according to the anticipated CRM provided 5 year local recurrence data, however only for 65 patients. The second study did not yet evaluate recurrence rates. Two randomized trials comparing sRT to primary TME showed significantly worse outcome for non-irradiated patients. Data from the Norwegian rectal cancer registry demonstrate that TME alone is associated with higher LRR than achievable with preoperative RT.Current evidence does not support the omission of neoadjuvant treatment for stage II-III rectal cancer on the basis of an MRI-predicted negative CRM. Randomized studies are warranted to clarify whether and for which subgroups TME alone is safe in terms of local recurrences.
EVALuna2:15138

MRI-Based Use of Neoadjuvant Chemoradiotherapy in Rectal Carcinoma: Surgical Quality and Histopathological Outcome of the OCUM Trial - Kreis, Martin E.; Ruppert, Reinhard; Kube, Rainer; Strassburg, Joachim; Lewin, Andreas; Baral, Joerg; Maurer, Christoph A.; Sauer, Joerg; Winde, Günther; Thomasmeyer, Rena; Stelzner, Sigmar; Bambauer, Cornelius; et al. (Annals of Surgical Oncology, 2019)
Background: Preoperative magnetic resonance imaging (MRI) allows highly reliable imaging of the mesorectal fascia (mrMRF) and its relationship to the tumor. The prospective multicenter observational study OCUM uses these findings to indicate neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. Methods: nCRT was indicated in patients with positive mrMRF (≤ 1 mm) in cT4 and cT3 carcinomas of the lower rectal third. Results: A total of 527 patients (60.2%) underwent primary total mesorectal excision, and 348 patients (39.8%) underwent long-term nCRT followed by surgery. The mrMRF was involved in 4.6% of the primary surgery group and 80.7% of the nCRT group. Rates of resections within the mesorectal plane (90.8%), sparing of pelvic nerves on both sides (97.8%), and number of regional lymph nodes (95.3% with ≥ 12 lymph nodes examined) are indicative of high-quality surgery. Resection was classified as R0 in 98.3%, the pathological circumferential resection margin (pCRM) was negative in 95.1%. Patients in the nCRT group had more advanced carcinomas with a significantly higher rate of abdominoperineal excision. Independent risk factors for pCRM positivity were advanced stage (T4), metastatic lymph nodes, resection in the muscularis propria plane, and location in the lower third. Conclusions: The risk classification of rectal cancer patients by MRI seems to be highly reliable and allows the restriction of nCRT to approximately half of the patients with clinical stage II and III rectal carcinoma, provided there is a high-quality MRI diagnostic protocol, high-quality surgery, and standardized examination of the resected specimen.
CRIS-Team Scopus Importer:2019-08-30

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer - Mlecnik, Bernhard; Bifulco, Carlo; Bindea, Gabriela; Marliot, Florence; Lugli, Alessandro; Lee, J. Jack; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Borger, Elisa; Hartmann, Arndt; et al. (Journal of Clinical Oncology, 2020)
PURPOSEThe purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).METHODSAn international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.RESULTSPatients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution 2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12).CONCLUSIONThis study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
CRIS-Team WoS Importer:2020-11-27

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer - Mlecnik, Bernhard; Lugli, Alessandro; Bindea, Gabriela; Marliot, Florence; Bifulco, Carlo; Lee, Jiun Kae Jack; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Börger, Elisa; Hartmann, Arndt; et al. (Cancers, 2023)
Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
CRIS-Team Scopus Importer:2023-02-03
Keywords: colon cancer; early-stage; Immunoscore; predictive biomarkers; prognosis; tumor microenvironment

Multicentric Sentinel Healthcare Research Project of Skin Cancer Centers in Nuremberg, Erlangen, Regensburg and Wuerzburg - Enzelsberger, K.; Debus, D.; Schultz, E.; Haferkamp, S.; Hegemann, M. V.; Stolze, I.; Erdmann, M.; Schellerer, Vera (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Multi-Dimensional Flow-Preserving Compressed Sensing (MuFloCoS) for Time-Resolved Velocity-Encoded Phase Contrast MRI - Hutter, Jana; Schmitt, Peter; Saake, Marc; Stübinger, Axel; Grimm, Robert; Forman, Christoph; Greiser, Andreas; Hornegger, Joachim; Maier, Andreas (IEEE Transactions on Medical Imaging, 2015)
4-D time-resolved velocity-encoded phase-contrast MRI (4-D PCI) is a fully non-invasive technique to assess hemodynamics in vivo with a broad range of potential applications in multiple cardiovascular diseases. It is capable of providing quantitative flow values and anatomical information simultaneously. The long acquisition time, however, still inhibits its wider clinical use. Acceleration is achieved at present using parallel MRI (pMRI) techniques which can lead to substantial loss of image quality for higher acceleration factors. Both the high-dimensionality and the significant degree of spatio-temporal correlation in 4-D PCI render it ideally suited for recently proposed compressed sensing (CS) techniques. We propose the Multi-Dimensional Flow-preserving Compressed Sensing (MuFloCoS) method to exploit these properties. A multi-dimensional iterative reconstruction is combined with an interleaved sampling pattern (I-VT), an adaptive masked and weighted temporal regularization (TMW) and fully automatically obtained vessel-masks. The performance of the novel method was analyzed concerning image quality, feasibility of acceleration factors up to 15, quantitative flow values and diagnostic accuracy in phantom experiments and an in vivo carotid study with 18 volunteers. Comparison with iterative state-of-the-art methods revealed significant improvements using the new method, the temporal normalized root mean square error of the peak velocity was reduced by 45.32% for the novel MuFloCoS method with acceleration factor 9. The method was furthermore applied to two patient cases with diagnosed high-grade stenosis of the ICA, which confirmed the performance of MuFloCoS to produce valuable results in the presence of pathological findings in 56 s instead of over 8 min (full sampling).
UnivIS-Import:2015-07-08:Pub.2015.tech.IMMD.IMMD5.multid
Keywords: Compressed sensing; hemodynamics; magnetic resonance imaging (MRI); phase contrast MRI

Multiple interferon regulatory factor and NF-κB sites cooperate in mediating cell-type-and maturation-specific activation of the human CD83 promoter in dendritic cells - Stein, Marcello F.; Lang, Stefan; Winkler, Thomas; Deinzer, Anja; Erber, Sebastian; Nettelbeck, Dirk M.; Naschberger, Elisabeth; Jochmann, Ramona; Stürzl, Michael; Slany, Robert; Werner, Thomas; Steinkasserer, Alexander; et al. (Molecular and Cellular Biology, 2013)
CD83 is one of the best-known surface markers for fully mature dendritic cells (mature DCs), and its cell-type-and maturationspecific regulation makes the CD83 promoter an interesting tool for the genetic modulation of DCs. To determine the mechanisms regulating this DC-and maturation-specific CD83 expression, chromatin immunoprecipitation (ChIP)-on-chip microarray, biocomputational, reporter, electrophoretic mobility shift assay (EMSA), and ChIP analyses were performed. These studies led to the identification of a ternary transcriptional activation complex composed of an upstream regulatory element, a minimal promoter, and an enhancer, which have not been reported in this arrangement for any other gene so far. Notably, these DNA regions contain a complex framework of interferon regulatory factor (IRF)-and NF-κB transcription factor-binding sites mediating their arrangement. Mutation of any of the IRF-binding sites resulted in a significant loss of promoter activity, whereas overexpression of NF-κB transcription factors clearly enhanced transcription. We identified IRF-1, IRF-2, IRF-5, p50, p65, and cRel to be involved in regulating maturation-specific CD83 expression in DCs. Therefore, the characterization of this promoter complex not only contributes to the knowledge of DC-specific gene regulation but also suggests the involvement of a transcriptional module with binding sites separated into distinct regions in transcriptional activation as well as cell-type-and maturation-specific transcriptional targeting of DCs. © 2013, American Society for Microbiology.

Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease - Regensburger, Adrian; Eckstein, Markus; Wetzl, Matthias; Raming, Roman; Paulus, Lars-Philip; Bühler, Adrian; Nedoschill, Emmanuel; Danko, Vera; Jüngert, Jörg; Wagner, Alexandra; Schnell, Alexander; Rückel, Aline; et al. (Photoacoustics, 2024)
Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn‘s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Multispectral optoacoustic tomography; Optoacoustic imaging; Paediatric inflammatory bowel disease

Multispectral Optoacoustic Tomography in Crohn's Disease: Noninvasive Imaging of Disease Activity - Waldner, Maximilian; Knieling, Ferdinand; Egger, Cornelia; Morscher, Stefan; Claussen, Jing; Vetter, Marcel; Kielisch, Christian; Fischer, Sören; Pfeifer, Lukas; Hagel, Alexander; Görtz, Rüdiger; Wildner, Dane; et al. (Gastroenterology, 2016)
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Multispectral optoacoustic tomography of the human intestine – temporal precision and the influence of postprandial gastrointestinal blood flow - Paulus, Lars-Philip; Wagner, Alexandra; Buehler, Adrian; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Günther, Josefine; Rother, Ulrich; Lang, Werner; Hörning, André; et al. (Photoacoustics, 2023)
Multispectral optoacoustic tomography (MSOT) holds great promise as a non-invasive diagnostic tool for inflammatory bowel diseases. Yet, reliability and the impact of physiological processes during fasting and after food intake on optoacoustic signals have not been studied. In the present investigator initiated trial (NCT05160077) the intestines of ten healthy subjects were examined by MSOT at eight timepoints on two days, one fasting and one after food intake. While within-timepoint and within-day reproducibility were good for single wavelength 800 nm and total hemoglobin (ICC 0.722–0.956), between-day reproducibility was inferior (ICC −0.137 to 0.438). However, temporal variability was smaller than variation between individuals (coefficients of variation 8.9%−33.7% vs. 17.0%−48.5%). After food intake and consecutive increased intestinal circulation, indicated by reduced resistance index of simultaneous Doppler ultrasound, optoacoustic signals did not alter significantly. In summary, this study demonstrates high reliability and temporal stability of MSOT for imaging the human intestine during fasting and after food intake.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Gut; Inflammatory bowel disease; Intestinal blood flow; Multispectral optoacoustic imaging; Optoacoustic; Photoacoustic; Postprandial; Reliability; Reproducibility

Muscle‐derived cytokines reduce growth, viability and migratory activity of pancreatic cancer cells - Schwappacher, Raphaela; Dieterich, Walburga; Reljic, Dejan; Pilarsky, Christian; Mukhopadhyay, Debabrata; Chang, David K.; Biankin, Andrew; Siebler, Jürgen; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Cancers, 2021)
The evidence that regular physical exercise reduces the risk of developing cancer is well described. However, the interaction between physical exercise and cancer is not fully clarified yet. Several myokines released by skeletal muscle appear to have a direct anti‐tumour function. There are few data on myokine secretion after exercise in patients with advanced tumours. Pancreatic cancer (PC) is a very aggressive and usually fatal cancer. To investigate the effects of exercise in PC, the blood of advanced‐stage PC patients was analysed after 12 weeks of resistance training using whole‐body electromyostimulation. After the 12‐week training period, the patient serum inhibited the proliferation and the motility of PC cells and enhanced PC cell apoptosis. The impact of exercise training was also investigated in an exercise‐mimicking in vitro model using electric pulse stimulation of human myotubes and revealed similar anti‐tumour effects on PC cells, clearly indicating direct cancer‐protective properties of activated skeletal muscle. Protein and gene expression analyses in plasma from exercise‐trained patients and in myotube cultures after in vitro exercise showed that interleukin 10 (IL10), C‐X‐C motif ligand 1 (CXCL1) and C‐C motif chemokine ligand 4 (CCL4) are myokines released from activated skeletal muscle. In accordance with the effects of serum from exercise‐trained patients, the supplementation with recombinant IL10, CXCL1 and CCL4 impaired growth and migration of PC cells. Treatment of PC cells with these myokines upregulated caspase 3/7 expression and the cleavage of poly(ADP‐ribose) polymerase, leading to enhanced PC cell death. The identification of myokines with anti‐tumour properties in advanced‐stage PC patients after exercise opens a new perspective in supportive therapy with sports and exercise for cancer patients.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Apoptosis; Electric pulse stimulation; Exercise; Migration; Myokine; Pancreatic cancer; Physical activity; Proliferation; Whole‐body electromyostimulation

Myocardial Protection During Aortic Arch Repair in a Piglet Model: Beating Heart Technique Compared With Crystalloid Cardioplegia - Janssen, Carina; Kellermann, Stephanie; Münch, Frank; Purbojo, Ariawan; Cesnjevar, Robert; Rueffer, Andre (Annals of Thoracic Surgery, 2015)
Selective myocardial perfusion enables repair of congenital aortic arch obstruction without cardiac arrest. This study was inspired by the lack of prospective controlled studies of the beating heart (BH) technique compared with cold crystalloid cardioplegia (CC) regarding effects on myocardial performance, ischemic damage, and serum electrolyte levels.In a prospective study, 20 male piglets weighing 11.1 ± 1.3 kg were operated on using cardiopulmonary bypass (CPB) and underwent 60 minutes of aortic cross-clamping. According to prospective randomization, myocardial protection included either a BH modification with selective myocardial perfusion using an individual roller pump or CC. Hemodynamic performance was evaluated by a conductance catheter technique before and after CPB and calculated in relation to baseline levels. Laboratory analysis included blood levels of troponin T and serum electrolytes.Eighteen piglets entered analysis. There were significantly higher slopes of end-systolic pressure-volume relations (168% ± 92% versus 89% ± 16%; p = 0.046) and preload-recruitable stroke work (PRSW) (139% ± 37% versus 103% ± 31%; p = 0.040) in BH piglets compared with those who underwent CC. Laboratory analysis during reperfusion revealed higher levels of troponin T (1.31 ± 0.28 ng/mL versus 0.49 ± 0.17 ng/mL; p < 0.01) and sodium (131 ± 4 mmol/L versus 120 ± 8 mmol/L; p = 0.003) and lower levels of potassium (4.8 ± 0.4 mmol/L versus 6.4 ± 1.0 mmol/L; p = 0.001) with BH compared with CC, whereas no significant differences were calculated at the end of the experiment.The BH technique is associated with improved contractility compared with standard CC. There is comparable ischemic damage in both groups, with an earlier rise in blood levels of troponin T after BH and more fluctuation of serum electrolytes with CC. Evidence of ischemic changes should dissuade one from using the BH technique imprudently.
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Myocutaneous transpelvic flaps do improve quality of life and help to reduce wound healing complications in patients receiving abdominoperineal resection in the real world - Horch, Raymund E.; Hohenberger, Werner; Weber, Klaus; Arkudas, Andreas; Beier, Justus (International Journal of Colorectal Disease, 2016)
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NAR score as surrogate for disease-free survival in the CAO/ARO/AIO-04 phase 3 rectal cancer trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G.; Wittekind, C.; Sauer, Rolf; Kaufmann, M.; et al. (2018)
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Nationwide In-hospital Mortality Following Pancreatic Surgery in Germany is Higher than Anticipated - Nimptsch, Ulrike; Krautz, Christian; Mansky, Thomas; Grützmann, Robert; Weber, Georg (Annals of Surgery, 2016)
We aimed to determine the unbiased mortality rates for pancreatic surgery procedures at the national level through a comprehensive analysis of every inpatient case in Germany.Several studies have proclaimed a general improvement of perioperative outcomes following pancreatic surgery. These results are challenged by recent analyses of large US databases that found strong volume-outcome relationships, with high mortality in low-volume facilities.All inpatient cases with a pancreatic surgery procedure code in Germany from 2009 to 2013 were identified from nationwide administrative hospital data. We determined the absolute number of patients and the in-hospital death rate for crucial subcategories such as medical indications and types of surgical procedure.A total of 58,003 inpatient episodes of pancreatic surgery were identified between 2009 and 2013. Annual case numbers increased significantly, which was primarily attributed to patients aged 70 years and older. The overall in-hospital mortality rate (10.1%) did not significantly change during the study period. Major pancreatic resections were associated with mortality ranging from 7.3% (distal pancreatectomy) to 22.9% (total pancreatectomy). Postoperative interventions indicative of severe complications were documented frequently (eg, more than 6 blood transfusions in 20% of all patients and relaparotomy in 16%). Their occurrence was associated with a dramatic increase in mortality.At the national level in Germany, perioperative mortality is higher than anticipated from previous studies. The absence of a significant reduction in overall mortality challenges current health policies that aim to improve the outcomes of high-risk surgical procedures in Germany.
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NCR, an Inflammation and Nutrition Related Blood-Based Marker in Colon Cancer Patients: A New Promising Biomarker to Predict Outcome - Langheinrich, Melanie; Siebenhüner, Alexander Reinhard; Baecker, Justus; Miragall, Maximilian; Wiesmüller, Felix; Schellerer, Vera; Merkel, Susanne; Brunner, Maximilian; Krautz, Christian; Weber, Klaus; Grützmann, Robert; Kersting, Stephan (Diagnostics, 2023)
Background: Colorectal carcinoma (CRC) is a heterogeneous disease, and differences in outcomes have been reported among patients diagnosed with the same disease stage. Prognostic and predictive biomarkers provide information for patient risk stratification and guide treatment selection. Although numerous studies have analyzed the effects of systemic inflammatory factors on CRC outcomes, clinical significance remains to be elucidated. In particular, the treatment strategy of colon cancer patients is different from that of rectal cancer due to outcome and recurrence differences. The identification of patients with a poor prognosis who might benefit from intensive treatment approaches is clinically necessary. Methods: This study aimed to evaluate the value of different blood-based markers and assess the significance of our newly developed inflammatory-nutrition-related biomarker (NCR = BMI × albumin/CRP) in patients with colon cancer. A two-stage design was used with 212 patients with colon cancer (CC) in the discovery cohort (n = 159) and in an external validation cohort (n = 53). Results: A lower preoperative NCR level was significantly correlated with a worse prognosis, sidedness, undifferentiated histology, nodal involvement, and advanced UICC stage. We compared the NCR with other established prognostic indices and showed that the NCR is a more reliable indicator of a poor prognosis for patients with CC. Patients with low NCR levels experienced a significantly shorter Overall Survival (OS) than patients with high levels. Multivariate analysis confirmed preoperative NCR levels as an independent predictor for overall survival with a hazard ratio of 3.3 (95% confidence interval 1.628–6.709, p < 0.001). Finally, we confirmed the predictive value of the NCR in an independent validation cohort and confirmed NCR as an independent prognostic factor for OS. Conclusion: Taken together, we discovered a new prognostic index (NCR) based on BMI, albumin, and CRP levels as an independent prognostic predictor of OS in patients with colon cancer. In all UICC stages, our newly developed NCR marker is able to distinguish patients with better and worse prognoses. We, therefore, propose that NCR may serve as a supplement to the TNM staging system to optimize the risk stratification in CC patients towards personalized oncology. In particular, NCR can be used in clinical trials to stratify patients with UICC II and III tumors and help better select patients who might benefit from adjuvant treatment.
CRIS-Team Scopus Importer:2023-01-20
Keywords: biomarker; colon cancer; colorectal cancer; inflammation; nutrition; prognosis; sidedness; tumor marker

Negative Pressure Wound Therapy Combined With Instillation for Sternoclavicular Joint Infection - Schreiner, Waldemar; Ludolph, Ingo; Dudek, Wojciech; Horch, Raymund E.; Sirbu, Horia (Annals of Thoracic Surgery, 2020)
Background: There is no consensus on the management of spontaneous sternoclavicular joint infection (SCJI). Negative pressure wound therapy (NPWT) has been widely accepted for SCJI. We reviewed our experience with the management of this condition comparing NPWT alone and NPWT combined with instillation and dwell time. Methods: We retrospectively analyzed the data of patients with spontaneous SCJI treated in our thoracic unit. Results: From March 2008 to October 2019, 27 patients (21 men and 6 women) underwent NPWT combined with muscle flap transfer after necrosectomy and chest wall resection for SCJI. The median age was 57.1 years (range, 35 to 85). Depending on management, the patients were divided into two groups: 16 patients with NPWT in group 1, and 11 patients with NPWT combined with instillation and dwell time in group 2. The severity of SCJI, extent of chest wall resection, and type of muscle flap were not significantly different (P = .35, P = .858, P = .705, respectively). Median duration of hospital stay and NPWT were shorter in group 2 (30 vs 25 days, and 20 vs 16 days, respectively). The required wound dressing changes were significantly lower in group 2 (P = .008). Statistical trend to higher bacterial eradication in group 2 was noted (P = .093). Postoperative complications including SCJI recurrence, wound seroma, and dehiscence were not significantly different between groups (P = .269). Conclusions: The NPWT combined with instillation and dwell time appears a useful strategy in patients with SCJI, leading to higher incidence of bacterial eradication and shorter wound care.
CRIS-Team Scopus Importer:2020-10-30

Neoadjuvant chemoradiation combined with regional hyperthermia in locally advanced or recurrent rectal cancer - Ott, Oliver; Gani, Cihan; Lindner, Lars H.; Schmidt, Manfred; Lamprecht, Ulf; Abdel-Rahman, Sultan; Hinke, Axel; Weissmann, Thomas; Hartmann, Arndt; Issels, Rolf D.; Zips, Daniel; Belka, Claus; et al. (Cancers, 2021)
Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Complete remission rate; Concurrent chemoradiation; Locally advanced rectal cancer; Locally recurrent rectal cancer; Regional hyperthermia; Tumor regression grading

Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer : Results of the first prospective randomized phase II trial - Golcher, Henriette; Brunner, Thomas; Witzigmann, Helmut; Marti, Lukas; Bechstein, Wolf-Otto; Bruns, Christiane; Jungnickel, Henry; Schreiber, Stefan; Grabenbauer, Gerhard; Meyer, Thomas; Merkel, Susanne; Fietkau, Rainer; et al. (Strahlentherapie und Onkologie, 2015)
In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging.Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS).The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48 % (A) and 52 % (B, P = 0.81) and (y)pN0 was 30 % (A) vs. 39 % (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79).This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.
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Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome - Willner, Alexander; Fechner, Katja; Agaimy, Abbas; Haller, Florian; Eckstein, Markus; Ott, Oliver; Putz, Florian; Gaipl, Udo; Kersting, S.; Meidenbauer, Norbert; Grützmann, Robert; Fietkau, Rainer; et al. (Strahlentherapie und Onkologie, 2021)
Purpose Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. Methods From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m(2) BSA/d3 q28 and ifosfamide 1.5 g/m(2) BSA/d1-5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. Results The median follow-up time was 53 months (+/- 56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (+/- 10.1%) and 66.3% (+/- 11.9%), distant metastasis-free survival was 67.2% (+/- 9.7%) and 59.7% (+/- 11.1%), and overall survival was 60.3% (+/- 10.5%) and 60.3% (+/- 10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. Conclusion Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.
CRIS-Team WoS Importer:2021-11-12

Neoadjuvant Radiochemotherapy Followed by Curative Resection in Patients with Advanced Non-Small Cell Lung Cancer in Stage IIIA/IIIB: Prognostic Factors and Results - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Gavrychenkova, S.; Rieker, R.; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2016)
The role of surgical lung resection following neo-adjuvant radio-chemotherapy (RCT) in patients with locally advanced non-small cell lung cancer (NSCLC) is yet not clearly defined. The aim of our study was to analyze the postoperative survival and to identify relevant prognostic factors. 46 patients underwent curative resections after neo-adjuvant RCT for locally advanced NSCLC (IIIA/IIIB) between February 2008 and February 2015. A retrospective data analysis regarding preoperative regression status, perioperative mortality, postoperative survival, patho-histological remission, relapse pattern and other prognostic factors was performed. A neo-adjuvant RCT with a median radiation dose of 50.4 [range, 45-60] Gy was performed in 44 (96 %) patients. Partial and/or complete regression was observed in 32 (70 %) patients. R0-resection was achieved in 44 (96 %) patients. The 30-day mortality was 4 % and the perioperative morbidity was 37 %. The overall and progression free 5-year survival rate was 47 % and respectively 45 % [in median 58 months]. The 5-year survival rate of 64 % in the "responder"-group was significantly better when compared with 24 % in the "non-responder"-group (p = 0.038). The tri-modality therapy improved the prognosis in patients with locally advanced NSCLC (stage IIIA/IIIB). The complete patho-histological remission is an important prognostic factor for better long term survival. Dividing the patients in "responder" and "non-responder" after neo-adjuvant RCT may have large therapeutically consequences in the future.
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Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Graeven, U.; Hofheinz, R-D; Koehne, C-H; et al. (Annals of Oncology, 2018)
Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
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Neoadjuvant Therapy for Resectable Pancreatic Cancer A New Standard of Care. Pooled Data From 3 Randomized Controlled Trials - Birrer, Dominique L.; Golcher, Henriette; Casadei, Riccardo; Haile, Sarah R.; Fritsch, Ralph; Hussung, Saskia; Brunner, Thomas B.; Fietkau, Rainer; Meyer, Thomas; Grützmann, Robert; Merkel, Susanne; Ricci, Claudio; et al. (Annals of Surgery, 2021)
Objective: The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome. Summary Background Data: Few underpowered studies have suggested benefits from neoadjuvant chemo (+/- radiation) for strictly resectable PDAC without offering conclusive recommendations. Methods: Three RCTs were identified comparing neoadjuvant chemo (+/- radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. Results: A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI(R)) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. Conclusion: Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.
CRIS-Team WoS Importer:2022-02-11

Netrank: network-based approach for biomarker discovery - Al-Fatlawi, Ali; Rusadze, Eka; Shmelkin, Alexander; Malekian, Negin; Ozen, Cigdem; Pilarsky, Christian; Schroeder, Michael (BMC Bioinformatics, 2023)
Background: Integrating multi-omics data is fast becoming a powerful approach for predicting disease progression and treatment outcomes. In light of that, we introduce a modified version of the NetRank algorithm, a network-based algorithm for biomarker discovery that incorporates the protein associations, co-expressions, and functions with its phenotypic association to differentiate different types of cancer. NetRank is introduced here as a robust feature selection method for biomarker selection in cancer prediction. We assess the robustness and suitability of the RNA gene expression data through scanning genomic data for 19 cancer types with more than 3000 patients from The Cancer Genome Atlas (TCGA). Results: The results of evaluating different cancer type profiles from the TCGA data demonstrate the strength of our approach to identifying interpretable biomarker signatures for cancer outcome prediction. NetRank’s biomarkers segregate most cancer types with an area under the curve (AUC) above 90% using compact signatures. Conclusion: In this paper we provide a fast and efficient implementation of NetRank, with a case study from The Cancer Genome Atlas, to assess the performance. We incorporated complete functionality for pre and post-processing for RNA-seq gene expression data with functions for building protein-protein interaction networks. The source code of NetRank is freely available (at github.com/Alfatlawi/Omics-NetRank) with an installable R library. We also deliver a comprehensive practical user manual with examples and data attached to this paper.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Biomarker; Cancer; Gene expression; Protein networks; R package; RNA

Neue Paradigmen in der patientenzentrierten Therapie von Patienten mit peripherer arterieller Verschlusskrankheit (PAVK)? Unsere Welt nach BEST-CLI und BASIL-2 - Behrendt, Christian Alexander; Larena-Avellaneda, Axel; Rother, Ulrich; Donas, Konstantinos P. (Gefässchirurgie, 2023)
CRIS-Team Scopus Importer:2023-07-21

Neue WSES-AAST-Leitlinie zum Trauma des Duodenums, des Pankreas und der extrahepatischen Gallengänge – Zusammenfassung und Kommentar - Hecker, A.; Hecker, M.; Riedel, J. G.; Hecker, B.; Doppstadt, C.; Weigand, M. A.; Coccolini, F.; Reichert, M.; Padberg, W.; Askevold, I.; Weber, Georg (Chirurg, 2020)
CRIS-Team Scopus Importer:2020-07-24

Neurological outcome at 24 months corrected age of prematurely born infants after preterm premature rupture of membranes (PPROM) of at least 7 days: a two-center experience in Germany - Müller, Hanna; Storbeck, Tobias; Katzer, David; Bruns, Nora; Wössner-Stegmann, Gaby; Ai, Maria; Köninger, Angela; Müller, Andreas; Felderhoff-Müser, Ursula; Bagci, Soyhan (Journal of Maternal-Fetal & Neonatal Medicine, 2018)
OBJECTIVE: Preterm premature rupture of membranes (PPROM) is a risk factor for chorioamnionitis (CA) and injury to the fetal brain. However, prolongation of gestation prevents morbidity and decreases complications of prematurity. The current investigation is to define risk factors for the adverse neurological outcome from the influence of PPROM of at least 7 days. METHODS: A case-control study included three groups of preterm infants born at the University Hospitals Bonn and Essen, Germany. The first group consisted of infants with PPROM of at least 7 days and no chorioamnionitis (CA) (PPROM group), the second included preterm infants with CA (CA group), and the third group consisted of infants without PPROM and CA (control group). The outcome was assessed using Bayley Scales of Infant Development at a corrected age of 24 months. Each group consisted of 20 corresponding infants with an identical birth weight and gestational age at birth. RESULTS: There was no significant difference between the mental development index (MDI) and psychomotor development index (PDI) scores (mean ± SD): the MDI score was 101 ± 14 in the PPROM group, 98 ± 12 in the CA group and 96 ± 17 in the control group; the PDI score 96 ± 10, 89 ± 16, and 90 ± 17, respectively. Multiple regression analysis revealed no significant influence of PPROM and CA on neurological outcome. CONCLUSIONS: PPROM of at least 7 days has no influence on neurodevelopmental outcome at a corrected age of 24 months when birth is initiated in the case of beginning CA.
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Neuromodulation in an era of rising need and cost: a time for multifaceted consideration - Matzel, Klaus (Diseases of the colon & rectum, 2014)
EVALuna2:15178

Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions. - Elrod, Julia; Heuer, Annika; Knopf, Jasmin; Schoen, Janina; Schönfeld, Lavinia; Trochimiuk, Magdalena; Stiel, Carolin; Appl, Birgit; Raluy, Laia Pagerols; Saygi, Ceren; Zlatar, Leticija; Hosari, Sami; et al. (iScience, 2023)
Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models. We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
EVALuna2:551953

Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Straube, Julia; Tripal, Philipp; Schmid, Benjamin; Geppert, Carol-Immanuel; Hartmann, Arndt; Munoz, Luis Enrique; Schoen, Janina; Völkl, Simon; et al. (Journal of Pathology, 2021)
Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity, and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA-antibody providing a novel and valuable tool to detect NETs in FFPE tissues. Using these markers, the clinical association of NETs has been investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (n = 37/n = 85, 44%) in colon cancer tissue sections and preferentially localized either only in the tumour centre or both, in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathologic tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelial- mesenchymal transition (EMT) promoting transcription factors (ZEB1 and Slug [SNAI2]) as well as decreased expression of the epithelial markers E-cadherin (CDH1) and EpCAM (EPCAM). These findings indicated that NETs activate an EMT-like process in CRC cells and may contribute to the metastatic progression of CRC.

'New' direct oral anticoagulants in the perioperative setting - Breuer, Georg; Weiss, Dominik R.; Ringwald, Jürgen (Current Opinion in Anaesthesiology, 2014)
Out of the anesthetist's perspective, some uncertainties remain with the perioperative management of the so-called NOACs. This review emphasizes on the question of bleeding and thromboembolic risk as well as the management of bleedings and the discontinuing intervals in the context of regional anesthesia.Managing patients with NOAC therapy, an interdisciplinary approach and consent with surgeons and specialist in hemostaseology has to be found. For severe and lifethreatening bleeding there are specific antidotes in development; however, until clinical provement is not yet finished the application of four-factor prothrombin complex concentrate may be the most promising approach.NOACs like dabigatran etexilate, rivaroxaban, apixaban and edoxaban are effective alternatives to warfarin in primary and secondary prophylaxis of thromboembolic conditions. In the perioperative setting, some uncertainties and evidence gaps remain in estimating the bleeding risks associated with surgical procedures, emergency trauma and neuroaxial anesthesia. A discontinuation of NOACs should be at least 1 day before elective operation. Renal and liver impairment, older age, or co-medications could afford longer intervals. As no specific reversal agents are yet available for life-threatening bleeding or emergency surgery; nonspecific prohemostatic therapies are mainly recommended. Oral charcoal, application of tranexamic acid or hemodialysis could bring additional benefit depending on the individual NOAC. Practitioners need to be aware that NOACs can interfere in different pathways with the measurement of common hemostasis parameters. Estimating the bleeding risks and reversal strategies requires careful evaluation also in the light of a potential risk of thromboembolic complications. In difference to warfarin, 'bridging' concepts are not generally recommended for NOACs.
EVALuna2:15984

New Technologies and Applications in Sacral Neuromodulation: An Update - De Wachter, Stefan; Knowles, Charles H.; Elterman, Dean S.; Kennelly, Michael J.; Lehur, Paul A.; Matzel, Klaus; Engelberg, Stefan; Van Kerrebroeck, Philip E.V. (Advances in Therapy, 2020)
Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.
CRIS-Team Scopus Importer:2020-02-14
Keywords: Fecal incontinence; Magnetic resonance imaging; Overactive bladder; Rechargeable battery; Sacral neuromodulation; Stimulator; Urology

NFATc1 Promotes Antitumoral Effector Functions and Memory CD8+ T-cell Differentiation during Non-Small Cell Lung Cancer Development - Heim, Lisanne; Friedrich, Juliane; Engelhardt, Marina; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (Cancer Research, 2018)
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T-cell receptor (TCR) and Ca2+ signaling that affects T-cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced-stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T-cell activation and function. Furthermore, in the absence of NFATc1, reduced IL2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased antitumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T-cell subsets, and in the regulation of T-cell exhaustion. These data underline the indispensability of NFATc1 for successful antitumor immune responses in patients with NSCLC.Significance: The multifaceted role of NFATc1 in the activation and function of T cells during lung cancer development makes it a critical participant in antitumor immune responses in patients with NSCLC. Cancer Res; 78(13); 3619-33. ©2018 AACR.
EVALuna2:34901

N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy - Krug, Julia; Rodrian, Gabriele; Petter, Katja; Yang, Hai; Khoziainova, Svetlana; Guo, Wei; Benard, Alan; Merkel, Susanne; Gellert, Susan; Maschauer, Simone; Spermann, Monika; Waldner, Maximilian; et al. (Gastroenterology, 2023)
Background & AIMS: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.
CRIS-Team Scopus Importer:2023-02-10
Keywords: Colon Cancer; IFNGR1; Immune Evasion

Nintedanib macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis - Huang, Jingang; Maier, Christiane; Zhang, Yun; Soare, Alina; Dees, Clara; Beyer, Christian; Harre, Ulrike; Chen, Chih-Wei; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg (Annals of the Rheumatic Diseases, 2017)
Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung diseas
EVALuna2:13441

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases - Weber, Simone; Sitte, Selina; Vögele, Anna-Lena; Sologub, Ludmilla; Wilfer, Angelika; Rath, Timo; Nägel, Andreas; Zundler, Sebastian; Franchi, Luigi; Opipari, Anthony W.; Sonnewald, Sophia; Reid, Stephen; et al. (Journal of Crohns & Colitis, 2023)
Background and Aims: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. Methods: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. Results: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1β and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1β. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1β in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. Conclusions: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.
CRIS-Team Scopus Importer:2023-11-17
Keywords: fibroblasts; fibrosis; IL-18; IL-1β; Inflammatory bowel diseases; mucosal immune system; NLRP3 inflammasome; small molecule inhibitor

No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment - Fang, Qi; Stehr, Antonia; Naschberger, Elisabeth; Knopf, Jasmin; Herrmann, Martin; Stürzl, Michael (Frontiers in Immunology, 2022)
The tumor immune microenvironment (TIME) controls tumorigenesis. Neutrophils are important components of TIME and control tumor progression and therapy resistance. Neutrophil extracellular traps (NETs) ejected by activated neutrophils are net-like structures composed of decondensed extracellular chromatin filaments decorated with a plethora of granules as well as cytoplasmic proteins. Many of these harbour post translational modifications. Cancer cells reportedly trigger NET formation, and conversely, NETs alter the TIME and promote tumor cell proliferation and migration. The specific interactions between NETs and TIME and the respective effects on tumor progression are still elusive. In certain tumors, a CD4(+) T helper (Th) 2 cell-associated TIME induces NETs and exerts immunosuppressive functions via programmed death 1 (PD-1)/PD-L1, both associated with poorer prognosis. In other cases, NETs induce the proliferation of Th1 cells, associated with an improved prognosis in cancer. In addition, NETs can drive macrophage polarization and often rely on macrophages to promote cancer cell invasion and metastasis. In turn, macrophages can swiftly clear NETs in an immunologically silent manner. The aim of this review is to summarize the knowledge about the mutual interaction between NETs and TIME and its impact on tumor growth and therapy.
CRIS-Team WoS Importer:2023-01-27

Noninvasive Bioluminescence Imaging of AKT Kinase Activity in Subcutaneous and Orthotopic NSCLC Xenografts: Correlation of AKT Activity with Tumor Growth Kinetics - Suchowski, Karina; Poechinger, Thomas; Rehemtulla, Alnawaz; Stürzl, Michael; Scheuer, Werner (Neoplasia, 2017)
Aberrant signaling through the AKT kinase mediates oncogenic phenotypes including cell proliferation, survival, and therapeutic resistance. Here, we utilize a bioluminescence reporter for AKT kinase activity (BAR) to noninvasively assess the therapeutic efficacy of the EGFR inhibitor erlotinib in KRAS-mutated lung cancer therapy. A549 non-small cell lung cancer cell line, engineered to express BAR, enabled the evaluation of compounds targeting the EGFR/PI3K/AKT pathway in vitro as well as in mouse models. We found that erlotinib treatment of resistant A549 subcutaneous and orthotopic xenografts resulted in significant AKT inhibition as determined by an 8- to 13-fold (P < .0001) increase in reporter activity 3 hours after erlotinib (100 mg/kg) administration compared to the control. This was confirmed by a 25% (P < .0001) decrease in pAKT ex vivo and a decrease in tumor growth. Treatment of the orthotopic xenograft with varying doses of erlotinib (25, 50, and 100 mg/kg) revealed a dose- and time-dependent increase in reporter activity (10-, 12-, and 23-fold). Correspondingly, a decrease in phospho-AKT levels (0%, 16%, and 28%, respectively) and a decrease in the AKT dependent proliferation marker PCNA (0%, 50%, and 50%) were observed. We applied ?-CT imaging for noninvasive longitudinal quantification of lung tumor load which revealed a corresponding decrease in tumor growth in a dose-dependent manner. These findings demonstrate the utility of BAR to noninvasively monitor AKT activity in preclinical studies in response to AKT modulating agents. These results also demonstrate that BAR can be applied to study drug dosing, drug combinations, and treatment efficacy in orthotopic mouse lung tumor models.
EVALuna2:15309

Noninvasive Sacral Neuromodulation in Children and Adolescents: A Case-Control Study of Patients With Chronic Refractory Constipation - Diez, Sonja; Kirchgatter, Annemarie; Adam, Dana; Füldner, Arne; Müller, Hanna; Matzel, Klaus; Besendörfer, Manuel (Neuromodulation, 2022)
Objectives: In adult patients with chronic refractory constipation, invasive sacral neuromodulation (SNM) has been applied successfully. There is a need for less invasive solutions while providing comparable therapeutic effects in children and adolescents. We present a prospective, interventional case-control study on the application of noninvasive SNM. Materials and Methods: Patients with chronic constipation refractory to conservative treatment were prospectively included in the study from 2018 to 2021 and randomized to either SNM (SNM group: single current stimulation for 24 h/d, frequency 15 Hz, pulse width 210 μs, intensity 1–10 mA) or conventional treatment (controls: full range of pharmacologic and nonpharmacologic options). Treatment was conducted for 12 weeks. Treatment effects were collected with specialized questionnaires and quality-of-life analysis (KINDLR). Outcome variables were defecation frequency, stool consistency, fecal incontinence (FI) episodes, and abdominal pain. Results: Analysis was conducted in 28 patients with SNM and 31 controls (median age 7.0, range 3–16 years). Overall responsiveness to treatment was 86% of the SNM group and 39% of the control group (p < 0.001). All outcome variables were positively influenced by SNM treatment. Defecation frequency improved in 46% of patients with SNM and in 19% of controls (p = 0.026), as did stool consistency in 57% of patients with SNM and in 26% of controls (p = 0.014). Fecal incontinence was significantly reduced in 76% of patients with SNM (n = 16/21 vs 42% of controls [n = 11/26], p = 0.042). Quality of life improved significantly during SNM treatment (71.32 [baseline] vs 85.00 [after 12 weeks], p < 0.001) and confirmed a positive influence of SNM treatment compared with the control group (85.00 [SNM after 12 weeks] vs 79.29 [controls after 12 weeks], p = 0.047). Conclusions: Outcome of noninvasive SNM treatment in patients with chronic refractory constipation is better than conventional treatment.
CRIS-Team Scopus Importer:2022-11-18
Keywords: Fecal incontinence; functional constipation; Hirschsprung disease; sacral nerve stimulation; sacral neuromodulation

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Notch3 signalling promotes tumour growth in colorectal cancer - Serafin, Valentina; Persano, Luca; Moserle, Lidia; Esposito, Giovanni; Ghisi, Margherita; Curtarello, Matteo; Bonanno, Laura; Masiero, Massimo; Ribatti, Domenico; Stürzl, Michael; Naschberger, Elisabeth; Croner, Roland S.; et al. (Journal of Pathology, 2011)
Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Created from Fastlane, Scopus look-up
Keywords: angiogenesis; colorectal cancer; DLL4; Notch3

Novel criteria for intratumoral budding with prognostic relevance for colon cancer and its histological subtypes - Pour Farid, Pantea; Eckstein, Markus; Merkel, Susanne; Grützmann, Robert; Hartmann, Arndt; Bruns, Volker; Benz, Michaela; Schneider-Stock, Regine; Geppert, Carol-Immanuel (International Journal of Molecular Sciences, 2021)
Peritumoral budding and intratumoral budding (ITB) are important prognostic factors for colorectal cancer patients. Scientists worldwide have investigated the role of budding in tumor progression and its prognosis, but guidelines for reliably identifying tumor buds based on morphology are lacking. In this study, next-generation tissue microarray (ngTMA® ) construction was used for tumor bud evaluation, and highly detailed rule-out annotation was used for tumor definition in pancytokeratin-stained tissue sections. Initially, tissues of 245 colon cancer patients were evaluated with high interobserver reliability, and a concordance of 96% was achieved. It was shown that high ITB scores were associated with poor distant metastasis-free survival (p = 0.006 with a cut-off of ≥10 buds). This cut-off was defined as the best maximum value from one of two/three ngTMA® cores (0.6 mm diameter). ITB in 30 cases of mucinous, medullary, and signet ring cell carcinoma was analyzed for the subsequent determination of differences in tumor bud analyses between those subtypes. In conclusion, blinded randomized punched cores in the tumor center can be useful for ITB detection. It can be assumed that this method is suitable for its adoption in clinical routines.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Histological subtypes; Immunohistochemistry; Medullary carcinoma; Metastasis; Mucinous carcinoma; Next-generation tissue microarray analysis; Prognostic biomarker; Signet ring cell carcinoma; Survival analysis; Tumor budding

Now Is the Time to Bring a Common but Unpopular Noncommunicable Disease into Focus: Peripheral Arterial Disease Takes Limbs and Lives, but It Must Also Touch Our Hearts! - Behrendt, Christian-Alexander; Peters, Frederik; Rother, Ulrich (Journal of Clinical Medicine, 2022)
CRIS-Team WoS Importer:2022-10-21

NPM-ALK-reactive T-cell responses in children and adolescents with NPM-ALK positive anaplastic large cell lymphoma - Singh, Vijay Kumar; Werner, Sebastian; Schwalm, Simone; Lennerz, Volker; Ruf, Stephanie; Stadler, Serena; Hackstein, Holger; Reiter, Alfred; Wölfel, Thomas; Damm-Welk, Christine; Woessmann, Wilhelm (OncoImmunology, 2019)
The oncoantigen nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces cellular and humoral immune responses in patients with NPM-ALK-positive anaplastic large cell lymphoma (ALCL). We characterize the NPM-ALK-specific T-cell responses in a cohort of pediatric and adolescent ALCL-patients in remission without Human Leucocyte Antigen (HLA)-preselection. First, we assessed NPM-ALK-reactive T-cell responses and their HLA-class I restriction in patients by using dendritic cells (DCs) transfected with in vitro transcribed (IVT) NPM-ALK-RNA for CD8 (n = 20) or CD3 (n = 9) T-cell stimulation. NPM-ALK-specific T-cells were detected in twelve of 29 patients (nine of 20 with CD8-selected and three of nine with CD3-selected cells). Recognition of NPM-ALK was restricted by HLA-C alleles in six of eight, and by HLA-B alleles in four of eight analyzed patients. No NPM-ALK-reactivity was detected in 20 healthy individuals. Second, in order to define possible immunogenic NPM-ALK-epitope regions, DCs pulsed with pools of overlapping long NPM-ALK-peptides were used to stimulate T-cells in further 22 patients and ten controls. Responsive T-cells were detected in 15 patients and in five controls. A peptide pool located in the middle of the kinase domain induced ALK-reactive T-cells in 14 of 15 responsive patients. We could narrow to single peptides between p327-p370 of NPM-ALK in four patients. In conclusion, using IVT-RNA, 40% of NPM-ALK-positive ALCL-patients in remission had detectable NPM-ALK-specific T-cell responses which were mainly restricted by HLA-B and -C alleles. Peptide stimulation of T-cells revealed responses in almost 70% of patients and allowed describing an immunogenic region located in the ALK-kinase domain.
CRIS-Team Scopus Importer:2019-07-09
Keywords: ALCL; IFN-γ ELISPOT; Immune response; NPM-ALK; T-cells

Nuclear factor-κB motif and interferon-α-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells - Naschberger, Elisabeth; Stürzl, Michael; et al. (Biochemical Journal, 2004)
The large GTPase GBP-1 (guanylate-binding protein -1) is a major IFN-γ (interferon-γ)-induced protein with potent anti-angiogenic activity in endothelial cells. An ISRE (IFN-α-stimulated response element) is necessary and sufficient for the induction of GBP-1 expression by IFN-γ. Recently, we have shown that in vivo GBP-1 expression is strongly endothelial-cell-associated and is, in addition to IFN-γ, also activated by interleukin-1β and tumour necrosis factor-α, both in vitro and in vivo [Lubeseder-Martellato, Guenzi, Jörg, Töpolt, Naschberger, Kremmer, Zietz, Tschachler, Hutzler, Schwemmle et al. (2002) Am. J. Pathol. 161, 1749-1759; Guenzi, Töpolt, Cornali, Lubeseder-Martellato, Jörg, Matzen, Zietz, Kremmer, Nappi, Schwemmle et al. (2001) EMBO J. 20, 5568-5577]. In the present study, we identified a NF-κB (nuclear factor κB)-binding motif that, together with ISRE, is required for the induction of GBP-1 expression by interleukin-1β and tumour necrosis factor-α. Deactivation of the NF-κB motif reduced the additive effects of combinations of these cytokines with IFN-γ by more than 50%. Importantly, NF-κB p50 rather than p65 activated the GBP-1 promoter. The NF-κB motif and ISRE were detected in an almost identical spatial organization, as in the GBP-1 promoter, in the promoter regions of various inflammation-associated genes. Therefore both motifs may constitute a cooperative inflammatory cytokine response module that regulates GBP-1 expression. Our findings may open new perspectives for the use of NF-κB inhibitors to support angiogenesis in inflammatory diseases including ischaemia.
Created from Fastlane, Scopus look-up
Keywords: Guanylate-binding protein-1 (GBP-1); Human umbilical-vein endothelial cells (HUVEC); Inflammation; Interleukin-1; Nuclear factor κB (NF-κB); Tumour necrosis factor

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1 - Shydlovskyi, Sergii; Zienert, Anke Y.; Ince, Semra; Dovengerds, Christine; Hohendahl, Annika; Dargazanli, Julia M.; Blum, Ailisa; Guenther, Saskia D.; Kladt, Nikolay; Stürzl, Michael; Schauss, Astrid C.; Kutsch, Miriam; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2017)
Dynamin-like proteins (DLPs) mediate various membrane fusion and fission processes within the cell, which often require the polymerization of DLPs. An IFN-inducible family of DLPs, the guanylate-binding proteins (GBPs), is involved in antimicrobial and antiviral responses within the cell. Human guanylate-binding protein 1 (hGBP1), the founding member of GBPs, is also engaged in the regulation of cell adhesion and migration. Here, we show how the GTPase cycle of farnesylated hGBP1 (hGBP1F) regulates its self-assembly and membrane interaction. Using vesicles of various sizes as a lipid bilayer model, we show GTP-dependent membrane binding of hGBP1F In addition, we demonstrate nucleotide-dependent tethering ability of hGBP1F Furthermore, we report nucleotide-dependent polymerization of hGBP1F, which competes with membrane binding of the protein. Our results show that hGBP1F acts as a nucleotide-controlled molecular switch by modulating the accessibility of its farnesyl moiety, which does not require any supportive proteins.
EVALuna2:15310

Nutcracker syndrome in children: Appearance, diagnostics, and treatment - A systematic review - Meyer, Johannes; Rother, Ulrich; Stehr, Maximilian; Meyer, Alexander (Journal of Pediatric Surgery, 2022)
Background: The nutcracker syndrome (NCS) is defined by compression of the left renal vein (LVR) and may present with a wide variety of symptoms. Due to its rarity in pediatric patients, incidence, diagnostics and performed therapy regimen are widely undefined. To this date, there are only case reports and small collectives of pediatric patients described but comprehensive research is lacking. Methods: A systematic literature research on pediatric NCS was carried out on Medline and Scopus databases according to PRISMA principles using predefined search terms and inclusion criteria. The PROSPERO registered review (CRD42021237415) identified patients’ characteristics regarding age, sex, clinical symptoms, applied diagnostic methods and treatment options. Results: In total 47 articles were included. Overall, 423 children (218 boys and 205 girls) with diagnosed NCS were included in the analysis. Mean age was 12.0 (boys 12.9, girls 12.0) years. Hematuria was most common presentation (55.5%), followed by proteinuria (49.9%). Classical flank pain was only detected in 19.1% of patients. Sonographic evaluation was the most commonly used diagnostic tool (99%). Invasive diagnostic studies were performed in 97 children. 86.8% patients were treated conservatively and 94.9% showed complete resolution (42.8%) or at least improvement (52.2%) of symptoms. Type of operative treatment comprised of open surgery with transposition of LRV, endovascular stenting and laparoscopy. Conclusions: Overall, data quality regarding NCS in children is poor. However, conservative approach in pediatric patients is recommended and should be regarded first treatment option. Diagnostic and treatment should follow a defined algorithm when NCS is suspected. Sufficient observation and follow-up must be assured in all patients to get significant results in this heterogenous syndrome. Level of evidence: V-IV
CRIS-Team Scopus Importer:2022-01-28
Keywords: Diagnostics pediatric NCS; Entrapment of left renal vein; NCS in children; Pediatric nutcracker syndrome; Treatment pediatric NCS

Nutrient free flaps with vascular bypasses for extremity salvage in patients with chronic limb ischemia - Horch, Raymund E.; Lang, Werner; Arkudas, Andreas; Taeger, Christian; Kneser, U.; Schmitz, Marweh; Beier, Justus (Journal of Cardiovascular Surgery, 2014)
Treatment of severe wounds remains a surgical challenge in patients with critical limb ischemia (CLI). In some patients with end stage disease a combined arterial and venous vascular bypass together with immediate or subsequent free soft tissue transfer can become necessary to salvage the limb. The aim of this paper was to develop an algorithm of differential approaches of interdisciplinary reconstructions with bypasses and free flaps for leg salvage.From our experiences with over 76 patients receiving a vascular bypass and a free microsurgical tissue transfer, we analyzed the various configurations of possible vascular constellations and treatment options. We derived an algorithm for the combined interdisciplinary surgical approach.We found the surgical technique to be one of the main predictors for the final outcome and categorized the various options and vascular configurations in combination with free flaps to salvage extremities. The overall complication rate with more than 20% revisional surgeries is higher than in routine free flap transfer for reconstructions in patient without CLI. We observed 3 failures (4%) with complete flap loss and bypass occlusion and found 3 patients (4%) with initially successful reconstructions to have secondary amputations within 6 to 18 months postoperatively.Given the multitude of concomitant diseases in patients with serious wounds and CLI the distinct choice of the individual reconstructive vascular/flap-procedure has to be thoroughly selected. Any treatment decision against revascularization must be made only with proper and adequate diagnosis based on proper and sufficient diagnostic imaging techniques following an interdisciplinary discussion of possible options for limb salvage. Based on our experience with a large series of this type of combined revascularization-flap reconstruction we developed a specific algorithm of surgical variants of bypass-free flap arterial and venous reconstructions that is presented in this paper.
EVALuna2:15174

Obstructed defaecation syndrome: European consensus guidelines on the surgical management - Picciariello, Arcangelo; O'Connell, P. R.; Hahnloser, D.; Gallo, Gaetano; Munoz-Duyos, A.; Schwandner, O.; Sileri, P.; Milito, G.; Riss, S.; Boccasanta, P. A.; Naldini, G.; Arroyo, A.; et al. (British Journal of Surgery, 2021)
Lay Summary Clinical decision-making in the treatment of patients with obstructed defaecation remains controversial and no international guidelines have been provided so far. This study reports a consensus among European opinion leaders on the management of obstructed defaecation in different possible clinical scenarios.
CRIS-Team WoS Importer:2021-11-26

OCT-Angiography: Mydriatic phenylephrine and tropicamide do not influence retinal microvasculature in macula and peripapillary region - Hohberger, Bettina; Müller, Manuela; Hosari, Sami; Mardin, Christian Y. (PLoS ONE, 2019)
PURPOSE: Optical coherence tomography angiography (OCT-A) enables visualization of retinal microcirculation. As a potential influence of mydriatic eye drops on retinal vessel density (VD) was proposed, the purpose of the present study was to investigate an influence of 5% phenylephrine and 0.5% tropicamide on macula and peripapillary VD. METHODS: 30 eyes of 30 healthy persons were measured by en face OCT-A (Spectralis OCT II, Heidelberg Engineering, Heidelberg). Scans of the macula (12 sectors, region of interest, ROI: 6.10 mm2) and peripapillary region (4 sectors, ROI: 2.67 mm2) were performed before (-) and 30 minutes after application of phenylephrine 5% and tropicamide 0.5% (+) eye drops (scan size was 8.41 mm2). Macula microcirculation was quantified in 3 retinal layers (superficial vascular plexus (SVP), deep capillary plexus (DCP), intermediate capillary plexus (ICP)). Data analysis was performed with the Erlangen-Angio-Tool. RESULTS: (I) Mean VD was 33.03±2.3 (SVP), 23.53±2.9 (ICP) and 25.48±4.2 (DCP) before and 33.12±2.4 (SVP), 23.74±2.9 (ICP) and 25.82±4.0 (DCP) with mydriasis respectively. (II) Sectorial analysis: 30.63±2.9-34.45±2.9 (-) and 31.04±2.9-34.34±2.7 (+) in SVP; 22.61±2.9-24.93±3.2 (-) and 22.75±2.5-25.20±3.0 (+) in ICP; 24.56±4.7-26.45±3.4 (-) and 25.00±4.1-27.07±3.5 (+) in DCP. (III) Peripapillary region showed a mean VD of 31.82±3.8 before and 31.59±4.3 after mydriasis. Sectorial analysis of VD yielded a range of 31.04±4.1-32.65±3.8 (-) and 30.98±4.4-31.89±4.1 (+). (IV) Macula and peripapillary VD were not different before and after mydriasis (p>0.05). CONCLUSION: Pharmacologic mydriasis did not influence retinal microcirculation in macula and peripapillary region enabling OCT-A scans with enhanced imaging process and scan quality.
CRIS-Team Scopus Importer:2019-10-25

O-GlcNAc transferase inhibits KSHV propagation and modifies replication relevant viral proteins as detected by systematic O-GlcNAcylation analysis. - Jochmann, Ramona; Pfannstiel, Jens; Chudasama, Priya; Kühn, Elisabeth; Konrad, Andreas; Stürzl, Michael (Glycobiology, 2013)
O-GlcNAcylation is an inducible, highly dynamic and reversible post-translational modification, mediated by a unique enzyme named O-linked N-acetyl-d-glucosamine (O-GlcNAc) transferase (OGT). In response to nutrients, O-GlcNAc levels are differentially regulated on many cellular proteins involved in gene expression, translation, immune reactions, protein degradation, protein-protein interaction, apoptosis and signal transduction. In contrast to eukaryotic cells, little is known about the role of O-GlcNAcylation in the viral life cycle. Here, we show that the overexpression of the OGT reduces the replication efficiency of Kaposi's sarcoma-associated herpesvirus (KSHV) in a dose-dependent manner. In order to investigate the global impact of O-GlcNAcylation in the KSHV life cycle, we systematically analyzed the 85 annotated KSHV-encoded open reading frames for O-GlcNAc modification. For this purpose, an immunoprecipitation (IP) strategy with three different approaches was carried out and the O-GlcNAc signal of the identified proteins was properly controlled for specificity. Out of the 85 KSHV-encoded proteins, 18 proteins were found to be direct targets for O-GlcNAcylation. Selected proteins were further confirmed by mass spectrometry for O-GlcNAc modification. Correlation of the functional annotation and the O-GlcNAc status of KSHV proteins showed that the predominant targets were proteins involved in viral DNA synthesis and replication. These results indicate that O-GlcNAcylation plays a major role in the regulation of KSHV propagation.

Ökonomische Auswirkung der COVID-19-Pandemie in der Allgemein- und Viszeralchirurgie: Ein Vergleich von Leistungs- und Erlösdaten zweier Kliniken aus Krankenhäusern unterschiedlicher Versorgungsstufen - Binder, Johannes; Brunner, Maximilian; Maak, Matthias; Denz, Axel; Grützmann, Robert; Krautz, Christian; Weber, Georg (Chirurg, 2021)
Background: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, German hospitals were required to limit the capacity for elective surgery to prevent the healthcare system from general overload. In March 2020, the German government passed the COVID-19 Hospital Relief Act that guaranteed compensation payments for these limitations. In this study the regional impact of this intervention were analyzed. Material and methods: The performance data and revenue figures for the departments of general and visceral surgery of the University Hospital of Erlangen (UKER) and the District Hospital St. Anna Höchstadt/Aisch (KKH) during the period from 1 April to 30 June 2019 were compared with the respective period in 2020. Results: There was a significant decrease in bed occupancy rates and case numbers of inpatient treatment. The latter declined by 20.06% in the UKER and 60.76% in the KKH. Nononcological elective surgery was reduced by 33.04% in the UKER and 60.87% in the KKH. The number of emergency procedures remained unchanged in the UKER, while they decreased by 51.58% in the KKH. The revenues from diagnosis-related groups (DRG) decreased by 22.12% (UKER) and 54% (KKH), respectively. After taking compensation payments and savings from variable material costs into account, the UKER recorded a loss of −3.87%, while there was a positive revenue effect of 6.5% in the KKH. Discussion: The nonselective restriction of elective surgery had a significant impact on patient care and revenue figures at both locations. With respect to the increase of intensive care capacities, such untargeted measures do not appear to be efficient. In addition, the fixed rate of compensation payments led to an unbalanced distribution of the financial aid between the two departments.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Coronavirus; DRG billing data; Hospital Relief Act; Surgery; Treatment quality

Old Age, nodular Melanoma, Tumor Thickness and Ulceration are Risk Factors for regional and systemic Metastases in Melanoma Patients after negative Sentinel Node Biopsy - Erdmann, M.; Dominik, S.; Göhl, Jonas; Grützmann, Robert; Schuler, Gerold; Schellerer, Vera (2017)
EVALuna2:15294

Oligometastatic non-small cell lung cancer–surgical options and therapy strategies - Schreiner, Waldemar; Semrau, S.; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2014)
The therapeutic strategies for oligometastatic non-small cell lung cancer have changed over the last decade from palliative to curative intent. The role of surgery in this multimodal treatment in selected patients remains a subject for open discussion.Data of 34 patients with one or two metastases treated from January 1998 to January 2013 were retrospectively analysed.The mean age was 59.7 (± 10.1) years. The male vs. female ratio was 20 vs. 14. Adenocarcinoma was the most common histological type (58.8 %). The synchronous metastases were present in 15 patients, the metachronous in 19 patients. Single metastases were present in 27 patients, two metastases in 7 patients. The most frequently involved organs were brain (58.8 %) and the lungs (23.6 %). The primary tumour resection was achievable in 20 patients as R0 and in 2 patients as R1. The median overall survival, the local and the systemic disease-free survivals in the entire group were 40, 38 and 25 months, respectively. The 5 year overall survival, the 5 year local and systemic disease-free survivals were 29.2, 26.9 and 16.5 %, respectively. The treatment strategies including surgery for primary tumour as well as for pulmonary metastases site, combined with the lymph node dissection and the resection of the extracerebral and cerebral metastases, were identified as independent prognostic factors for long-term survival.Surgery in oligometastatic non-small cell lung carcinoma is feasible for primary tumour and for metastases. It is an effective option in the multimodal treatment in highly selected patients. The lymph node dissection should remain an important integral part of the surgical treatment.
EVALuna2:18244

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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Omega suture technique for minimally invasive rectal anastomosis – a video vignette - Brunner, Maximilian; Weber, Klaus; Denz, Axel; Langheinrich, Melanie; Kersting, Stephan; Weber, Georg; Grützmann, Robert; Krautz, Christian (Colorectal Disease, 2023)
CRIS-Team Scopus Importer:2023-05-19

Oncogenesis in HIV-infection. - Albini, Adriana; Aluigi, M; Benelli, Roberto; Biberfeld, Peter; Blasig, C; Calabro, M; Calvo, F; Chieco-Bianchi, L; Corbellino, M; Del Mistro, A; Ekman, M; Favero, A; et al. (International Journal of Oncology, 1996)
The presence of human Kaposi's sarcoma associated herpesvirus-like sequences (KSHV) was examined in different epidemiological variants of Kaposi's sarcoma (KS) and in KS-derived cell cultures by polymerase chain reaction (PCR). KSHV DNA was present in all tumor biopsies of AIDS-associated KS (59 biopsies), endemic KS (26 biopsies; 21 African endemic KS, 5 Greek endemic KS), sporadic/classical KS (28 biopsies) and post-transplant/iatrogenic KS (6 of 7 biopsies). On the contrary, these sequences were only detected rarely in non-involved skin of KS patients (3 positive specimens of 12), in the peripheral blood mononuclear cells of HIV-infected patients (3 positive specimens of 54) and in lymphoma-biopsies (3 positive specimens of 47). Cell cultures derived from KS skin lesions were positive for KSHV DNA only in the first two passages. However, two longer-term positive cultures from a biopsy of a patient affected with sporadic KS and a biopsy of a patient affected with epidemic KS was identified. A strong association of KSHV with KS tissue was observed in all the different epidemiological variants of KS. Long-term positive KS-derived cell cultures will be an important tool to study the herpesvirus-like agent and to investigate its functional role in the initiation and progression of KS.

Oncological colorectal surgery during the COVID-19pandemic—a national survey - Brunner, Maximilian; Krautz, Christian; Kersting, Stephan; Stinner, Benno; Benz, Stefan R.; Grützmann, Robert; Weber, Georg (International Journal of Colorectal Disease, 2020)
Purpose: The aim of this study was to clarify the surgical supply situation of oncological colorectal patients in Germany during limitations of the OR caseload due to the COVID-19 pandemic. Methods: Between 11th and 19th April 2020, all members of a consortium of German colorectal cancer centers were invited to participate in a web-based survey on the current status of surgical care situation of colorectal cancer patients in Germany. Results: A total of 112 colorectal surgeons of 101 German hospitals participated in the survey. Eighty-seven percent of the participating hospitals had to reduce their total surgical caseload and 34% their surgical volume for oncological colorectal patients during COVID-19 pandemic. Restrictions of the surgical caseload were independent of the size of the hospital and the number of cases of COVID-19 in the federal state of the hospital. Sixteen percent of colorectal surgeons consider surgical limitations to be not justified and 78% to be justified only if the care of oncological patients is ensured. Ninety-five percent of the colorectal surgeons interviewed stated that all oncological colorectal patients with an indication for surgery should be operated in time, despite the current reservations for COVID-19 patients. For the majority of the respondents (63% and 51%, respectively), an extended waiting time for surgery of up to 2 weeks was acceptable for non-metastatic and metastatic patients, respectively. Conclusion: In Germany, there is a temporarily relevant reduction of surgical volume in oncological colorectal patients. Most colorectal surgeons stated that oncological colorectal surgery should not be compromised despite the measures taken during the COVID-19 pandemic.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Colorectal surgery; COVID-19 pandemic; Oncological surgery; SARS-CoV-2 infection; Surgical caseload

Oncological outcome after hyperthermic isolated limb perfusion for primarily unresectable versus locally recurrent soft tissue sarcoma of extremities - Vassos, N.; Brunner, Maximilian; Perrakis, A.; Göhl, Jonas; Grützmann, Robert; Hohenberger, Werner; Croner, R. S. (Surgical Oncology-Oxford, 2020)
Introduction: The management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP. Patients and methods: Data about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed. Results: The cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13–142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events. Discussion: ILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Isolated limb perfusion; Recurrent; Soft tissue sarcoma

Oncological outcome after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer Trial - Ruppert, R.; Junginger, Theodor; Ptok, H.; Strassburg, J.; Maurer, C. A.; Brosi, P.; Sauer, J.; Baral, J.; Kreis, M.; Wollschlaeger, D.; Hermanek, Peter; Merkel, Susanne (British Journal of Surgery, 2018)
BACKGROUND: It is not clear whether all patients with rectal cancer need chemoradiotherapy. A restrictive use of neoadjuvant chemoradiotherapy (nCRT) based on MRI findings for rectal cancer was investigated in this study. METHODS: This prospective multicentre observational study included patients with stage cT2-4 rectal cancer, with any cN and cM0 status. Carcinomas in the middle and lower third that were 1 mm or less from the mesorectal fascia, all cT4 tumours, and all cT3 tumours of the lower third were classified as high risk, and these patients received nCRT followed by total mesorectal excision (TME). All other carcinomas with a minimum distance of more than 1 mm from the mesorectal fascia and those in the upper third were classified as low risk; these patients underwent TME alone (no nCRT). Patients were followed for at least 3 years. Outcomes were the rates of local recurrence, distant metastasis and survival. RESULTS: Among 545 patients included, 428 were treated according to the study protocol: 254 (59·3 per cent) had TME alone and 174 (40·7 per cent) received nCRT and TME. Median follow-up was 60 months. The 3- and 5-year local recurrence rates were 1·3 and 2·7 per cent respectively, with no differences between the two treatment protocols. Patients with disease requiring nCRT had higher 3- and 5-year rates of distant metastasis (17·3 and 24·9 per cent respectively versus 8·9 and 14·4 per cent in patients who had TME alone; P = 0·005) and worse disease-free survival compared with that in patients who did not need nCRT (3- and 5-year rates 76·7 and 66·7 per cent, versus 84·9 and 76·0 per cent in the TME-alone group; P = 0·016). CONCLUSION: Restriction of nCRT to high-risk patients achieved good results.
EVALuna2:212692

One-lung ventilation after rapid-sequence intubation: a novel approach using an ETView tracheoscopic ventilation tube for placement of an EZ-Blocker without bronchoscopy - Moritz, Andreas; Schreiner, Waldemar; Schmidt, Joachim (Journal of Clinical Anesthesia, 2016)
EVALuna2:16729

One Step Nucleic Acid Amplification (OSNA) - a new method for lymph node staging in colorectal carcinomas - Croner, Roland S.; Schellerer, Vera; Demund, Helene; Schildberg, Claus; Papadopulos, Thomas; Naschberger, Elisabeth; Stürzl, Michael; Matzel, Klaus E.; Hohenberger, Werner; Schlabrakowski, Anne (Journal of Translational Medicine, 2010)
Background: Accurate histopathological evaluation of resected lymph nodes (LN) is essential for the reliable staging of colorectal carcinomas (CRC). With conventional sectioning and staining techniques usually only parts of the LN are examined which might lead to incorrect tumor staging. A molecular method called OSNA (One Step Nucleic Acid Amplification) may be suitable to determine the metastatic status of the complete LN and therefore improve staging.Methods: OSNA is based on a short homogenisation step and subsequent automated amplification of cytokeratin 19 (CK19) mRNA directly from the sample lysate, with result available in 30-40 minutes. In this study 184 frozen LN from 184 patients with CRC were investigated by both OSNA and histology (Haematoxylin & Eosin staining and CK19 immunohistochemistry), with half of the LN used for each method. Samples with discordant results were further analysed by RT-PCR for CK19 and carcinoembryonic antigen (CEA).Results: The concordance rate between histology and OSNA was 95.7%. Three LN were histology+/OSNA- and 5 LN histology-/OSNA+. RT-PCR supported the OSNA result in 3 discordant cases, suggesting that metastases were exclusively located in either the tissue analysed by OSNA or the tissue used for histology. If these samples were excluded the concordance was 97.2%, the sensitivity 94.9%, and the specificity 97.9%. Three patients (3%) staged as UICC I or II by routine histopathology were upstaged as LN positive by OSNA. One of these patients developed distant metastases (DMS) during follow up.Conclusion: OSNA is a new and reliable method for molecular staging of lymphatic metastases in CRC and enables the examination of whole LN. It can be applied as a rapid diagnostic tool to estimate tumour involvement in LN during the staging of CRC. © 2010 Croner et al; licensee BioMed Central Ltd.
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On peripheral arterial disease (PAD) Rund um die periphere arterielle Verschlusskrankheit (PAVK) - Behrendt, Christian Alexander; Rother, Ulrich (Gefässchirurgie, 2023)
CRIS-Team Scopus Importer:2023-05-26

On Sweat Analysis for Quantitative Estimation of Dehydration during Physical Exercise - Ring, Matthias; Lohmüller, Clemens; Rauh, Manfred; Eskofier, Björn (Proceedings of the 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2015)
Quantitative estimation of water loss during physical exercise is of importance because dehydration can impair both muscular strength and aerobic endurance. A physiological indicator for deficit of total body water (TBW) might be the concentration of electrolytes in sweat. It has been shown that concentrations differ after physical exercise depending on whether water loss was replaced by fluid intake or not. However, to the best of our knowledge, this fact has not been examined for its potential to quantitatively estimate TBW loss. Therefore, we conducted a study in which sweat samples were collected continuously during two hours of physical exercise without fluid intake. A statistical analysis of these sweat samples revealed significant correlations between chloride concentration in sweat and TBW loss (r = 0.41, p < 0.01), and between sweat osmolality and TBW loss (r = 0.43, p < 0.01). A quantitative estimation of TBW loss resulted in a mean absolute error of 0.49 l per estimation. Although the precision has to be improved for practical applications, the present results suggest that TBW loss estimation could be realizable using sweat samples.

Operationsindikationen bei neuroendokrinen Neoplasien des Pankreas - Bösch, Florian; Belyaev, Orlin; Brunner, Maximilian; Müller-Debus, Charlotte Friederieke; Grützmann, Robert; Keck, Tobias; Uhl, Waldemar; Witzigmann, Helmut; Werner, Jens (Zentralblatt für Chirurgie, 2020)
Neuroendocrine neoplasms of the pancreas (pNEN) have an increasing incidence and prevalence. Thus, this entity is of increasing clinical significance. Patients with pNEN become clinically apparent due to different and unspecific symptoms. Some tumours secrete hormones and peptides and become clinically symptomatic. In general, these tumours can metastasise early and even small tumours lead to distant metastases. Nonetheless, primary tumour size and grading are important prognostic factors. On the basis of a systematic literature research and the formulation of key issues according to the PICO system, therapeutic concepts were established. These concepts were evaluated with a Delphi process among the members of the pancreas research group and the indications for surgery group of the German Society of General and Visceral Surgery. Thus this article gives an overview of the surgical treatment modalities and indications for the treatment of pNEN. Surgery is still the gold standard in treatment and the only potential chance of cure. Surgery is indicated for sporadic as well as hereditary pNEN > 2 cm independent of the functional activity. A so called wait and see strategy might be indicated in smaller pNEN; however, there is little evidence for this approach. In this respect, pNEN of 1-2 cm represent a surgical indication. The treatment of hereditary pNEN is challenging and should be interdisciplinary. Even in the case of distant metastases, a curative approach might be feasible and multimodal treatment is indicated.
CRIS-Team Scopus Importer:2020-08-07
Keywords: neuroendocrine neoplasm; operative indication; pancreas; pancreatic surgery; tumour size

Operationsindikationen bei zystischen Tumoren des Pankreas - Brunner, Maximilian; Belyaev, Orlin; Bösch, Florian; Müller-Debus, Charlotte Friederieke; Radulova-Mauersberger, Olga; Wellner, Ulrich Friedrich; Keck, Tobias; Uhl, Waldemar; Werner, Jens; Witzigmann, Helmut; Grützmann, Robert (Zentralblatt für Chirurgie, 2020)
A steady improvement in modern imaging as well as increasing age in society have led to an increasing number of cystic pancreatic tumours being detected. Pancreatic cysts are a clinically challenging entity because they span a broad biological spectrum and their differentiation is often difficult, especially in small tumours. Therefore, they require a differentiated indication for indication of surgery. To determine recommendations for the surgical indication in cystic tumours of the pancreas, a quality committee for pancreatic diseases of the German Society for General and Visceral Surgery performed a systematic literature search and created this review. Based on the current evidence, signs of malignancy and high-risk criteria (icterus due to cystic pancreatic duct obstruction in the bile duct, enhancing mural nodules ≥ 5 mm or solid components in the cyst or pancreatic duct ≥ 10 mm), as well as symptoms, are a surgical indication, independently of the cyst entity (except pseudocysts). If the entity of the pancreatic cyst is detectable by diagnostic imaging, all main duct IPMN and IPMN of the mixed type, all MCN > 4 cm and all SPN should be resected. SCN and branch-duct IPMN without worrisome features do not constitute an indication for surgery. The indication of operation in branch-duct IPMN with relative risk criteria and MCN < 4 cm is the subject of current discussions and should be individualised. By defining indication recommendations, the present work aims to improve the indication quality in cystic pancreatic tumours. However, the surgical indication should always be individualised, taking into account age, comorbidities and the patient's wishes.
CRIS-Team Scopus Importer:2020-09-04

Organ injuries due to thoracic trauma : Diagnostics, clinical importance and treatment principles - Schreiner, Waldemar; Castellanos, I.; Dudek, Wojciech; Sirbu, Horia (Unfallchirurg, 2018)
Thoracic trauma can be a life-threatening condition due to the involvement of vital organs, such as the heart, lungs, tracheobronchial tree and the great vessels. A coordinated interdisciplinary management is vital for the survival of the injured person. Modern diagnostic procedures provide an essential basis for the surgical treatment of patients. Surgical treatment principles include insertion of chest drainage, emergency thoracotomy, complex bronchoplastic and vascular reconstructive techniques and cardiac surgical maneuvers. For this reason highly complex surgical procedures are available, which can be effectively and specifically integrated into an interdisciplinary concept. In this review, the most frequent and prognostically relevant conditions, the indicated diagnostics and their significance as well as the surgical treatment principles, are comprehensively presented under consideration of the clinical situation.
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Orphan Nuclear Receptor Ror alpha Is a Key Regulator of Tgf beta- and WNT-Signaling in Fibrotic Diseases - Kagwiria, Rosebeth; Liang, Ruifang; Matei, Alexandru-Emil; Sihler, Niclas; Chen, Chih-Wei; Burris, Thomas; Distler, Oliver; Schett, Georg; Distler, Jörg (2018)
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Outcome and complications of endoscopic balloon dilatations in various types of ileocaecal and colonic stenosis in patients with Crohn's disease - Hagel, Alexander; Hahn, Anna; Dauth, Wolfgang; Matzel, Klaus; Konturek, Peter C.; Neurath, Markus; Raithel, Martin (Surgical Endoscopy, 2014)
We examined the outcome and the complications of endoscopic balloon dilatation (EBD) of ileocaecal and colonic strictures due to Crohn's disease.We examined 237 dilatation procedures in 77 patients with symptomatic ileocaecal and colonic stenosis regarding outcome, individual perforation risk, the need for further interventions, and other complications within a 10 years observation period.In 50 of 77 patients (64.9%), endoscopic dilatation procedures were successful within a median follow-up period of 24 months (25th and 75th percentile 10-38.5 months). Thirty five patients (45.5%) were successfully dilated with only one endoscopic procedure, while the remaining patients required two or more EBDs. Albeit the EBD, 27 patients of the whole cohort (35.1%) underwent surgical repair of the stenosis in due course. Overall complication rate was 7.6%, with postdilatation bleeding in 1.7% and abdominal pain longer than 24 h in 4.2%. Perforation occurred in 4 of 77 patients (5.2%), resulting in a perforation rate of 1.7% per intervention, or, more importantly, for the individual patient in a long-term perforation rate of 5.2% per patient, respectively.Endoscopic balloon dilatation (EBD) is a safe and effective approach to ileocaecal and colonic stenosis in approximately 65% of Crohn's disease patients. Even in case of recurrence, further endoscopic treatments can be undertaken. The perforation rate depending on the number of interventions is low, but for the individual patient a cumulative per patient perforation risk of 5.2% in the long-term should be considered during patient information and decisions for or against surgical interventions.
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Outcome, comorbidity, hospitalization and 30-day mortality after closure of acute perforations and postoperative anastomotic leaks by the over-the-scope clip (OTSC) in an unselected cohort of patients - Raithel, M.; Albrecht, H.; Scheppach, W.; Farnbacher, M.; Haupt, Werner; Hagel, Alexander; Schellerer, Vera; Vitali, Francesco; Neurath, Markus; Schneider, H. T. (Surgical Endoscopy, 2016)
Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC).Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity.In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively.In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.
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Outcome of bowel function following anterior resection for rectal cancer-an analysis using the low anterior resection syndrome (LARS) score - Kupsch, Juliane; Jackisch, Thomas; Matzel, Klaus E.; Zimmer, Joerg; Schreiber, Andreas; Sims, Anja; Witzigmann, Helmut; Stelzner, Sigmar (International Journal of Colorectal Disease, 2018)
PURPOSE: Severity of anorectal dysfunction after low anterior resection is associated with various patient- and treatment-related factors. We aimed to quantify anorectal dysfunction after treatment for rectal cancer using the low anterior resection syndrome (LARS) score. METHODS: We retrieved from a prospective database 331 eligible patients on whom anterior resection for rectal cancer had been performed from 2000 to 2014. All patients were sent a LARS score accompanied by a supplementary questionnaire. Response rate was 78.8% (261 patients). The main outcome measure was the relation of the LARS score to potentially associated patient and treatment factors. Secondary endpoints were further measures that reflect anorectal dysfunction, e.g., Vaizey score. RESULTS: Overall, 144 (55.2%) patients exhibited scores > 20 reflecting minor (n = 51 (19.5%)) or major (n = 93 (35.6%)) LARS. A significant difference for scores > 20 was found for intersphincteric resection (IR, 73.2% affected patients) compared to total mesorectal excision (TME, 58.4%) and partial mesorectal excision (PME, 38.0%, p = 0.001). Radio(chemo)therapy resulted in LARS scores > 20 in 64.6% of patients compared to 43.1% in patients without irradiation (p = 0.001). Type of procedure (TME and IR as compared to PME), radio(chemo)therapy, and younger age were independently associated with LARS in logistic regression analysis. However, younger age remained the only independent factor for higher scores after exclusion of PME. CONCLUSIONS: The LARS score identified a substantial proportion of patients after surgery for rectal cancer with anorectal dysfunction. The extent of surgical procedure is independently associated with the severity of symptoms whereas the role of radiotherapy needs further assessment.
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Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study - Klompmaker, Sjors; Van Hilst, Jony; Gerritsen, Sarah L.; Adham, Mustapha; Quer, M. Teresa Albiol; Bassi, Claudio; Berrevoet, Frederik; Boggi, Ugo; Busch, Olivier R.; Cesaretti, Manuela; Dalla Valle, Raffaele; Darnis, Benjamin; et al. (Annals of Surgical Oncology, 2018)
BACKGROUND: Western multicenter studies on distal pancreatectomy with celiac axis resection (DP-CAR), also known as the Appleby procedure, for locally advanced pancreatic cancer are lacking. We aimed to study overall survival, morbidity, mortality and the impact of preoperative hepatic artery embolization (PHAE). METHODS: Retrospective cohort study within the European-African Hepato-Pancreato-Biliary-Association, on DP-CAR between 1-1-2000 and 6-1-2016. Primary endpoint was overall survival. Secondary endpoints were radicality (R0-resection), 90-day mortality, major morbidity, and pancreatic fistulae (grade B/C). RESULTS: We included 68 patients from 20 hospitals in 12 countries. Postoperatively, 53% of patients had R0-resection, 25% major morbidity, 21% an ISGPS grade B/C pancreatic fistula, and 16% mortality. In total, 82% received (neo-)adjuvant chemotherapy and median overall survival in 62 patients with pancreatic ductal adenocarcinoma patients was 18 months (CI 10-37). We observed no impact of PHAE on ischemic complications. CONCLUSIONS: DP-CAR combined with chemotherapy for locally advanced pancreatic cancer is associated with acceptable overall survival. The 90-day mortality is too high and should be reduced. Future studies should investigate to what extent increasing surgical volume or better patient selection can improve outcomes.
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Outcomes and Fate of the Distal Landing Zone Compared Between Prosthetic and Autologous Grafts After Infrainguinal Graft Occlusions - Rother, Ulrich; Gruber, Marc; Behrendt, Christian-Alexander; Günther, Josefine; Lang, Werner; Meyer, Alexander (JOURNAL OF VASCULAR SURGERY, 2022)
Background: Due to an increasing life expectancy, more and more patients experience the failure of peripheral arterial revascularization. This study aims to investigate patients treated for the failure of infra-inguinal bypass grafts, and to investigate the interaction of different bypass materials [great saphenous vein (GSV) and polytetrafluoroethylene (PTFE)] and the further outcome. Methods: Retrospective single-center analysis of consecutive patients treated for acute or chronic occlusion of infra-inguinal bypasses at a university hospital was conducted. Hospitalizations from 1st January 2010 through 31st December 2019 were included. Perioperative parameters from the index operation including graft material (prosthetic vs. autologous) were assessed. After bypass occlusion, the grade of ischemia, as well as the distal landing zone of the redo bypass compared with the primary bypass was investigated. Results: In this study, 158 (65% men and 35% women with a m mean age of 70.5 years) eligible patients were included (57% vein and 42% prosthetic bypass grafts). After graft occlusion, 47% of the patients presented with symptoms of acute limb-threatening ischemia, 53% with symptoms of chronic leg ischemia. The rate of acute limb-threatening ischemia was significantly higher when prosthetic graft material was used during the index operation (p =0.016). Additionally, in case of reoperation, the landing zone of the redo bypass was significantly more distally located after occlusion of prosthetic bypass graft (p = 0.014). Conclusion: Occlusions of prosthetic bypass grafts were associated with significantly higher rates of acute symptoms compared with vein grafts. Additionally, a shift to a more distal landing zone was recognized after the failure of a prosthetic bypass graft during the redo bypass operatio
CRIS-Team WoS Importer:2022-06-03
Keywords: graft failure; infrainguinal bypass; limb-threatening ischemia; prosthetic graft; vein bypass

Outcomes and Fate of the Distal Landing Zone Compared Between Prosthetic and Autologous Grafts After Infra-Inguinal Graft Occlusions - Rother, Ulrich; Gruber, Marc; Behrendt, Christian-Alexander; Günther, Josefine; Lang, Werner; Meyer, Alexander (Frontiers in Surgery, 2022)
Background: Due to an increasing life expectancy, more and more patients experience the failure of peripheral arterial revascularization. This study aims to investigate patients treated for the failure of infra-inguinal bypass grafts, and to investigate the interaction of different bypass materials [great saphenous vein (GSV) and polytetrafluoroethylene (PTFE)] and the further outcome. Methods: Retrospective single-center analysis of consecutive patients treated for acute or chronic occlusion of infra-inguinal bypasses at a university hospital was conducted. Hospitalizations from 1st January 2010 through 31st December 2019 were included. Perioperative parameters from the index operation including graft material (prosthetic vs. autologous) were assessed. After bypass occlusion, the grade of ischemia, as well as the distal landing zone of the redo bypass compared with the primary bypass was investigated. Results: In this study, 158 (65% men and 35% women with a m mean age of 70.5 years) eligible patients were included (57% vein and 42% prosthetic bypass grafts). After graft occlusion, 47% of the patients presented with symptoms of acute limb-threatening ischemia, 53% with symptoms of chronic leg ischemia. The rate of acute limb-threatening ischemia was significantly higher when prosthetic graft material was used during the index operation (p =0.016). Additionally, in case of reoperation, the landing zone of the redo bypass was significantly more distally located after occlusion of prosthetic bypass graft (p = 0.014) Conclusion: Occlusions of prosthetic bypass grafts were associated with significantly higher rates of acute symptoms compared with vein grafts. Additionally, a shift to a more distal landing zone was recognized after the failure of a prosthetic bypass graft during the redo bypass operation.
CRIS-Team Scopus Importer:2022-03-18
Keywords: graft failure; infrainguinal bypass; limb-threatening ischemia; prosthetic graft; vein bypass

Outcomes and Influence of the Pedal Arch in Below-the-Knee Angioplasty in Patients with End-Stage Renal Disease and Critical Limb Ischemia - Meyer, Alexander; Schinz, Katharina; Lang, Werner; Schmid, Andrea; Regus, Susanne; Rother, Ulrich (Annals of Vascular Surgery, 2016)
Management of dialysis patients with critical limb ischemia (CLI) still represents a challenge to vascular medicine, whereas the effects of the pedal arch quality in these patients with predominant affection of the infrapopliteal vessels have rarely been evaluated. Therefore, our aim was to analyze the outcomes of infrapopliteal angioplasty in the setting of chronic renal failure (end-stage renal disease) and evaluate the influence of the pedal arch involvement on clinical success.Prospective follow-up of 32 ERSD patients on hemodialysis (mean age, 72 years) with CLI and consecutive infrapopliteal angioplasty over a 5-year period 2010-2014 was performed. Mean follow-up was 10 months (range, 0-51 months). Statistical end points were defined for amputation-free survival, overall survival, and wound healing. Each patient's pedal arch was classified in 4 categories according to patency on completion angiography and the influence of the pedal arch quality on end points was assessed.A total of 44 vessels in 32 ischemic legs were treated. Technical success was achieved in 96% of patients, no major complications were observed. A 30-day mortality rate amounted 6% with no procedure-related deaths. The 1-year amputation-free survival rate was 56% and 34% at 2 years. Two major amputations were required. Subsequent revascularization procedures were necessary in 11 patients (10 redo angioplasty, 1 pedal bypass graft). The pedal arch was classified as category I in 1 patient (3%), category IIa in 12 (38%), IIb in 3 (9%), and III in 16 patients (50%). No statistical significant differences in terms of survival or wound-healing rate were observed between those groups, and the pedal arch quality had no impact on predefined end points.End-stage renal disease patients represent a subgroup with poor prognosis of limb salvage in CLI. Amputation-free survival remains poor and based on these data, an endovascular therapy is feasible and safe in these highly multimorbid patients. The quality of the pedal arch was not found to have any impact on wound healing or survival in the present study.
EVALuna2:14613

Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis - Klompmaker, Sjors; Peters, Niek A.; Van Hilst, Jony; Bassi, Claudio; Boggi, Ugo; Busch, Olivier R.; Niesen, Willem; Van Gulik, Thomas M.; Javed, Ammar A.; Kleeff, Jorg; Kawai, Manabu; Lesurtel, Mickael; et al. (Annals of Surgical Oncology, 2019)
BackgroundDistal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes.MethodsThis multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival.ResultsFor 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months).ConclusionsWhen performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor.
CRIS-Team WoS Importer:2019-02-21

Outcomes research in pancreatic cancer surgery - Krautz, Christian; Grützmann, Robert (Onkologe, 2017)
Background. Numerous international studies have identified hospital volume as a significant independent variable of death following complex surgery. Based on these data many countries aimed to centralize complex procedures, such as pancreatic surgery by the introduction of minimum caseload requirements. Objective. To summarize the current body of outcomes research on pancreatic cancer surgery and to investigate international experiences with the centralization of surgical care in this field. Material and methods. A systematic literature search was performed to identify studies that examined volume-outcome relationships and the effects of minimum caseload requirements on care structures and outcomes of pancreatic cancer surgery. Results. Several national and international studies confirmed that patients undergoing pancreatic surgery have better outcomes when treated in facilities with high annual caseloads. In countries with a relevant centralization of care structures impressive improvements of surgical outcomes have been reported. In Germany, a large proportion of hospitals that perform pancreatic surgery still do not meet the minimum caseload requirements. As a result of insufficient centralization in the recent past, mortality rates on the national level in Germany have remained unchanged. Conclusion. In view of the impressive results of other countries, efficient concentration of care structures seems to be the key to improvement of surgical outcomes in pancreatic surgery.
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Over-the-scope-clipping in colonic perforation caused small-bowel fixation and pneumoperitoneum requiring surgical repair - Albrecht, Heinz; Naegel, Andreas; Hagel, Alexander; Rösler, Wolf; Förtsch, Thomas; Neurath, Markus; Atreya, Raja; Raithel, Martin (Endoscopy, 2014)
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Overview of Subtypes and Therapies of acute Mesenteric Ischemia EAMI, TAMI, VAMI, NOMI - How to detect and treat them - Eckhardt, Daniel; Schmid, Axel; Grützmann, Robert (Zentralblatt für Chirurgie, 2019)
CRIS-Team WoS Importer:2021-10-18

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial - Roedel, Claus; Graeven, Ullrich; Fietkau, Rainer; Hohenberger, Werner; Hothorn, Torsten; Arnold, Dirk; Hofheinz, Ralf-Dieter; Ghadimi, Michael; Wolff, Hendrik A.; Lang-Welzenbach, Marga; Raab, Hans-Rudolf; Wittekind, Christian; et al. (Lancet Oncology, 2015)
Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy.In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076.Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group.Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer.German Cancer Aid (Deutsche Krebshilfe).
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p21 Prevents the Exhaustion of CD4+ T Cells Within the Antitumor Immune Response Against Colorectal Cancer - Thoma, Oana-Maria; Naschberger, Elisabeth; Kubánková, Markéta; Larafa, Imen; Kramer, Viktoria; Menchicchi, Bianca; Merkel, Susanne; Britzen-Laurent, Nathalie; Jefremow, André; Grützmann, Robert; Koop, Kristina; Neufert, Clemens; et al. (Gastroenterology, 2024)
Background & Aims: T cells are crucial for the antitumor response against colorectal cancer (CRC). T-cell reactivity to CRC is nevertheless limited by T-cell exhaustion. However, molecular mechanisms regulating T-cell exhaustion are only poorly understood. Methods: We investigated the functional role of cyclin-dependent kinase 1a (Cdkn1a or p21) in cluster of differentiation (CD) 4+ T cells using murine CRC models. Furthermore, we evaluated the expression of p21 in patients with stage I to IV CRC. In vitro coculture models were used to understand the effector function of p21-deficient CD4+ T cells. Results: We observed that the activation of cell cycle regulator p21 is crucial for CD4+ T-cell cytotoxic function and that p21 deficiency in type 1 helper T cells (Th1) leads to increased tumor growth in murine CRC. Similarly, low p21 expression in CD4+ T cells infiltrated into tumors of CRC patients is associated with reduced cancer-related survival. In mouse models of CRC, p21-deficient Th1 cells show signs of exhaustion, where an accumulation of effector/effector memory T cells and CD27/CD28 loss are predominant. Immune reconstitution of tumor-bearing Rag1−/− mice using ex vivo-treated p21-deficient T cells with palbociclib, an inhibitor of cyclin-dependent kinase 4/6, restored cytotoxic function and prevented exhaustion of p21-deficient CD4+ T cells as a possible concept for future immunotherapy of human disease. Conclusions: Our data reveal the importance of p21 in controlling the cell cycle and preventing exhaustion of Th1 cells. Furthermore, we unveil the therapeutic potential of cyclin-dependent kinase inhibitors such as palbociclib to reduce T-cell exhaustion for future treatment of patients with colorectal cancer.
CRIS-Team Scopus Importer:2024-01-19
Keywords: CD4; Colorectal Cancer; p21; Palbociclib

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern - Haller, Florian; Knopf, Jasmin; Ackermann, Andreas; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E.; Giedl, Josef; Carbon, Roman; et al. (Journal of Pathology, 2016)
Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.
EVALuna2:6792

Palliativchirurgie beim kolorektalen Karzinom – welche Faktoren können bei der Wahl des operativen Vorgehens helfen? - Konopke, Ralf; Schubert, Joerg; Stoeltzing, Oliver; Thomas, Tina; Kersting, Stephan; Denz, Axel (Zentralblatt für Chirurgie, 2020)
Background The surgical procedure for patients with colorectal cancer (CRC) in the palliative situation cannot be adequately standardised. The present study was initiated to identify criteria for the decision for resection of the malignancy with or without anastomosis. Patients/Material and Methods In a unicentric retrospective analysis, 103 patients after palliative resection with or without anastomosis due to CRC were examined. Using univariate and logistic regression analysis, the influence of a total of 40 factors on postoperative morbidity and mortality was assessed. Results In 46 cases, resection with primary anastomosis and in 57 cases a discontinuity resection was performed. Postoperative morbidity was 44.7% and mortality 17.5%. After one-stage resection with anastomosis, nicotine abuse (OR 4.2; p = 0.044), hypalbuminaemia (OR 4.0; p = 0.012), ASA score > 2 (OR 3.7; p = 0.030) and liver remodelling/cirrhosis (OR 3.6; p = 0.031) increased the risk for postoperative complications. Hypalbuminaemia (OR 1.8; p = 0.036), cachexia (OR 1.8; p = 0.043), anaemia (OR 1.5; p = 0.038) and known alcohol abuse (OR 1.9; p = 0.023) were identified as independent risk factors for early postoperative mortality. After discontinuity resection, renal failure (OR 2.1; p = 0.042) and cachexia (OR 1.5; p = 0.045) led to a significant increase in the risk of postoperative morbidity, alcohol abuse (OR 1.8; p = 0.041) in mortality. Hypalbuminaemia (OR 2.8; p = 0.019) and an ASA score > 2 (OR 2.6; p = 0.004) after resection and reconstruction increased the risk of major complications according to Clavien-Dindo, while pre-existing renal failure (OR 1.6; p = 0.023) increased the risk after discontinuity resection. In univariate analysis, an ASA score > 2 (p = 0.038) after simultaneous tumour resection and reconstruction, and urgent surgery in both groups with or without primary anastomosis were additionally identified as significant parameters with a negative influence on mortality (p = 0.010 and p = 0.017). Conclusion Palliative resections of colorectal carcinomas have high morbidity and mortality. Especially in cases of pre-existing alcohol abuse and/or urgent indication for surgery, more intensive monitoring should be performed. In the case of anaemia, cachexia, hypalbuminemia and an ASA score > 2, discontinuity resection may be the more appropriate procedure.
CRIS-Team Scopus Importer:2020-12-25
Keywords: colorectal carcinoma; morbidity; mortality; palliative medicine

Palliative therapy concepts for pancreatic carcinoma - Brunner, Michaela; Grützmann, Robert; Weber, Georg (Chirurg, 2018)
The majority of patients with ductal pancreatic adenocarcinoma are already in a locally advanced or metastatic stage at the time of diagnosis and require palliative therapy. Interventional and operative measures are available for the restoration of biliary outflow in bile duct obstruction and the continuity of the upper intestinal lumen in duodenal or gastric outlet obstruction. In the presence of tumor-related pain, pain therapy according to the World Health Organization (WHO) scheme or a truncus coeliacus blockade, in cachexia a nutritional therapy and in thromboembolic events an anticoagulant therapy are used. An individualized palliative chemotherapy regimen should be selected for each patient, taking into account the patient's general condition and the side effects profile of the chemotherapeutic agents. Radiochemotherapy and local ablative therapies should currently only be used within the framework of studies. A palliative resection is not recommended according to current knowledge.
EVALuna2:212624

Palliative treatment of colorectal cancer in Germany: cost of care and quality of life - Emmert, Martin; Pohl-Dernick, Katharina; Wein, Axel; Dörje, Frank; Merkel, Susanne; Boxberger, Frank; Männlein, Gudrun; Joost, Robert; Harich, Hans-Detlev; Lamberti, Christof; Neurath, Markus; Hohenberger, Werner; et al. (European Journal of Health Economics, 2012)
<div class="AbstractSection" id="ASec1" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Introduction <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> To estimate the costs of palliative care for colorectal cancer (CRC) from the perspective of German statutory health insurance and to measure the patients’ quality of life (QoL) for a 2-year time period. <div class="AbstractSection" id="ASec2" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Methods <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> A prospective observational multicentre study was carried out to estimate the direct costs of care over a 2-year period. Case report forms, medical records, and claims data were all applied to document medical and resource usage data in real-world settings. QoL was measured by using the Short Form-12 Health Survey. <div class="AbstractSection" id="ASec3" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Results <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> In total 101 patients (mean age 67.09 ± 11.13 years, 68 % male) from 12 different settings were included. The mean costs per patient during the 1st and 2nd years were calculated to be 42,361€ and 32,023€, respectively. Highest mean costs were calculated for the second quarter, which reached an amount of 12,900€ (95 % CI: 11,127€–14,673€). Mean physical summary scores and mean mental summary scores were 41.8 and 49.7, respectively. <div class="AbstractSection" id="ASec4" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Discussion <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> This is the first study assessing the costs of palliative care and the quality of life of patients with CRC in real-world health-care delivery in Germany. It could be shown that CRC treatment represents an enormous economic burden to the German health-care system. Increased efforts in promoting effective and efficient treatment options, or performance-based medication reimbursement schemes, might be helpful in reducing the costs.
WiSo-Import:2015-03-26:4180
Keywords: Colorectal cancer; Palliative care; Cost of care Health service research; Quality of life; SF-12

Palliative Treatment of Colorectal Cancer with Secondary Metastasis Resection in Germany - Impact of the Multidisciplinary Treatment Approach on Prognosis and Cost: The Northern Bavaria IVOPAK I Project - Wein, Axel; Emmert, Martin; Merkel, Susanne; Harich, Hans-Detlev; Thiemann, Roland; Lamberti, Christof; Göttler, Bernhard; Fries, Stefan; Kiani, Alexander; Schlag, Rudolf; Grüner, Marcus; Steinbild, Simone; et al. (Oncology, 2015)
Purpose The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. Patients and Methods 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). Results First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. Conclusion A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addresse
Keywords: Interdisciplinary cooperation; Costs; Colorectal cancer; Palliative treatment results

Pancreatic cystic space-occupying lesions-Diagnostics, treatment and follow-up care Current recommendations taking the current German S3 guidelines on pancreatic cancer into account - Brunner, Maximilian; Haeberle, Lena; Esposito, Irene; Grützmann, Robert (Chirurg, 2022)
Due to their increased detection pancreatic cystic space-occupying lesions are becoming increasingly relevant in the clinical routine and represent a morphologically and biologically heterogeneous and thus clinically demanding as well as potentially (pre)malignant entity. As a result, recommendations for the diagnostics and treatment of pancreatic cystic tumors have now been incorporated into the current German S3 guidelines on pancreatic cancer. The diagnostics of pancreatic cystic space-occupying lesions are based on the following three elements: collection of relevant clinical information, performance of high-resolution imaging procedures and if diagnostic uncertainty persists, puncture diagnostics. Differentiated diagnostics are of essential importance as these represent the basis for an adequate treatment decision. Pancreatic cystic lesions with a relevant risk of malignant transformation, e.g., main duct intraductal papillary mucinous neoplasms (IPMN), followed by mucinous cystic neoplasms (MCN), solid pseudopapillary neoplasms (SPN) and generally pancreatic cystic lesions with risk factors independent of the entity, should be resected, whereas a differentiated and individualized approach is necessary, especially for branch-duct IPMNs. The serous cystic neoplasms (SCN) have no malignant potential and do not require any treatment if they are asymptomatic. Important principles in surgery of pancreatic cancer, such as adequate surgical resection taking oncological standards into account and standardized appropriate histopathological processing of the specimens as well as intraoperative frozen section analysis also play an important role in pancreatic cystic space-occupying lesions. An annual follow-up seems to be meaningful, especially for IPMNs.
CRIS-Team WoS Importer:2022-04-01

Pancreatoduodenectomy with or without prophylactic falciform ligament wrap around the hepatic artery for prevention of postpancreatectomy haemorrhage: randomized clinical trial (PANDA trial) - Welsch, Thilo; Muessle, Benjamin; Korn, Sandra; Sturm, Dorothee; Bork, Ulrich; Distler, Marius; Graehlert, Xina; Klimova, Anna; Trebesius, Nicole; Kleespies, Axel; Kees, Stefan; Beckert, Stefan; et al. (British Journal of Surgery, 2022)
Background: Postpancreatectomy haemorrhage (PPH) is a rare but potentially fatal complication after pancreatoduodenectomy. Preventive strategies are lacking with scarce data for support. The aim of this study was to investigate whether a prophylactic falciform ligament wrap around the hepatic and gastroduodenal artery can prevent PPH from these vessels.
CRIS-Team WoS Importer:2022-02-11

Partial pancreatoduodenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicentre, randomised, controlled, double-blind ChroPac trial - Diener, Markus K.; Huettner, Felix J.; Kieser, Meinhard; Knebel, Phillip; Doerr-Harim, Colette; Distler, Marius; Grützmann, Robert; Wittel, Uwe A.; Schirren, Rebekka; Hau, Hans-Michael; Kleespies, Axel; Heidecke, Claus-Dieter; et al. (Lancet, 2017)
There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery.This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013.Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference -2·3, 95% CI -6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity.No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting.German Research Foundation (DFG).
EVALuna2:15300

Pathogenic, immunologic, and clinical aspects of sepsis - update 2016 - Uhle, Florian; Chousterman, Benjamin G.; Grützmann, Robert; Brenner, Thorsten; Weber, Georg (Expert Review of Anti-Infective Therapy, 2016)
Sepsis is a major cause of death worldwide but its orchestrating components remain incompletely understood. On the one hand, development of sepsis results from an infectious focus that cannot be controlled by the immune system, but on the other, responding immune cells that can eliminate the infection inflict damage to the host by contributing to complications such as endothelial leakage, septic shock, and multiorgan failure.In this review we give a comprehensive overview of how sepsis occurs, which exogenous and endogenous factors might affect the immune-pathophysiological course of sepsis and finally how this knowledge translates into up-to-date definitions and therapeutic approaches. Expert commentary: Although new immunological mechanisms altering the course of sepsis have been identified recently, future research needs to address the limitations of experimental approaches, redirect the research focus into translational approaches, and finally evaluate personalized treatment strategies.
EVALuna2:15252

Pathological function of neutrophil extracellular traps in human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Tripal, Philipp; Geppert, Carol-Immanuel; Merkel, Susanne; Herrmann, Martin; Stürzl, Michael (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Pathologic complete response after induction therapy and surgery is an independed long-term survival prognostic factor in locally advanced non-small cell lung cancer - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (2018)
EVALuna2:35736

Pathologic complete response after induction therapy-the role of surgery in stage IIIA/B locally advanced non-small cell lung cancer - Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Rieker, Ralf; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Journal of Thoracic Disease, 2018)
Background: Pathologic complete response (pCR) is dominant prognostic factor determining favorable outcome in locally advanced non-small cell lung cancer (NSCLC) after induction therapy (IT). There is no non-operative diagnostics that adequately estimates the pCR. Aim of this retrospective study was to assess the correlation between clinical and pathological factors in patients with pCR. Methods: Twenty-five patients with pCR after curative lung resection following IT were assessed using univariate and multivariate Cox regression and descriptive analysis. The survival rate was estimated by Kaplan-Meier method. Results: The IT included chemoradiation with median doses of 50.4 Gy (range, 45-59.4 Gy) combined with platinum-based chemotherapy in 23 patients (92%) and induction platinum-based chemotherapy in 2 patients (8%). Clinical tumor stage before IT was IIIA in 21, IIIB in 4 patients. Mean interval between IT and surgery was 8.1±3.0 weeks. Perioperative morbidity and 30-day mortality was 32% and 4%, respectively. There was no significant correlation of pCR and different clinical and pathological factors. The estimated 5-year long-term survival (LTS) and progressive-free survival (PFS) was 57% and 54%, respectively. The median LTS and PFS was not reached. Conclusions: pCR in patients with locally advanced NSCLC following IT is an independent prognostic factor, without correlation with pathological and clinical factors. Non-operative accurate assessment of pCR is currently impossible. Surgical resection enables secure identification of pCR and might improve the patient stratification for additive therapy.
EVALuna2:35733

Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases - Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S.; Stürzl, Michael (World Journal of Gastroenterology, 2016)
Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-?-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-? on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.
EVALuna2:15238

Patient's quality of life after surgery and radiotherapy for extremity soft tissue sarcoma-a retrospective single-center study over ten years - Götzl, Rebekka; Sterzinger, Sebastian; Semrau, Sabine; Vassos, Nikolaos; Hohenberger, Werner; Grützmann, Robert; Agaimy, Abbas; Arkudas, Andreas; Horch, Raymund E.; Beier, Justus (Health and Quality of Life Outcomes, 2019)
Background and objectives: The purpose of this study is to analyze major complication rates and different aspects of health-related quality of life (HRQoL) in extremity soft tissue sarcoma (STS) patients treated with or without radio (chemo) therapy and surgery. Methods: We performed a retrospective analysis of all patients who underwent Extremity STS excision from 2004 to 2014 (182 patients included). Patients' data were collected from patients' records. HRQoL was assessed by using EORTC QLQ-C30. Results: A total of 182 patients underwent sarcoma resection. After neoadjuvant radiochemotherapy (RCT), the major-complication rate amounted to 28% (vs. 7%, no radiotherapy, p < 0.001). Major-complication rates after adjuvant radiotherapy (RT) occurred in 8% (vs. 7%, no radiotherapy, p = 0.265). Comparison QoL scores between treating with neoadjuvant RCT or without RT revealed significant worse scores with neoadjuvant RCT. Further stratification of disease control of these patients showed significant reduced scores in the group of disease-free patients with neoadjuvant RCT compared to irradiated disease-free patients. Discussion: To date, there have only been a few investigations of QoL in STS. Retrospective study on quality of life have limitations, like a lack of baseline evaluation of QoL. Patient candidated to radiation therapy could have had worse QoL baseline due to more advanced disease. Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not. Conclusion: This study might assist in further improving the understanding of QoL in STS patients and may animate for prospective studies examining the oncological therapies impact on HRQoL.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Health related quality of life; QLQ-C30; Sarcoma major complication rates; Sarcoma radiotherapy; Soft tissue sarcoma

Patients with COVID-19: in the dark-NETs of neutrophils - Ackermann, Maximilian; Anders, Hans-Joachim; Bilyy, Rostyslav; Bowlin, Gary L.; Daniel, Christoph; De Lorenzo, Rebecca; Egeblad, Mikala; Henneck, Timo; Hidalgo, Andres; Hoffmann, Markus; Hohberger, Bettina; Kanthi, Yogendra; et al. (Cell Death and Differentiation, 2021)
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
CRIS-Team Scopus Importer:2021-06-04

PCR-synthesized single-stranded DNA: a useful tool for 'hyb' and 'HAP' standardization for construction of subtraction libraries. - Stürzl, Michael; Roth, Willy Kurt (Trends in Genetics, 1990)

PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease - Kannenkeril, Dennis; Bosch, Agnes; Kolwelter, Julie; Striepe, Kristina; Pietschner, Robert; Ott, Christian; Schiffer, Mario; Achenbach, Susanne; Schmieder, Roland (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis - Hecht, Markus; Buettner-Herold, Maike; Erlenbach-Wuensch, Katharina; Haderlein, Marlen; Croner, Roland; Grützmann, Robert; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (European Journal of Cancer, 2016)
The influence of neoadjuvant radiochemotherapy (RCT) on programmed death-ligand 1 (PD-L1) expression, a predictive marker for programmed cell death protein 1 (PD-1) inhibitor therapy, was studied on tumour and inflammatory cells in rectal adenocarcinoma patients along with its prognostic value.PD-L1 immunohistochemistry was performed on tissue microarrays of 103 pre-RCT biopsies and 159 post-RCT surgical specimens (central tumour, invasive front and normal tissue) of 199 patients. In 63 patients, both samples were available. Proportion and maximum intensity of PD-L1-positive (PD-L1+) cells were evaluated.RCT increased the proportion of PD-L1-expressing cancer cells from 2.1% to 7.8% in the central tumour (p < 0.001) or 9.3% in the invasive front (p < 0.001). Cancer cell PD-L1 on its own could not predict prognosis. High PD-L1 expression on pre-RCT inflammatory cells (maximum intensity: p = 0.048) and post-RCT invasive front inflammatory cells (p = 0.010) correlated with improved no evidence of disease survival. In multivariate analysis, the combination of low PD-L1 in cancer and inflammatory cells was an independent negative prognostic marker for overall survival (OS) pre-RCT (Cox's proportional hazard ratio 0.438, p = 0.045) and in the invasive front post-RCT (Cox's proportional hazard ratio 0.257, p = 0.030).Neoadjuvant RCT is associated with an increased PD-L1 expression in rectal adenocarcinoma patients, which should prompt clinical trials combining radiotherapy and PD-1/PD-L1 pathway blockade. Combined low PD-L1 expression on tumour and inflammatory cells is an independent negative prognostic marker for OS in RCT of rectal adenocarcinoma.
EVALuna2:6814

Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes - Weber, Marie; Schneider, Dominik T.; Offenmüller, Sonja; Kaatsch, Peter; Einsiedel, Hagen Graf; Benesch, Martin; Claviez, Alexander; Ebinger, Martin; Kramm, Christof; Kratz, Christian; Lawlor, Jennifer; Leuschner, Ivo; et al. (Pediatric Blood & Cancer, 2016)
Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage.Thirty-one patients with CRC age <= 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology.The age range was 9-18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1-124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mismatch repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively.Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS.
EVALuna2:15175

Pediatric Cullen gangrene: Case report of postoperative pyoderma gangrenosum in a preterm infant with a complex gastrointestinal malformation - Diez, Sonja; Syed, Julia; Müller, Hanna; Besendörfer, Manuel; Schellerer, Vera (International Journal of Surgery Case Reports, 2020)
Introduction: Pyoderma gangrenosum (PG) is a rare condition in infants, children and adolescents. The postoperative variant of this rapidly progressive ulceration is known as Cullen gangrene. Only a few case reports of pediatric Cullen gangrene have been published. Presentation of case: We present a male infant (gestational age 31 + 6 weeks) with gastroschisis and intrauterine volvulus. After multiple operations due to his complex gastrointestinal malformation, the patient showed classical symptoms of postoperative PG (PPG) 4 weeks after birth. Diagnosis could be made early in an interdisciplinary approach, differentiating intraabdominal infection (vancomycin resistant enterococcus (VRE), candida albicans) from epifascial occurrence. Treatment with high-dose steroids and immunoglobulins was initiated immediately and led to rapid recovery. Discussion: The unusual combination of a complex gastrointestinal malformation and an intraabdominal infection with VRE and candida albicans made the diagnosis difficult. However, early diagnosis is crucial in the treatment of Cullen gangrene. Conclusion: This is the first case report of Cullen gangrene presenting in an infant (at 4 weeks of age).
CRIS-Team Scopus Importer:2020-01-21
Keywords: Cullen gangrene; Gastroschisis; Pediatric surgery; Pyoderma gangrenosum

Pediatric patients undergoing arteriovenous fistula surgery without intraoperative heparin - Regus, Susanne; Almási-Sperling, Veronika; Lang, Werner (Journal of Vascular Access, 2016)
Arteriovenous fistula (AVF) creation in children could be extremely challenging for vascular surgeons due to small vessels with a high tendency of vasospasm. This could be one reason for primary failures (PF) and early access thrombosis. There exists no guideline for the need of intraoperative heparin administration during hemodialysis fistula creation. The aim of this study was to evaluate the effect of intra-operative heparin administration on immediate outcome.Medical records of 42 pediatric patients aged between 7 and 17 years were retrospectively reviewed. All received an AVF under inpatient conditions by exclusively one vascular surgeon with many years of professional experience. The intraoperative anticoagulation standards changed by the years 2001 based on the decision of the vascular surgeon. Therefore, we build two groups (group 1: 14 patients with 5000 IU of intravenous heparin during surgery and group 2: 28 patients without heparin). Major complications included hematoma or bleeding leading to surgery. PF was defined as the inability to use the AVF even once due to absent maturation or occlusion within 4 weeks after creation.We found 6 (14%) PF with the need of immediate surgical access revision (three from group 1 and three from group 2; p = 0.350). There were no bleedings leading to surgery in all cases, but 5 (12%) hematomas without the need of surgical revision (three from group 1 and two from group 2; p = 0.736).We found no benefit of heparin administration during clamping the arteries while performing the arteriovenous fistula in pediatric patients.
EVALuna2:15269

Peri-Prosthetic Fracture as a Rare Cause of Critical Limb Ischaemia - Li, Yi; Schmid, Axel (European Journal of Vascular and Endovascular Surgery, 2023)
CRIS-Team Scopus Importer:2023-04-28

Permacol collagen paste for cryptoglandular and Crohn's anal fistula - Brunner, Michaela; Schneider, Ignaz Hans Friedrich; Guenther, K.; Grützmann, Robert; Matzel, Klaus (Techniques in Coloproctology, 2019)
BackgroundPermacol collagen paste, an acellular crosslinked porcine dermal collagen matrix suspension, is a new treatment option for anal fistula. Data remain limited, however, and as yet only the results of one case of Crohn's fistula treated with Permacol paste has been reported. The aim of this study was to assess the use of Permacol collagen paste in patients with cryptoglandular and Crohn's perianal fistulae.MethodsA prospective study was conducted on patients with anal fistula, treated with Permacol paste. Patients were followed at 1week, 6 and 12months, and on demand thereafter. The main focus was on fistula healing and postoperative continence. The former was defined as the absence of signs of recurrence on clinical examination, proctoscopy and rigid rectoscopy. Fecal incontinence was assessed before surgery and at each follow-up.ResultsThirty patients (19 women, 11 men; mean age 46years), 12 (40%) of whom had Crohn's disease were included. The average number of previous fistula operations was 6. All patients had 6months of follow-up, and 24 patients (80%) had 12months of follow-up. The healing rate in all patients was 57% (17 of 30 patients) at 6months and 63% (15 of 24 patients) at 12months. One patient reported a worsening of fecal incontinence at 12 months; 2 patients had adverse events (perianal pain: n=1, fluid accumulation n=1) requiring fistula drainage. Patient characteristics, healing, incontinence, and adverse events did not differ significantly between patients with and without Crohn's disease.ConclusionsOur data indicate that Permacol paste is a safe and moderately effective treatment for cryptoglandular and Crohn's fistulae.
CRIS-Team WoS Importer:2019-04-12

Permeability analyses and three dimensional imaging of interferon gamma-induced barrier disintegration in intestinal organoids - Bardenbacher, Marco; Ruder, Barbara; Britzen-Laurent, Nathalie; Schmid, Benjamin; Waldner, Maximilian; Naschberger, Elisabeth; Scharl, Michael; Mueller, Werner; Günther, Claudia; Becker, Christoph; Stürzl, Michael; Tripal, Philipp (Stem Cell Research, 2019)
The aberrant regulation of the epithelial barrier integrity is involved in many diseases of the digestive tract, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial cell organoid cultures provide new perspectives for analyses of the intestinal barrier in vitro. However, established methods of barrier function analyses from two dimensional cultures have to be adjusted to the analysis of three dimensional organoid structures. Here we describe the methodology for analysis of epithelial barrier function and molecular regulation in intestinal organoids. Barrier responses to interferon-y of intestinal organoids with and without epithelial cellspecific deletion of the interferon-y-receptor 2 gene were used as a model system. The established method allowed monitoring of the kinetics of interferon-y-induced permeability changes in living organoids. Proteolytic degradation and altered localization of the tight junction proteins claudin-2, -7, and - 15 was detected using confocal spinning disc microscopy with 3D reconstruction. Hessian analysis was used for quantification of relocalization of claudins. In summary, we provide a novel methodologic approach for quantitative analyses of intestinal epithelial barrier functions in the 3D organoid model.
CRIS-Team WoS Importer:2019-03-12

Personality rather than clinical variables determines quality of life after major colorectal surgery - Siassi, Ramin Michael; Weiss, Maren; Hohenberger, Werner; Lösel, Friedrich; Matzel, Klaus (Diseases of the colon & rectum, 2009)
PURPOSE: Clinical factors, especially the presence of a stoma, have been presumed to be the major determinants of quality of life after colorectal surgery. We investigated the relative influence of other variables, e.g., patient's personality, sense of coherence, and coping strategies, to determine the validity of this long-held assumption. METHODS: We investigated 79 patients undergoing major colorectal surgery. Quality of Life was assessed with the Short Form-36 and Gastrointestinal Quality of Life Index questionnaires at three and 12 months postsurgery. Additionally, baseline psychologic data on personality and sense of coherence were assessed. The results were analyzed in both a bivariate manner and by multivariate hierarchical regression analysis. RESULTS: In the bivariate analysis, clinical parameters had a small and temporary effect on quality of life, if any. In the multivariate model the character of the underlying disease and the presence of a stoma did not affect quality of life significantly. In contrast, emotional lability, extraversion, and sense of coherence had a strong and lasting influence, accounting for 49 percent of variance (Delta R2) for emotional quality of life, 22 percent for physical and 32 percent for disease-specific Quality of Life. CONCLUSION: Personality exerts a strong and lasting effect on quality of life after colorectal surgery. This effect by far exceeds the influence of common clinical variables.

Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling - Chen, Chih-Wei; Beyer, Christian; Liu, Jun; Maier, Christiane; Li, Chun; Thuong Trinh-Minh,; Xu, Xiaohan; Cole, Stuart H.; Hsieh, Mindy H.; Ng, Nicholas; Althage, Alana; Meeusen, Shelly; et al. (Annals of the Rheumatic Diseases, 2017)
Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-?-receptor I.Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.
EVALuna2:13348

Physician Made Bovine Pericardial Tube Grafts in Aortic Infection: A European Multicentre Study - Weiss, Salome; Hugas Mallorqui, Maria; Czerny, Martin; Walter, Tim; Biro, Gabor; Puttini, Ilaria; Almási-Sperling, Veronika; Lang, Werner; Schmidli, Jürg; Wyss, Thomas R. (European Journal of Vascular and Endovascular Surgery, 2024)
Objective: This study examines outcome and durability of physician made bovine pericardial tube grafts in aortic infections in all anatomical locations. Methods: This was a retrospective and prospective international multicentre study. Peri-operative and long term outcomes of patients undergoing in situ aortic reconstruction for native or graft infections with physician made bovine pericardial tube grafts between January 2008 and December 2020 in four European tertiary referral centres were analysed. The primary endpoint was recurrent aortic infection. Secondary endpoints were persistent infection, aortic re-operation for infection, graft related complications, and death. Results: One hundred and sixty eight patients (77% male, mean age 67 ± 11 years) were identified: 38 (23%) with native and 130 (77%) with aortic graft infection. The thirty day mortality rate was 15% (n = 26) overall, 11% (n = 4), and 17% (n = 22) for native and aortic graft infections, respectively (p = .45). Median follow up was 26 months (interquartile range [IQR] 10, 51). Estimated survival at one, two, three, and five years was 64%, 60%, 57%, and 50%, and significantly better for native (81%, 77%, 77%, and 69%) than for graft infections (58%, 55%, 51%, and 44%; p = .011). Nine patients (5.3%) had persistent infection and 10 patients (6%) had aortic re-infection after a median of 10 months (IQR 5, 22), resulting in an estimated freedom from re-infection at one, two, three, and five years of 94%, 92%, 90%, and 86%. Estimated freedom from graft complications at one, two, three, and five years was 91%, 89%, 87%, and 87%. Conclusion: This multicentre study demonstrates low re-infection rates when using physician made bovine pericardial tube grafts, comparable to those of other biological grafts. The rate of graft complications, mainly anastomotic aneurysms and stenoses, was low, while graft degeneration was absent. Physician made bovine pericardial tube grafts are an excellent tool for in situ reconstruction in the setting of native aortic infection or aortic graft infection.
CRIS-Team Scopus Importer:2024-03-15
Keywords: In situ reconstruction; Infective native aortic aneurysm (INAA); Mycotic aneurysm; Pericardial tube grafts; Vascular (endo-) graft infection (VGEI)

Physiologically relevant aspirin concentrations trigger immunostimulatory cytokine production by human leukocytes - Brox, Regine; Hackstein, Holger (PLoS ONE, 2021)
Acetylsalicylic acid is a globally used non-steroidal anti-inflammatory drug (NSAID) with diverse pharmacological properties, although its mechanism of immune regulation during inflammation (especially at in vivo relevant doses) remains largely speculative. Given the increase in clinical perspective of Acetylsalicylic acid in various diseases and cancer prevention, this study aimed to investigate the immunomodulatory role of physiological Acetylsalicylic acid concentrations (0.005, 0.02 and 0.2 mg/ml) in a human whole blood of infection-induced inflammation. We describe a simple, highly reliable whole blood assay using an array of toll-like receptor (TLR) ligands 1-9 in order to systematically explore the immunomodulatory activity of Acetylsalicylic acid plasma concentrations in physiologically relevant conditions. Release of inflammatory cytokines and production of prostaglandin E-2 (PGE(2)) were determined directly in plasma supernatant. Experiments demonstrate for the first time that plasma concentrations of Acetylsalicylic acid significantly increased TLR ligand-triggered IL-1 beta, IL-10, and IL-6 production in a dose-dependent manner. In contrast, indomethacin did not exhibit this capacity, whereas cyclooxygenase (COX)-2 selective NSAID, celecoxib, induced a similar pattern like Acetylsalicylic acid, suggesting a possible relevance of COX-2. Accordingly, we found that exogenous addition of COX downstream product, PGE(2), attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro-inflammatory cytokines. Low PGE(2) levels were at least involved in the enhanced IL-1 beta production by Acetylsalicylic acid.
CRIS-Team WoS Importer:2021-09-10

Pilot Assessment of the Angiosome Concept by Intra-operative Fluorescence Angiography After Tibial Bypass Surgery - Rother, Ulrich; Lang, Werner; Horch, Raymund E.; Ludolph, Ingo; Meyer, Alexander; Gefeller, Olaf; Regus, Susanne (European Journal of Vascular and Endovascular Surgery, 2018)
OBJECTIVES: The "angiosome" concept as a model for decision making in revascularisation of patients with critical limb ischaemia (CLI) has been subject to lively discussion in recent years. The aim of this prospective pilot study was to use intra-operative fluorescence angiography to provide further data on the angiosome concept on the level of microcirculation after tibial bypass surgery. DESIGN, MATERIALS, AND METHODS: This was a prospective analysis of 40 patients presenting with CLI Rutherford stage IV to VI before and after tibial bypass surgery. The macrocirculation was measured by the ankle brachial index. Skin microcirculation was assessed by intra-operative fluorescence angiography. The alteration of microcirculation was compared in direct and indirect revascularised angiosomes. Clinical follow-up investigations were performed and the wound healing rate was compared between the different revascularisation methods. RESULTS: Cumulated microcirculation parameters showed a significant improvement after surgery (ingress, ingress rate p<.001). Likewise, general microcirculatory improvement was observed in each foot angiosome after revascularisation, regardless of the tibial artery revascularised. Furthermore, a comparison of the direct (DR) and the indirect revascularised (IR) angiosomes did not show a significant difference concerning the improvement of microcirculation (difference DR-IR, ingress: 1.69, 95% CI 71.73-75.11; ingress rate: 0.08, 95% CI -12.91 to 13.07). The wound healing rate was similar in both groups, although the time to wound healing was faster by on average 2.5 months in the DR group (p=.083). CONCLUSION: Microcirculatory improvement was seen over the whole foot after tibial bypass. Therefore, fluorescence angiography is a promising tool to evaluate the angiosome concept in future larger studies. Clinicaltrials.gov: NCT03012750.
EVALuna2:35687

Pilot assessment of the effect of negative pressure wound therapy on microperfusion of chronic and acute wounds - Rother, Ulrich; Theune, Mona; Lang, Werner; Meyer, Alexander (Clinical Hemorheology and Microcirculation, 2021)
BACKGROUND: Negative pressure wound therapy (NPWT) has been established over years for treatment of chronic and complex wounds.
CRIS-Team WoS Importer:2022-01-07

Pilot study using intraoperative fluorescence angiography during arteriovenous hemodialysis access surgery - Regus, Susanne; Klingler, Felix; Lang, Werner; Meyer, Alexander; Almási-Sperling, Veronika; May, Matthias; Wüst, Wolfgang; Rother, Ulrich (Journal of Vascular Access, 2019)
Introduction: In this pilot study, we used indocyanine green fluorescence angiography during hemodialysis access surgery. The aim was to evaluate its relevance as a diagnostic tool to visualize changes in hand microperfusion. Patients and methods: In this prospective single-center study, 47 adult patients (33 male, 14 female) with renal disease (24 preemptive, 23 endstage) were enrolled. Surgical creation of an arteriovenous fistula was performed (22 forearm, 25 upper arm). Microperfusion of the ipsilateral hand and fingers was evaluated intraoperatively using indocyanine green fluorescence angiography. We compared the cumulated microperfusion parameters ingress (In) and ingress rate (InR) before and after opening of the anastomosis. To compare the dimension of microcirculatory decline, we calculated the ratios of the parameters (RatioIn and RatioInR) after to those before anastomosis opening. Results: The cumulated microperfusion parameters In and InR showed a significant decrease after completion of anastomosis and declamping. This effect has been seen in all patients for the hand and for each finger consecutively. During follow-up (mean 4.6, range 3-11 months), 5 patients (10.6%) complained about hemodialysis access-induced distal ischemia. The ratio of intraoperative microperfusion in those five hemodialysis access-induced ischemia patients was significantly lower compared to asymptomatic patients (RatioIn 0.23 vs 0.58, p = 0.001, and RatioInR 0.25 vs 0.62, p = 0.003). Conclusion: Intraoperative fluorescence angiography could visualize the deterioration of ipsilateral hand microperfusion after surgical creation of an arteriovenous fistula. It seems to be a promising tool to detect patients at risk for hemodialysis access-induced distal ischemia early in the peri- or even intraoperative stage.
CRIS-Team WoS Importer:2019-03-06

Plasmacytoid dendritic cell depletion modifies FoxP3+ T cell homeostasis and the clinical course of bacterial pneumonia in mice - Lippitsch, Anne; Baal, Nelli; Chukovetskyi, Yuri; Cunningham, Sarah; Michel, Gabriela; Dietert, Kristina; Gurtner, Corinne; Gruber, Achim D.; Bein, Gregor; Hackstein, Holger (Journal of Leukocyte Biology, 2019)
Plasmacytoid dendritic cells (pDC) are critical to antiviral defense because of their high production of type I IFNs; less is known regarding their functions in bacterial infection. Moreover, pDC are involved in immunomodulation. A stable pool of regulatory T cells (Treg) is crucial for maintaining immune homeostasis. However, interactions between pDC and Treg regarding the regulation of Treg homeostasis are understudied. By using BDCA2-DTR mice as a systemic pDC depletion model, we identified increased steady-state numbers of FoxP3+ T cells with an effector Treg-like phenotype in lungs, liver, and spleen tissues. During sublethal, pulmonary Klebsiella pneumoniae infection, pDC deficiency also elevated respiratory FoxP3+ T cell numbers. Additionally, the improvement in acute pneumonia survival until day 5 post infection was accompanied by impaired proinflammatory cytokine production. In contrast, pDC-depleted mice exhibited a delayed clinical recovery during the post-acute phase. Therefore, we assume that pDC act as immunomodulators supporting the rapid onset of immune response in a proinflammatory manner and regulate inflammation or tissue regeneration in the post-acute phase. In summary, pDC assist in FoxP3+ T cell homeostasis and the regulation of Klebsiella-pneumonia progression.
CRIS-Team Scopus Importer:2019-07-16
Keywords: bacterial infection; BDCA2-DTR mice; immunomodulation; inflammation; Klebsiella pneumoniae; regulatory T cells

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls - Wagner, Nicola; Eberhardt, Martin; Vera, Julio; Cuomo, Federica; Blume, Katja; Galster, Silvia; Achenbach, Susanne; Laffert, Bernd; Kahlert, Helga; Schuler, Gerold; Berking, Carola; Baur, Andreas (World Allergy Organization Journal, 2021)
Background: Allergies are on the rise globally, with an enormous impact on affected individuals’ quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. Objectives: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. Methods: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. Results: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. Conclusions: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Allergy; Biomarkers; Extracellular vesicles-exosomes; Immune mediators; bioinformatics

Plasma extracellular vesicle messenger RNA profiling identifies prognostic EV signature for non-invasive risk stratification for survival prediction of patients with pancreatic ductal adenocarcinoma - Han, Yi; Drobisch, Pascal; Krüger, Alexander; William, Doreen; Grützmann, Konrad; Böthig, Lukas; Polster, Heike; Seifert, Lena; Seifert, Adrian M.; Distler, Marius; Pecqueux, Mathieu; Riediger, Carina; et al. (Journal of Hematology & Oncology, 2023)
Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6–8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery. Methods: Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan–Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR. Results: Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis. Conclusion: This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Extracellular vesicles; mRNA biomarkers; Pancreatic ductal adenocarcinoma; Plasma extracellular vesicle; Prognosis

Plasma Metabolic Profiling Identify Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma - Mahajan, U. M.; Alnatsha, A.; Li, Q.; Oehrle, B.; Weiss, U.; Sendler, M.; Distler, M.; Uhl, W.; Fahlbusch, T.; Goni, E.; Beyer, G.; Chromik, A.; et al. (PANCREAS, 2021)
CRIS-Team WoS Importer:2021-10-29

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma - Mahajan, Ujjwal Mukund; Alnatsha, Ahmed; Li, Qi; Oehrle, Bettina; Weiss, Frank-Ulrich; Sendler, Matthias; Distler, Marius; Uhl, Waldemar; Fahlbusch, Tim; Goni, Elisabetta; Beyer, Georg; Chromik, Ansgar; et al. (Cells, 2021)
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP(R) Global Profiling and MxP(R) Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.
CRIS-Team WoS Importer:2021-08-06

Plastisch-chirurgische Rekonstruktionsverfahren des Ulcus Cruris - Boos, Anja; Hillenbrand, M.; Beier, Justus; Arkudas, Andreas; Meyer, Alexander; Lang, Werner; Horch, Raymund E. (Internistische Praxis, 2020)
The treatment of leg ulcers requires a comprehensive assessment of the patient and the underlying pathogenesis and is subject of multimodal concepts. After unsuccessful conservative treatments, the surgical wound debridement is the treatment of choice. This is complemented by local vacuum therapy or in case of chronic infected wounds by applying an instillation therapy. After adequate wound conditioning and need for plastic surgical reconstruction, minimally invasive procedures such as skin transplantation in superficial defects, up to microsurgical tissue transplantation in severe losses of substance are available. If a perfusion disorder of the affected limb is presented, a revascularisation by bypasses or AV-loops is required. With new methods in wound healing, the success rate and therefore also the quality of life of patients with chronic wounds may be improved.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Av-loop; Bypass; Free flap; Leg ulcers; Surgical therapy

Platelet Transfusion and Hemorrhage - Zimmermann, Robert; Zingsem, Jürgen; Eckstein, Reinhold (Deutsches Ärzteblatt international, 2015)
EVALuna2:15989

Pleural Resident Macrophages and Pleural IRA B Cells Promote Efficient Immunity Against Pneumonia by Inducing Early Pleural Space Inflammation - Benard, Alan; Podolska, Malgorzata; Czubayko, Franziska; Kutschick, Isabella; Klösch, Bettina; Jacobsen, Anne; Naschberger, Elisabeth; Brunner, Maximilian; Krautz, Christian; Trufa, Denis; Sirbu, Horia; Lang, Roland; et al. (Frontiers in Immunology, 2022)
Airway infection is a major cause of mortality worldwide. The identification of new mechanisms aiding in effective host immune response is therefore required. Here, we show that the specific depletion of the pleural immune cell compartment during bacterial pneumonia resulted in a reduced pulmonary immune response and increased mortality in mice. Bacterial airway infection provoked early pleural space (PS) inflammation characterized by innate response activator (IRA) B cell development and pleural large resident macrophage (LRM) necroptosis, the repopulation of LRMs being driven by cellular proliferation in situ. Necroptotic LRMs amplified PS inflammation by stimulating pleural Mincle-expressing macrophages whereas IRA B cells contributed partially to GM-CSF-induced PS inflammation. Upon pulmonary infection, the induction of PS inflammation resulted in reduced bacterial burden whereas the specific depletion of pleural resident macrophages led to increased mortality and bacterial burden and reduced pulmonary immunity. Moreover, mice in which B cells were unable to produce GM-CSF exhibited reduced CD103+ dendritic cells and reduced CD4+ T cell numbers in the draining lymph node. Altogether, our results describe a previously unrecognized mechanism of pleural space inflammation necessary for effective protection against bacterial airway infection.
CRIS-Team Scopus Importer:2022-05-13
Keywords: bacterial airway infection; IRA B cells; mincle; necroptosis; pleural resident macrophages; pleural space

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis - Zhang, Yun; Pötter, Sebastian; Chen, Chih-Wei; Liang, Ruifang; Gelse, Kolja; Ludolph, Ingo; Horch, Raymund E.; Distler, Oliver; Schett, Georg; Distler, Jörg; Dees, Clara (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. RESULTS: The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. CONCLUSION: PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.
EVALuna2:34150

Popliteal Artery Occlusion Caused by Entrapment Syndrome in a Female Long Distance Runner - Regus, Susanne; Lang, Werner (European Journal of Vascular and Endovascular Surgery, 2016)
EVALuna2:15244

Possible reasons for variable leukapheresis collection outcomes with automated apheresis systems - Steininger, Philipp; Zimmermann, Robert; Eckstein, Reinhold; Strasser, Erwin (Transfusion, 2014)
EVALuna2:15986

Postoperative pain in small-for-gestational age infants after hernia repair, orchidopexy and urethral reconstruction surgery: A pilot study - Schüssler, Stephanie C.; Kußmann, Franziska; Fahlbusch, Fabian B.; Münster, Tino; Hirsch, Karin; Carbon, Roman; Albrecht, Sven; Dötsch, Jörg; Rascher, Wolfgang (Early Human Development, 2019)
Background: Small-for-gestational-age (SGA) birth bears an enhanced risk of developing hypertension, obesity, insulin resistance and mental health disorders in later life as a consequence of adaptive processes in utero. Only a small number of studies on pain perception in SGA infants exist. These are indicative of a blunted stress response to pain in SGA newborns. Aim: We initiated a pilot study investigating differences in postoperative pain perception between SGA and appropriate-for-gestational-age (AGA) infants. Methods: Pain and alertness levels of 10 formerly SGA and 14 AGA infants at the age 0.5–2 years were evaluated by the FLACC scale, Steward and Aldrete Scores following hernia repair, reconstructive surgery of hypospadia and orchidopexy. In addition, the postoperative consumption of non-steroidal anti-inflammatory drugs was compared between SGA and AGA. Results: Postoperative pain and alertness levels were not significantly different in SGA and AGA children. We did not observe significant group differences regarding the consumption of non-steroidal anti-inflammatory drugs. Conclusion: While previous studies were suggestive of a suppressed stress response to pain in SGA newborns, these findings did not fully translate into an altered response to pain beyond the newborn age. Further studies in a larger cohort seem necessary to verify this finding.
CRIS-Team Scopus Importer:2019-07-16

Precision Medicine in Inflammatory Bowel Diseases - Fischer, Sören; Neurath, Markus (Clinical Pharmacology & Therapeutics, 2017)
Inflammatory bowel diseases (IBDs) are a lifelong condition of chronic, recurrent inflammation in the gut. The introduction of immunomodulators and biologic agents markedly improved the treatment of IBDs. Therefore, the use of biologics became an essential element in the rational therapy of IBDs. Various substances are currently evaluated in clinical trials, addressing different target structures and offering further approaches in the field of IBD. Regarding the growing number of treatment options, the need for prediction of therapy response became a necessity and is the subject of the present research.
EVALuna2:33803

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer - Dreyer, Stephan B; Pinese, Mark; Jamieson, Nigel B.; Scarlett, Christopher J; Colvin, Emily K; Pajic, Marina; Johns, Amber L.; Humphris, Jeremy; Wu, Jianmin; Cowley, Mark J.; Chou, Angela; Nagrial, Adnan M.; et al. (Annals of Surgery, 2018)
OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.
EVALuna2:212801

Pre-clinical Models of Metastasis in Pancreatic Cancer - Miquel Sedo, Maria; Zhang, Shuman; Pilarsky, Christian (Frontiers in Cell and Developmental Biology, 2021)
Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.
CRIS-Team Scopus Importer:2021-11-19
Keywords: GEMMs; metastasis; metastasis models; organoids; pancreatic cancer; PDAC – pancreatic ductal adenocarcinoma

Predicting Clinical Outcomes in Colorectal Cancer Using Machine Learning - Gründner, Julian; Prokosch, Hans-Ulrich; Stürzl, Michael; Croner, Roland S.; Christoph, Jan; Toddenroth, Dennis (Studies in health technology and informatics, 2018)
Using gene markers and other patient features to predict clinical outcomes plays a vital role in enhancing clinical decision making and improving prognostic accuracy. This work uses a large set of colorectal cancer patient data to train predictive models using machine learning methods such as random forest, general linear model, and neural network for clinically relevant outcomes including disease free survival, survival, radio-chemotherapy response (RCT-R) and relapse. The most successful predictive models were created for dichotomous outcomes like relapse and RCT-R with accuracies of 0.71 and 0.70 on blinded test data respectively. The best prediction models regarding overall survival and disease-free survival had C-Index scores of 0.86 and 0.76 respectively. These models could be used in the future to aid a decision for or against chemotherapy and improve survival prognosis. We propose that future work should focus on creating reusable frameworks and infrastructure for training and delivering predictive models to physicians, so that they could be readily applied to other diseases in practice and be continuously developed integrating new data.
EVALuna2:209471

Predicting major bleeding events in patients with peripheral arterial disease: the OAC(3)-PAD risk score - Behrendt, Christian-Alexander; Rother, Ulrich; Uhl, Christian; Goertz, Hartmut; Stavroulakis, Konstantinos; Gombert, Alexander (Gefässchirurgie, 2022)
Although patients with peripheral arterial disease (PAD) are at a high risk of major bleeding owing to their comorbidity and risk profile, no validated tools exist to predict bleeding risk. To make matters worse, several randomized and controlled trials have excluded patients who are at a high risk of bleeding. Using routine health insurance claims data and machine learning methods, a pragmatic prediction model was developed and internally validated. The OAC(3)-PAD risk score identified eight variables that can predict major bleeding events within 1 year of inpatient treatment for PAD. This risk score can help to carry out a tailored patient-centered risk-benefit assessment in order to obtain the maximum potential from available antithrombotic treatment strategies.
CRIS-Team WoS Importer:2022-03-25
Keywords: PAD; Risk Prediction; Antithrombotics; Bleeding; Coagulation

Prediction of High Bell Stages of Necrotizing Enterocolitis Using a Mathematic Formula for Risk Determination - Diez, Sonja; Bell, Lea Emilia; Moosmann, Julia; Weiss, Christel; Müller, Hanna; Besendörfer, Manuel (Children, 2022)
Necrotizing enterocolitis (NEC) continues to cause high morbidity and mortality. Identifying early predictors for severe NEC is essential to improve therapy and optimize timing for surgical intervention. We present a retrospective study of patients with NEC, treated between 2010 and 2020, trying to identify factors influencing the severity of NEC. Within the study period, 88 affected infants with NEC or NEC-like symptoms are analyzed. A multiple logistic regression analysis reveals the following three independent predictors for NEC in Bell stage III: red blood cell transfusion (p = 0.027 with odds ratio (OR) = 3.298), sonographic findings (p = 0.037; OR = 6.496 for patients with positive vs. patients without pathological findings) and cardiac anatomy (p = 0.015; OR = 1.922 for patients with patent ductus arteriosus (PDA) vs. patients with congenital heart disease (CHD); OR = 5.478/OR = 2.850 for patients with CHD/PDA vs. patients without cardiac disease). Results are summarized in a clinical score for daily application in clinical routine. The score is easy to apply and combines clinically established parameters, helping to determine the timing of surgical intervention.
CRIS-Team Scopus Importer:2022-05-13
Keywords: Bell stage; clinical score; congenital heart disease; fulminant NEC; NEC; necrotizing enterocolitis

Prediction of persistent post-operative pain: Pain-specific psychological variables compared with acute post-operative pain and general psychological variables - Horn-Hofmann, C.; Scheel, J.; Dimova, V.; Parthum, A.; Carbon, R.; Grießinger, Norbert; Sittl, R.; Lautenbacher, S. (European Journal of Pain, 2018)
BACKGROUND: Psychological variables and acute post-operative pain are of proven relevance for the prediction of persistent post-operative pain. We aimed at investigating whether pain-specific psychological variables like pain catastrophizing add to the predictive power of acute pain and more general psychological variables like depression. METHODS: In all, 104 young male patients undergoing thoracic surgery for pectus excavatum correction were studied on the pre-operative day (T0) and 1 week (T1) and 3 months (T2) after surgery. They provided self-report ratings (pain-related: Pain Catastrophizing Scale, Pain Anxiety Symptoms Scale = PASS, Pain Vigilance and Awareness Questionnaire = PVAQ; general psychological: Screening for Somatoform Symptoms, State-Anxiety Inventory-X1, Center for Epidemiologic Studies Depression Scale = CES-D). Additional predictors (T1) as well as criterion variables (T2) were pain intensity (Numerical Rating Scale) and pain disability (Pain Disability Index). RESULTS: Three months after surgery, 25% of the patients still reported clinically relevant pain (pain intensity ≥3) and over 50% still reported pain-related disability. Acute post-operative pain as well as general psychological variables did not allow for a significant prediction of persistent post-operative pain; in contrast, pain-related psychological variables did. The best single predictors were PASS for pain intensity and PVAQ for pain disability. CONCLUSIONS: Pain-related psychological variables derived from the fear-avoidance model contributed significantly to the prediction of persistent post-operative pain. The best possible compilation of these measures requires further research. More general psychological variables may become relevant predictors later in the medical history. SIGNIFICANCE: Our results suggest that pain-specific psychological variables such as pain anxiety and pain hypervigilance add significantly to the prediction of persistent post-operative pain and might even outperform established predictors such as acute pain and general psychological variables. Clinicians might benefit from the development of time-economic screening tools based on these variables.
EVALuna2:36086

Predictive factors for better bypass patency and limb salvage after prosthetic above-knee bypass reconstruction - Klingelhoefer, Eric; Bergert, Hendrik; Kersting, Stephan; Ludwig, Stefan; Weiss, Norbert; Schoenleben, Frank; Grützmann, Robert; Gaebel, Gabor (Journal of Vascular Surgery, 2016)
Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction.Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction.Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P < .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P < .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (>6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon.In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter (>6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected.
EVALuna2:15254

Predictive factors of early outcome after palliative surgery for colorectal carcinoma - Konopke, Ralf; Schubert, Jörg; Stöltzing, Oliver; Thomas, Tina; Kersting, Stephan; Denz, Axel (Innovative Surgical Science, 2020)
A significant number of patients with colorectal cancer are presented with various conditions requiring surgery in an oncologically palliative setting. We performed this study to identify risk factors for early outcome after surgery to facilitate the decision-making process for therapy in a palliative disease. We performed a retrospective chart review of 142 patients who underwent palliative surgery due to locally advanced, complicated, or advanced metastatic colorectal carcinoma between January 2010 and April 2018 at the "Elbland"Medical Center Riesa. We performed a logistic regression analysis of 43 factors to identify independent predictors for complications and mortality. Surgery included resections with primary anastomosis (n=31; 21.8%) or discontinuous resections with colostomy (n=38; 26.8%), internal bypasses (n=27; 19.0%) and stoma formation only (n=46; 32.4%). The median length of hospitalization was 12 days (2-53 days), in-hospital morbidity was 50.0% and the mortality rate was 18.3%. Independent risk factors of in-hospital morbidity were age (HR: 1.5, p=0.046) and various comorbidities of the patients [obesity (HR: 1.8, p=0.036), renal failure (HR: 1.6, p=0.040), diabetes (HR: 1.6, p=0.032), alcohol abuse (HR: 1.3, p=0.023)] as well as lung metastases (HR: 1.6, p=0.041). Arteriosclerosis (HR: 1.4; p=0.045) and arterial hypertension (HR: 1.4, p=0.042) were independent risk factors for medical complications in multivariate analysis. None of the analyzed factors predicted the surgical morbidity after the palliative procedures. Emergency surgery (HR: 10.2, p=0.019), intestinal obstruction (HR: 9.2, p=0.006) and ascites (HR: 5.0, p=0.034) were multivariate significant parameters of in-hospital mortality. Palliatively treated patients with colorectal cancer undergoing surgery show high rates of morbidity and mortality after surgery. In this retrospective chart review, independent risk factors for morbidity and in-hospital mortality were identified that are similar to patients in curative care. An adequate selection of patients before palliative operation should lead to a better outcome after surgery. Especially in patients with intestinal obstruction and ascites scheduled for emergency surgery, every effort should be made to convey these patients to elective surgery by interventional therapy, such as a stent or minimally invasive stoma formation.
CRIS-Team Scopus Importer:2020-11-20
Keywords: colorectal cancer; metastasis; palliative surgery; palliative treatment; surgery

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab - Brueggemann, C.; Kirchberger, M. C.; Goldinger, S. M.; Weide, B.; Konrad, A.; Erdmann, M.; Schadendorf, D.; Croner, R. S.; Krahenbuhl, L.; Kaehler, K. C.; Hafner, C.; Leisgang, W.; et al. (Journal of Cancer Research and Clinical Oncology, 2017)
PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab.Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings.The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.
EVALuna2:15289

Predictors and severity of intestinal ischaemia following on-pump cardiac surgery: a retrospective, propensity-matched analysis - Wiesmueller, Felix; Bryan, Darren S.; Krautz, Christian; Grützmann, Robert; Weyand, Michael; Strecker, Thomas (European Journal of Cardio-Thoracic Surgery, 2022)
OBJECTIVES: Risk factors associated with intestinal ischaemia after heart surgery have been previously explored; however, a paucity of data exists with regard to extent of intestinal ischaemia in patients requiring surgical intervention. The purpose of this study is to assess predictors of abdominal exploration and extent of ischaemia following cardiac surgery.
CRIS-Team WoS Importer:2022-03-11

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial - Roedel, Claus; Liersch, Torsten; Becker, Heinz; Fietkau, Rainer; Hohenberger, Werner; Hothorn, Torsten; Graeven, Ullrich; Arnold, Dirk; Lang-Welzenbach, Marga; Raab, Hans-Rudolf; Suelberg, Heiko; Wittekind, Christian; et al. (Lancet Oncology, 2012)
BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe).
EVALuna2:5332

Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study - Gerbitz, Armin; Gary, Regina; Aigner, Michael; Moosmann, Andreas; Kremer, Anita; Schmid, Christoph; Hirschbuehl, Klaus; Wagner, Eva; Hauptrock, Beate; Teschner, Daniel; Rösler, Wolf; Spriewald, Bernd; et al. (Frontiers in Immunology, 2023)
Introduction: Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Methods: We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. Results: Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. Discussion: Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02227641.
CRIS-Team Scopus Importer:2023-11-24
Keywords: allogeneic; cytomegalovirus CMV; epitope specificity; Epstein-Barr virus EBV; prevention; reactivation; stem cell transplantation (SCT)

Primary and recurrent sporadic desmoids: Prognostic factors influencing recurrence-free survival after complete gross resection - Mueller, Christian; Croner, Roland; Klein, Peter; Grützmann, Robert; Vassos, Nikolaos (International Journal of Surgery, 2016)
There is continuing controversy over the significance of prognostic factors in sporadic desmoid-type fibromatosis (DF). Further, only limited data is available in the literature concerning second recurrence in patients with recurrent DF. The purpose of this study was to identify prognostic factors influencing recurrence-free survival (RFS) and to determine rates of local recurrence (LR) in patients with primary and recurrent DF.Fifty-three consecutive patients with DF who underwent surgery at a single institution were identified. As a result of strict exclusion criteria, a homogeneous cohort of thirty-two patients who received macroscopically complete resection was included in this study and split into a primary (PG) and recurrent disease (RG) group. Clinicopathological parameters and immunohistochemical markers were retrospectively and independently analyzed in both groups.The local recurrence rate was 35% for the PG and 33% for the RG. The PG's calculated median time to relapse was 17 months, and the RG's was 29 months. The estimated 1-, 5-, and 8-year RFS rates for the PG were 75%, 64%, and 55% while the corresponding RFS rates for the RG were 69%, 69%, and 52%, respectively. In primary disease, extraabdominal tumor location was the only significant adverse prognostic factor associated with worse RFS (p = 0.008). Whereas in recurrent disease, age >=40 yrs (p = 0.022) and R0 margin status (p = 0.049) correlated with a significantly better outcome.Recurrence in primary and recurrent DF is characterized by different predictive factors and benefits from distinct therapeutic strategies. Immunohistochemical markers are valuable tools in the diagnosis of DF, although have limited potential in predicting the outcome.
EVALuna2:15243

Primary aortoduodenal fistula - Overlooked because of guidelines? - Wiesmüller, Felix; Neufert, Clemens; Croner, Roland; Lang, Werner; Grützmann, Robert; Siebler, Jürgen (Innovative Surgical Science, 2020)
Primary aortoduodenal fistula is an uncommon yet mostly lethal finding. We present a case of a 63 year-old male who exhibited significant upper gastrointestinal bleeding and hemorrhagic shock. Repeated endoscopies did not detect any source of bleeding. Emergency laparotomy disclosed an aortoduodenal fistula. Despite intense medical efforts for several months the patient did not fully recover and treatment was limited to palliative care. In light of the substantial mortality associated with this condition, computed tomography imaging should be performed in case of doubt to prevent delayed diagnosis.
CRIS-Team Scopus Importer:2020-11-20
Keywords: aortoduodenal fistula; aortoenteric fistula; gastrointestinal bleeding; PADF; primary aortoduodenal fistula

Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity - Naschberger, Elisabeth; Geissdorfer, Walter; Bogdan, Christian; Tripal, Philipp; Kremmer, Elisabeth; Stürzl, Michael; Britzen-Laurent, Nathalie (Journal of Cellular and Molecular Medicine, 2017)
Human guanylate binding protein-1 (GBP-1) belongs to the family of large GTPases. The expression of GBP-1 is inducible by inflammatory cytokines, and the protein is involved in inflammatory processes and host defence against cellular pathogens. GBP-1 is the first GTPase which was described to be secreted by eukaryotic cells. Here, we report that precipitation of GBP-1 with GMP-agarose from cell culture supernatants co-purified a 47-kD fragment of GBP-1 (p47-GBP-1) in addition to the 67-kD full-length form. MALDI-TOF sequencing revealed that p47-GBP-1 corresponds to the C-terminal helical part of GBP-1 and lacks most of the globular GTPase domain. In silico analyses of protease target sites, together with cleavage experiments in vitro and in vivo, showed that p67-GBP-1 is cleaved by the inflammatory caspases 1 and 5, leading to the formation of p47-GBP-1. Furthermore, the secretion of p47-GBP-1 was found to occur via a non-classical secretion pathway and to be dependent on caspase-1 activity but independent of inflammasome activation. Finally, we showed that p47-GBP-1 represents the predominant form of secreted GBP-1, both in cell culture supernatants and, in vivo, in the cerebrospinal fluid of patients with bacterial meningitis, indicating that it may represent the biologically active form of extracellular GBP-1. These findings confirm the involvement of caspase-1 in non-classical secretion mechanisms and open novel perspectives for the extracellular function of secreted GBP-1.
EVALuna2:7752

Prognosis of patients with colonic carcinoma before, during and after implementation of complete mesocolic excision - Merkel, Susanne; Weber, K.; Matzel, Klaus; Agaimy, Abbas; Göhl, Jonas; Hohenberger, Werner (British Journal of Surgery, 2016)
The implementation of complete mesocolic excision (CME) for colonic cancer was accompanied by other important changes, including more patients with early diagnosis by screening and the introduction of adjuvant chemotherapy in patients with stage III disease. The contribution of CME remains unclear.In this observational study, data from patients with stage I-III colonic carcinoma were analysed by comparing five time intervals: 1978-1984 (pre-CME), 1985-1994 (CME development), 1995-2002 (CME implementation), 2003-2009 (CME) and 2010-2014 (CME), with a special focus on indicators of process and outcome quality.During the observed periods, the median age of patients increased (from 65 to 67 years), there were more right-sided carcinomas (from 17·0 to 32·4 per cent), more stage I disease (from 14·0 to 27·7 per cent) and fewer patients with regional lymph node metastases (from 42·7 to 32·0 per cent). The proportion of patients with pN0 disease and at least 12 examined regional lymph nodes increased (from 84·8 to 100 per cent) as did the R0 resection rate (from 97·0 to 100 per cent). Overall morbidity increased, whereas the in-hospital mortality rate was stable (range 1·8-3·7 per cent). Use of adjuvant chemotherapy in stage III colonic carcinoma increased from 0 to 79 per cent. The improvement in outcome quality was more evident in stage III than in stage I-II tumours. In stage III, the 5-year locoregional recurrence rate decreased from 14·8 to 4·1 per cent (P = 0·046) and the 5-year cancer-related survival rate increased from 61·7 to 80·9 per cent (P = 0·010).With CME, the quality indicators of process and outcome quality improved, especially in stage III colonic carcinoma. Adjuvant chemotherapy in stage III and multidisciplinary approaches in patients with metachronous distant metastases contributed to further outcome improvement.
EVALuna2:6780

Prognostic and diagnostic value of procalcitonin in the post-transplant setting after liver transplantation - Perrakis, Aristotelis; Stirkat, Falk; Croner, Roland S.; Vassos, Nikolaos; Raptis, Dimitrios; Yedibela, Süleyman; Hohenberger, Werner; Mueller, Volker (Archives of Medical Science, 2016)
The aim of the study was to assess the diagnostic accuracy of procalcitonin (PCT) as a marker for complications and as a prognostic factor for mortality after liver transplantation.Liver transplant patients between January 2007 and April 2011 were prospectively included in the study. Procalcitonin serum concentration was recorded before, 6 h after reperfusion and then daily. Postoperative clinical course was prospectively analyzed from admission to discharge. Main surgical data such as operating procedure, type of reperfusion, operating and ischemic times, high urgency (HU) status and MELD score at the time of transplantation were also recorded.Sixteen patients with initial PCT > 5 ng/ml suffered >= 1 complication (p = 0.03). However, there was no association between the level of the 1(st) peak PCT and the further postoperative course or the occurrence of complications. Patients in whom a 2(nd) PCT peak occurred had a significantly higher risk for a complicated course, for a complicated sepsis course and for mortality (p < 0.0001). Warm ischemic time over 58 min, operating time over 389 min and HU status were significant independent factors for a complicated postoperative course (p < 0.001, p < 0.001 and p = 0.03 respectively).Based on our results, we believe that PCT course and the occurrence of a 2(nd) peak seem to possess important diagnostic and prognostic power in the post-transplant setting after liver transplantation.
EVALuna2:15234

Prognostic subdivision of pT2 rectal carcinomas - Merkel, Susanne; Weber, Klaus; Brunner, Maximilian; Baecker, Justus; Agaimy, Abbas; Göhl, Jonas; Hohenberger, Werner; Schellerer, Vera; Grützmann, Robert (International Journal of Colorectal Disease, 2019)
Purpose The aim of the present study is to explore the prognostic impact of a subdivision of pT2 by the depth of invasion into the muscularis propria in rectal carcinomas.
CRIS-Team WoS Importer:2019-04-18

Prognostic subdivision of ypT3 rectal tumours according to extension beyond the muscularis propria - Merkel, Susanne; Weber, K.; Schellerer, Vera; Göhl, Jonas; Fietkau, Rainer; Agaimy, Abbas; Hohenberger, Werner; Hermanek, Peter (British Journal of Surgery, 2014)
The subdivision of T3 in rectal carcinoma according to the depth of invasion into perirectal fat has been recommended in the TNM Supplement since 1993. This study assessed the prognostic impact of this pathological staging in tumours removed after neoadjuvant chemoradiotherapy (ypT3).Data from patients with ypT3 rectal carcinoma (less than 12 cm from the anal verge) treated with neoadjuvant chemoradiation and total mesorectal excision were analysed. Tumour category ypT3 was subdivided into ypT3a (5 mm or less) and ypT3b (more than 5 mm), based on histological measurements of maximal tumour invasion beyond the outer border of the muscularis propria.Important differences between ypT3a (81 patients) and ypT3b (43) were found in 5-year rates of locoregional recurrence (7 versus 18 per cent; P = 0·049), distant metastasis (20 versus 41 per cent; P = 0·002), disease-free survival (73 versus 47 per cent; P = 0·001), overall survival (79 versus 74 per cent; P = 0·036) and cancer-related survival (81 versus 74 per cent; P = 0·007). In Cox regression analyses, the ypT3 subclassification was identified as an independent prognostic factor for disease-free (ypT3b: hazard ratio (HR) 2·13, 95 per cent confidence interval 1·16 to 3·89; P = 0·014), observed (ypT3b: HR 2·02, 1·05 to 3·87; P = 0·035) and cancer-related (ypT3b: HR 2·46, 1·20 to 5·04; P = 0·014) survival. Extramural venous invasion was found to be an additional prognostic factor, but the pathological node category after chemoradiotherapy (ypN) did not influence survival.In ypT3 rectal carcinomas, the proposed subclassification is superior to ypN in predicting prognosis.
EVALuna2:6571

Prognostic value of different biomarkers for cardiovascular death in unselected older patients in the emergency department - Bahrmann, Philipp; Christ, Michael; Hofner, Benjamin; Bahrmann, Anke; Achenbach, Susanne; Sieber, Cornel; Bertsch, Thomas (European Heart Journal: Acute Cardiovascular Care, 2016)
Risk stratification of elderly patients presenting with heart failure (HF) to an emergency department (ED) is an unmet challenge. We prospectively investigated the prognostic performance of different biomarkers in unselected older patients in the ED.We consecutively enrolled 302 non-surgical patients ?70 years presenting to the ED with a wide range of cardiovascular and non-cardiovascular comorbid conditions. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), ultrasensitive C-terminal pro-arginine-vasopressin (Copeptin-us) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of HF after reviewing all available baseline data using circulating NT-proBNP levels. A final diagnosis of HF was found in 120 (40%) of the 302 patients. All patients were followed up for cardiovascular death within the following 12 months. In order to test the prognostic performance of the investigated biomarkers we used boosting models with age and sex as mandatory covariates. Boosting is a statistical learning technique with built-in variable selection developed to obtain sparse and interpretable prediction models.Follow-up was 100% complete. During a median follow-up time of 225 days (interquartile range (IQR) 156-319 days), 30 (9.9%) of 302 patients (aged 81±6 years) had cardiovascular deaths. Of these 30 patients, 21 had HF and nine had no HF diagnosed prior to admission. The boosting model selected MR-proADM and hs-cTNT as predictors of cardiovascular deaths. The median values of MR-proADM and hs-cTnT at presentation were significantly higher in patients with cardiovascular deaths compared to surviving patients during follow-up (2.56 nmol/L (IQR 1.62-4.48) vs. 1.11 nmol/L (IQR 0.83-1.80), P<0.001 and 81 ng/L (IQR 38-340) vs. 17 ng/L (IQR 0.9-38), P=0.004). One unit increase in the log-transformed MR-proADM levels was associated with a 1.99-fold risk of death (95% confidence interval (CI) 1.61-2.45, P<0.001). The second marker, hs-cTnT, showed an increased predicted risk but was not significantly correlated to event-free survival (hazard ratio 3.22, 95% CI 0.97-10.68, P=0.056).Within different biomarkers, MR-proADM was the only predictor of cardiovascular deaths in unselected older patients presenting to the ED.
EVALuna2:10605

Prognostic value of β1 integrin expression in colorectal liver metastases. - Vassos, Nikolaos; Rau, Tilman; Merkel, Susanne; Feiersinger, Fabian; Geppert, Carol-Immanuel; Stürzl, Michael; Hohenberger, Werner; Croner, Roland S. (International Journal of Clinical and Experimental Pathology, 2014)
Integrins are cell surface adhesion molecules (CAM) that regulate via intercellular and cell-matrix signaling various cellular processes including wound healing, cell differentiation, division, growth, migration and metastatic dissemination. Although a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, has been reported, its role in colorectal liver metastases remains unclear. This study aimed to evaluate the expression of β1 integrin in colorectal liver metastases and to correlate the pattern of expression with clinicopathological features and to investigate the putative role of β1 integrin expression on survival of these patients. Formalin-fixed, paraffin-embedded (FFPE) tumor samples of 81 patients who were operated because of colorectal liver metastases without any neoadjuvant therapy were obtained and stained with hematoxylin and eosin (H & E). An immunohistochemical examination was performed using Dako, Peroxidase/DAB kit and a primary monoclonal β1 integrin (CD29, fibronectin receptor subunit beta; ab3167, Abcam plc). β1 integrin expression was evaluated according to the immunoreactive score of Remmele and Stegner and was related with clinicopathological features of prognostic significance and with disease-free and overall survival as well. Statistical analysis was performed using SPSS version 21.0. β1 integrin was overexpressed in tumor cells in 37 (48%) patients and in stromal cell in 27 (33%) patients. The β1 expression was not statistically correlated with clinicopathological features of the primary tumors but it was statistically correlated (p=0.03) with the histological grading of liver metastases. Kaplan-Meier survival analysis showed that there is a tendency but no statistically significant correlation in disease-free and overall survival. Considering that expression of β1 integrin in colorectal liver metastases remains controversial, specially its relation with survival of patients, we showed that the β1 expression represents a reliable prognostic factor regarding the grading of liver metastases of CRC and our findings imply that β1 integrin expression profiles may have further potential in identifying the stage of colorectal liver metastases and being a marker of prognosis in these patients. UNLABELLED METHODS RESULTS CONCLUSION

Programming Algorithms for Sacral Neuromodulation: Clinical Practice and Evidence—Recommendations for Day-to-Day Practice - Lehur, Paul A.; Sørensen, Michael; Dudding, Thomas C.; Knowles, Charles H.; de Wachter, Stefan; Engelberg, Stefan; Matzel, Klaus E. (Neuromodulation, 2020)
Background: In sacral neuromodulation (SNM), stimulation programming plays a key role to achieve success of the therapy. However to date, little attention has been given to the best ways to set and optimize SNM programming during the test and chronic stimulation phases of the procedure. Objective: Standardize and make SNM programming easier and more efficient for the several conditions for which SNM is proposed. Methods: Systematic literature review and collective clinical experience report. Results: The basic principles of SNM programming are described. It covers choice of electrode configuration, stimulation amplitude, pulse frequency and pulse widths, while use of cycling is also briefly discussed. Step-by-step practical flow charts developed by a group of 13 European experts are presented. Conclusions: Programming of SNM therapy is not complex. There are few programming settings that seem beneficial or significantly impact patient outcomes. Only four basic electrode configurations could be identified according to four different options to define the cathode. In a majority of patients, the proposed stimulation parameters will allow a satisfactory improvement for long periods of time. A regular follow-up is, however, necessary to assess and eventually optimize results, as well as to reassure patients.
CRIS-Team Scopus Importer:2020-03-20
Keywords: Basic programming; electric stimulation; fecal incontinence; pelvic organ dysfunction; sacral neuromodulation; urinary incontinence

Proposal for a new M1 subclassification in colorectal carcinoma - Merkel, Susanne; Weber, K.; Croner, R.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (2016)
EVALuna2:2176

Proposal of a Standardized Questionnaire to Structure Clinical Peer Reviews of Mortality and Failure of Rescue in Pancreatic Surgery - Brunner, Maximilian; Mücke, Franziska; Langheinrich, Melanie; Struller, Florian; Rueckert, Felix; Welsch, Thilo; Distler, Marius; Kersting, Stephan; Grützmann, Robert; Krautz, Christian; Weber, Georg (Journal of Clinical Medicine, 2021)
Background: Quality management tools such as clinical peer reviews facilitate root cause analysis and may, ultimately, help to reduce surgery-related morbidity and mortality. This study aimed to evaluate the reliability of a standardized questionnaire for clinical peer reviews in pancreatic surgery. Methods: All cases of in-hospital-mortality following pancreatic surgery at two high-volume centers (n = 86) were reviewed by two pancreatic surgeons. A standardized mortality review questionnaire was developed and applied to all cases. In a second step, 20 cases were randomly assigned to an online re-review that was completed by seven pancreatic surgeons. The overall consistency of the results between the peer review and online re-review was determined by Cohen's kappa (kappa). The inter-rater reliability of the online re-review was assessed by Fleiss' kappa (kappa). Results: The clinical peer review showed that 80% of the patient mortality was related to surgery. Post-operative pancreatic fistula (POPF) (36%) followed by post-pancreatectomy hemorrhage (PPH) (22%) were the most common surgical underlying (index) complications leading to in-hospital mortality. Most of the index complications yielded in abdominal sepsis (62%); 60% of the cases exhibited potential of improvement, especially through timely diagnosis and therapy (42%). There was a moderate to substantial strength of agreement between the peer review and the online re-review in regard to the category of death (surgical vs. non-surgical; kappa = 0.886), type of surgical index complication (kappa = 0.714) as well as surgical and non-surgical index complications (kappa = 0.492 and kappa = 0.793). Fleiss' kappa showed a moderate to substantial inter-rater agreement of the online re-review in terms of category of death (kappa = 0.724), category of common surgical index complications (kappa = 0.455) and surgical index complication (kappa = 0.424). Conclusion: The proposed questionnaire to structure clinical peer reviews is a reliable tool for root cause analyses of in-hospital mortality and may help to identify specific options to improve outcomes in pancreatic surgery. However, the reliability of the peer feedback decreases with an increasing specificity of the review questions.
CRIS-Team WoS Importer:2021-05-28

Proposal of a T3 Subclassification for Colon Carcinoma. - Merkel, Susanne; Brunner, Maximilian; Geppert, Carol-Immanuel; Grützmann, Robert; Weber, Klaus; Agaimy, Abbas (Cancers, 2022)
The TNM classification system is one of the most important factors determining prognosis for cancer patients. In colorectal cancer, the T category reflects the depth of tumor invasion. T3 is defined by a tumor that invades through the muscularis propria into pericolorectal tissues. The data of 1047 patients with complete mesocolic excision were analyzed. The depth of invasion beyond the outer border of the muscularis propria into the subserosa or into nonperitonealized pericolic tissue was measured and categorized in 655 pT3 patients: pT3a (≤1 mm), pT3b,c (>1-15 mm) and pT3d (>15 mm). The prognosis of these categories was compared. Five-year distant metastasis increased significantly from pT3a (5.7%) over pT3b,c (17.7%) to pT3d (37.2%; p = 0.001). There was no difference between pT2 (5.3%) and pT3a or between pT3d and pT4a (42.1%) or pT4b (33.7%). The 5-year disease-free survival decreased significantly from pT3a (77.4%) over pT3b,c (65.4%) to pT3d (50.1%; p = 0.015). No significant difference was found between pT2 (80.5%) and pT3a or between pT3d and pT4a (43.9%; p = 0.296) or pT4b (53.4%). The prognostic inhomogeneity in pT3 colon carcinoma has been demonstrated. A three-level subdivision of T3 for colon carcinoma in the TNM system into T3a (≤1 mm), T3b (>1-15 mm), and T3c (>15 mm) is recommended.
EVALuna2:514502

Protein S Erlangen: a novel PROS1 gene mutation associated with quantitative protein S deficiency - Schneider, Sabine; Reissig, Julian; Weisbach, Volker Günter; Achenbach, Susanne; Hackstein, Holger; Strobel, Julian (Blood Coagulation & Fibrinolysis, 2022)
The members of a Caucasian family were genetically analyzed on suspicion of hereditary protein S deficiency. A novel mutation, c.1904T>C, associated with severe quantitative protein S deficiency was found. The novel PROS1 mutation was identified by sequencing of the PROS1 gene coding sequence. The identified c.1904T>C point mutation results in p.Phe635Ser amino acid exchange, which is located in the Laminin G-like 2 domain of protein S. Computational analysis indicates that this amino acid exchange affects the correct folding of the protein S antigen. Furthermore, this mutation is located in a region of the Laminin G-like 2 domain where changes in the amino acid sequence often result in decreased secretion. We postulate that the novel p.Phe635Ser mutation might lead to an incorrect folding, and thus, to a strongly impaired secretion of this protein S variant. We named this novel variant protein.
CRIS-Team Scopus Importer:2022-06-10

Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development - Katkeviciute, Egle; Hering, Larissa; Montalban-Arques, Ana; Busenhart, Philipp; Schwarzfischer, Marlene; Manzini, Roberto; Conde, Javier; Atrott, Kirstin; Lang, Silvia; Rogler, Gerhard; Naschberger, Elisabeth; Schellerer, Vera; et al. (Journal of Clinical Investigation, 2021)
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell- and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.
CRIS-Team Scopus Importer:2021-01-15

Psychological prophylaxis training for coping with postoperative pain. Long-term effects - Scheel, J.; Parthum, A.; Dimova, V.; Horn-Hoffmann, C.; Meinfelder, F.; Carbon, R.; Grießinger, Norbert; Sittl, R.; Lautenbacher, S. (Schmerz, 2014)
The present study was performed to investigate the effect of multidimensional psychological prophylaxis training focusing on coping with cognitive-emotional pain on recovery within the first 12 months after surgery. The training included the following three components: (1) education about pain, analgesia and psychological aspects of coping with pain, (2) training for coping with pain and (3) body-centered relaxation.In the study 48 young male patients (surgical correction of a chest malformation) were assessed 1 day before surgery, at discharge and 3, 6 and 12 months postoperatively concerning postoperative pain intensity and pain disability as well as pain anxiety, pain catastrophizing and pain hypervigilance. Additionally, 24 of these patients received training on cognitive-emotional coping with pain 1 day before surgery and 1-3 days after surgery (each session 1 h).The proportion of patients with clinically relevant improvement was significantly higher in the training group compared to the control group. This was the case for acute pain intensity (approximately 1 week after surgery), pain disability 3 months later and pain anxiety 12 months after surgery.The resurgence of pain anxiety after 12 months could only be found in the control group and could be due to the upcoming surgical removal of the transsternal metal implant. The prophylaxis training can therefore be seen as a protective factor for long-term management of surgery-related consequences and future pain experiences.
EVALuna2:15688

PU.1 controls fibroblast polarization and tissue fibrosis - Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif Bülent; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; et al. (Nature, 2019)
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
EVALuna2:35476

Pulmonary metastasectomy for sarcoma-survival and prognostic analysis - Dudek, Wojciech; Schreiner, Waldemar; Mykoliuk, Iurii; Higaze, Mostafa; Sirbu, Horia (Journal of Thoracic Disease, 2019)
Background: Pulmonary metastasectomy (PM) has commonly been performed in patients with controlled metastatic sarcoma. We reviewed our single-institution experience with pulmonary resections for sarcoma to analyse clinical outcome and to identify prognostic factors associated with patient survival.
CRIS-Team WoS Importer:2019-09-20

Pylorus-Preserving Pancreaticoduodenectomy (PPPD) with Segmental Portal Vein Resection - Brunner, Maximilian; Krautz, Christian; Maak, Matthias; Weber, Georg; Grützmann, Robert (Zentralblatt für Chirurgie, 2021)
CRIS-Team WoS Importer:2021-08-06

QoL after multimodal treatment of rectal cancer with/without oxaliplatin (phase 3, CAO/ARO/AIO-04) - Kosmala, R.; Fokas, E.; Flentje, M.; Sauer, Rolf; Liersch, T.; Graeven, U.; Fietkau, Rainer; Hohenberger, Werner; Arnold, D.; Hofheinz, R.; Ghadimi, M.; Raab, H.; et al. (RADIOTHERAPY AND ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-06-18

Qualität der Chirurgie als Prognosefaktor beim Rektumkarzinom nach neoadjuvanter Radiochemotherapie - Brunner, M.; Perrakis, Aristotelis; Merkel, Susanne; Weber, K.; Grützmann, Robert (Chirurgische Praxis, 2019)
The prognosis of patients with rectal carcinoma has improved significantly in recent years, in particular through the introduction of TME (total mesorectal excision) surgery and neoadjuvant therapy with radiation or chemoradiotherapy in locally advanced carcinomas. Even in the era of TME surgery and neoadjuvant chemoradiation high-quality surgical therapy plays an important role for the prognosis of patients with rectal cancer, especially for local tumor control. Prognostically relevant surgical quality indicators represent the quality of TME, the R0 resection, the negative circumferential resection margin (CRM) and the avoidance of intraoperative local tumor cell dissemination. These four factors mainly affect the local recurrence rate, but are also significant in terms of overall survival.
CRIS-Team Scopus Importer:2021-04-20
Keywords: Neoadjuvant therapy; Preoperative chemoradiation; Prognostic factors; Quality of surgery; Rectal carcinoma; TME

Qualitätsindikatoren für die Pankreaschirurgie - Wellner, U. F.; Grützmann, Robert; Keck, T.; Nuessler, N.; Witzigmann, H. E.; Buhr, H. -J. (Chirurg, 2018)
Quality indicators are by definition indirect measures of quality. The selection for the field of pancreatic surgery was based on the clinical relevance and controllability, scientific evidence and the practicability of data acquisition. In terms of outcome quality, hospital mortality, the composite endpoint MTL30 (mortality-transfer-length of stay), and major complications (Clavien-Dindo classification grades 3b and 4) were chosen as being essential. With respect to structural quality, the presence of interventional radiology with constant availability was considered essential. To evaluate target values two strategies were used: a systematic literature search and evaluation of the current numbers from the German Society for General and Visceral Surgery (DGAV) StuDoQ|Pancreas registry for the years 2014-2016. The results are presented in the following consensus statement.
EVALuna2:212863

Quality of Clotting Factor Activity in Fresh Frozen Plasma at Thaw with a Microwave System and after Storage at 4 degrees C for 48 Hours - Kuta, Piotr; Hauck-Dlimi, Barbara; Strobel, Joachim; Zimmermann, Robert; Eckstein, Reinhold (Clinical Laboratory, 2016)
BACKGROUND: Uncontrolled hemorrhage in polytrauma patients usually results in rapid need of blood products. Despite the shorter thawing times of microwave devices for heating fresh frozen plasma (FFP), their use has remained controversial, and just a few laboratory analyses have been published on this topic. The aim of this study was to analyse the quality of clotting factors immediately after thawing FFP with a microwave device and after 48-hour post thaw storage at 4 degrees C. METHODS: 24 FFP units of all four ABO blood groups (six of each blood group) were thawed with a Transfusio-therm 2000 and later stored at 4 degrees C for 48 hours. Samples were drawn aseptically and investigated on various clotting factors and protein proteases (fibrinogen, antithrombin, FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, vWF antigen and activity, protein S, and protein C) using standard coagulation and chromogenic assays immediately after thawing and again after a 48-hour storage period at 4 degrees C. All units were tested for both anaerobic and aerobic microbial contamination using standard operating procedures immediately after thawing. RESULTS: After thawing, all coagulation factors and protein protease activities were within normal ranges. Blood group O individuals had approximately 25% lower plasma levels of vWF antigen and activity. After a 48-hour storage period at 4 degrees C, FVIII and FIX activities declined significantly in all blood groups, whereas the remaining clotting factors remained comparably stable. CONCLUSIONS: Immediately after rapid thawing using a microwave system, all FFP units contained adequate coagulation factor activities to maintain hemostatic activity at the time of product thaw. The post thaw refrigerated storage caused an anticipated decrease in factor VIII and IX activities, but retained normal coagulation factor levels of many plasma proteins. Therefore we conclude that the Transfusio-therm 2000 has no clinically significant influence on the activity of clotting factors and plasma proteases in FFP units.
EVALuna2:32776

Quality of life and patient’s expectations after closure of a temporary stoma - Siassi, Ramin Michael; Hohenberger, Werner; Lösel, Friedrich; Weiss, Maren (International Journal of Colorectal Disease, 2008)
Introduction Little is known about the changes in quality of life following reversal of a temporary loop ileostomy after rectal cancer surgery. We therefore conducted a prospective study assessing physical symptoms, quality of life, problems in everyday life, and patient’s expectations and complaints. Materials and methods We investigated 35 patients who received a temporary stoma after colorectal surgery between 15/11/2002 and 15/11/2003. The patients were followed up for 1 year. Quality of life was assessed using the Short-Form 36 (SF-36) and the Gastrointestinal Quality of Life Index (GLQI). In addition, we performed a semi-structured interview that assessed quality of life, function, patient’s expectations, and complaints. Results The interviews showed a significant improvement in body image and leisure activities while the questionnaires showed no change in qol. Conversely, there was a significant increase in gastrointestinal problems that persisted until 1 year after primary surgery. An increasing proportion of patients stated that they felt worse than they expected after stoma closure. That was accompanied by an increased number of complaints about the hospital and the medical staff. Conclusion Although from the surgeon’s point of view, stoma closure is only a minor procedure, it causes significant functional problems for the patients that lead to considerable dissatisfaction. Other than usually presupposed, there is no general improvement in quality of life and everyday life after stoma closure. Therefore, thorough preoperative counseling about the consequences of stoma reversal is mandatory.

Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial - Kosmala, Rebekka; Fokas, Emmanouil; Flentje, Michael; Sauer, Rolf; Liersch, Torsten; Graeven, Ullrich; Fietkau, Rainer; Hohenberger, Werner; Arnold, Dirk; Hofheinz, Ralf Dieter; Ghadimi, Michael; Ströbel, Philipp; et al. (European Journal of Cancer, 2021)
Background: The CAO/ARO/AIO trial has shown that oxaliplatin added to preoperative chemoradiotherapy and postoperative chemotherapy significantly improved disease-free survival in locally advanced rectal cancer (LARC). Here, we present a post-hoc analysis of quality of life (QoL) in disease-free patients. Patients and methods: Between 2006 and 2010, 1236 patients with LARC were randomly assigned either to preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy (N = 623) or combined with oxaliplatin (N = 613). QoL questionnaires (EORTC QLQ-C30, colorectal module CR38) were completed at baseline, after postoperative chemotherapy and during follow-up. Analysis was performed according intent-to-treat. Results: Available questionnaires (baseline) were 82% (N = 512) in the control and 84% (N = 513) in the investigational group. Response rates were 49% (533 of 1086) at 1 year and 43% (403 of 928) at 3 years. Global health status (GHS) for disease-free patients was stable in both groups (range 0–100). At baseline: standard arm 62.0 (mean, SD 21.6; N = 491) versus oxaliplatin arm 63.2 (mean, SD 22; N = 503); at 3 years: 69.4 (SD 19.3; N = 187) versus 65.4 (SD 22.2; N = 202). After treatment and at 3 years, no significant differences (≥10 points) between groups were found in QoL subscales. Disease-free patients experiencing neurotoxic side-effects (grade 1–4) showed reduced GHS at 3 years versus patients without neurotoxicity (mean 59.2 versus 69.3; P < 0.001), while grade 3–4 rate was low. Conclusion: The addition of oxaliplatin was not associated with worse overall QoL. This information is of interest to patients in many ongoing rectal cancer trials. Trial registration information: NCT00349076.
CRIS-Team Scopus Importer:2021-01-08
Keywords: Chemoradiotherapy; Oxaliplatin; Quality of life; Rectal neoplasms

Quality of life of GIST patients with and without current tyrosine kinase inhibitor treatment: Cross-sectional results of a German multicentre observational study (PROSa) - Eichler, Martin; Pink, Daniel; Menge, Franka; Jakob, Jens; Hentschel, Leopold; Richter, Stephan; Hohenberger, Peter; Kasper, Bernd; Andreou, Dimosthenis; Singer, Susanne; Grützmann, Robert; Dmytrow, Diana I.; et al. (European Journal of Cancer Care, 2021)
Objective: We investigated the health-related quality of life (HRQoL) of patients with gastrointestinal stromal tumours (GIST). Methods: In the multicentre PROSa study, the HRQoL of adult GIST patients was assessed between 2017 and 2019 using the European Organisation for Research and Treatment of Cancer HRQoL questionnaire (EORTC QLQ-C30). We performed group comparisons and multivariate linear regressions. Results: Among 130 patients from 13 centres, the mean global HRQoL was 63.3 out of 100 points. Higher sores indicate better HRQoL. The highest restrictions were in emotional, social, role functioning, insomnia, fatigue, and pain. In multivariate linear regression, we found no significant differences between patients receiving tyrosine kinase inhibitor (TKI) treatment and those without TKI treatment as well as between patients treated with curative or with palliative intent. Patients who received multiple lines of TKI treatment had the most restrictions, notably in physical (unstandardized regression coefficient [B] = −15.7), role (B = −25.7), social (B = −18.4), and cognitive functioning (B = −19.7); fatigue (B = 15.93); general health (B = −14.23); and EORTC-sum score (B = −13.82) compared to all other patients. Conclusion: The highest HRQoL restrictions were in GIST patients receiving multiple lines of TKI therapy. Underlying causes need further investigation.
CRIS-Team Scopus Importer:2021-08-13
Keywords: clinically important restrictions and symptoms; gastrointestinal stromal tumours; health-related quality of life; observational study; rare disease; tyrosine kinase inhibitors

Quality of Mesorectal Excision ("Plane of Surgery") - Which Quality Targets are Adequate? - Hermanek, Peter; Merkel, Susanne; Ptok, H.; Hohenberger, Werner (Zentralblatt für Chirurgie, 2015)
Today, the examination of rectal cancer specimens includes the obligate macroscopic assessment of the quality of mesorectal excision by the pathologist reporting the plane of surgery. The frequency of operations in the muscularis propria plane of surgery (earlier described as incomplete mesorectal excision) is essential. The quality of mesorectal excision is important for the prognosis, especially as local recurrences are observed more frequently after operations in the muscularis propria plane of surgery. For the definition of quality targets, data of 13 studies published between 2006 and 2012, each with more than 100 patients and adequate specialisation and experience of the surgeons (5413 patients), data of the prospective multicentric observation study "Quality Assurance - Rectal Cancer" (at the Institute for Quality Assurance in Operative Medicine at the Otto-von-Guericke University at Magdeburg) from 2005 to 2010 (8044 patients) and data of the Department of Surgery, University Hospital Erlangen, from 1998 to 2011 (991 patients) were analysed. The total incidence of operations in the muscularis propria plane of surgery was 5.0 % (721/14 448). Even with adequate specialisation and experience of the surgeon, the frequency of operations in the muscularis propria plane of surgery is higher in abdominoperineal excisions than in sphincter-preserving surgery (8.4 vs. 2.8 %, p < 0.001). Thus, the quality target for the frequency of operations in the muscularis propria plane should be defined as < 5 % for sphincter-preserving procedures and as < 10 % for abdominoperineal excisions.
EVALuna2:15146

Quality of Surgery for Stage III Colon Cancer: Comparison Between England, Germany, and Japan - Kobayashi, Hirotoshi; West, Nicholas P.; Takahashi, Keiichi; Perrakis, Aristotelis; Weber, Klaus; Hohenberger, Werner; Quirke, Philip; Sugihara, Kenichi (Annals of Surgical Oncology, 2014)
A number of studies have demonstrated that lymph node metastasis is a poor prognostic factor in colon cancer. Advances of surgical procedure have improved the outcomes of colon cancer treatment. The aim of this study was to compare the characteristics of surgery for stage III colon cancer between England, Germany, and Japan.Using the data of patients with colon cancer from one English, one German, and two Japanese centers, the characteristics of clinicopathologic features were compared. Conventional surgery, complete mesocolic excision (CME) with central vascular ligation, and D3 lymph node dissection were performed in England, Germany, and Japan, respectively.Nineteen English, 26 German, and 60 Japanese patients were enrolled. There was no difference in tumor location, pT, and pN factors among the three groups. The length of resected bowel and the area of resected mesentery of the English and CME specimens were significantly greater than those of the D3 specimens (P < 0.0001 and P < 0.0001, respectively), whereas the length of the vascular tie to the bowel wall was similar between the CME and D3 specimens (P = 0.87), which was longer than that of the English specimens. The number of lymph nodes retrieved in the CME specimens was greatest among three groups (P < 0.0001), although the number of positive nodes was comparable (P = 0.64). The rates of mesocolic plane surgery in the English, CME, and D3 specimens were 47.4, 88.5, and 71.7 %, respectively (P = 0.022).Three types of surgery for colon cancer differed in terms of the length of the resected bowel and the area of mesentery, although the length of the vascular tie to the bowel wall was similar between CME and D3 specimens. The high rates of mesocolic plane surgery were demonstrated in the CME and D3 specimens.
EVALuna2:15164

Quantification of 24 circulating endocannabinoids, endocannabinoid-related compounds, and their phospholipid precursors in human plasma by UHPLC-MS/MS. - Röhrig, Waldemar; Achenbach, Susanne; Deutsch, Birgit; Pischetsrieder, Monika (Journal of Lipid Research, 2019)
Endocannabinoids and endocannabinoid-related compounds (ERCs) are involved in many physiological processes. They are released on demand from phosphoinositide and N-acylphosphatidyl ethanolamine (NAPE) precursors and comprise 2-monoacylglycerols (2-MGs) and FA ethanolamides (FEAs). Despite the abundance of advanced quantitative methods, however, their determined concentrations in blood plasma are inconsistent because 2-MGs and FEAs undergo artifactual de novo formation, chemical isomerization, and degradation during sample collection and storage. For a comprehensive survey of these compounds in blood and plasma, we have developed and validated an ultra-HPLC-MS/MS method to quantify 24 endocannabinoids, ERCs, and their phospholipid precursors. Immediate acidification of EDTA-blood to pH 5.8 blocked artifactual FEA formation for at least 4 h on ice. The 2-MGs were stabilized after plasma harvest with 0.5 M potassium thiocyanate at pH 4.7. FEA and MG plasma concentrations in six healthy volunteers ranged between 0.04-3.48 and 0.63-6.18 ng/ml, respectively. Interestingly, only 1-5% of circulating FEAs were present in their free form, while the majority was bound to NAPEs. Similarly, 97% of 2-arachidonoylglycerol (2-AG) was bound to a potential phosphoinositide pool. The herein-described stabilization and extraction methods may now be used to reliably and comprehensively quantify endocannabinoids, ERCs, and their phospholipid precursors in clinical studies.
Keywords: fatty acid ethanolamide; 2-arachidonoylglycerol; 2-monoacylglycerol; N-acylphosphatidyl ethanolamine; phosphatidyl ethanolamine; arachidonoyl phosphoinositid; Orlistat; blood; lipases; phospholipases

Quantitative Assessment of Intraoperative Laser Fluorescence Angiography With Indocyanine Green Predicts Early Graft Function After Kidney Transplantation - Gerken, Andreas L. H.; Nowak, Kai; Meyer, Alexander; Weiss, Christel; Krueger, Bernd; Nawroth, Nina; Karampinis, Ioannis; Heller, Katharina M.; Apel, Hendrik; Reissfelder, Christoph; Schwenke, Kay; Keese, Michael; et al. (Annals of Surgery, 2022)
Objective: This study was designed to demonstrate the predictive ability of quantitative indocyanine green (ICG) fluorescence angiography for the short-term postoperative outcome, the occurrence of delayed graft function (DGF), and long-term graft survival. Summary Background Data: DGF is a relevant problem after kidney transplantation; sufficient microperfusion of the allograft is crucial for postoperative organ function. Fluorescence angiography with ICG can serve as an intraoperative quality control of microperfusion. Methods: This prospective diagnostic study, conducted in 2 German transplantation centers from November 2015 to October 2018, included 128 consecutive kidney transplantations. Intraoperative assessment of the allograft microperfusion was performed by near-infrared fluorescence angiography with ICG; a software was used for quantitative analysis. The associations between perfusion parameters (eg, ICG Ingress) and donor, recipient, peri-procedural, and postoperative characteristics were evaluated. Results: DGF occurred in 23 (24%) kidney recipients from deceased donors. ICG Ingress (P = 0.0027), donor age (P = 0.0452), recipient age (P = 0.0139), and recipient body mass index (P = 0.0017) were associated with DGF. ICG Ingress correlated significantly with recipient age (r = -0.27662, P = 0.0016), cold and warm ischemia time (r = -0.25204, P = 0.0082; r = -0.19778, P = 0.0283), operating time (r = -0.32208, P = 0.0002), eGFR on postoperative days 1 (r =+0.22674, P = 0.0104) and 7 (r = +0.33189, P = 0.0001). The cutoff value for ICG Ingress was 106.23 AU with sensitivity of 78.3% and specificity of 80.8% (P < 0.0001) for the prediction of DGF. Conclusion: Fluorescence angiography with ICG allows intraoperative quantitative assessment of microperfusion during kidney transplantation. The parameter ICG Ingress reflects recipient and procedure characteristics and is able to predict the incidence of DGF.
CRIS-Team WoS Importer:2022-07-22

Quantitative assessment of microperfusion by indocyanine green angiography in kidney transplantation resembles chronic morphological changes in kidney specimens - Rother, Ulrich; Amann, Kerstin Ute; Adler, Werner; Nawroth, Nina; Karampinis, Ioannis; Keese, Michael; Manap, Serhat; Regus, Susanne; Meyer, Alexander; Porubsky, Stefan; Hilgers, Karl Friedrich; Krämer, Bernhard K.; et al. (Microcirculation, 2019)
OBJECTIVE: Indocyanine green fluorescence angiography enables a quantitative real-time perfusion assessment in kidney transplantation. The results of intraoperative microperfusion of the kidney allograft were compared to the renal chronicity score in pre-transplantation kidney biopsy specimens. The intrarenal resistance index was calculated by duplex sonography as a method of reference. METHODS: Seventy-seven patients with end stage renal disease undergoing kidney transplantation were prospectively included in two centers. Correlation analysis of chronic changes in kidney biopsy specimens and the ingress of ICG fluorescence signal were investigated. RESULTS: The results yielded a significantly negative correlation for the renal chronicity (r= -0.294, p=0.017) as well as the intestinal fibrosis and tubular atrophy score (r=-0.328, p=0.007). There was a significant inverse relationship between the ingress and the mean RI values of the upper pole of the kidney allograft. CONCLUSION: In summary, fluorescence angiography reflects preexisting morphological changes of the renal cortex. ICG angiography may serve as an alternative method for the assessment of microperfusion of the kidney allograft. This article is protected by copyright. All rights reserved.
EVALuna2:35427

Quantitative proteome profiling of lymph node-positive vs. -negative colorectal carcinomas pinpoints MX1 as a marker for lymph node metastasis - Croner, Roland S.; Stürzl, Michael; Rau, Tilman; Metodieva, Gergana; Geppert, Carol-Immanuel; Naschberger, Elisabeth; Lausen, Berthold; Metodiev, Metodi V. (International Journal of Cancer, 2014)
We used high-resolution mass spectrometry to measure the abundance of more than 9,000 proteins in 19 individually dissected colorectal tumors representing lymph node metastatic (n = 10) and nonmetastatic (n = 9) phenotypes. Statistical analysis identified MX1 and several other proteins as overexpressed in lymph node-positive tumors. MX1, IGF1-R and IRF2BP1 showed significantly different expression in immunohistochemical validation (Wilcoxon test p = 0.007 for IGF1-R, p = 0.04 for IRF2BP1 and p = 0.02 for MX1 at the invasion front) in the validation cohort. Knockout of MX1 by siRNA in cell cultures and wound healing assays provided additional evidence for the involvement of this protein in tumor invasion. The collection of identified and quantified proteins to our knowledge is the largest tumor proteome dataset available at the present. The identified proteins can give insights into the mechanisms of lymphatic metastasis in colorectal carcinoma and may act as prognostic markers and therapeutic targets after further prospective validation.
EVALuna2:6585