139th Congress of the German Society of Surgery (DGCH)

Abstract

Background: Barrett’s esophagus (BE), the result of chronic exposure of esophageal mucosa to acid exposure, predisposes to the development of esophageal adenocarcinoma (EAC). While the incidence of EAC is rapidly increasing, its prognosis remains poor, with a five-year survival rate of 20%. For advanced cancer stages, chemotherapy together with surgery is considered to be the standard in therapy. Consequently, the discovery of new molecular targets for an efficient characterization of EAC patients is necessary. CKAP4 has been attributed to be increased in various cancer entities and has a role in tumorigenesis. However, its role in EAC development and progression is widely unknown. Materials and Methods: In a Barrett’s esophagus, in vitro cell culture model of BE and EAC, CKAP4 expression levels were verified with qPCR and western blot. In OE33 and OE19 cells a knockdown of CKAP4-expression was done by siRNA for 48h and 72h. In siCKAP4 transfected cells FACS (apoptosis), western blot analysis, colony forming assays, spheroid formation and proliferation assays were performed. Using western blot, the impact of CKAP4-knockdown on the phosphorylation of Akt, MAP-Kinase, GSK3ß and ß-Catenin investigated. Furthermore, Ki67- and p21-mRNA-expression was analyzed in siCKAP4 cells using qPCR. Results: CKAP4 was present in all cell lines of the Barrett’s sequence (squamous epithelium, metaplasia, dysplasia CKAP4 OE19 OE33 Background: Adhesion molecules play a crucial role in tumor growth and metastasis. Histone deacetylase (HDAC) are responsible for epigenetic modifications even in cancer cells. Whether the inhibition of HDACs has an effect in the metastasis and intercellular Background: The HLA-genotype of a person defines the repertoire of peptides that can be presented to T cells. We aimed to determine if HLA-I homozygosity could translate in a smaller repertoire of tumour neoantigens potentially predisposing such individuals with a disadvantage to fight a nascent tumour. Materials and Methods: High-resolution HLA-genotyping combined with cancer EGA and nonsynonymous called used to predict high and moderate affinity binders the Epitope Data Base” and gene were performed Results: Frequency of HLA homozygosity in EGA patients Abstracts our Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with one of the lowest 5-year survival rates of all solid tumors. The determination of prognostic factors with PDAC is essential for predicting the outcomes and for identifying appropriate treatment strategies. Lymph node 8a is located above the pancreas head and was shown to have prognostic value for predicting severity in PDAC patients. The characteristic feature of lymph node 8a is the presence of abundant leucocytes representing both lymphoid and myeloid lineages. One major cellular compart-ment of lymph nodes are CD20+ B cells, which have been shown to be involved in the tumorigenesis of solid tumors. In this study, we sought to phenotype B cells, their subtypes and the IL3-producing B cells in lymph node 8a of PDAC patients and LN12b of patients undergoing laparoscopic cholecystectomy serving as controls. Materials and Methods: outcomes and developing novel therapy options in the field of pancreatic cancer. Background: The prognosis and outcome of colorectal cancer (CRC) patients is mostly determined by the development of distant metastasis. Tumor mouse models are common tools to study mechanisms of tumor initiation and progression. Unfortunately, no suitable mouse model to reliably model the development of sporadic distant metastasis of CRC in immunocompetent mice as 3D cell cultures of tumor cells, called “tumor spheroids” or “organoids” be derived from primary lesions of genetically modified mouse models. The aim of this work is to establish orthotopic transplantation models that can be used to study sporadic distant metastasis using novel syngenic CRC organoids in immunocompetent mice. Materials and Methods: Three different CRC organoid lines have been orthotopically injected into the submucosa of C57Bl/6 mice with different cell counts. The injected mice received a weekly follow up colonoscopy over three months to monitor the primary tumor development. The colon, lung and liver were harvested after three months and analysed by haematoxylin and eosin-staining to assess the primary lesion growth and distant metastasis. Results: Orthotopic implantation of 27 mice with three different syngenic CRC organoids resulted in 24 mice (88.8%) developing a primary tumor in the colon, two mice Background: Several ablative methods have been developed for the treatment of hepatic cancer in patients with unresectable tumor tissue as a bridging therapy to transplantation or in selected patients as combination with surgical resection. Recent studies and guidelines recommend radiofrequency Background: The x-linked inhibitor of apoptosis protein (XIAP) is a member of the IAP protein family which has frequently been shown to be upregulated in different cancer entities. Based on its ability to bind and to inhibit caspases, XIAP has been viewed as a promising target in cancer in order to enhance the cytotoxic activity of anti-cancer therapy. The initial therapeutic targeting strategies using small molecules designed to target XIAP (such as birinapant), however, failed to antagonize XIAP or consistently induce cytotoxic action. Independently, the notion is explored that the elevated XIAP expression observed in malignant tissues is, at least, not exclusively responsible for the resistance of tumor cells to cytostatic treatment; rather, the function of XIAP seems to be conducive to the process of malignant transformation and/or progression. Materials and Methods: We analysed Tisse-micro arrays stained against XIAP and correlated the intensity of tumor cell XIAP staining to patient survival. We furthermore crossed genetically engineered mice that express Cre under the control of an intestinal epithelial cell specific promoter (Villin-Cre) with mice that carry two XIAP floxed alleles resulting in intestine specific XIAP knock-out (IEC XIAP KO) mice and their control litter-mates. These mice underwent a colitis-associated adenoma protocol (by AOM/DSS treatment) to induce tumor formation in the distal mouse colon. Results: The absence of tumor cell XIAP expression is associated with long term survival in CRC patients. Epithelium-specific XIAP KO decreases tumor progression in AOM/DSS treated mice which is accompanied by reduced immune-cell infiltration to colonic adenoma/carcinoma. Additionally, IEC-specific XIAP KO significantly decelerated progression of adenoma to carcinoma compared to WT XIAP animals. Conclusion: Our data suggest XIAP as a strong prognostic factor in curable CRC. Targeting XIAP could offer a promising novel treatment strategy in CRC. Background: Colorectal cancer (CRC)-associated mortality is usually a result of distant metastasis rather than local disease. protein in the CRC to identify specific gene expression signatures of from CRC. Background: Pancreatic ductal adenocarcinoma (PDAC) Background: Sepsis is a grave clinical condition that causes millions of deaths worldwide. Despite extensive research efforts, the pathophysiology is still far from understood. A noticeable but and hitherto not studied phenomenon during sepsis is the correlation of reduced platelet count and decreased blood sphingosine-1-phosphate (S1P) levels with an increased disease severity. The major source of plasma S1P are erythrocytes, but platelets also secrete S1P after their activation. While S1P receptor type 4 (S1P 4 ) has been implicated in terminal megakaryocyte differentiation and platelet aggregation, the link between platelets and S1P during sepsis has not been investigated yet. The present work investigates the role of S1P 4 -mediated signaling on thrombus formation and disseminated intravascular coagulation (DIC). Materials and Methods: To investigate the role of S1P 4, a murine knock-out model ( s1pr 4 –/– ) has been used. Thrombus formation was studied using collagen-coated flow chamber assays and confocal microscopy in vitro . The impact of S1P 4 on platelet biology during polymicrobial abdominal sepsis was analyzed in a murine model of colon ascendens stent peritonitis (CASP). The extent of DIC was quantified using deep–learning. Transferability of results to human platelets was tested using pharmacological S1P 4 modulators in ex vivo aggregation assays on blood from healthy volunteers. Results: In vitro platelet aggregation of s1pr 4 –/– platelets was strikingly different from wildtype controls. Massively increased fibrinogen binding of s1pr 4 –/– platelets lead to accelerated and uncoordinated thrombus formation. During sepsis, increased hepatic DIC and reduced platelet counts were observed in s1pr 4 –/– animals. Concordantly, these mice exhibited increased organ fail-ure and mortality. Rapid aggregation could be observed in blood from healthy volunteers after treatment with a selective S1P 4 antagonist. Finally, application of a selective agonist for S1P 4 resulted in reduced aggregability of platelets in vitro . Conclusion: For the first time, we demonstrate a definitive mechanistic link between platelet function and S1P concentrations during sepsis. S1P 4 is identified as an important receptor mediating the effects of S1P on platelet function. It suppresses exuberant platelet activation, thereby ensuring coordinated thrombus formation during sepsis. The possibility of pharmacological modulation of S1P 4 mediated signaling in humans has been demonstrated. Further experiments to evaluate the therapeutic potential of S1P 4 agonists during sepsis are warranted. Background: Enteric glial cells (EGCs) modulate we confirmed our murine conserved gliosis genes. Our findings show that ME-Macs therapies motility Background: Tertiary lymphoid structures (TLS) are gaining attention in the recent years as secondary lymphoid or