Das Mikroenvironment des Follikulären Lymphoms zum Zeitpunkt der Primärdiagnose und des Rezidivs

Introduction: Follicular lymphoma (FL) presents the second common non-Hodgkin lymphoma in the western world. FL histological imitate the growth pattern and the cytology of reactive follicles. The translocation t(14;18) is characteristic. The translocation juxtaposes the anti-apoptotic protein BCL2 and the high expressed immunoglobulin heavy-chain gene in B-cells, thus it leads to an overexpression of BCL2- genes. The translocation is not sufficient to develop a FL, other secondary genetic hits are necessary to transform a t(14;18)-positive B-cell into a neoplastic cell. The clinical course is mostly indolent, except the cases of FL that experience a histological transformation to diffuse large B-cell lymphoma, which leads to a poorer prognosis. Within the tumor FL shows numerous non-neoplastic bystander cells. This so-called microenvironment is associated with the prognosis in its composition. A composition with predominant macrophages is associated with a favorable prognosis, whereas a dominance of dendritic cells is associated with an unfavorable prognosis. These results are still controversial. In previous studies the research group showed that the composition of the microenvironment correlates with the stage of disease at the point of diagnosis. In this study we research if changes in the microenvironment of FL are detectable during the course of the disease. We especially examine whether there is a transformation of the microenvironment from a physiological imitating microenvironment to a neoplastic specific microenvironment. Methods/Material: Sequential biopsies from patients were accessed, by examining the tissue at the primary diagnosis and the relapse. Therefore Immunohistochemical staining and analysis were performed on formalin fixed and paraffin-embedded samples from 20 patients who we identified in the files of the Lymph Node Regisrty. Immunohistochemical staining was done for specific compartments of the microenvironment e.g. Forkhead Box Protein 3 (FoxP3) and Programmed Death-1 (PD-1) to detect regulatory T-cells or follicular T-helper cells. Manual counting or digital image analysis assessed the content of positively stained cells. Furthermore by the means of NanoString digital gene expression the FL microenvironment will be analysed. The RNA was isolated with the ExpressArt FFPE Clear RNA ready kit from AmpTec. Results: Comparing primary diagnosis and relapses the Immunohistochemical analysis yielded no change in the composition of the microenvironment. Rudimentary two tendencies could be assumed, but it was not yet possible to state these tendencies precisely as the cohort is too small. The Validation of the NanoString/nCounter Technologies is currently ongoing. First results show no striking difference between primary diagnoses and relapse gene expressions. Conclusion: To strengthen our assumption the cohort got enlarged and the validation is ongoing

Preoperative TIPS prevents the development of postoperative acute-on-chronic liver failure in patients with high CLIF-C AD score

Background & Aims: Acute-on-chronic liver failure (ACLF) is a syndrome associated with organ failure and high short-term mortality. Recently, the role of surgery as a precipitating event for ACLF has been characterised. However, the impact of preoperative transjugular intrahepatic portosystemic shunt (TIPS) placement on ACLF development in patients with cirrhosis undergoing surgery has not been investigated yet. Methods: A total of 926 patients (363 with cirrhosis undergoing surgery and 563 patients with TIPS) were screened. Forty-five patients with preoperative TIPS (TIPS group) were 1:1 propensity matched to patients without preoperative TIPS (no-TIPS group). The primary endpoint was the development of ACLF within 28 and 90 days after surgery. The secondary endpoint was 1-year mortality. Results were confirmed by a differently 1:2 matched cohort (n = 176). Results: Patients in the no-TIPS group had significantly higher rates of ACLF within 28 days (29 vs. 9%; p = 0.016) and 90 days (33 vs. 13%; p = 0.020) after surgery as well as significantly higher 1-year mortality (38 vs. 18%; p = 0.023) compared with those in the TIPS group. Surgery without preoperative TIPS and Chronic Liver Failure Consortium–Acute Decompensation (CLIF-C AD) score were independent predictors for 28- and 90-day ACLF development and 1-year mortality after surgery, especially in patients undergoing visceral surgery. In the no-TIPS group, a CLIF-C AD score of >45 could be identified as cut-off for patients at risk for postoperative ACLF development benefiting from TIPS. Conclusions: This study suggests that preoperative TIPS may result in lower rates of postoperative ACLF development especially in patients undergoing visceral surgery and with a CLIF-C AD score above 45. Lay summary: Acute-on-chronic liver failure (ACLF) is a syndrome that is associated with high short-term mortality. Surgical procedures are a known precipitating event for ACLF. This study investigates the role of preoperative insertion of a transjugular intrahepatic portosystemic shunt (TIPS) on postoperative mortality and ACLF development. Patients with TIPS insertion before a surgical procedure exhibit improved postoperative survival and lower rates of postoperative ACLF, especially in patients undergoing visceral surgery and with a high CLIF-C AD prognostic score. Thus, this study suggests preoperative TIPS insertion in those high-risk patients

Extrahepatic surgery in cirrhosis significantly increases portal pressure in preclinical animal models

Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model. Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed. Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model. Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis