TY - JOUR A1 - Banales, Jesus M. A1 - Cardinale, Vincenzo A1 - Carpino, Guido A1 - Marzioni, Marco A1 - Andersen, Jesper B. A1 - Invernizzi, Pietro A1 - Lind, Guro E. A1 - Folseraas, Trine A1 - Forbes, Stuart J. A1 - Fouassier, Laura A1 - Geier, Andreas A1 - Calvisi, Diego F. A1 - Mertens, Joachim C. A1 - Trauner, Michael A1 - Benedetti, Antonio A1 - Maroni, Luca A1 - Vaquero, Javier A1 - Macias, Rocio I. R. A1 - Raggi, Chiara A1 - Perugorria, Maria J. A1 - Gaudio, Eugenio A1 - Boberg, Kirsten M. A1 - Marin, Jose J. G. A1 - Alvaro, Domenico T1 - Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) JF - Nature Reviews Gastroenterology & Hepatology N2 - Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted. KW - primary sclerosing cholangitis KW - growth-factor-receptor KW - biliary-tract cancer KW - epithelial-mesenchymal transition KW - fine-needle-aspiration KW - human intrahepatic cholangiocarcinoma KW - induce cyclooxygenase-2 expression KW - human cholangiocellular carcinoma KW - nucleoside transporter KW - hepatic stellate cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189077 VL - 13 IS - 5 ER - TY - JOUR A1 - Raselli, Tina A1 - Hearn, Tom A1 - Wyss, Annika A1 - Atrott, Kirstin A1 - Peter, Alain A1 - Frey-Wagner, Isabelle A1 - Spalinger, Marianne R. A1 - Maggio, Ewerton M. A1 - Sailer, Andreas W. A1 - Schmitt, Johannes A1 - Schreiner, Philipp A1 - Moncsek, Anja A1 - Mertens, Joachim A1 - Scharl, Michael A1 - Griffiths, William J. A1 - Bueter, Marco A1 - Geier, Andreas A1 - Rogler, Gerhard A1 - Wang, Yuqin A1 - Misselwitz, Benjamin T1 - Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis JF - Journal of Lipid Research N2 - Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH. KW - nonalcoholic fatty liver disease KW - Epstein-Barr virus-induced gene 2 KW - cholesterol 25 hydroxylase KW - 25-hydroxycholesterol 7 alpha-hydroxylase KW - mouse feeding model Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225004 VL - 60 IS - 7 ER - TY - JOUR A1 - Hecht, Markus A1 - Meier, Friedegund A1 - Zimmer, Lisa A1 - Polat, Bülent A1 - Loquai, Carmen A1 - Weishaupt, Carsten A1 - Forschner, Andrea A1 - Gutzmer, Ralf A1 - Utikal, Jochen S. A1 - Goldinger, Simone M. A1 - Geier, Michael A1 - Hassel, Jessica C. A1 - Balermpas, Panagiotis A1 - Kiecker, Felix A1 - Rauschenberg, Ricarda A1 - Dietrich, Ursula A1 - Clemens, Patrick A1 - Berking, Carola A1 - Grabenbauer, Gerhard A1 - Schadendorf, Dirk A1 - Grabbe, Stephan A1 - Schuler, Gerold A1 - Fietkau, Rainer A1 - Distel, Luitpold V. A1 - Heinzerling, Lucie T1 - Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients JF - British Journal of Cancer N2 - Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002). Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed. KW - radiation KW - radiotherapy KW - BRAF KW - vemurafenib KW - dabrafenib Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227970 VL - 118 ER -