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 - TY - JOUR A1 - Schierer, Stefan A1 - Ostalecki, Christian A1 - Zinser, Elisabeth A1 - Lamprecht, Ricarda A1 - Plosnita, Bianca A1 - Stich, Lena A1 - Doerrie, Jan A1 - Lutz, Manfred B A1 - Schuler, Gerold A1 - Baur, Andreas S T1 - Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC JF - Life Science Alliance N2 - During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell-activating and IL-12p70-secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation. KW - medical research KW - immunology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228587 VL - 1 IS - 6 ER - TY - JOUR A1 - Lutz, Manfred B. A1 - Strobl, Herbert A1 - Schuler, Gerold A1 - Romani, Nikolaus T1 - GM-CSF monocyte-derived cells and Langerhans cells as part of the dendritic cell family JF - Frontiers in Immunology N2 - Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14\(^{+}\) peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte-derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function. KW - macrophages KW - dendritic cells KW - GM-CSF KW - monocytes KW - Langerhans cells Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158730 VL - 8 IS - 1388 ER -