TY - JOUR A1 - Hohenauer, Tobias A1 - Berking, Carola A1 - Schmidt, Andreas A1 - Haferkamp, Sebastian A1 - Senft, Daniela A1 - Kammerbauer, Claudia A1 - Fraschka, Sabine A1 - Graf, Saskia Anna A1 - Irmler, Martin A1 - Beckers, Johannes A1 - Flaig, Michael A1 - Aigner, Achim A1 - Höbel, Sabrina A1 - Hoffmann, Franziska A1 - Hermeking, Heiko A1 - Rothenfusser, Simon A1 - Endres, Stefan A1 - Ruzicka, Thomas A1 - Besch, Robert T1 - The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival JF - EMBO Molecular Medicine N2 - Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis. KW - oncogene-induced senescence KW - BRN-3A KW - DNA KW - DNA damage KW - tumourigenesis KW - P53 KW - in-vitro KW - neural crest factors KW - family KW - apoptosis KW - melanoma KW - BRAF mutations KW - domain Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122193 SN - 1757-4676 VL - 5 ER - TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Hohberger, Bettina A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus T1 - Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis JF - Cancers N2 - Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ\(^2\) tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - liver metastasis KW - treatment resistance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242603 SN - 2072-6694 VL - 13 IS - 13 ER - TY - JOUR A1 - Lodde, Georg A1 - Forschner, Andrea A1 - Hassel, Jessica A1 - Wulfken, Lena M. A1 - Meier, Friedegund A1 - Mohr, Peter A1 - Kähler, Katharina A1 - Schilling, Bastian A1 - Loquai, Carmen A1 - Berking, Carola A1 - Hüning, Svea A1 - Schatton, Kerstin A1 - Gebhardt, Christoffer A1 - Eckardt, Julia A1 - Gutzmer, Ralf A1 - Reinhardt, Lydia A1 - Glutsch, Valerie A1 - Nikfarjam, Ulrike A1 - Erdmann, Michael A1 - Stang, Andreas A1 - Kowall, Bernd A1 - Roesch, Alexander A1 - Ugurel, Selma A1 - Zimmer, Lisa A1 - Schadendorf, Dirk A1 - Livingstone, Elisabeth T1 - Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients JF - Cancers N2 - Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI. KW - melanoma KW - adjuvant treatment KW - checkpoint blocker KW - targeted therapy KW - BRAF KW - PD-1 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239583 SN - 2072-6694 VL - 13 IS - 10 ER - TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus V. T1 - Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity JF - Cancers N2 - Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - re-induction KW - treatment resistance KW - toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254814 SN - 2072-6694 VL - 14 IS - 3 ER - TY - JOUR A1 - Schön, Michael P. A1 - Berking, Carola A1 - Biedermann, Tilo A1 - Buhl, Timo A1 - Erpenbeck, Luise A1 - Eyerich, Kilian A1 - Eyerich, Stefanie A1 - Ghoreschi, Kamran A1 - Goebeler, Matthias A1 - Ludwig, Ralf J. A1 - Schäkel, Knut A1 - Schilling, Bastian A1 - Schlapbach, Christoph A1 - Stary, Georg A1 - von Stebut, Esther A1 - Steinbrink, Kerstin T1 - COVID‐19 and immunological regulations – from basic and translational aspects to clinical implications JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - The COVID‐19 pandemic caused by SARS‐CoV‐2 has far‐reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS‐CoV‐2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS‐CoV‐2/COVID‐19 with mediators of the acute phase of inflammation (TNF, IL‐1, IL‐6), type 1 and type 17 immune responses (IL‐12, IL‐23, IL‐17, IL‐36), type 2 immune reactions (IL‐4, IL‐13, IL‐5, IL‐31, IgE), B‐cell immunity, checkpoint regulators (PD‐1, PD‐L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non‐specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte‐mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS‐CoV‐2/COVID‐19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID‐19 pandemic; some even appear to alleviate COVID‐19. KW - COVID-19 KW - SARS-CoV-2 KW - immunology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218205 VL - 18 IS - 8 SP - 795 EP - 807 ER - TY - JOUR A1 - Haist, Maximilian A1 - Stege, Henner A1 - Lang, Berenice Mareen A1 - Tsochataridou, Aikaterini A1 - Salzmann, Martin A1 - Mohr, Peter A1 - Schadendorf, Dirk A1 - Ugurel, Selma A1 - Placke, Jan-Malte A1 - Weichenthal, Michael A1 - Gutzmer, Ralf A1 - Leiter, Ulrike A1 - Kaatz, Martin A1 - Haferkamp, Sebastian A1 - Berking, Carola A1 - Heppt, Markus A1 - Tschechne, Barbara A1 - Schummer, Patrick A1 - Gebhardt, Christoffer A1 - Grabbe, Stephan A1 - Loquai, Carmen T1 - Response to first-line treatment with immune-checkpoint inhibitors in patients with advanced cutaneous squamous cell carcinoma: a multicenter, retrospective analysis from the German ADOReg registry JF - Cancers N2 - Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates. KW - advanced cutaneous squamous cell carcinoma KW - checkpoint inhibitor therapy KW - cemiplimab KW - immunosuppression KW - response durability KW - real-world data Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297506 SN - 2072-6694 VL - 14 IS - 22 ER -