170 results on '"Ugurel, S."'
Search Results
2. Sex differences and its impact on treatment outcomes of advanced melanoma in Germany – a DeCOG study on 2032 patients of the multicenter prospective skin cancer registry ADOREG
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Leven, A.-S., primary, Peters, T., additional, Rajcsanyi, L.S., additional, Weichenthal, M., additional, Mohr, P., additional, Meier, F., additional, von Wasielewski, I., additional, Gutzmer, R., additional, Utikal, J., additional, Terheyden, P., additional, Herbst, R., additional, Haferkamp, S., additional, Pföhler, C., additional, Leiter, U., additional, Kreuter, A., additional, Gebhardt, C., additional, Weishaupt, C., additional, Grabbe, S., additional, Debus, D., additional, Hassel, J.C., additional, Tasdogan, A., additional, Placke, J.-M., additional, Zimmer, L., additional, Livingstone, E., additional, Schadendorf, D., additional, Roesch, A., additional, Hinney, A., additional, and Ugurel, S., additional
- Published
- 2024
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3. 787O Adjuvant immunotherapy with nivolumab (NIVO) versus observation in completely resected Merkel cell carcinoma (MCC): Disease-free survival (DFS) results from ADMEC-O, a randomized, open-label phase II trial
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Becker, J.C., primary, Ugurel, S., additional, Leiter-Stoppke, U., additional, Meier, F., additional, Gutzmer, R., additional, Haferkamp, S., additional, Zimmer, L., additional, Livingstone, E., additional, Eigentler, T., additional, Hauschild, A., additional, Kiecker, F., additional, Hassel, J.C., additional, Mohr, P., additional, Fluck, M., additional, Thomas, I., additional, Garzarolli, M., additional, Grimmelmann, I., additional, Drexler, K., additional, Eckhardt, S., additional, and Schadendorf, D., additional
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- 2022
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4. Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.
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Müller-Jensen, L, Zierold, S, Versluis, JM, Boehmerle, W, Huehnchen, P, Endres, M, Mohr, R, Compter, A, Blank, CU, Hagenacker, T, Meier, F, Reinhardt, L, Gesierich, A, Salzmann, M, Hassel, JC, Ugurel, S, Zimmer, L, Banks, P, Spain, L, Soon, JA, Enokida, T, Tahara, M, Kähler, KC, Seggewiss-Bernhardt, R, Harvey, C, Long, GV, Schöberl, F, von Baumgarten, L, Hundsberger, T, Schlaak, M, French, LE, Knauss, S, Heinzerling, LM, Müller-Jensen, L, Zierold, S, Versluis, JM, Boehmerle, W, Huehnchen, P, Endres, M, Mohr, R, Compter, A, Blank, CU, Hagenacker, T, Meier, F, Reinhardt, L, Gesierich, A, Salzmann, M, Hassel, JC, Ugurel, S, Zimmer, L, Banks, P, Spain, L, Soon, JA, Enokida, T, Tahara, M, Kähler, KC, Seggewiss-Bernhardt, R, Harvey, C, Long, GV, Schöberl, F, von Baumgarten, L, Hundsberger, T, Schlaak, M, French, LE, Knauss, S, and Heinzerling, LM
- Abstract
Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.
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- 2022
5. Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial
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Egberts, F., Gutzmer, R., Ugurel, S., Becker, J.C., Trefzer, U., Degen, A., Schenck, F., Frey, L., Wilhelm, T., Hassel, J.C., Schadendorf, D., Livingstone, E., Mauch, C., Garbe, C., Berking, C., Rass, K., Mohr, P., Kaehler, K.C., Weichenthal, M., and Hauschild, A.
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- 2011
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6. 1079P Comparison of effectiveness and safety of nivolumab monotherapy or in combination therapy with ipilimumab in therapy-naïve and pretreated patients with advanced melanoma within the German noninterventional study NICO
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Gutzmer, R., primary, Eigentler, T., additional, Mohr, P., additional, Weichenthal, M., additional, Dücker, P., additional, Gebhardt, C., additional, Göppner, D., additional, Grimmelmann, I., additional, Haferkamp, S., additional, Kähler, K.C., additional, Meier, F., additional, Pföhler, C., additional, Sickmann, T., additional, Sindrilaru, A., additional, Terheyden, P., additional, Ugurel, S., additional, Ulrich, J., additional, Utikal, J., additional, Weishaupt, C., additional, and Schadendorf, D., additional
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- 2021
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7. A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival
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Ugurel, S., Loquai, C., Kähler, K., Hassel, J., Berking, C., Zimmer, L., Haubitz, I., Satzger, I., Müller-Brenne, T., Mikhaimer, N. C., Becker, J. C., Kilian, K. J., Schadendorf, D., Heinzerling, L., Kaatz, M., Utikal, J., Göppner, D., Pföhler, C., Pflugfelder, A., Mössner, R., and Gutzmer, R.
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- 2015
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8. Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
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Spieth, K., Kaufmann, R., Dummer, R., Garbe, C., Becker, J.C., Hauschild, A., Tilgen, W., Ugurel, S., Beyeler, M., Bröcker, E.B., Kaehler, K.C., Pföhler, C., Gille, J., Leiter, U., and Schadendorf, D.
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- 2008
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9. Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study
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Stege, H. M., primary, Haist, M., additional, Schultheis, S., additional, Fleischer, M. I., additional, Mohr, P., additional, Ugurel, S., additional, Terheyden, P., additional, Thiem, A., additional, Kiecker, F., additional, Leiter, U., additional, Becker, J. C., additional, Meissner, M., additional, Kleeman, J., additional, Pföhler, C., additional, Hassel, J., additional, Grabbe, S., additional, and Loquai, C., additional
- Published
- 2021
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10. Real World-Daten zur Anwendung von Nivolumab (Nivo) als Monotherapie oder in Kombination mit Ipilimumab (Nivo+Ipi) in der Behandlung des fortgeschrittenen Melanoms: Zwischenergebnisse der nicht-interventionellen Studie NICO [Poster Abstract]
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Ugurel, S., Satzger, I., Eigentier, T., Mohr, P., Göppner, D., Herber, M., Herbst, R., Kähler, K. C., Meier, F., Meiß, F., Pföhler, C., Sachse, M. M., Schneider, S. W., Terheyden, P., Ulrich, J., Utikal, J. S., Welzel, Julia, Schadendorf, D., and Gutzmer, R.
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ddc:610 - Published
- 2020
11. GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma
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Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., Griewank, K. G., Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., and Griewank, K. G.
- Abstract
Background GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. Objectives To characterize these tumours in terms of clinical behaviour and genetic characteristics. Methods Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. Results We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). Conclusions Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanom
- Published
- 2020
12. Agranulocytosis with Immune Checkpoint-Blockade - a retrospective, multicenter Evaluation
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Zaremba, A., Martaki, A., Salzmann, M., Baroudjian, B., Sachse, M. M., Gesierich, A., Reinhardt, L., Meier, F., Hassel, J. C., Ugurel, S., Roesch, A., Schadendorf, D., Livingstone, E., Broeckelmann, P., Kramer, R., Heinzerling, L., Zimmer, L., Zaremba, A., Martaki, A., Salzmann, M., Baroudjian, B., Sachse, M. M., Gesierich, A., Reinhardt, L., Meier, F., Hassel, J. C., Ugurel, S., Roesch, A., Schadendorf, D., Livingstone, E., Broeckelmann, P., Kramer, R., Heinzerling, L., and Zimmer, L.
- Published
- 2020
13. The diagnostic Significance of CT-controlled Puncture in Skin Cancer Patients
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Franklin, C., Wetter, A., Baba, H. A., Cosgarea, I., Mauch, C., Livingstone, E., Zimmer, L., Schadendorf, D., Ugurel, S., Franklin, C., Wetter, A., Baba, H. A., Cosgarea, I., Mauch, C., Livingstone, E., Zimmer, L., Schadendorf, D., and Ugurel, S.
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- 2020
14. SERIO - Side Effect Registry Immuno-Oncology Side Effect Registry for rare, severe and complex Side Effects of Immunotherapy
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Kramer, R., Mentzer, D., Erdmann, M., Knauss, S., Broeckelmann, P. J., Hassel, J. C., Ugurel, S., Pavel, M., Nickel, F. T., Landendinger, M., Fuchs, F., Meidenbauer, N., Jefremow, A., Manger, B., Gutzmer, R., Loquai, C., Kaehler, K., Zimmer, L., Berking, C., Keller-Stanislawski, B., Heinzerling, L., Kramer, R., Mentzer, D., Erdmann, M., Knauss, S., Broeckelmann, P. J., Hassel, J. C., Ugurel, S., Pavel, M., Nickel, F. T., Landendinger, M., Fuchs, F., Meidenbauer, N., Jefremow, A., Manger, B., Gutzmer, R., Loquai, C., Kaehler, K., Zimmer, L., Berking, C., Keller-Stanislawski, B., and Heinzerling, L.
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- 2020
15. Preclinical and clinical assessment of immune checkpoint inhibitor-associated left ventricular dysfunction
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Michel, L, primary, Hendgen-Cotta, U.B, additional, Mincu, R.I, additional, Helfrich, I, additional, Korste, S, additional, Mrotzek, S.M, additional, Rischpler, C, additional, Herrmann, K, additional, Ugurel, S, additional, Zimmer, L, additional, Coman, C, additional, Ahrends, R, additional, Schadendorf, D, additional, Rassaf, T, additional, and Totzeck, M, additional
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- 2020
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16. CD4+CD7− leukemic T cells from patients with Sézary syndrome are protected from galectin-1-triggered T cell death
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Rappl, G, Abken, H, Muche, JM, Sterry, W, Tilgen, W, André, S, Kaltner, H, Ugurel, S, Gabius, H-J, and Reinhold, U
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- 2002
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17. Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study
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Schadendorf, D., Hauschild, A., Ugurel, S., Thoelke, A., Egberts, F., Kreissig, M., Linse, R., Trefzer, U., Vogt, T., Tilgen, W., Mohr, P., and Garbe, C.
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- 2006
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18. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG
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Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F.O., Enk, A., Bröcker, E.-B., Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tüttenberg, A., Becker, J.C., Keikavoussi, P., Kämpgen, E., and Schuler, G.
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- 2006
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19. 1104P Nivolumab (NIVO) monotherapy or combination therapy with ipilimumab (NIVO+IPI) in advanced melanoma patients with brain metastases: Real-world evidence from the German non-interventional study NICO
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Gutzmer, R., primary, Eigentler, T., additional, Mohr, P., additional, Weichenthal, M., additional, Dücker, P., additional, Gebhardt, C., additional, Göppner, D., additional, Haferkamp, S., additional, Kähler, K., additional, Meier, F., additional, Pföhler, C., additional, Satzger, I., additional, Sickmann, T., additional, Sindrilaru, A., additional, Terheyden, P., additional, Ugurel, S., additional, Ulrich, J., additional, Utikal, J., additional, Weishaupt, C., additional, and Schadendorf, D., additional
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- 2020
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20. Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma
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Ugurel, S., primary, Schadendorf, D., additional, Horny, K., additional, Sucker, A., additional, Schramm, S., additional, Utikal, J., additional, Pföhler, C., additional, Herbst, R., additional, Schilling, B., additional, Blank, C., additional, Becker, J.C., additional, Paschen, A., additional, Zimmer, L., additional, Livingstone, E., additional, Horn, P.A., additional, and Rebmann, V., additional
- Published
- 2020
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21. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG
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Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F. O., Enk, A., Bröcker, E.-B, Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tüttenberg, A., Becker, J. C., Keikavoussi, P., Kämpgen, E., and Schuler, G.
- Abstract
Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index
- Published
- 2017
22. Interleukin-2 and Checkpoint Inhibition as a successful Therapy Sequence for metastatic Melanoma: Case Report and retrospective Analysis in 52 Patients
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Cosgarea, I, Zimmer, L., Weide, B., Gutzmer, R., Heinzerling, L., Weishaupt, C., Pfoehler, C., Gesierich, A., Herbst, R., Kaehler, K., Schlaak, M., Loquai, C., Utikal, J., Kaatz, M., Berking, C., Kreuter, A., Ulrich, J., Mohr, P., Dippel, E., Livingstone, E., Weichenthal, M., Schadendorf, D., Ugurel, S., Cosgarea, I, Zimmer, L., Weide, B., Gutzmer, R., Heinzerling, L., Weishaupt, C., Pfoehler, C., Gesierich, A., Herbst, R., Kaehler, K., Schlaak, M., Loquai, C., Utikal, J., Kaatz, M., Berking, C., Kreuter, A., Ulrich, J., Mohr, P., Dippel, E., Livingstone, E., Weichenthal, M., Schadendorf, D., and Ugurel, S.
- Published
- 2017
23. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG
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Schadendorf, D, Ugurel, S, Schuler-Thurner, B, et al, University of Zurich, and Schadendorf, D
- Subjects
2720 Hematology ,610 Medicine & health ,2730 Oncology ,142-005 142-005 - Published
- 2006
24. Denileukin Diftitox plus Total Skin Electron Beam Radiation in Patients with Treatment-refractory Cutaneous T-cell Lymphoma (Mycosis Fungoides): Report of Four Cases
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Buder, K, primary, Müller, P, additional, Beckmann, G, additional, Ugurel, S, additional, Bröcker, E, additional, and Becker, J, additional
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- 2014
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25. Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the dermatologic cooperative oncology group (DeCOG)
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Spieth, K, Kaufmann, R, Dummer, R, Garbe, C, Becker, J C, Hauschild, A, Tilgen, W, Ugurel, S, Beyeler, M, Bröcker, E B, Kaehler, K C, Pföhler, C, Gille, J, Leiter, U, Schadendorf, D, Spieth, K, Kaufmann, R, Dummer, R, Garbe, C, Becker, J C, Hauschild, A, Tilgen, W, Ugurel, S, Beyeler, M, Bröcker, E B, Kaehler, K C, Pföhler, C, Gille, J, Leiter, U, and Schadendorf, D
- Abstract
BACKGROUND: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNalpha-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. PATIENTS AND METHODS: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 mug peg-IFNalpha-2b s.c. per week and oral TMZ 200 mg/m(2) (days 1-5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. RESULTS: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. CONCLUSIONS: The efficacy of TMZ plus peg-IFNalpha-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNalpha-2b seems to be similar to non-peg-IFN when combined with TMZ.
- Published
- 2008
26. Antitumoral action of 2-deoxy-D-glucose tetraacetate in human melanoma cells
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Reinhold, Uwe, Ugurel, S, Tilgen, W, Kadiata, Marcel, Olivares Fontt, Elizabeth, Bakkali Nadi, Abdellatif, Malaisse, Willy, Reinhold, Uwe, Ugurel, S, Tilgen, W, Kadiata, Marcel, Olivares Fontt, Elizabeth, Bakkali Nadi, Abdellatif, and Malaisse, Willy
- Abstract
info:eu-repo/semantics/published
- Published
- 2000
27. Lack of clinical efficacy of imatinib in metastatic melanoma
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Ugurel, S, primary, Hildenbrand, R, additional, Zimpfer, A, additional, La Rosée, P, additional, Paschka, P, additional, Sucker, A, additional, Keikavoussi, P, additional, Becker, J C, additional, Rittgen, W, additional, Hochhaus, A, additional, and Schadendorf, D, additional
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- 2005
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28. Dose-dependent severe cutaneous reactions to imatinib
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Ugurel, S, primary, Hildenbrand, R, additional, Dippel, E, additional, Hochhaus, A, additional, and Schadendorf, D, additional
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- 2003
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29. The CD7− subset of CD4+ memory T cells is prone to accelerated apoptosis that is prevented by interleukin-15 (IL-15)
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Rappl, G, primary, Abken, H, additional, Hasselmann, D O, additional, Tilgen, W, additional, Ugurel, S, additional, and Reinhold, U, additional
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- 2001
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30. Dacarbazine and interferon α with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG)
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Hauschild, A, primary, Garbe, C, additional, Stolz, W, additional, Ellwanger, U, additional, Seiter, S, additional, Dummer, R, additional, Ugurel, S, additional, Sebastian, G, additional, Nashan, D, additional, Linse, R, additional, Achtelik, W, additional, Mohr, P, additional, Kaufmann, R, additional, Fey, M, additional, Ulrich, J, additional, and Tilgen, W, additional
- Published
- 2001
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31. CD4+CD7- leukemic T cells from patients with Sézary syndrome are protected from galectin-1-triggered T cell death.
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Rappl, G, Abken, H, Muche, J M, Sterry, W, Tilgen, W, André, S, Kaltner, H, Ugurel, S, Gabius, H-J, and Reinhold, U
- Subjects
T cells ,APOPTOSIS ,TUMORS - Abstract
In early stages of cutaneous T cell lymphoma (Sézary syndrome) both CD4[SUP+]CD7[SUP-] and CD4[SUP+]CD7[SUP+] T cells clonally expand whereas in late stages of the disease CD7[SUP-] cells are predominant in number, giving rise to the question whether CD7[SUP-]T cells have a survival advantage in the skin. Galectin-1, a cell-bound lectin, was recently reported to trigger apoptosis in activated CD7[SUP+] T cells. Here, we demonstrate that in contrast to activated CD7[SUP+] T cells, quiescent and activated CD69[SUP+]CD7[SUP-] T cells from healthy donors and from Sézary patients are resistant to galectin-1-mediated cell death. CD7[SUP-] T cells are apoptosis-resistant even during coculture with IFN-γ-stimulated endothelial cells that constitutively express galectin-1 in high amounts. These data imply that resistance of CD7[SUP-] T cells to galectin-1-induced apoptosis may contribute to the accumulation of CD7[SUP-] Sézary T cells during progression of the disease. [ABSTRACT FROM AUTHOR]
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- 2002
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32. The CD7- subset of CD4+ memory T cells is prone to accelerated apoptosis that is prevented by interleukin-15 (IL-15).
- Author
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Rappl, G, Abken, H, Hasselmann, D O, Tilgen, W, Ugurel, S, and Reinhold, U
- Subjects
T cells ,APOPTOSIS - Abstract
The CD7[sup -] subset of CD4[sup +] T cells reflects a stable differentiation state of post-thymic helper T cells with CD45R0[sup +]CD45RA[sup -] 'memory' phenotype. Here we report that CD4[sup +]CD7[sup -] T cells are prone to increased spontaneous apoptosis in vitro compared to CD4[sup +]CD7[sup +] T cells. Spontaneous apoptosis is prevented by IL-15, but not by IL-2. Moreover, IL-15 increases Bcl-2 and decreases CD95/Fas expression of CD7[sup -], but not of CD7[sup +] T cells. Because IL-15 is physiologically not secreted but expressed in a membranebound form, we cocultured T cells with TNF-α stimulated fibroblasts that expose membrane IL-15. TNF-α stimulated fibroblasts rescue CD4[sup +]CD7[sup -] Tcells from apoptosis whereas unstimulated fibroblasts do not. Rescue from apoptosis requires cell-cell contact and is abolished by addition of neutralizing antibodies to IL-15. We conclude that membrane IL-15 prevents accelerated apoptosis of CD4[sup +]CD7[sup -] T cells. This mechanism may contribute to accumulation of CD7[sup -] T cells in chronic inflammatory skin lesions. [ABSTRACT FROM AUTHOR]
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- 2001
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33. Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
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Spieth, K., Kaufmann, R., Dummer, R., Garbe, C., Becker, J. C., Hauschild, A., Tilgen, W., Ugurel, S., Beyeler, M., Bröcker, E. B., Kaehler, K. C., Pföhler, C., Gille, J., Leiter, U., Schadendorf, D., Spieth, K., Kaufmann, R., Dummer, R., Garbe, C., Becker, J. C., Hauschild, A., Tilgen, W., Ugurel, S., Beyeler, M., Bröcker, E. B., Kaehler, K. C., Pföhler, C., Gille, J., Leiter, U., and Schadendorf, D.
- Abstract
Background: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNα-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. Patients and methods: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 μg peg-IFNα-2b s.c. per week and oral TMZ 200 mg/m2 (days 1-5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. Results: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. Conclusions: The efficacy of TMZ plus peg-IFNα-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNα-2b seems to be similar to non-peg-IFN when combined with TMZ
34. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG
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Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F. O., Enk, A., Bröcker, E.-B, Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tüttenberg, A., Becker, J. C., Keikavoussi, P., Kämpgen, E., Schuler, G., Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F. O., Enk, A., Bröcker, E.-B, Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tüttenberg, A., Becker, J. C., Keikavoussi, P., Kämpgen, E., and Schuler, G.
- Abstract
Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines
35. Single-cell RNA and T-cell receptor sequencing unveil mycosis fungoides heterogeneity and a possible gene signature.
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Srinivas N, Peiffer L, Horny K, Lei KC, Buus TB, Kubat L, Luo M, Yin M, Spassova I, Sucker A, Farahpour F, Kehrmann J, Ugurel S, Livingstone E, Gambichler T, Ødum N, and Becker JC
- Abstract
Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL). Comprehensive analysis of MF cells in situ and ex vivo is complicated by the fact that is challenging to distinguish malignant from reactive T cells with certainty., Methods: To overcome this limitation, we performed combined single-cell RNA (scRNAseq) and T-cell receptor TCR sequencing (scTCRseq) of skin lesions of cutaneous MF lesions from 12 patients. A sufficient quantity of living T cells was obtained from 9 patients, but 2 had to be excluded due to unclear diagnoses (coexisting CLL or revision to a fixed toxic drug eruption)., Results: From the remaining patients we established single-cell mRNA expression profiles and the corresponding TCR repertoire of 18,630 T cells. TCR clonality unequivocally identified 13,592 malignant T cells. Reactive T cells of all patients clustered together, while malignant cells of each patient formed a unique cluster expressing genes typical of naive/memory, such as CD27, CCR7 and IL7R , or cytotoxic T cells, e.g., GZMA, NKG7 and GNLY . Genes encoding classic CTCL markers were not detected in all clusters, consistent with the fact that mRNA expression does not correlate linearly with protein expression. Nevertheless, we successfully pinpointed distinctive gene signatures differentiating reactive malignant from malignant T cells: keratins ( KRT81 , KRT86 ), galectins ( LGALS1 , LGALS3 ) and S100 genes ( S100A4 , S100A6 ) being overexpressed in malignant cells., Conclusions: Combined scRNAseq and scTCRseq not only allows unambiguous identification of MF cells, but also revealed marked heterogeneity between and within patients with unexpected functional phenotypes. While the correlation between mRNA and protein abundance was limited with respect to established MF markers, we were able to identify a single-cell gene expression signature that distinguishes malignant from reactive T cells., Competing Interests: SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre. EL reports personal fees, honoraria, and support for attending meetings or travel grants from Bristol Myers Squibb, Medac, Novartis, Pierre Fabre, and Sun Pharma, and honoraria from MSD, Recordati, and Sanofi. EL participated on a drug safety monitoring or advisory board for Bristol Myers Squibb, Novartis, Sanofi, and Sun Pharma. TG has received speakers and/or advisory board honoraria from BMS, Sano-fi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. JB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, Merck Serono, Pfizer, 4SC and Sanofi/Regeneron. His group receives research grants from Bristol Myers Squibb, Merck Serono, HTG, IQVIA and Alcedis GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Srinivas, Peiffer, Horny, Lei, Buus, Kubat, Luo, Yin, Spassova, Sucker, Farahpour, Kehrmann, Ugurel, Livingstone, Gambichler, Ødum and Becker.)
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- 2024
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36. Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events.
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Koch EAT, Petzold A, Dippel E, Erdmann M, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Kähler KC, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schell B, Terheyden P, Thoms KM, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, and Heppt MV
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Neoplasm Metastasis, Uveal Neoplasms mortality, Uveal Neoplasms drug therapy, Uveal Neoplasms immunology, Uveal Neoplasms pathology, Melanoma drug therapy, Melanoma mortality, Melanoma immunology, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors therapeutic use
- Abstract
Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable., Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57)., Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively)., Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens., Competing Interests: AG speaker´s honoraria from Allmirall, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, MSD Sharp & Dohme, Pfizer, and Roche. CB declares speaker´s and/or consultancy honoraria from Almirall, Bristol-Myers Squibb, Delcath, Immunocore, Leo Pharma, Miltenyi, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals, Regeneron, and Sanofi-Aventis outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol-Myers Squibb, Roche, Merck Serono, MSD Sharp & Dohme, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, and LEO. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Sanofi, and Immunocore and research funding from Novartis and Roche. FZ declares speakers and advisory board honoraria and/or travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi-Aventis outside the submitted work. JCH declares research support from Bristol Myers Squibb, Sanofi, and Sunpharma, advisory board honoraria from GSK, Pierre Fabre Pharmaceuticals, Sun Pharma, speaker honoraria from Amgen, Bristol-Myers Squibb, Delcath, GSK, Immuno core, MSD Sharp & Dohme, Novartis, Sanofi and Sun Pharma and travel support from Bristol-Myers Squibb, Iovance and Sun Pharma. SH declares speakers and advisory board honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Sanofi, Sun Pharma, and Pierre Fabre Pharmaceuticals. JUl: Speakers and advisory board honoraria from Bristol-Myers Squibb, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Sanofi, and travel support from Pierre Fabre Pharmaceuticals. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals, Roche, Sanofi outside the submitted work. KCK serves as a consultant to Philogen, Bristol-Myers Squibb, MSD Sharp & Dohme, Sanofi Aventis, and Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support by Novartis. K-MT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, Sanofi Genzyme, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, and Candela. ME declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi, outside the submitted work. MVH: Honoraria from MSD Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma. PM Research support: Novartis, Bristol-Myers Squibb, MSD Sharp & Dohme. Honoraria for lectures: Roche, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Merck-Serono, Pierre Fabre Pharmaceuticals, Sanofi, Sun Pharma, Baiersdorf; Honoraria for advisory boards: Roche Pharma, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, Immunocore, Sun Pharma, Sanofi. PT: Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, CureVac, Roche, Kyowa Kirin, Biofrontera, Invited Speaker, Personal BMS, Novartis, Pierre Fabre Pharmaceuticals, Merck Serono, Sanofi, Roche, Kyowa Kirin, Advisory Board, Personal BMS, Pierre Fabre Pharmaceuticals, Other, Personal, Travel support. RG Research support: Amgen, MSD Sharp & Dohme, Sun Pharma, Sanofi/Regeneron, Almirall, Kyowa Kirin. Honoraria for lectures: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, MSD Sharp & Dohme, Sun, Pierre Fabre Pharmaceuticals, Sanofi/Regeneron, Sun Pharma Honoraria for advisory boards: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, 4SC, Immunocore, Sun Pharma, Sanofi/Regeneron, Delcath. SU declares research support from Bristol-Myers Squibb and MSD Sharp & Dohme; speakers and advisory board honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol-Myers Squibb, and MSD Sharp & Dohme. UL declares research support from MSD Sharp & Dohme; speakers and advisory board honoraria from MSD Sharp & Dohme, Novartis, Sanofi, and Sun Pharma, and travel support from Pierre Fabre Pharmaceuticals and Sun Pharma. BS Speakers honoria and/or travel support from Amgen, Bristol-Myers Squibb, MSD Sharp & Dohme, Jansen, Novartis, Roche, Sun Pharma, abbvie, Sanofi, Pierre Fabre Pharmaceuticals, Boehringer Ingelheim and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AT declared a past co-authorship with the author RG, JH, SH, KCK, CL, FM, MM, PT, K-MT, FZ, and MVH to the handling editor., (Copyright © 2024 Koch, Petzold, Dippel, Erdmann, Gesierich, Gutzmer, Hassel, Haferkamp, Kähler, Kreuzberg, Leiter, Loquai, Meier, Meissner, Mohr, Pföhler, Rahimi, Schell, Terheyden, Thoms, Ugurel, Ulrich, Utikal, Weichenthal, Ziller, Berking and Heppt.)
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- 2024
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37. Incidence and Relative Survival of Patients with Merkel Cell Carcinoma in North Rhine-Westphalia, Germany, 2008-2021.
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Stang A, Möller L, Wellmann I, Claaßen K, Kajüter H, Ugurel S, and Becker JC
- Abstract
Background: To date, only a few population-representative studies have been carried out on the rare Merkel cell carcinoma (MCC). We provide incidence and survival estimates of MCC, including the conditional relative survival., Methods: We analyzed data from the cancer registry of North Rhine-Westphalia, Germany, 2008-2021, covering a population of 18 million. We included all newly diagnosed MCCs and calculated age-standardized (old European Standard population) incidence rates and unconditional and conditional relative survival., Results: Our analysis included 2164 MCC patients. The age-standardized incidence of MCC was 5.2 (men) and 3.8 (women) per million person-years. The 5-year relative survival was 58.8% (men) and 70.7% (women). Survival was lower among men than women in all age-sex groups and was highest for MCC of the upper extremity in both men (68.2%) and women (79.3%). The sex difference in survival is particularly due to the better survival of women with MCC of the head and neck. In terms of survival, the first two years are particularly critical., Conclusions: Our data validate the worse survival among men and highlights a more favorable prognosis for MCCs located on the limbs. The first two years after diagnosis of MCC are the years with the highest excess mortality.
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- 2024
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38. Clinical and genetic characteristics of BAP1 -mutated non-uveal and uveal melanoma.
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Matull J, Placke JM, Lodde G, Zaremba A, Utikal J, Terheyden P, Pföhler C, Herbst R, Kreuter A, Welzel J, Kretz J, Möller I, Sucker A, Paschen A, Livingstone E, Zimmer L, Hadaschik E, Ugurel S, Schadendorf D, Thielmann CM, and Griewank KG
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Adult, Aged, 80 and over, Prognosis, Ubiquitin Thiolesterase genetics, Melanoma genetics, Melanoma mortality, Melanoma therapy, Uveal Neoplasms genetics, Uveal Neoplasms mortality, Uveal Neoplasms therapy, Tumor Suppressor Proteins genetics, Mutation
- Abstract
Background: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized., Methods: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome., Results: BAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1 , BRAF V600 and NRAS Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating BAP1 mutations., Conclusion: In contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective., Competing Interests: JM: Declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. J-MP: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos, outside the submitted work. GL: Declares travel support from Sun Pharma, outside the submitted work. AZ: Declares travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work. JU: Is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. PT: served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. CP: Received honoraria speaker honoraria and advisory-board honoraria and travel support from BMS, MSD, Novartis, Merck Serono, Pierre Fabre, Sunpharma, AbbVie, LEO, and Kyona Kirin, outside the submitted work. RH: Is an employee of Helios Kliniken Erfurt GmbH. JW: Received honoraria and travel support from Almirall, Bristol Myers Squibb, Novartis, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. EL: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. LZ: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol- Myers Squibb, Amgen, Pierre-Fabre, Sunpharma and Novartis, outside the submitted work. SU: Research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. DS: Reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matull, Placke, Lodde, Zaremba, Utikal, Terheyden, Pföhler, Herbst, Kreuter, Welzel, Kretz, Möller, Sucker, Paschen, Livingstone, Zimmer, Hadaschik, Ugurel, Schadendorf, Thielmann and Griewank.)
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- 2024
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39. Case report: Durable complete response of a mucosal melanoma of the rectum after neoadjuvant immunotherapy with ipilimumab plus nivolumab.
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Krueger O, Eisenburger R, Tasdogan A, Zimmer L, Livingstone E, Hadaschik E, Theurer S, Brodin B, Schadendorf D, and Ugurel S
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- Humans, Male, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors administration & dosage, Immunotherapy methods, Middle Aged, Ipilimumab administration & dosage, Ipilimumab therapeutic use, Nivolumab therapeutic use, Nivolumab administration & dosage, Melanoma therapy, Melanoma drug therapy, Neoadjuvant Therapy methods, Rectal Neoplasms therapy, Rectal Neoplasms drug therapy, Rectal Neoplasms pathology, Rectal Neoplasms immunology
- Abstract
Melanoma causes the majority of skin cancer-related deaths. Despite novel therapy options, metastatic melanoma still has a poor prognosis. Immune checkpoint inhibition (ICI) therapy has been shown to prolong overall survival in patients with advanced melanoma, but mucosal melanomas respond less favorably compared to melanomas of cutaneous origin. We report on a patient with a mucosal melanoma of the rectum diagnosed in June 2020. Since a surgical intervention in order to achieve a tumor-free situation would have required an amputation of the rectum, a neo-adjuvant systemic immunotherapy with ipilimumab and nivolumab was initiated. As restaging and colonoscopy after four doses of this combination immunotherapy showed a partial response, the patient decided against the pre-planned surgery and a maintenance therapy with nivolumab was started. Repeated colonoscopy showed a complete response after four doses of nivolumab. After ongoing ICI therapy with nivolumab and no evidence of tumor relapse, immunotherapy was stopped in July 2022 after nearly 2 years of continuous treatment. The patient remained tumor-free during further follow-up. Neo-adjuvant immunotherapy is getting more explored in advanced melanoma. By administering ICI therapy before surgical resection of an essentially operable tumor, a stronger and more diverse immunological response is supposed to be achieved. Our reported case demonstrates that this approach could also be effective in mucosal melanoma despite of its generally lower response to immunotherapy., Competing Interests: AT declares speakers honoraria from Merck Sharp & Dohme. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work. DS reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Neracare, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Krueger, Eisenburger, Tasdogan, Zimmer, Livingstone, Hadaschik, Theurer, Brodin, Schadendorf and Ugurel.)
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- 2024
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40. Comparison of visual diagnostic accuracy of dermatologists practicing in Germany in patients with light skin and skin of color.
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Krefting F, Moelleken M, Hölsken S, Placke JM, Eisenburger RT, Albrecht LJ, Tasdogan A, Schadendorf D, Ugurel S, Dissemond J, and Sondermann W
- Subjects
- Adult, Female, Humans, Male, Dermatologists, Germany, Surveys and Questionnaires, Ethnic and Racial Minorities, Skin Diseases diagnosis, Skin Pigmentation
- Abstract
Visual clinical diagnosis of dermatoses in people of color (PoC) is a considerable challenge in daily clinical practice and a potential cause of misdiagnosis in this patient cohort. The study aimed to determine the difference in visual diagnostic skills of dermatologists practicing in Germany in patients with light skin (Ls) and patients with skin of color (SoC) to identify a potential need for further education. From April to June 2023, German dermatologists were invited to complete an online survey with 24 patient photographs depicting 12 skin diseases on both Ls and SoC. The study's primary outcomes were the number of correctly rated photographs and the participants' self-assessed certainty about the suspected visual diagnosis in Ls compared to SoC. The final analysis included surveys from a total of 129 dermatologists (47.8% female, mean age: 39.5 years). Participants were significantly more likely to correctly identify skin diseases by visual diagnostics in patients with Ls than in patients with SoC (72.1% vs. 52.8%, p ≤ 0.001, OR 2.28). Additionally, they expressed higher confidence in their diagnoses for Ls than for SoC (73.9 vs. 61.7, p ≤ 0.001). Therefore, further specialized training seems necessary to improve clinical care of dermatologic patients with SoC., (© 2024. The Author(s).)
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- 2024
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41. Correlation of tumor PD-L1 expression in different tissue types and outcome of PD-1-based immunotherapy in metastatic melanoma - analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM.
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Placke JM, Kimmig M, Griewank K, Herbst R, Terheyden P, Utikal J, Pföhler C, Ulrich J, Kreuter A, Mohr P, Gutzmer R, Meier F, Dippel E, Welzel J, Engel DR, Kreft S, Sucker A, Lodde G, Krefting F, Stoffels I, Klode J, Roesch A, Zimmer L, Livingstone E, Hadaschik E, Becker JC, Weichenthal M, Tasdogan A, Schadendorf D, and Ugurel S
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- Humans, B7-H1 Antigen metabolism, Cohort Studies, Immunotherapy, Prognosis, Programmed Cell Death 1 Receptor, Prospective Studies, Melanoma immunology, Melanoma therapy, Skin Neoplasms immunology, Skin Neoplasms therapy, Immune Checkpoint Inhibitors therapeutic use
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Background: PD-1-based immune checkpoint inhibition (ICI) is the major backbone of current melanoma therapy. Tumor PD-L1 expression represents one of few biomarkers predicting ICI therapy outcome. The objective of the present study was to systematically investigate whether the type of tumor tissue examined for PD-L1 expression has an impact on the correlation with ICI therapy outcome., Methods: Pre-treatment tumor tissue was collected within the prospective DeCOG cohort study ADOREG/TRIM (CA209-578; NCT05750511) between February 2014 and May 2020 from 448 consecutive patients who received PD-1-based ICI for non-resectable metastatic melanoma. The primary study endpoint was best overall response (BOR), secondary endpoints were progression-free (PFS) and overall survival (OS). All endpoints were correlated with tumor PD-L1 expression (quantified with clone 28-8; cutoff ≥5%) and stratified by tissue type., Findings: Tumor PD-L1 was determined in 95 primary tumors (PT; 36.8% positivity), 153 skin/subcutaneous (34.0% positivity), 115 lymph node (LN; 50.4% positivity), and 85 organ (40.8% positivity) metastases. Tumor PD-L1 correlated with BOR if determined in LN (OR = 0.319; 95% CI = 0.138-0.762; P = 0.010), but not in skin/subcutaneous metastases (OR = 0.656; 95% CI = 0.311-1.341; P = 0.26). PD-L1 positivity determined on LN metastases was associated with favorable survival (PFS, HR = 0.490; 95% CI = 0.310-0.775; P = 0.002; OS, HR = 0.519; 95% CI = 0.307-0.880; P = 0.014). PD-L1 positivity determined in PT (PFS, HR = 0.757; 95% CI = 0.467-1.226; P = 0.27; OS; HR = 0.528; 95% CI = 0.305-0.913; P = 0.032) was correlated with survival to a lesser extent. No relevant survival differences were detected by PD-L1 determined in skin/subcutaneous metastases (PFS, HR = 0.825; 95% CI = 0.555-1.226; P = 0.35; OS, HR = 1.083; 95% CI = 0.698-1.681; P = 0.72)., Interpretation: For PD-1-based immunotherapy in melanoma, tumor PD-L1 determined in LN metastases was stronger correlated with therapy outcome than that assessed in PT or organ metastases. PD-L1 determined in skin/subcutaneous metastases showed no outcome correlation and therefore should be used with caution for clinical decision making., Funding: Bristol-Myers Squibb (ADOREG/TRIM, NCT05750511); German Research Foundation (DFG; Clinician Scientist Program UMEA); Else Kröner-Fresenius-Stiftung (EKFS; Medical Scientist Academy UMESciA)., Competing Interests: Declaration of interests Jürgen C. Becker is receiving speaker's bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. Ralf Gutzmer reported Personal Honoraria from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall, SUN, Sanofi, Pierre-Fabre; Consultant or Advisory Role (personal) for BMS, Roche, Novartis, Almirall, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Immunocore; Research Funding (to institution) from Novartis, Pfizer, Amgen, Merck-Serono, SUN, KyowaKirin, Almirall; and Travel, Accommodations, Expenses from SUN, Pierre-Fabre, Boehringer-Ingelheim; outside the submitted work. Rudolf Herbst is employee of Helios Klinikum Erfurt GmbH. Joachim Klode reported grants and or personal fees from Novartis, LaVision Bio Tec and Sastomed. Sophia Kreft has received honoraria from Sun Pharma and reports travel support from Sanofi Genzyme. Frederik Krefting received travel support for participation in congresses and/or (speaker) honoraria from Novartis, Almirall and Boehringer Ingelheim outside the submitted work. Elisabeth Livingstone received honoraria from Novartis, Medac, Bristol Myers Squibb, Sanofi, Sun Pharma, and Pierre Fabre, reports consulting/advisory roles with Bristol Myers Squibb, Pierre Fabre and Novartis; and received travel/accommodations/expenses from Pierre Fabre, Bristol Myers Squibb, Medac, and Sun Pharma. Georg Lodde received travel support from Sun Pharma. Friedegund Meier has received travel support or/and speaker's fees or/and advisor's honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. Peter Mohr declares research support from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Beiersdorf, Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Immunocore, Sanofi and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, and Pierre Fabre, outside the submitted work. Claudia Pföhler received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO, outside the submitted work. Jan-Malte Placke served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. Alexander Roesch reported grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Teva. Dirk Schadendorf reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) support; grants (or contracts) from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. Patrick Terheyden has received honoraria from Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera and travel support from Bristol-Myers Squibb and Pierre Fabre. Selma Ugurel declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. Jens Ulrich received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Bristol-Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Regeneron, Sunpharma outside the submitted work. Jochen Utikal is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. Michael Weichenthal received grants from Bristol-Myers Squibb and Merck Sharp & Dohme, consulting fees from Merck Sharp & Dohme, Immunocore and Novartis, lecture honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and Pierre-Fabre, and advisory board honoraria from Merck Sharp & Dohme. Julia Welzel received travel grants from Bristol-Myers Squibb and Almriall as well as lecture honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Almirall. Lisa Zimmer declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. The other authors did not report conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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42. Treatment management for BRAF -mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.
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Haist M, Stege H, Rogall F, Tan Y, von Wasielewski I, Klespe KC, Meier F, Mohr P, Kähler KC, Weichenthal M, Hauschild A, Schadendorf D, Ugurel S, Lodde G, Zimmer L, Gutzmer R, Debus D, Schilling B, Kreuter A, Ulrich J, Meiss F, Herbst R, Forschner A, Leiter U, Pfoehler C, Kaatz M, Ziller F, Hassel JC, Tronnier M, Sachse M, Dippel E, Terheyden P, Berking C, Heppt MV, Kiecker F, Haferkamp S, Gebhardt C, Simon JC, Grabbe S, and Loquai C
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- Humans, Proto-Oncogene Proteins B-raf genetics, Cohort Studies, Neoplasm Recurrence, Local genetics, Prospective Studies, Registries, Adjuvants, Immunologic, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Melanoma drug therapy, Melanoma genetics
- Abstract
Background: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAF V600-mutant ( BRAF mut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy., Methods: For this multicenter cohort study, we identified 515 BRAF mut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments., Results: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004)., Conclusions: BRAF mut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are: PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. KCK declareds speakers and advisory board Honoria from Novartis and BMS, as well as travel support from Novartis, Pierre Fabre, Kyowa Kirin and Sun Pharma. FMeier has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. GL has received travel support for congress participation by Sun Pharma, Pierre-Fabre and research funding from Novartis. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. RG served as consultant or/and has received Honoria from Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Pierre Fabre, Merck-Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, 4SC, Delcath, received travel support from Sun Pharma, Pierre Fabre, and Boehringer-Ingelheim. AH received consultancy and advisory board fees from Agenus Bio, Almirall Hermal, Amgen, Beiersdorf, BMS, Dermagnostix, Eisai, Highlight Therapeutics, Incyte, IO Biotech, Immunocore, MSD/Merck, MerckPfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme, Seagen and Xenthera. UL served as consultant to Roche, Novartis, MSD, Almirall Hermal, Sanofi and Sun Pharma; received travel support from Sun Pharma and Pierre-Fabre, received speaker fees from Roche, Novartis, MSD, Sun Pharma and Sanofi, outside the submitted work. She reports institutional research grants from MSD. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. DD has been on the advisory board or has received honoraria from BMS, MSD, Novartis, Pierre Fabre. IvW declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. JCH received research grants from BMS, Sanofi and Sunpharma and served as a consultant and/or received honoria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi and Sunpharma, outside of the submitted work. MVH reports honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Pierre Fabre, Immunocore. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre Pharmaceuticals, and travel support from Novartis, Roche, Bristol-Myers Squibb and Pierre Fabre Pharma, outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. FZ served as consultant and/or has received honoria from BMS, MSD, Novartis, Pierre-Fabre, Sanofi, Sun Pharma. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FMeiss served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. SG declares honoraria for advisory boards, oral presentations, and travel expenses from Roche, Novartis, MSD, and BMS outside the submitted work. CL declares speakers, advisory board honoraria, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Pierre Fabre, Sun Pharma, Kiowa Kirin, Sanofi, Biontech, and Almirall Hermal outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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43. Editorial: Women in skin cancer vol II: 2022.
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Ugurel S and Patel SP
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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44. Retraction Note: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.
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Hill R, Madureira PA, Ferreira B, Baptista I, Machado S, Colaҫo L, Dos Santos M, Liu N, Dopazo A, Ugurel S, Adrienn A, Kiss-Toth E, Isbilen M, Gure AO, and Link W
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45. Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.
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Franklin C, Mohr P, Bluhm L, Meier F, Garzarolli M, Weichenthal M, Kähler K, Grimmelmann I, Gutzmer R, Utikal J, Terheyden P, Herbst R, Haferkamp S, Pfoehler C, Forschner A, Leiter U, Ziller F, Meiss F, Ulrich J, Kreuter A, Gebhardt C, Welzel J, Schilling B, Kaatz M, Scharfetter-Kochanek K, Dippel E, Nashan D, Sachse M, Weishaupt C, Löffler H, Gambichler T, Loquai C, Heinzerling L, Grabbe S, Debus D, Schley G, Hassel JC, Weyandt G, Trommer M, Lodde G, Placke JM, Zimmer L, Livingstone E, Becker JC, Horn S, Schadendorf D, and Ugurel S
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- Humans, CTLA-4 Antigen, Proto-Oncogene Proteins B-raf genetics, Programmed Cell Death 1 Receptor, Prospective Studies, Registries, Mitogen-Activated Protein Kinase Kinases, Brain pathology, Melanoma pathology, Skin Neoplasms drug therapy, Brain Neoplasms pathology
- Abstract
Background: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy., Methods: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS)., Results: Of 1704 patients, 916 were BRAF wild-type (BRAF wt ) and 788 were BRAF V600 mutant (BRAF mut ). Median follow-up time after start of 1L-therapy was 40.4 months. BRAF wt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAF mut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAF mut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAF mut patients. In BRAF wt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAF wt patients. For BRAF mut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK., Conclusions: In BRAF mut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAF wt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1., Competing Interests: Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are as following: CF has been on the advisory board or has received honoraria from Bristol Myers Squibb, Immunocore and Novartis and received travel grants from Bristol Myers Squibb, Novartis and Pierre Fabre. PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. LB received honoraria from Amgen, Bristol-Myers Squibb and Sun Pharma. FriM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. KK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. IG declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RG: Invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre. JU is on the advisory board or has received travel support from: Amgen, BMS, GSK, Immunocore, Leo Pharma, MSD, Novartis, Pierre Fabre, Sanofi, Roche. JU has received research support from Novartis; speakers and advisory board honoraria. PT has been on the advisory board or has received honoraria from Almirall, Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, Biofrontera, and 4SC and received travel grants from Bristol Myers Squibb, and Pierre Fabre. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre Fabre and Sanofi Aventis. FraM (Frank Meiss) served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre and travel support from Novartis, Roche, BMS and Pierre Fabre. AK reports receiving lecture fees and fees for serving on advisory boards from MSD Sharp & Dohme, Almirall, Infectopharm, and Boehringer Ingelheim. JW has been on the advisory board, received honoraria and/or travel grants from Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. TG has received speakers and/or advisory board honoraria and travel support from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono. CL has received speaker’s fees, advisory board honoraria and travel reimbursements from Merck, MSD, Roche, Almirall Hermal, Biontech, Sanofi, Sun Pharma, Kyowa Kirin, Immonocore, BMS, Pierre Fabre, Novartis. LH has received consultancy and speaker fees from Amgen, Biome Dx, BMS, Curevac, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi and SUN. SG has been on the advisory board and/or has received travel support from Bristol Myers Squibb, MSD, Sun Pharma and Novartis and received research support from Novartis and Pierre Fabre. DD has been on the advisory board or has received honoraria from BMS, Kyowa Kirin, MSD, Novartis, Pierre Fabre, Sanofi and received travel grants from Boehringer, Mylan, Pfizer. GS has received honoraria from BMS. GL has received travel support from Sun Pharma. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Amgen, Pierre Fabre, Sunpharma, Sanofi and Novartis. EL served as consultant and/or has received honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Medac, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis. JCB received speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. DS declares relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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46. COVID-19 vaccination in psoriasis patients receiving systemic treatment: A prospective single-center study.
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Lodde GC, Krefting F, Placke JM, Schneider L, Fiedler M, Dittmer U, Becker JC, Hölsken S, Schadendorf D, Ugurel S, and Sondermann W
- Subjects
- Humans, Middle Aged, COVID-19 Vaccines, Cohort Studies, Prospective Studies, Tumor Necrosis Factor-alpha, Methotrexate, Antibodies, Viral, Immunoglobulin G, COVID-19 prevention & control, Psoriasis drug therapy
- Abstract
Background: The rate of seroconversion after COVID-19 vaccination in patients with moderate to severe psoriasis requiring systemic treatment is poorly understood., Objectives: The aim of this prospective single-center cohort study performed between May 2020 and October 2021 was to determine the rate of seroconversion after COVID-19 vaccination in patients under active systemic treatment for moderate to severe psoriasis., Methods: Inclusion criteria were systemic treatment for moderate to severe psoriasis, known COVID-19 vaccination status, and repetitive anti-SARS-CoV-2-S IgG serum quantification. The primary outcome was the rate of anti-SARS-CoV-2-S IgG seroconversion after complete COVID-19 vaccination., Results: 77 patients with a median age of 55.9 years undergoing systemic treatment for moderate to severe psoriasis were included. The majority of patients received interleukin- (n=50, 64.9%) or tumor necrosis factor (TNF)-α inhibitors (n=16, 20.8%) as systemic treatment for psoriasis; nine patients (11.7%) were treated with methotrexate (MTX) monotherapy, and one patient each received dimethyl fumarate (1.3%), respectively apremilast (1.3%). All included patients completed COVID-19 vaccination with two doses over the course of the study. Serum testing revealed that 74 patients (96.1%) showed an anti-SARS-CoV-2-S IgG seroconversion. While all patients on IL-17A, -12 or -12/23 inhibitors (n=50) achieved seroconversion, three of 16 patients (18.8%) receiving MTX and/or a TNF-α inhibitor as main anti-psoriatic treatment did not. At follow-up, none of the patients had developed symptomatic COVID-19 or died from COVID-19., Conclusions: Anti-SARS-CoV-2-S IgG seroconversion rates following COVID-19 vaccination in psoriasis patients under systemic treatment were high. An impaired serological response, however, was observed in patients receiving MTX and/or TNF-α inhibitors, in particular infliximab., Competing Interests: GL has received travel support from Sun Pharma. FK has received travel support and/or personal fees from Novartis and Almirall. MF has given a paid lecture for Dia Sorin. UD reports consulting fees from Biontech and Moderna, and advisory board honoraria from Moderna outside the submitted work. J-MP served as consultant and/or has received honoraria from Bristol-Myers Squibb and Novartis, and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. JB declares speaker honoraria from Amgen and Sanofi; advisory board honoraria from 4SC, Almirall, Amgen, MerckSerono, Novartis, InProTher, and Sanofi; research funding from Alcedis, Bristol-Myers Squibb, HTG, IQVIA, and MerckSerono; travel support from 4SC and Incyte. DS reports grants or contracts from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. WS reports grants and/or personal fees and/or speaker honoraria from medi GmbH Bayreuth, Abbvie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme und UCB outside the submitted work. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Lodde, Krefting, Placke, Schneider, Fiedler, Dittmer, Becker, Hölsken, Schadendorf, Ugurel and Sondermann.)
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- 2023
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47. Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.
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Nuñez NG, Berner F, Friebel E, Unger S, Wyss N, Gomez JM, Purde MT, Niederer R, Porsch M, Lichtensteiger C, Kramer R, Erdmann M, Schmitt C, Heinzerling L, Abdou MT, Karbach J, Schadendorf D, Zimmer L, Ugurel S, Klümper N, Hölzel M, Power L, Kreutmair S, Capone M, Madonna G, Cevhertas L, Heider A, Amaral T, Hasan Ali O, Bomze D, Dimitriou F, Diem S, Ascierto PA, Dummer R, Jäger E, Driessen C, Levesque MP, van de Veen W, Joerger M, Früh M, Becher B, and Flatz L
- Subjects
- Humans, Immune Checkpoint Inhibitors adverse effects, Leukocytes, Mononuclear pathology, CD8-Positive T-Lymphocytes pathology, Ki-67 Antigen, Prospective Studies, Proteomics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Melanoma drug therapy, Immune System Diseases drug therapy
- Abstract
Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs., Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs., Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67
+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs., Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs., Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen., Competing Interests: Declaration of interests L.F. has/had advisory roles for Novartis, Sanofi, Philogen, and Bristol-Myers Squibb, all which took place outside the submitted work. P.A.A. has/had consultant/advisory roles for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, Bio-Al Health, and ValoTx; he also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, Sanofi, and Pfizer, as well as travel support from Merck Sharp & Dhome and Pfizer, all which was outside the submitted work. T.A. served as consultant to Bristol-Myers Squibb, Novartis, and CeCaVa; received travel support from Bristol-Myers Squibb and Novartis; received speaker fees from Novartis, Bristol-Myers Squibb, Pierre Fabre, and CeCaVa; received institutional funding from Neracare, Novartis, Sanofi, and SkylineDX; and received institutional research grants from Novartis outside the submitted work. R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME, all which took place outside the submitted work. W.v.d.V. declares research support from the Novartis research foundation and the PROMEDICA Stiftung and serves as a consultant for Mabylon outside the submitted work. S.U. declares research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre outside the submitted work. L.Z. declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; research support from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma, and Novartis outside the submitted work. F.D. receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, and Sun Pharma outside the submitted work. L.H. declares research support from Therakos and speakers and advisory board honoraria from Amgen, BiomeDx, Bristol-Myers Squibb, Curevac, Merck, Merck Sharp & Dohme, Myoncare, Novartis, Pierre Fabre, Sanofi, SUN, and Roche, outside the submitted work. M.E. declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, and Novartis outside the submitted work. R.K. declares travel support from Pierre Fabre and Sun Pharma outside the submitted work. M.J. declares advisory roles (institutional) for Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Debiopharm, Merck Sharp & Dhome, Roche, and Sanofi; research funding from Swiss Cancer Research; and travel grants from Roche, Sanofi, and Takeda. D.S. has/had consultant/advisory roles in the last 3 years for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pfizer, Pierre Fabre, Sun Pharma, Sanofi, Regeneron, Ultimovacs, Sandoz, Immunocore, 4SC, Neracare, Nektar, Daiichi Sankyo, Oncosec, Amgen, BioCon, Immatics, InFlarX, Innovent, Labcorp, Replimune, and Haystack; his institution also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, and Merck Sharp & Dhome, all of which took place outside the submitted work. N.K. received personal fees, travel costs, and speaker’s honoraria from Astellas, Novartis, Ipsen, and Photocure, all of which took place outside the submitted work. M.P.L. has received project-specific research funding from Roche, Novartis, Molecular Partners, and Oncobit., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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48. 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.
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Haist M, Stege H, Lang BM, Tsochataridou A, Salzmann M, Mohr P, Schadendorf D, Ugurel S, Placke JM, Weichenthal M, Gutzmer R, Leiter U, Kaatz M, Haferkamp S, Berking C, Heppt M, Tschechne B, Schummer P, Gebhardt C, Grabbe S, and Loquai C
- Abstract
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.
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- 2022
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49. Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG.
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Glutsch V, Schummer P, Kneitz H, Gesierich A, Goebeler M, Klein D, Posch C, Gebhardt C, Haferkamp S, Zimmer L, Becker JC, Leiter U, Weichenthal M, Schadendorf D, Ugurel S, and Schilling B
- Subjects
- Humans, Ipilimumab pharmacology, Ipilimumab therapeutic use, Nivolumab pharmacology, Nivolumab therapeutic use, Programmed Cell Death 1 Receptor, Prospective Studies, Registries, Immune Checkpoint Inhibitors, Carcinoma, Merkel Cell drug therapy, Skin Neoplasms drug therapy
- Abstract
Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43-not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma., Competing Interests: Competing interests: VG has received honoraria from Bristol-Myers Squibb and reports travel support from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi Genzyme and SUN Pharmaceuticals Industries, outside the submitted work. PS has received honoraria from Bristol-Myers Squibb, an institutional research grant from Novartis, reports travel support from Bristol-Myers Squibb, Lilly, Sanofi-Aventis, Novartis, Pierre Fabre Pharmaceuticals and Sun Pharmaceuticals. HK declares no conflicts of interest. AG speaker's honoraria from Allmiral, Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. MG has received speaker’s and advisory board honoraria from Argenx, Biotest, GSK, Janssen, Leo Pharma, Lilly, Novartis and UCB outside the submitted work. DK declares no conflicts of interest. CP received honoraria and travel support from BMS, MSD, Pierre-Fabre, Sanofi, MERCK, SunPharma, Pelpharma, Almirall, and Novartis outside the submitted work. CG is on the advisory board or has received honoraria from Almirall, Amgen, Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Janssen, MSD Sharp & Dohme, Novartis, Pierre-Fabre Pharma, Roche, Sanofi Genzyme, SUN Pharma and Sysmex Inostics, research funding from Novartis and Sanofi Genzyme, and travel support from Bristol-Myers Squibb, Pierre Fabre Pharma and SUN Pharma, outside the submitted work; he is co-founder of Dermagnostix and Dermagnostix R&D and holds leadership roles for DeCOG, Hiege-Stiftung and Roggenbuck Stiftung. SH has received speaker and advisory board honoraria from Bristol-Myers Squibb and MSD Sharp & Dohme. LZ served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sunpharma, Sanofi and Novartis, outside the submitted work. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. UL is receiving speaker’s honoraria from Sanofi, Sun Pharma, is a paid advisory board member Almirall, Sanofi/Regeneron, Sun Pharma, MSD, Novartis and Roche and gets travel support from Sun Pharma and Sanofi. Her group receives research grants from MSD outside the submitted work. MW declares research support from BMS and MSD; speaker and/or advisory board honoraria from BMS, MSD, Merck Serono, Medac, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma and Takeda. DS reports grants (or contracts) from (with) Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre Pharmaceuticals, and travel support from Novartis, Roche, Bristol-Myers Squibb and Pierre Fabre Pharma, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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50. Circulating cell-free messenger RNA enables non-invasive pan-tumour monitoring of melanoma therapy independent of the mutational genotype.
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Albrecht LJ, Höwner A, Griewank K, Lueong SS, von Neuhoff N, Horn PA, Sucker A, Paschen A, Livingstone E, Ugurel S, Zimmer L, Horn S, Siveke JT, Schadendorf D, Váraljai R, and Roesch A
- Subjects
- Humans, Biomarkers, Tumor genetics, Mutation, Genotype, RNA, Messenger, Melanoma genetics, Melanoma pathology, Cell-Free Nucleic Acids genetics, Nevus
- Abstract
Background: Plasma-derived tumour-specific cell-free nucleic acids are increasingly utilized as a minimally invasive, real-time biomarker approach in many solid tumours. Circulating tumour DNA of melanoma-specific mutations is currently the best studied liquid biopsy biomarker for melanoma. However, the combination of hotspot genetic alterations covers only around 80% of all melanoma patients. Therefore, alternative approaches are needed to enable the follow-up of all genotypes, including wild-type., Methods: We identified KPNA2, DTL, BACE2 and DTYMK messenger RNA (mRNA) upregulated in melanoma versus nevi tissues by unsupervised data mining (N = 175 melanoma, N = 20 normal skin, N = 6 benign nevi) and experimentally confirmed differential mRNA expression in vitro (N = 18 melanoma, N = 8 benign nevi). Circulating cell-free RNA (cfRNA) was analysed in 361 plasma samples (collected before and during therapy) from 100 melanoma patients and 18 healthy donors. Absolute cfRNA copies were quantified on droplet digital PCR., Results: KPNA2, DTL, BACE2 and DTYMK cfRNA demonstrated high diagnostic accuracy between melanoma patients' and healthy donors' plasma (AUC > 86%, p < .0001). cfRNA copies increased proportionally with increasing tumour burden independently of demographic variables and even remained elevated in individuals with radiological absence of disease. Re-analysis of single-cell transcriptomes revealed a pan-tumour origin of cfRNA, including endothelial, cancer-associated fibroblasts, macrophages and B cells beyond melanoma cells as cellular sources. Low baseline cfRNA levels were associated with significantly longer progression-free survival (PFS) (KPNA2 HR = .54, p = .0362; DTL HR = .60, p = .0349) and overall survival (KPNA2 HR = .52, p = .0237; BACE2 HR = .55, p = .0419; DTYMK HR = .43, p = .0393). Lastly, we found that cfRNA copies significantly increased during therapy in non-responders compared to responders regardless of therapy and mutational subtypes and that the increase of KPNA2 (HR = 1.73, p = .0441) and DTYMK (HR = 1.82, p = .018) cfRNA during therapy was predictive of shorter PFS., Conclusions: In sum, we identified a new panel of cfRNAs for a pan-tumour liquid biopsy approach and demonstrated its utility as a prognostic, therapy-monitoring tool independent of the melanoma mutational genotype., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
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- 2022
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