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1,565 results on '"Becker, Jürgen C"'

6. Wnt/β-Catenin–Activated Nonpilomatrical Carcinoma of the Skin: A Case Series

Author

Kervarrec, Thibault, Cheok Lei, Kuan, Sohier, Pierre, Macagno, Nicolas, Jullie, Marie-Laure, Frouin, Eric, Goto, Keisuke, Taniguchi, Kohei, Hamard, Aymeric, Taillandier, Antoine, Tallet, Anne, Bonenfant, Christine, Sahin, Yusuf, Barry, Fatoumata, Taibjee, Saleem, Cokelaere, Kristof, Houben, Roland, Schrama, David, Nardin, Charlee, Aubin, Francois, Doucet, Laurent, Pissaloux, Daniel, Tirode, Franck, Fouchardière, Arnaud de la, Balme, Brigitte, Laurent-Roussel, Sara, Becker, Jürgen C., von Deimling, Andreas, Samimi, Mahtab, Cribier, Bernard, Battistella, Maxime, Calonje, Eduardo, and Guyétan, Serge

Published
2024
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7. Early versus late response to PD-1-based immunotherapy in metastatic melanoma

Author

Lodde, Georg C., Zhao, Fang, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Weichenthal, Michael, Jansen, Philipp, Kowall, Bernd, Galetzka, Wolfgang, Hörst, Fabian, Kleesiek, Jens, Hellwig, Birte, Rahnenführer, Jörg, Rajcsanyi, Luisa, Peters, Triinu, Hinney, Anke, Placke, Jan-Malte, Sucker, Antje, Paschen, Annette, Becker, Jürgen C., Livingstone, Elisabeth, Zimmer, Lisa, Tasdogan, Alpaslan, Roesch, Alexander, Hadaschik, Eva, Schadendorf, Dirk, Griewank, Klaus, and Ugurel, Selma

Published
2024
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13. 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

Author

Placke, Jan-Malte, Kimmig, Mona, Griewank, Klaus, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Welzel, Julia, Engel, Daniel Robert, Kreft, Sophia, Sucker, Antje, Lodde, Georg, Krefting, Frederik, Stoffels, Ingo, Klode, Joachim, Roesch, Alexander, Zimmer, Lisa, Livingstone, Elisabeth, Hadaschik, Eva, Becker, Jürgen C., Weichenthal, Michael, Tasdogan, Alpaslan, Schadendorf, Dirk, and Ugurel, Selma

Published
2023
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14. Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial

Author

van Akkooi, Alexander, van Houdt, Winan, Wilhelm, Tabea, Farmer, Kimberley, Ulrich, Claas, Gambichler, Thilo, Bluhm, Leonie, Schinagl, Heidemarie, Kellner, Ivonne, Herbst, Rudolf, Meiß, Frank, Rafei-Shamsabadi, David, Sell, Sabine, Kaatz, Martin, Wulfken, Lena, Hartmann, Martin, Kähler, Katharina, Ziemer, Mirjana, Simon, Jan, Terheyden, Patrick, Thaci, Diamant, Loquai, Carmen, Mitzel-Rink, Heidrun, Grabbe, Stephan, Stege, Henner, Gaiser, Maria, Utikal, Jochen, Berking, Carola, Heinzerling, Lucie, Schlaak, Max, Tomsitz, Dirk, Dyballa, Jörg, Magnolo, Nina, Weishaupt, Carsten, Berneburg, Mark, Garbe, Claus, Flatz, Lukas, Gesierich, Anja, Schilling, Bastian, Becker, Jürgen C, Ugurel, Selma, Leiter, Ulrike, Meier, Friedegund, Gutzmer, Ralf, Haferkamp, Sebastian, Zimmer, Lisa, Livingstone, Elisabeth, Eigentler, Thomas K, Hauschild, Axel, Kiecker, Felix, Hassel, Jessica C, Mohr, Peter, Fluck, Michael, Thomas, Ioannis, Garzarolli, Marlene, Grimmelmann, Imke, Drexler, Konstantin, Spillner, Alexandra N, Eckhardt, Sebastian, and Schadendorf, Dirk

Published
2023
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15. Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases

Author

Westphal, Dana, Meinhardt, Matthias, Grützmann, Konrad, Schöne, Lisa, Steininger, Julian, Neuhaus, Lena T., Wiegel, Miriam, Schrimpf, Daniel, Aust, Daniela E., Schröck, Evelin, Baretton, Gustavo B., Beissert, Stefan, Juratli, Tareq A., Schackert, Gabriele G., Gravemeyer, Jan, Becker, Jürgen C., von Deimling, Andreas, Koelsche, Christian, Klink, Barbara, Meier, Friedegund, Schulz, Alexander, Muders, Michael H., and Seifert, Michael

Published
2023
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16. Characterisation and outcome of RAC1 mutated melanoma

Author

Lodde, Georg C., Jansen, Philipp, Herbst, Rudolf, Terheyden, Patrick, Utikal, Jochen, Pföhler, Claudia, Ulrich, Jens, Kreuter, Alexander, Mohr, Peter, Gutzmer, Ralf, Meier, Friedegund, Dippel, Edgar, Weichenthal, Michael, Sucker, Antje, Placke, Jan-Malte, Zaremba, Anne, Albrecht, Lea Jessica, Kowall, Bernd, Galetzka, Wolfgang, Becker, Jürgen C., Tasdogan, Alpaslan, Zimmer, Lisa, Livingstone, Elisabeth, Hadaschik, Eva, Schadendorf, Dirk, Ugurel, Selma, and Griewank, Klaus

Published
2023
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17. Cutaneous Aspects of Leukemia

Author

Ugurel, Selma, Becker, Jürgen C., Kaufmann, Roland, Section editor, Plewig, Gerd, editor, French, Lars, editor, Ruzicka, Thomas, editor, Kaufmann, Roland, editor, and Hertl, Michael, editor

Published
2022
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18. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma

Author

Gluud, Maria, Pallesen, Emil M. H., Buus, Terkild B., Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Kamstrup, Maria R., Bzorek, Michael, Danielsen, Maria, Bech, Rikke, Monteiro, Madalena N., Blümel, Edda, Willerslev-Olsen, Andreas, Lykkebo-Valløe, Anders, Vadivel, Chella Krishna, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menne, Geisler, Carsten, Becker, Jürgen C., Koralov, Sergei B., Iversen, Lars, Litman, Thomas, Woetmann, Anders, and Ødum, Niels

Published
2023
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19. German S3 guideline “actinic keratosis and cutaneous squamous cell carcinoma” – Long version of the update 2023

Author

Leiter, Ulrike, Heppt, Markus V., Steeb, Theresa, Alter, Mareike, Amaral, Teresa, Bauer, Andrea, Bechara, Falk G., Becker, Jürgen C., Breitbart, Eckhard W., Breuninger, Helmut, Diepgen, Thomas, Dirschka, Thomas, Eigentler, Thomas, El Gammal, A.K. Stephan, Felcht, Moritz, Flaig, Michael J., Follmann, Markus, Fritz, Klaus, Grabbe, Stephan, Greinert, Rüdiger, Gutzmer, Ralf, Hauschild, Axel, Hillen, Uwe, Ihrler, Stephan, John, Swen Malte, Kofler, Lukas, Koelbl, Oliver, Krause-Bergmann, Albrecht, Kraywinkel, Klaus, Krohn, Steffen, Langer, Thomas, Loquai, Carmen, Löser, Christoph R., Mohr, Peter, Nashan, Dorothée, Nothacker, Monika, Pfannenberg, Christina, Salavastru, Carmen, Schmitz, Lutz, Stockfleth, Eggert, Szeimies, Rolf-Markus, Ulrich, Claas, Voelter-Mahlknecht, Susanne, Vordermark, Dirk, Weichenthal, Michael, Welzel, Julia, Wermker, Kai, Wiegand, Susanne, Garbe, Claus, and Berking, Carola

Published
2023
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21. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial

Author

Livingstone, Elisabeth, Zimmer, Lisa, Hassel, Jessica C, Fluck, Michael, Eigentler, Thomas K, Loquai, Carmen, Haferkamp, Sebastian, Gutzmer, Ralf, Meier, Friedegund, Mohr, Peter, Hauschild, Axel, Schilling, Bastian, Menzer, Christian, Kiecker, Felix, Dippel, Edgar, Roesch, Alexander, Ziemer, Mirjana, Conrad, Beate, Körner, Silvia, Simon, Jan-Christoph, Herbst, Rudolf A, Berking, Carola, Utikal, Jochen, Sell, Sabine, Martens, Uwe M, Terheyden, Patrick, Stadler, Rudolf, Windemuth-Kieselbach, Christine, Schwarz, Leonora, Garbe, Claus, Becker, Jürgen C, and Schadendorf, Dirk

Published
2022
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22. Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

Author

Kervarrec, Thibault, Westphal, Danna, Pissaloux, Daniel, Legrand, Mélanie, Tirode, Franck, Neuhart, Anne, Drouot, Francoise, Becker, Jürgen C, Macagno, Nicolas, Seris, Alice, Jouary, Thomas, Beltzung, Fanny, Jullie, Marie‐Laure, Harms, Paul W, Cribier, Bernard, Mourah, Samia, Jouenne, Fanélie, Fromont, Gaelle, Louveau, Baptiste, and Mancini, Maxence

Subjects
ANDROGEN receptors, IMMUNOSTAINING, SWEAT glands, RNA sequencing, CD47 antigen
Abstract

Aims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2‐fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. Methods and Results: Five patients were male and the median age was 79 years (ranges: 59–95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Persister state-directed transitioning and vulnerability in melanoma

Author

Chauvistré, Heike, Shannan, Batool, Daignault-Mill, Sheena M., Ju, Robert J., Picard, Daniel, Egetemaier, Stefanie, Váraljai, Renáta, Gibhardt, Christine S., Sechi, Antonio, Kaschani, Farnusch, Keminer, Oliver, Stehbens, Samantha J., Liu, Qin, Yin, Xiangfan, Jeyakumar, Kirujan, Vogel, Felix C. E., Krepler, Clemens, Rebecca, Vito W., Kubat, Linda, Lueong, Smiths S., Forster, Jan, Horn, Susanne, Remke, Marc, Ehrmann, Michael, Paschen, Annette, Becker, Jürgen C., Helfrich, Iris, Rauh, Daniel, Kaiser, Markus, Gul, Sheraz, Herlyn, Meenhard, Bogeski, Ivan, Rodríguez-López, José Neptuno, Haass, Nikolas K., Schadendorf, Dirk, and Roesch, Alexander

Published
2022
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26. A Prospective Study Investigating Immune Checkpoint Molecule and CD39 Expression on Peripheral Blood Cells for the Prognostication of COVID-19 Severity and Mortality

Author

Gambichler, Thilo, primary, Rüth, Jonas, additional, Goesmann, Silke, additional, Höxtermann, Stefan, additional, Skrygan, Marina, additional, Susok, Laura, additional, Becker, Jürgen C., additional, Overheu, Oliver, additional, Schmidt, Wolfgang, additional, and Reinacher-Schick, Anke, additional

Published
2024
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28. S1‐Leitlinie Talgdrüsenkarzinom

Author

Utikal, Jochen, primary, Nagel, Pia, additional, Müller, Verena, additional, Becker, Jürgen C., additional, Dippel, Edgar, additional, Frisman, Alexander, additional, Gschnell, Martin, additional, Griewank, Klaus, additional, Hadaschik, Eva, additional, Helbig, Doris, additional, Hillen, Uwe, additional, Leiter, Ulrike, additional, Pföhler, Claudia, additional, Krönig, Lisa, additional, Ziemer, Mirjana, additional, and Ugurel, Selma, additional

Published
2024
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33. T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma

Author

Hansen, Ulla Kring, Church, Candice D., Simões, Ana Micaela Carnaz, Frej, Marcus Svensson, Bentzen, Amalie Kai, Tvingsholm, Siri A., Becker, Jürgen C., Fling, Steven P., Ramchurren, Nirasha, Topalian, Suzanne L., Nghiem, Paul T., Hadrup, Sine Reker, Hansen, Ulla Kring, Church, Candice D., Simões, Ana Micaela Carnaz, Frej, Marcus Svensson, Bentzen, Amalie Kai, Tvingsholm, Siri A., Becker, Jürgen C., Fling, Steven P., Ramchurren, Nirasha, Topalian, Suzanne L., Nghiem, Paul T., and Hadrup, Sine Reker

Abstract

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag–specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag–reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag–derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag–specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag–specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag–specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.

Published
2024

36. Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation.

Author

Kervarrec, Thibault, Appenzeller, Silke, Gramlich, Susanne, Coyaud, Etienne, Bachiri, Kamel, Appay, Romain, Macagno, Nicolas, Tallet, Anne, Bonenfant, Christine, Lecorre, Yannick, Kapfer, Jean, Kettani, Sami, Srinivas, Nalini, Lei, Kuan Cheok, Lange, Anja, Becker, Jürgen C, Sarosi, Eva Maria, Sartelet, Hervé, von Deimling, Andreas, and Touzé, Antoine

Subjects
MERKEL cell carcinoma, MERKEL cells, OLDER men, SQUAMOUS cell carcinoma, DNA methylation
Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV‐negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high‐grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T‐truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC‐typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Published
2024
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37. Single-cell RNA and T-cell receptor sequencing unveil mycosis fungoides heterogeneity and a possible gene signature.

Author

Srinivas, Nalini, Peiffer, Lukas, Horny, Kai, Kuan Cheok Lei, Buus, Terkild B., Kubat, Linda, Meng Luo, Menghong Yin, Spassova, Ivelina, Sucker, Antje, Farahpour, Farnoush, Kehrmann, Jan, Ugurel, Selma, Livingstone, Elisabeth, Gambichler, Thilo, Ødum, Niels, and Becker, Jürgen C.

Subjects
CYTOTOXIC T cells, CUTANEOUS T-cell lymphoma, DRUG eruptions, CANCER cells, T cells, MYCOSIS fungoides
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. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Introducing MCC-PS: a novel prognostic score for Merkel cell carcinoma.

Author

Rached, Nessr Abu, Becker, Jürgen C., Lonsdorf, Anke S., Keller, Aric, Zeglis, Ioannis A., and Gambichler, Thilo

Subjects
MERKEL cell carcinoma, RECEIVER operating characteristic curves, INTERNATIONAL normalized ratio, PROGRESSION-free survival, SKIN cancer
Abstract

Introduction: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a poor prognosis, which only improved with the introduction of immunotherapies. An MCC prediction model with high diagnostic accuracy is lacking. The aim was to develop an MCC prognostic score (MCC-PS) based on combinations of previously proposed risk factors. Methods: A multicentric, retrospective study was conducted to develop MCCPS, which included age, neuron-specific enolase (NSE), C-reactive protein (CRP), creatinine, bilirubin, and international normalized ratio (INR). Creatinine, bilirubin, and INR were used to calculate the model of end-stage liver disease (MELD) score. A total of 98 patients were included in the study, including 36.7% with stage I according to American Joint Committee on Cancer 2018 (n = 36), 30.6% with stage II (n = 30), 25.5% with stage III (n = 25), and 7.1% with stage IV (n = 7). Survival data of MCC patients were correlated with selected laboratory parameters and risk factors. Primary endpoint was MCC-specific survival (MSS) and the secondary endpoint was progression-free survival. Several statistical methods were used to develop the prognostic score, including correlation analysis, Kaplan-Meier curves, Cox regression, and time-dependent receiver operating characteristic analysis. Results: The MCC-PS is based on the sum of the following baseline variables: elevated CRP (≥5.5 mg/l), elevated NSE (≥22.8 μg/l), MELD score ≥ 11, and age ≥ 75 years. An MELD score ≥ 11 was scored as 4 points, elevated NSE level as 3 points, elevated CRP level as 2 points, and age ≥ 75 years as 1 point. A high-risk group according to the MCC-PS was characterized by a score of 4 or more points. The high-risk group was associated with a worse prognosis than the lowrisk group (1-year MSS 62%, 2-year 43.1%, 5-year 17.6% as compared to 1-year MSS 79.5%, 3-year 75%, 5-year 72%). Notably, the developed MCC-PS predicts MCC outcome measures with high accuracy (3-year MSS: area under the curve (AUC) 0.934, sensitivity 87.5% and specificity 82.2%; 5-year MSS: AUC 0.93, sensitivity 89% and specificity 82%). Conclusion: MCC-PS is the first prognostic score predicting MCC outcome with a high accuracy based on five easily available laboratory parameters and patient's age. An MCC-PS of 4 or more indicates a high-risk patient associated with a poor prognosis. Conclusion: MCC-PS is the first prognostic score predicting MCC outcome with a high accuracy based on five easily available laboratory parameters and patient's age. An MCC-PS of 4 or more indicates a high-risk patient associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Merkel cell polyomavirus pan‐T antigen knockdown reduces cancer cell stemness and promotes neural differentiation independent of RB1.

Author

Lei, Kuan Cheok, Srinivas, Nalini, Chandra, Mitalee, Kervarrec, Thibault, Coyaud, Etienne, Spassova, Ivelina, Peiffer, Lukas, Houben, Roland, Shuda, Masahiro, Hoffmann, Daniel, Schrama, David, and Becker, Jürgen C.

Subjects
MERKEL cells, GENE regulatory networks, CANCER cells, POLYOMAVIRUSES, MERKEL cell carcinoma, TRANSCRIPTION factors
Abstract

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with integration of Merkel cell polyomavirus (MCPyV). MCPyV‐encoded T‐antigens (TAs) are pivotal for sustaining MCC's oncogenic phenotype, i.e., repression of TAs results in reactivation of the RB pathway and subsequent cell cycle arrest. However, the MCC cell line LoKe, characterized by a homozygous loss of the RB1 gene, exhibits uninterrupted cell cycle progression after shRNA‐mediated TA repression. This unique feature allows an in‐depth analysis of the effects of TAs beyond inhibition of the RB pathway, revealing the decrease in expression of stem cell‐related genes upon panTA‐knockdown. Analysis of gene regulatory networks identified members of the E2F family (E2F1, E2F8, TFDP1) as key transcriptional regulators that maintain stem cell properties in TA‐expressing MCC cells. Furthermore, minichromosome maintenance (MCM) genes, which encodes DNA‐binding licensing proteins essential for stem cell maintenance, were suppressed upon panTA‐knockdown. The decline in stemness occurred simultaneously with neural differentiation, marked by the increased expression of neurogenesis‐related genes such as neurexins, BTG2, and MYT1L. This upregulation can be attributed to heightened activity of PBX1 and BPTF, crucial regulators of neurogenesis pathways. The observations in LoKe were confirmed in an additional MCPyV‐positive MCC cell line in which RB1 was silenced before panTA‐knockdown. Moreover, spatially resolved transcriptomics demonstrated reduced TA expression in situ in a part of a MCC tumor characterized by neural differentiation. In summary, TAs are critical for maintaining stemness of MCC cells and suppressing neural differentiation, irrespective of their impact on the RB‐signaling pathway. [ABSTRACT FROM AUTHOR]

Published
2024
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40. T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma

Author

Farah, Maya, Reuben, Alexandre, Spassova, Ivelina, Yang, Richard K., Kubat, Linda, Nagarajan, Priyadharsini, Ning, Jing, Li, Wen, Aung, Phyu P., Curry, Jonathan L., Torres-Cabala, Carlos A., Hudgens, Courtney W., Ugurel, Selma, Schadendorf, Dirk, Gumbs, Curtis, Little, Latasha D., Futreal, Andrew, Wistuba, Ignacio I., Prieto, Victor G., Wang, Linghua, Wong, Michael K., Wargo, Jennifer A., Becker, Jürgen C., and Tetzlaff, Michael T.

Published
2020
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41. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial

Author

Berking, Carola, Herbst, Rudolf A, Martens, Uwe M, Sell, Sabine, Stadler, Rudolf, Terheyden, Patrick, Utikal, Jochen, Zimmer, Lisa, Livingstone, Elisabeth, Hassel, Jessica C, Fluck, Michael, Eigentler, Thomas, Loquai, Carmen, Haferkamp, Sebastian, Gutzmer, Ralf, Meier, Friedegund, Mohr, Peter, Hauschild, Axel, Schilling, Bastian, Menzer, Christian, Kieker, Felix, Dippel, Edgar, Rösch, Alexander, Simon, Jan-Christoph, Conrad, Beate, Körner, Silvia, Windemuth-Kieselbach, Christine, Schwarz, Leonora, Garbe, Claus, Becker, Jürgen C, and Schadendorf, Dirk

Published
2020
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42. Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019

Author

Ugurel, Selma, Röhmel, Joachim, Ascierto, Paolo A., Becker, Jürgen C., Flaherty, Keith T., Grob, Jean J., Hauschild, Axel, Larkin, James, Livingstone, Elisabeth, Long, Georgina V., Lorigan, Paul, McArthur, Grant A., Ribas, Antoni, Robert, Caroline, Zimmer, Lisa, Schadendorf, Dirk, and Garbe, Claus

Published
2020
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45. T antigen–specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma

Author

Hansen, Ulla Kring, primary, Church, Candice D., additional, Carnaz Simões, Ana Micaela, additional, Frej, Marcus Svensson, additional, Bentzen, Amalie Kai, additional, Tvingsholm, Siri A., additional, Becker, Jürgen C., additional, Fling, Steven P., additional, Ramchurren, Nirasha, additional, Topalian, Suzanne L., additional, Nghiem, Paul T., additional, and Hadrup, Sine Reker, additional

Published
2024
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50. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

Author

Johnson, Douglas B, Menzies, Alexander M, Zimmer, Lisa, Eroglu, Zeynep, Ye, Fei, Zhao, Shilin, Rizos, Helen, Sucker, Antje, Scolyer, Richard A, Gutzmer, Ralf, Gogas, Helen, Kefford, Richard F, Thompson, John F, Becker, Jürgen C, Berking, Carola, Egberts, Friederike, Loquai, Carmen, Goldinger, Simone M, Pupo, Gulietta M, Hugo, Willy, Kong, Xiangju, Garraway, Levi A, Sosman, Jeffrey A, Ribas, Antoni, Lo, Roger S, Long, Georgina V, and Schadendorf, Dirk

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Antineoplastic Agents, Australia, Biomarkers, Tumor, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Europe, Female, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Melanoma, Middle Aged, Mutation, Phenotype, Proportional Hazards Models, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Risk Factors, Signal Transduction, Skin Neoplasms, Time Factors, Treatment Outcome, United States, BRAF, Vemurafenib, Dabrafenib, Resistance, Acquired, MAPK, NRAS, Splice, MEK1, Meta-analysis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms.ConclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.

Published
2015

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