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5,696 results on '"Stilgenbauer"'

8. The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma—a randomized, open-label phase III trial of the European mantle cell lymphoma network

Author

Fischer, Luca, Jiang, Linmiao, Dürig, Jan, Schmidt, Christian, Stilgenbauer, Stephan, Bouabdallah, Krimo, Solal-Celigny, Philippe, Scholz, Christian W., Feugier, Pierre, de Wit, Maike, Trappe, Ralf Ulrich, Hallek, Michael, Graeven, Ullrich, Hänel, Mathias, Hoffmann, Martin, Delwail, Vincent, Macro, Margaret, Greiner, Jochen, Giagounidis, Aristoteles A. N., Dargel, Beate, Durot, Eric, Foussard, Charles, Silkenstedt, Elisabeth, Weigert, Oliver, Pott, Christiane, Klapper, Wolfram, Hiddemann, Wolfgang, Unterhalt, Michael, Hoster, Eva, Ribrag, Vincent, and Dreyling, Martin

Published
2024
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9. repDilPCR: a tool for automated analysis of qPCR assays by the dilution-replicate method

Author

Deyan Yordanov Yosifov, Michaela Reichenzeller, Stephan Stilgenbauer, and Daniel Mertens

Subjects
QPCR, Dilution-replicate design, RT-PCR, Polymerase chain reaction, Automation, Plotting, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The dilution-replicate experimental design for qPCR assays is especially efficient. It is based on multiple linear regression of multiple 3-point standard curves that are derived from the experimental samples themselves and thus obviates the need for a separate standard curve produced by serial dilution of a standard. The method minimizes the total number of reactions and guarantees that Cq values are within the linear dynamic range of the dilution-replicate standard curves. However, the lack of specialized software has so far precluded the widespread use of the dilution-replicate approach. Results Here we present repDilPCR, the first tool that utilizes the dilution-replicate method and extends it by adding the possibility to use multiple reference genes. repDilPCR offers extensive statistical and graphical functions that can also be used with preprocessed data (relative expression values) obtained by usual assay designs and evaluation methods. repDilPCR has been designed with the philosophy to automate and speed up data analysis (typically less than a minute from Cq values to publication-ready plots), and features automatic selection and performance of appropriate statistical tests, at least in the case of one-factor experimental designs. Nevertheless, the program also allows users to export intermediate data and perform more sophisticated analyses with external statistical software, e.g. if two-way ANOVA is necessary. Conclusions repDilPCR is a user-friendly tool that can contribute to more efficient planning of qPCR experiments and their robust analysis. A public web server is freely accessible at https://repdilpcr.eu without registration. The program can also be used as an R script or as a locally installed Shiny app, which can be downloaded from https://github.com/deyanyosifov/repDilPCR where also the source code is available.

Published
2024
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10. Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial

Author

Langerbeins, Petra, Robrecht, Sandra, Nieper, Pascal, Cramer, Paula, Fürstenau, Moritz, Al-Sawaf, Othman, Simon, Florian, Fink, Anna-Maria, Kreuzer, Karl-Anton, Vehling-Kaiser, Ursula, Tausch, Eugen, Schneider, Christof, Müller, Lothar, Eckart, Michael Josef, Schlag, Rudolf, Freier, Werner, Gaska, Tobias, Balser, Christina, Reiser, Marcel, Stauch, Martina, Zahn, Mark-Oliver, Dörfel, Steffen, Staib, Peter, Behlendorf, Timo, Hensel, Manfred, Hebart, Holger, Klaproth, Holger, Block, Andreas, Liersch, Rüdiger, Hauch, Ulrich, Heinrich, Bernhard, Wendtner, Clemens-Martin, Fischer, Kirsten, Stilgenbauer, Stephan, Eichhorst, Barbara, and Hallek, Michael

Published
2024
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11. Impairment of α-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion

Author

Junnan Liu, Xue Wang, Wencheng Jiang, Anca Azoitei, Tim Eiseler, Markus Eckstein, Arndt Hartmann, Stephan Stilgenbauer, Mohamed Elati, Meike Hohwieler, Alexander Kleger, Axel John, Felix Wezel, Friedemann Zengerling, Christian Bolenz, and Cagatay Günes

Subjects
Spindle orientation, Chromosomal imbalance, Invadopodia, Metastasis, MIBC, Cytology, QH573-671
Abstract

Abstract Background We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved. Methods GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment. Results We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation. Conclusion We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination. Graphical Abstract

Published
2024
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12. Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation

Author

Stefanie Enzenmüller, Alexandra Niedermayer, Felix Seyfried, Vera Muench, Daniel Tews, Ulrich Rupp, Eugen Tausch, Alexander Groß, Pamela Fischer-Posovszky, Paul Walther, Stephan Stilgenbauer, Hans A. Kestler, Klaus-Michael Debatin, and Lüder Hinrich Meyer

Subjects
Cytology, QH573-671
Abstract

Abstract Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

Published
2024
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15. Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL

Author

Thomas Chatzikonstantinou, Lydia Scarfò, Eva Minga, Georgios Karakatsoulis, Dimitra Chamou, Jana Kotaskova, Gloria Iacoboni, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al‐Shemari, Thérèse Aurran‐Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Rosa Collado, Zadie Davis, Marcos Daniel deDeus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El‐Ashwah, Alicia Enrico, Andrzej Frygier, Sara Galimberti, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Romain Guieze, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José‐Ángel Hernández‐Rivas, Ozren Jaksic, Elżbieta Kalicińska, Kamel Laribi, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Maya Koren‐Michowitz, Ioannis Kotsianidis, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez‐Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor‐Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Almudena Navarro‐Bailón, Jacopo Olivieri, Irina Panovska‐Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Gianluigi Reda, Gian M. Rigolin, Rosa Ruchlemer, Mattia Schipani, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Stephan Stilgenbauer, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, George Vrachiolias, Vojin Vukovic, Renata Walewska, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Francesc Bosch, Paolo Sportoletti, Blanca Espinet, Gerassimos A. Pangalis, Viola M. Popov, Stephen Mulligan, Maria Angelopoulou, Fatih Demirkan, Tomas Papajík, Bella Biderman, Roberta Murru, Marta Coscia, Constantine Tam, Antonio Cuneo, Gianluca Gaidano, Rainer Claus, Niki Stavroyianni, Livio Trentin, Darko Antic, Lukas Smolej, Olga B. Kalashnikova, Mark Catherwood, Martin Spacek, Sarka Pospisilova, Michael Doubek, Eugene Nikitin, Anastasia Chatzidimitriou, Paolo Ghia, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2024
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16. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Author

Parry, Erin M, Leshchiner, Ignaty, Guièze, Romain, Johnson, Connor, Tausch, Eugen, Parikh, Sameer A, Lemvigh, Camilla, Broséus, Julien, Hergalant, Sébastien, Messer, Conor, Utro, Filippo, Levovitz, Chaya, Rhrissorrakrai, Kahn, Li, Liang, Rosebrock, Daniel, Yin, Shanye, Deng, Stephanie, Slowik, Kara, Jacobs, Raquel, Huang, Teddy, Li, Shuqiang, Fell, Geoff, Redd, Robert, Lin, Ziao, Knisbacher, Binyamin A, Livitz, Dimitri, Schneider, Christof, Ruthen, Neil, Elagina, Liudmila, Taylor-Weiner, Amaro, Persaud, Bria, Martinez, Aina, Fernandes, Stacey M, Purroy, Noelia, Anandappa, Annabelle J, Ma, Jialin, Hess, Julian, Rassenti, Laura Z, Kipps, Thomas J, Jain, Nitin, Wierda, William, Cymbalista, Florence, Feugier, Pierre, Kay, Neil E, Livak, Kenneth J, Danysh, Brian P, Stewart, Chip, Neuberg, Donna, Davids, Matthew S, Brown, Jennifer R, Parida, Laxmi, Stilgenbauer, Stephan, Getz, Gad, and Wu, Catherine J

Subjects
Cancer, Rare Diseases, Lymphoma, Genetics, Hematology, Human Genome, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Serine-Arginine Splicing Factors, Medical and Health Sciences, Immunology
Abstract

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Published
2023

17. Molecular map of chronic lymphocytic leukemia and its impact on outcome

Author

Knisbacher, Binyamin A, Lin, Ziao, Hahn, Cynthia K, Nadeu, Ferran, Duran-Ferrer, Martí, Stevenson, Kristen E, Tausch, Eugen, Delgado, Julio, Barbera-Mourelle, Alex, Taylor-Weiner, Amaro, Bousquets-Muñoz, Pablo, Diaz-Navarro, Ander, Dunford, Andrew, Anand, Shankara, Kretzmer, Helene, Gutierrez-Abril, Jesus, López-Tamargo, Sara, Fernandes, Stacey M, Sun, Clare, Sivina, Mariela, Rassenti, Laura Z, Schneider, Christof, Li, Shuqiang, Parida, Laxmi, Meissner, Alexander, Aguet, François, Burger, Jan A, Wiestner, Adrian, Kipps, Thomas J, Brown, Jennifer R, Hallek, Michael, Stewart, Chip, Neuberg, Donna S, Martín-Subero, José I, Puente, Xose S, Stilgenbauer, Stephan, Wu, Catherine J, Campo, Elias, and Getz, Gad

Subjects
Hematology, Clinical Research, Cancer, Human Genome, Rare Diseases, Biotechnology, Genetics, Lymphoma, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Immunoglobulin Variable Region, Mutation, Prognosis, Genomics, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

Published
2022

18. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Author

Al-Sawaf, Othman, Ligtvoet, Rudy, Robrecht, Sandra, Stumpf, Janina, Fink, Anna-Maria, Tausch, Eugen, Schneider, Christof, Boettcher, Sebastian, Mikusko, Martin, Ritgen, Matthias, Schetelig, Johannes, von Tresckow, Julia, Vehling-Kaiser, Ursula, Gaska, Tobias, Wendtner, Clemens Martin, Chapuy, Bjoern, Fischer, Kirsten, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Staber, Philipp, Niemann, Carsten, Hallek, Michael, and Eichhorst, Barbara

Published
2024
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19. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study

Author

Al-Sawaf, Othman, Robrecht, Sandra, Zhang, Can, Olivieri, Stefano, Chang, Yi Meng, Fink, Anna Maria, Tausch, Eugen, Schneider, Christof, Ritgen, Matthias, Kreuzer, Karl-Anton, Sivchev, Liliya, Niemann, Carsten Utoft, Schwarer, Anthony, Loscertales, Javier, Weinkove, Robert, Strumberg, Dirk, Kilfoyle, Allanah, Manzoor, Beenish S., Jawaid, Dureshahwar, Emechebe, Nnadozie, Devine, Jacob, Boyer, Michelle, Runkel, Eva D., Eichhorst, Barbara, Stilgenbauer, Stephan, Jiang, Yanwen, Hallek, Michael, and Fischer, Kirsten

Published
2024
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20. T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia

Author

Roessner, Philipp M., Seufert, Isabelle, Chapaprieta, Vicente, Jayabalan, Ruparoshni, Briesch, Hannah, Massoni-Badosa, Ramon, Boskovic, Pavle, Benckendorff, Julian, Roider, Tobias, Arseni, Lavinia, Coelho, Mariana, Chakraborty, Supriya, Vaca, Alicia M., Sivina, Mariela, Muckenhuber, Markus, Rodriguez-Rodriguez, Sonia, Bonato, Alice, Herbst, Sophie A., Zapatka, Marc, Sun, Clare, Kretzmer, Helene, Naake, Thomas, Bruch, Peter-Martin, Czernilofsky, Felix, ten Hacken, Elisa, Schneider, Martin, Helm, Dominic, Yosifov, Deyan Y., Kauer, Joseph, Danilov, Alexey V., Bewarder, Moritz, Heyne, Kristina, Schneider, Christof, Stilgenbauer, Stephan, Wiestner, Adrian, Mallm, Jan-Philipp, Burger, Jan A., Efremov, Dimitar G., Lichter, Peter, Dietrich, Sascha, Martin-Subero, José I., Rippe, Karsten, and Seiffert, Martina

Published
2024
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21. The role of trephine bone marrow biopsies in the era of measurable residual disease—Results from the CLL10 trial of the German CLL Study Group (GCLLSG)

Author

Nadine Kutsch, Sandra Robrecht, Anna Fink, Elisabeth Lange, Rudolf Weide, Michael G. Kiehl, Martin Sökler, Rudolf Schlag, Ursula Vehling‐Kaiser, Georg Köchling, Christoph Plöger, Michael Gregor, Torben Plesner, Michael R. Clausen, Ilske Oschlies, Matthias Ritgen, Marco Herling, Kirsten Fischer, Hartmut Döhner, Clemens‐Martin Wendtner, Karl‐Anton Kreuzer, Stephan Stilgenbauer, Michael Hallek, Sebastian Böttcher, Wolfram Klapper, and Barbara Eichhorst

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2024
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22. Regional outcome disparities in German head and neck cancer patients: Shorter survival in Eastern Germany

Author

Julius M. Vahl, Gabriele Nagel, Tsima Abou Kors, Matthias Brand, Adrian vonWitzleben, Michael Sonntag, Ayla Grages, Marie N. Theodoraki, Jens Greve, Michael Denkinger, Dhayana Dallmeier, Christian Idel, Stephan Stilgenbauer, Thomas K. Hoffmann, and Simon Laban

Subjects
age, cancer registry data, demographic change, socioeconomic health disparity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Introduction Demographics are important prognostic factors in malignant diseases. A nationwide analysis concerning the prognostic impact of demographics in head and neck cancer (HNC) patients (HNCP) has not been performed previously. Methods A retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) and the Federal Statistical Office (Destatis) between 2002 and 2017 was performed. A total of 212′920 HNCP were included. Incidence, tumor stage, age development, sex distribution, age‐, residence‐, and diagnosis‐time‐specific survival were examined. Results Mean age of HNCP increased more rapidly than in the general population (slope coefficient: 0.29 vs. 0.20; p 70 years was found. Furthermore, an OS disadvantage was observed for East Germany compared to West Germany (median 47 vs. 60 months; p

Published
2023
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24. Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial

Author

Fürstenau, Moritz, Giza, Adam, Weiss, Jonathan, Kleinert, Fanni, Robrecht, Sandra, Franzen, Fabian, Stumpf, Janina, Langerbeins, Petra, Al-Sawaf, Othman, Simon, Florian, Fink, Anna-Maria, Schneider, Christof, Tausch, Eugen, Schetelig, Johannes, Dreger, Peter, Böttcher, Sebastian, Fischer, Kirsten, Kreuzer, Karl-Anton, Ritgen, Matthias, Schilhabel, Anke, Brüggemann, Monika, Stilgenbauer, Stephan, Eichhorst, Barbara, Hallek, Michael, and Cramer, Paula

Published
2024
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25. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies

Author

Langerbeins, Petra, Giza, Adam, Robrecht, Sandra, Cramer, Paula, von Tresckow, Julia, Al-Sawaf, Othman, Fink, Anna Maria, Fürstenau, Moritz, Kutsch, Nadine, Simon, Florian, Goede, Valentin, Hoechstetter, Manuela, Niemann, Carsten Utoft, da Cunha-Bang, Caspar, Kater, Arnon, Dubois, Julie, Gregor, Michael, Staber, Philipp Bernhard, Tausch, Eugen, Schneider, Christof, Stilgenbauer, Stephan, Eichhorst, Barbara, Fischer, Kirsten, and Hallek, Michael

Published
2024
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26. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial

Author

Fürstenau, Moritz, Kater, Arnon P, Robrecht, Sandra, von Tresckow, Julia, Zhang, Can, Gregor, Michael, Thornton, Patrick, Staber, Philipp B, Tadmor, Tamar, Lindström, Vesa, Juliusson, Gunnar, Janssens, Ann, Levin, Mark-David, da Cunha-Bang, Caspar, Schneider, Christof, Goldschmidt, Neta, Vandenberghe, Elisabeth, Rossi, Davide, Benz, Rudolf, Nösslinger, Thomas, Heintel, Daniel, Poulsen, Christian B, Christiansen, Ilse, Frederiksen, Henrik, Enggaard, Lisbeth, Posthuma, Eduardus F M, Issa, Djamila E, Visser, Hein P J, Bellido, Mar, Kutsch, Nadine, Dürig, Jan, Stehle, Alexander, Vöhringer, Matthias, Böttcher, Sebastian, Schulte, Clemens, Simon, Florian, Fink, Anna-Maria, Fischer, Kirsten, Holmes, Emily E, Kreuzer, Karl-Anton, Ritgen, Matthias, Brüggemann, Monika, Tausch, Eugen, Stilgenbauer, Stephan, Hallek, Michael, Niemann, Carsten U, and Eichhorst, Barbara

Published
2024
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27. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Author

Dreyling, Martin, Doorduijn, Jeanette, Giné, Eva, Jerkeman, Mats, Walewski, Jan, Hutchings, Martin, Mey, Ulrich, Riise, Jon, Trneny, Marek, Vergote, Vibeke, Shpilberg, Ofer, Gomes da Silva, Maria, Leppä, Sirpa, Jiang, Linmiao, Stilgenbauer, Stephan, Kerkhoff, Andrea, Jachimowicz, Ron D, Celli, Melania, Hess, Georg, Arcaini, Luca, Visco, Carlo, van Meerten, Tom, Wirths, Stefan, Zinzani, Pier Luigi, Novak, Urban, Herhaus, Peter, Benedetti, Fabio, Sonnevi, Kristina, Hanoun, Christine, Hänel, Matthias, Dierlamm, Judith, Pott, Christiane, Klapper, Wolfram, Gözel, Döndü, Schmidt, Christian, Unterhalt, Michael, Ladetto, Marco, and Hoster, Eva

Published
2024
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28. Activation of Notch and Myc signaling via B cell-restricted depletion of Dnmt3a generates a consistent murine model of chronic lymphocytic leukemia

Author

Biran, Anat, Yin, Shanye, Kretzmer, Helene, Ten Hacken, Elisa, Parvin, Salma, Lucas, Fabienne, Uduman, Mohamed, Gutierrez, Catherine, Dangle, Nathan, Billington, Leah, Regis, Fara Faye, Rassenti, Laura Z, Mohammad, Arman, Hoffmann, Gabriela Brunsting, Stevenson, Kristen, Zheng, Mei, Witten, Elizabeth, Fernandes, Stacey M, Tausch, Eugen, Sun, Clare, Stilgenbauer, Stephan, Brown, Jennifer R, Kipps, Thomas J, Aster, John C, Gnirke, Andreas, Neuberg, Donna S, Letai, Anthony, Wang, Lili, Carrasco, Ruben D, Meissner, Alexander, and Wu, Catherine J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Lymphatic Research, Cancer, Cancer Genomics, Hematology, Human Genome, Lymphoma, Rare Diseases, 2.1 Biological and endogenous factors, Animals, Anti-Bacterial Agents, Apoptosis, Biomarkers, Tumor, Cell Proliferation, DNA Methyltransferase 3A, Daptomycin, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Prognosis, Proto-Oncogene Proteins c-myc, RNA-Seq, Receptors, Notch, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc-expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. SIGNIFICANCE: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition.

Published
2021

29. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial

Author

Byrd, John C, Hillmen, Peter, Ghia, Paolo, Kater, Arnon P, Chanan-Khan, Asher, Furman, Richard R, O'Brien, Susan, Yenerel, Mustafa Nuri, Illés, Arpad, Kay, Neil, Garcia-Marco, Jose A, Mato, Anthony, Pinilla-Ibarz, Javier, Seymour, John F, Lepretre, Stephane, Stilgenbauer, Stephan, Robak, Tadeusz, Rothbaum, Wayne, Izumi, Raquel, Hamdy, Ahmed, Patel, Priti, Higgins, Kara, Sohoni, Sophia, and Jurczak, Wojciech

Subjects
Clinical Research, Hematology, Lymphoma, Cancer, Rare Diseases, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adenine, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Prognosis, Prospective Studies, Pyrazines, Survival Rate, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeAmong Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).MethodsPatients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).ResultsOverall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.ConclusionIn this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Published
2021

30. Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia

Author

Stilgenbauer, Stephan, Tausch, Eugen, Roberts, Andrew W., Davids, Matthew S., Eichhorst, Barbara, Hallek, Michael, Hillmen, Peter, Schneider, Christof, Schetelig, Johannes, Böttcher, Sebastian, Kater, Arnon P., Jiang, Yanwen, Boyer, Michelle, Popovic, Relja, Ghanim, Majd T., Moran, Michael, Sinai, Wendy J., Wang, Xifeng, Mukherjee, Nabanita, Chyla, Brenda, Wierda, William G., and Seymour, John F.

Published
2024
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32. Profile of the multicenter cohort of the German Cancer Consortium’s Clinical Communication Platform

Author

Maier, Daniel, Vehreschild, Jörg Janne, Uhl, Barbara, Meyer, Sandra, Berger-Thürmel, Karin, Boerries, Melanie, Braren, Rickmer, Grünwald, Viktor, Hadaschik, Boris, Palm, Stefan, Singer, Susanne, Stuschke, Martin, Juárez, David, Delpy, Pierre, Lambarki, Mohamed, Hummel, Michael, Engels, Cäcilia, Andreas, Stefanie, Gökbuget, Nicola, Ihrig, Kristina, Burock, Susen, Keune, Dietmar, Eggert, Angelika, Keilholz, Ulrich, Schulz, Hagen, Büttner, Daniel, Löck, Steffen, Krause, Mechthild, Esins, Mirko, Ressing, Frank, Schuler, Martin, Brandts, Christian, Brucker, Daniel P., Husmann, Gabriele, Oellerich, Thomas, Metzger, Patrick, Voigt, Frederik, Illert, Anna L., Theobald, Matthias, Kindler, Thomas, Sudhof, Ursula, Reckmann, Achim, Schwinghammer, Felix, Nasseh, Daniel, Weichert, Wilko, von Bergwelt-Baildon, Michael, Bitzer, Michael, Malek, Nisar, Öner, Öznur, Schulze-Osthoff, Klaus, Bartels, Stefan, Haier, Jörg, Ammann, Raimund, Schmidt, Anja Franziska, Guenther, Bernd, Janning, Melanie, Kasper, Bernd, Loges, Sonja, Stilgenbauer, Stephan, Kuhn, Peter, Tausch, Eugen, Runow, Silvana, Kerscher, Alexander, Neumann, Michael, Breu, Martin, Lablans, Martin, and Serve, Hubert

Published
2023
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33. Author Correction: Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

Author

Al-Sawaf, Othman, Zhang, Can, Jin, Hyun Yong, Robrecht, Sandra, Choi, Yoonha, Balasubramanian, Sandhya, Kotak, Alex, Chang, Yi Meng, Fink, Anna Maria, Tausch, Eugen, Schneider, Christof, Ritgen, Matthias, Kreuzer, Karl-Anton, Chyla, Brenda, Paulson, Joseph N., Pallasch, Christian P., Frenzel, Lukas P., Peifer, Martin, Eichhorst, Barbara, Stilgenbauer, Stephan, Jiang, Yanwen, Hallek, Michael, and Fischer, Kirsten

Published
2023
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34. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

Author

Al-Sawaf, Othman, Zhang, Can, Jin, Hyun Yong, Robrecht, Sandra, Choi, Yoonha, Balasubramanian, Sandhya, Kotak, Alex, Chang, Yi Meng, Fink, Anna Maria, Tausch, Eugen, Schneider, Christof, Ritgen, Matthias, Kreuzer, Karl-Anton, Chyla, Brenda, Paulson, Joseph N., Pallasch, Christian P., Frenzel, Lukas P., Peifer, Martin, Eichhorst, Barbara, Stilgenbauer, Stephan, Jiang, Yanwen, Hallek, Michael, and Fischer, Kirsten

Published
2023
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35. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Broséus, Julien, Hergalant, Sébastien, Vogt, Julia, Tausch, Eugen, Kreuz, Markus, Mottok, Anja, Schneider, Christof, Dartigeas, Caroline, Roos-Weil, Damien, Quinquenel, Anne, Moulin, Charline, Ott, German, Blanchet, Odile, Tomowiak, Cécile, Lazarian, Grégory, Rouyer, Pierre, Chteinberg, Emil, Bernhart, Stephan H., Tournilhac, Olivier, Gauchotte, Guillaume, Lomazzi, Sandra, Chapiro, Elise, Nguyen-Khac, Florence, Chery, Céline, Davi, Frédéric, Hunault, Mathilde, Houlgatte, Rémi, Rosenwald, Andreas, Delmer, Alain, Meyre, David, Béné, Marie-Christine, Thieblemont, Catherine, Lichter, Peter, Ammerpohl, Ole, Guéant, Jean-Louis, Guièze, Romain, Martin-Subero, José Ignacio, Cymbalista, Florence, Feugier, Pierre, Siebert, Reiner, and Stilgenbauer, Stephan

Published
2023
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40. Cancer care in German centers of excellence during the first 2 years of the COVID-19 pandemic

Author

Arndt, Volker, Doege, Daniela, Fröhling, Stefan, Albers, Peter, Algül, Hana, Bargou, Ralf, Bokemeyer, Carsten, Bornhäuser, Martin, Brandts, Christian H., Brossart, Peter, Brucker, Sara Yvonne, Brümmendorf, Tim H., Döhner, Hartmut, Gattermann, Norbert, Hallek, Michael, Heinemann, Volker, Keilholz, Ulrich, Kindler, Thomas, von Levetzow, Cornelia, Lordick, Florian, Neumann, Ulf Peter, Peters, Christoph, Schadendorf, Dirk, Stilgenbauer, Stephan, Zander, Thomas, Zips, Daniel, Braun, Delia, Seufferlein, Thomas, Nettekoven, Gerd, and Baumann, Michael

Published
2023
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41. Relationship Between Venetoclax Exposure and Undetectable Minimal Residual Disease Rates in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of Six Clinical Studies

Author

Sathej Gopalakrishnan, Rajeev Menon, Ahmed A. Suleiman, Arnon P. Kater, Stephan Stilgenbauer, John F. Seymour, Brenda Chyla, Tong Lu, Su Young Kim, Andrew W. Roberts, Jennifer A. Woyach, Sven Mensing, and Ahmed Hamed Salem

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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42. Final analysis of the CLL2-GIVe trial: obinutuzumab, ibrutinib, and venetoclax for untreated CLL with del(17p)/TP53mut

Author

Huber, Henriette, Tausch, Eugen, Schneider, Christof, Edenhofer, Simone, von Tresckow, Julia, Robrecht, Sandra, Giza, Adam, Zhang, Can, Fürstenau, Moritz, Dreger, Peter, Ritgen, Matthias, Illmer, Thomas, Illert, Anna Lena, Dürig, Jan, Böttcher, Sebastian, Niemann, Carsten U., Kneba, Michael, Al-Sawaf, Othman, Kreuzer, Karl-Anton, Fink, Anna-Maria, Fischer, Kirsten, Döhner, Hartmut, Hallek, Michael, Eichhorst, Barbara, and Stilgenbauer, Stephan

Published
2023
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43. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial

Author

Seymour, John F., Byrd, John C., Ghia, Paolo, Kater, Arnon P., Chanan-Khan, Asher, Furman, Richard R., O’Brien, Susan, Brown, Jennifer R., Munir, Talha, Mato, Anthony, Stilgenbauer, Stephan, Bajwa, Naghmana, Miranda, Paulo, Higgins, Kara, John, Ellie, de Borja, Marianne, Jurczak, Wojciech, and Woyach, Jennifer A.

Published
2023
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44. High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations

Author

Fürstenau, Moritz, Thus, Yvonne J., Robrecht, Sandra, Mellink, Clemens H. M., van der Kevie-Kersemaekers, Anne-Marie, Dubois, Julie, von Tresckow, Julia, Patz, Michaela, Gregor, Michael, Thornton, Patrick, Staber, Philipp B., Tadmor, Tamar, Levin, Mark-David, da Cunha-Bang, Caspar, Schneider, Christof, Poulsen, Christian Bjoern, Illmer, Thomas, Schöttker, Björn, Janssens, Ann, Christiansen, Ilse, Nösslinger, Thomas, Baumann, Michael, Hebart, Holger, Gaska, Tobias, Regelink, Josien C., Dompeling, Ellen C., Lindström, Vesa, Juliusson, Gunnar, Widmer, Anouk, Goede, Jeroen, Goldschmidt, Neta, Simon, Florian, De Silva, Nisha, Fink, Anna-Maria, Fischer, Kirsten, Wendtner, Clemens-Martin, Ritgen, Matthias, Brüggemann, Monika, Tausch, Eugen, Spaargaren, Marcel, Eldering, Eric, Stilgenbauer, Stephan, Niemann, Carsten U., Hallek, Michael, Eichhorst, Barbara, Kreuzer, Karl-Anton, and Kater, Arnon P.

Published
2023
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46. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

Author

Othman Al-Sawaf, Can Zhang, Hyun Yong Jin, Sandra Robrecht, Yoonha Choi, Sandhya Balasubramanian, Alex Kotak, Yi Meng Chang, Anna Maria Fink, Eugen Tausch, Christof Schneider, Matthias Ritgen, Karl-Anton Kreuzer, Brenda Chyla, Joseph N. Paulson, Christian P. Pallasch, Lukas P. Frenzel, Martin Peifer, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, and Kirsten Fischer

Subjects
Science
Abstract

Abstract Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26–0.46], p

Published
2023
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47. Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia

Author

Jiang, Qu, Stachelscheid, Johanna, Bloehdorn, Johannes, Pacholewska, Alicja, Aszyk, Christoph, Grotenhuijs, Francien, Müller, Tony, Onder, Ozlem, Wagle, Prerana, Herling, Carmen D., Kleppe, Maria, Wang, Zhefang, Coombes, Kevin R., Robrecht, Sandra, Dalvi, Priya S., Plosnita, Bianca, Mayer, Petra, Abruzzo, Lynne V., Altmüller, Janine, Gathof, Birgit, Persigehl, Thorsten, Fischer, Kirsten, Jebaraj, Billy, Rienhoff, Hugh Y., Ecker, Rupert, Zhao, Yue, Bruns, Christiane J., Stilgenbauer, Stephan, Elenitoba-Johnson, Kojo, Hallek, Michael, Schweiger, Michal R., Odenthal, Margarete, Vasyutina, Elena, and Herling, Marco

Published
2023
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49. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Julien Broséus, Sébastien Hergalant, Julia Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos-Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan H. Bernhart, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Elise Chapiro, Florence Nguyen-Khac, Céline Chery, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie-Christine Béné, Catherine Thieblemont, Peter Lichter, Ole Ammerpohl, Jean-Louis Guéant, ICGC MMML-Seq Consortium, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, and Stephan Stilgenbauer

Subjects
Science
Abstract

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Published
2023
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50. The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL

Author

Stachelscheid, Johanna, Jiang, Qu, Aszyk, Christoph, Warner, Kathrin, Bley, Nadine, Müller, Tony, Vydzhak, Olga, Symeonidis, Konstantinos, Crispatzu, Giuliano, Mayer, Petra, Blakemore, Stuart James, Goehring, Gudrun, Newrzela, Sebastian, Hippler, Stephanie, Robrecht, Sandra, Kreuzer, Karl-Anton, Pallasch, Christian, Krüger, Marcus, Lechner, Axel, Fischer, Kirsten, Stilgenbauer, Stephan, Beutner, Dirk, Hallek, Michael, Auguin, Daniel, Hüttelmaier, Stefan, Bloehdorn, Johannes, Vasyutina, Elena, and Herling, Marco

Published
2023
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