161 results on '"Bonzheim I"'
Search Results
2. Die genetische Evolution der in situ follikulären Neoplasie zum t(14;18)-positiven aggressiven B‑Zell-Lymphom
- Author
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Vogelsberg, A., Steinhilber, J., Mankel, B., Federmann, B., Schmidt, J., Montes-Mojarro, I. A., Hüttl, K., Rodriguez-Pinilla, M., Baskaran, P., Nahnsen, S., Piris, M. A., Ott, G., Quintanilla-Martinez, L., Bonzheim, I., and Fend, F.
- Published
- 2021
- Full Text
- View/download PDF
3. GENE EXPRESSION PROFILING OF T(14;18)‐NEGATIVE CD23+ FOLLICLE CENTER LYMPHOMA DEMONSTRATES ACTIVATION OF THE IL4/JAK/STAT6 PATHWAY AND A ROLE IN ITS PATHOGENESIS
- Author
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Schade, T., primary, Nann, D., additional, Rau, A., additional, Chott, A., additional, Leoncini, L., additional, Fend, F., additional, Salaverria, I., additional, Campo, E., additional, Jaffe, E., additional, Bonzheim, I., additional, and Quintanilla‐Martinez de Fend, L., additional
- Published
- 2023
- Full Text
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4. Pediatric Langerhans cell histiocytosis: the impact of mutational profile on clinical progression and late sequelae
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Nann, D., Schneckenburger, P., Steinhilber, J., Metzler, G., Beschorner, R., Schwarze, C. P., Lang, P., Handgretinger, R., Fend, Falko, Ebinger, M., and Bonzheim, I.
- Published
- 2019
- Full Text
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5. Multicenter validation of cancer gene panel-based next-generation sequencing for translational research and molecular diagnostics
- Author
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Hirsch, B., Endris, V., Lassmann, S., Weichert, W., Pfarr, N., Schirmacher, P., Kovaleva, V., Werner, M., Bonzheim, I., Fend, F., Sperveslage, J., Kaulich, K., Zacher, A., Reifenberger, G., Köhrer, K., Stepanow, S., Lerke, S., Mayr, T., Aust, D. E., Baretton, G., Weidner, S., Jung, A., Kirchner, T., Hansmann, M. L., Burbat, L., von der Wall, E., Dietel, M., and Hummel, M.
- Published
- 2018
- Full Text
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6. PEDIATRIC NODAL MARGINAL ZONE LYMPHOMA AND PEDIATRIC-TYPE FOLLICULAR LYMPHOMA SHARE A COMMON MOLECULAR PROFILE
- Author
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Salmeron-Villalobos, J., primary, Egan, C., additional, Borgmann, V., additional, Müller, I., additional, Gonzalez-Farre, B., additional, Ramis-Zaldivar, J., additional, Nann, D., additional, Balagué, O., additional, Lopez-Guerra, M., additional, Colomer, D., additional, Oschlies, I., additional, Klapper, W., additional, Glaser, S., additional, Ko, Y., additional, Bonzheim, I., additional, Siebert, R., additional, Fend, F., additional, Pittaluga, S., additional, Campo, E., additional, Salaverria, I., additional, Jaffe, E., additional, and Quintanilla-Martinez, L., additional
- Published
- 2022
- Full Text
- View/download PDF
7. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM)
- Author
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Janning, M., primary, Süptitz, J., additional, Albers-Leischner, C., additional, Delpy, P., additional, Tufman, A., additional, Velthaus-Rusik, J.-L., additional, Reck, M., additional, Jung, A., additional, Kauffmann-Guerrero, D., additional, Bonzheim, I., additional, Brändlein, S., additional, Hummel, H.-D., additional, Wiesweg, M., additional, Schildhaus, H.-U., additional, Stratmann, J.A., additional, Sebastian, M., additional, Alt, J., additional, Buth, J., additional, Esposito, I., additional, Berger, J., additional, Tögel, L., additional, Saalfeld, F.C., additional, Wermke, M., additional, Merkelbach-Bruse, S., additional, Hillmer, A.M., additional, Klauschen, F., additional, Bokemeyer, C., additional, Buettner, R., additional, Wolf, J., additional, Loges, S., additional, Simon, Ronald, additional, Sauter, Guido, additional, Volk, Alexander, additional, Neumann, Jens, additional, Klauschen, Frederick, additional, Weichert, Wilko, additional, Kalhori, Naser, additional, Lüthen, Reinhard, additional, Stöhr, Robert, additional, Schubart, Chistoph, additional, Wacker, Heidemarie, additional, Fuchs, Florian, additional, Hartmann, Nils, additional, Graf, Stefanie, additional, Brandts, Christian, additional, Wild, Peter, additional, Demes, Melanie, additional, Reis, Henning, additional, and Rohde, Gernot, additional
- Published
- 2022
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8. Differenzialdiagnose spezifischer Hautinfiltrate bei chronischer myelomonozytärer Leukämie
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Federmann, B., Metzler, G., Bonzheim, I., and Fend, F.
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- 2015
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9. 1055P Prognostic relevance of tumor-infiltrating lymphocytes in early-stage melanoma
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Chatziioannou, E., primary, Rossner, J., additional, Niessner, H., additional, Forchhammer, S., additional, Bonzheim, I., additional, Garbe, C., additional, Flatz, L., additional, Eigentler, T., additional, Aung, T., additional, Rimm, D., additional, Sinnberg, T., additional, and Amaral, T.M.S., additional
- Published
- 2021
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10. Molekulare Subtypisierung: Grenzen der individuellen Therapie
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Fend, F. and Bonzheim, I.
- Published
- 2014
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- View/download PDF
11. Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma
- Author
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Schmidt, J, Salaverria, I, Haake, A, Bonzheim, I, Adam, P, Montes-Moreno, S, Piris, M A, Fend, F, Siebert, R, and Quintanilla-Martinez, L
- Published
- 2014
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12. Prädiktive Biomarker tumorrelevanter Signalwege in der molekularen Pathologie
- Author
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Bonzheim, I. and Fend, F.
- Published
- 2014
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13. TRIPLE POSITIVE (CD10+BCL6+MUM1+) DIFFUSE LARGE B‐CELL LYMPHOMAS IN ADULTS ARE A HETEROGENEOUS GROUP ENRICHED IN LARGE B‐CELL LYMPHOMAS WITH IRF4 REARRANGEMENT
- Author
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Frauenfeld, L., primary, Castrejon‐de‐Anta, N., additional, Ramis‐Zaldivar, J. E., additional, Otto, F., additional, Streich, S., additional, Salmerón‐Villalobos, J., additional, Mayer, A., additional, Steinhilber, J., additional, Pinyol, M., additional, Mankel, B., additional, Bonzheim, I., additional, Fend, F., additional, Rimza, L., additional, Salaverria, I., additional, Campo, E., additional, Balagué, O., additional, and Quintanilla‐Martinez, L., additional
- Published
- 2021
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- View/download PDF
14. Knochenmarkbiopsie: Aufarbeitung und Einsatzmöglichkeiten molekularpathologischer Methoden
- Author
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Quintanilla-Martinez, L., Tinguely, M., Bonzheim, I., and Fend, F.
- Published
- 2012
- Full Text
- View/download PDF
15. Periphere NK/T-Zell-Lymphome
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Rüdiger, T., Zettl, A., Adam, P., Bonzheim, I., Geissinger, E., and Müller-Hermelink, H.K.
- Published
- 2007
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16. Epigenetic activation of O-linked β-N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia
- Author
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Kampa-Schittenhelm, K.M., primary, Haverkamp, T., additional, Bonin, M., additional, Tsintari, V., additional, Bühring, H.J., additional, Haeusser, L., additional, Blumenstock, G., additional, Dreher, S.T., additional, Ganief, T., additional, Akmut, F., additional, Illing, B., additional, Mau-Holzmann, U.A., additional, Bonzheim, I., additional, Schleicher, E., additional, Vogel, W., additional, and Schittenhelm, M.M., additional
- Published
- 2020
- Full Text
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17. 045 - PEDIATRIC NODAL MARGINAL ZONE LYMPHOMA AND PEDIATRIC-TYPE FOLLICULAR LYMPHOMA SHARE A COMMON MOLECULAR PROFILE
- Author
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Salmeron-Villalobos, J., Egan, C., Borgmann, V., Müller, I., Gonzalez-Farre, B., Ramis-Zaldivar, J., Nann, D., Balagué, O., Lopez-Guerra, M., Colomer, D., Oschlies, I., Klapper, W., Glaser, S., Ko, Y., Bonzheim, I., Siebert, R., Fend, F., Pittaluga, S., Campo, E., Salaverria, I., Jaffe, E., and Quintanilla-Martinez, L.
- Published
- 2022
- Full Text
- View/download PDF
18. A prospective, randomized, single blinded multicentre trial to evaluate molecular genetic characterisation of primary diagnosed or relapsed non small cell lung cancer by single or combination of diagnostic procedures : The PROFILER study
- Author
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Häntschel, M., Böckeler, M., Bonzheim, I., Schimmele, F., Spengler, W., Stanzel, F., Petermann, C., Darwiche, Kaid, Büttner, R., Tiemann, M., Schmid, Kurt Werner, Muche, R., Bösmüller, H., Zender, L., Fend, F., and Hetzel, J.
- Subjects
Medizin - Published
- 2019
19. Nodal peripheral T-cell lymphomas correspond to distinct mature T-cell populations
- Author
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Geissinger, E, Bonzheim, I, Krenács, L, Roth, S, Reimer, P, Wilhelm, M, Müller-Hermelink, H K, and Rüdiger, T
- Published
- 2006
- Full Text
- View/download PDF
20. GENOME WIDE-ANALYSIS OF T(14;18)-NEGATIVE FOLLICULAR LYMPHOMA
- Author
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Müller, I., primary, Ramis-Zaldívar, J., additional, Schmidt, J., additional, Egan, C., additional, Gonzalez-Farre, B., additional, Salmeron-Villalobos, J., additional, Mattern, S., additional, Szablewski, V., additional, Dojcinov, S., additional, Chott, A., additional, Copie-Bergman, C., additional, Bonzheim, I., additional, Campo, E., additional, Fend, F., additional, Jaffe, E.S., additional, Salaverria, I., additional, and Quintanilla de Fend, L., additional
- Published
- 2019
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- View/download PDF
21. MOLECULAR CHARACTERIZATION OF EXTRANODAL NATURAL KILLER (NK)/T-CELL LYMPHOMAS, NASAL TYPE FROM LATIN AMERICA
- Author
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Quintanilla-Fend, L., primary, Montes-Mojarro, I., additional, Steinhilber, J., additional, Lome-Maldonado, C., additional, Ramirez-Ibarguen, A.F., additional, Acosta, B., additional, Barrionuevo, C., additional, Duenas, D., additional, Narbaitz, M., additional, Bonzheim, I., additional, and Fend, F., additional
- Published
- 2017
- Full Text
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22. Knochenmarkbiopsie
- Author
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Quintanilla-Martinez, L, Tinguely, M, Bonzheim, I, Fend, F, University of Zurich, and Quintanilla-Martinez, L
- Subjects
2734 Pathology and Forensic Medicine ,10049 Institute of Pathology and Molecular Pathology ,610 Medicine & health - Published
- 2012
23. Molekulare Subtypisierung
- Author
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Fend, F., primary and Bonzheim, I., additional
- Published
- 2014
- Full Text
- View/download PDF
24. Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma
- Author
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Schmidt, J, primary, Salaverria, I, additional, Haake, A, additional, Bonzheim, I, additional, Adam, P, additional, Montes-Moreno, S, additional, Piris, M A, additional, Fend, F, additional, Siebert, R, additional, and Quintanilla-Martinez, L, additional
- Published
- 2013
- Full Text
- View/download PDF
25. Knochenmarkbiopsie
- Author
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Quintanilla-Martinez, L., primary, Tinguely, M., additional, Bonzheim, I., additional, and Fend, F., additional
- Published
- 2012
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- View/download PDF
26. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations
- Author
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Geissinger, E., primary, Sadler, P., additional, Roth, S., additional, Grieb, T., additional, Puppe, B., additional, Muller, N., additional, Reimer, P., additional, Vetter-Kauczok, C. S., additional, Wenzel, J., additional, Bonzheim, I., additional, Rudiger, T., additional, Muller-Hermelink, H. K., additional, and Rosenwald, A., additional
- Published
- 2010
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27. C/EBP expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway
- Author
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Anastasov, N., primary, Bonzheim, I., additional, Rudelius, M., additional, Klier, M., additional, Dau, T., additional, Angermeier, D., additional, Duyster, J., additional, Pittaluga, S., additional, Fend, F., additional, Raffeld, M., additional, and Quintanilla-Martinez, L., additional
- Published
- 2009
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28. Angioimmunoblastic T-cell lymphoma is derived from terminally differentiated CD4+ helper cells
- Author
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Geissinger, E., primary, Bonzheim, I., additional, Krenács, L., additional, Roth, S., additional, Reimer, P., additional, Wilhelm, M., additional, Müller-Hermelink, H.K., additional, and Rüdiger, T., additional
- Published
- 2004
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29. Angioimmunoblastic T-cell lymphoma is derived from terminally differentiated CD4+ helper cells
- Author
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Geissinger, E., Bonzheim, I., Krenács, L., Roth, S., Reimer, P., Wilhelm, M., Müller-Hermelink, H.K., and Rüdiger, T.
- Published
- 2004
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30. Extranodal lymphoproliferative disorders with emphasis on skin.
- Author
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Norris, D., Said, Jonathan, Geissinger, E., Rüdiger, T., Bonzheim, I., Zettl, A., Müller-Hermelink, H. K., Ellis, D., Chan, John K. C., and Gascoyne, Randy D.
- Subjects
LYMPHOPROLIFERATIVE disorders ,LYMPHOMAS ,MYCOSIS fungoides ,CELL proliferation ,LYMPHATIC diseases ,IMMUNOLOGICAL deficiency syndromes - Abstract
Studies extranodal lymphoproliferative disorders with emphasis on skin. Comparison between the World Health Organization and the EORTC classification for cutaneous lymphoma; Variants of mycosis fungoides; Clinical features of cutaneous CD30-positive lymphoproliferative disorders and peripheral T-cell lymphomas.
- Published
- 2004
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31. Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
- Author
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Michael Grau, Kirsty Wienand, Pia Veratti, Gustavo Tapia, Tabea Erdmann, Eva González-Barca, Falko Fend, Jan-Niklas Heming, Björn Chapuy, Irina Bonzheim, Sophia Ehrenfeld, Alexandar Tzankov, Javier Menárguez, Mathias Lutz, Philip Sander, Matthew R. Wilson, José-Tomás Navarro, Julia Richter, Wolfram Klapper, Stefan Dirnhofer, Cornelius Miething, Pau Abrisqueta, Andreas Rosenwald, Fina Climent, Ioannis Anagnostopoulos, Mario Lamping, Wendan Xu, Annette M. Staiger, Georg Lenz, Myroslav Zapukhlyak, Philipp Berning, Vanessa Borgmann, Wolfgang Hartmann, Peter Lenz, Teresa Aldamiz, Fabian Frontzek, German Ott, Maria Joao Baptista, Josep Castellví, Antonio Salar, Jose Luis Mate, Heike Horn, John R. Goodlad, Ramona Wullenkord, Institut Català de la Salut, [Frontzek F, Zapukhlyak M, Xu W] Department of Medicine A, Department of Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany. [Staiger AM] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tübingen, Germany. Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany. [Bonzheim I, Borgmann V] Institute of Pathology and Neuropathology, Eberhard Karls University of TübingenComprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany. [Castellvi J] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Abrisqueta P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Male ,Limfomes ,Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::Whole Genome Sequencing::Whole Exome Sequencing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.medical_treatment ,Gene Dosage ,General Physics and Astronomy ,Interferó ,Aggressive lymphoma ,Disease ,Translocation, Genetic ,Whole Exome Sequencing ,Cohort Studies ,hemic and lymphatic diseases ,MCL1 ,Molecular Targeted Therapy ,B-cell lymphoma ,Càncer ,Cancer genetics ,Sistema limfàtic - Càncer - Mortalitat ,Exome sequencing ,Otros calificadores::/terapia [Otros calificadores] ,Cancer ,Aged, 80 and over ,Multidisciplinary ,Immunosuppression ,Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse::Plasmablastic Lymphoma [DISEASES] ,Middle Aged ,STAT Transcription Factors ,Interferon Regulatory Factors ,Plasmablastic Lymphoma ,Female ,técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::secuenciación del genoma completo::secuenciación del exoma completo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Adult ,neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso::linfoma plasmablástico [ENFERMEDADES] ,Adolescent ,Science ,Cèl·lules B ,Mapatge cromosòmic humà ,Cèl·lules B - Tumors - Tractament ,General Biochemistry, Genetics and Molecular Biology ,Article ,Young Adult ,Exome Sequencing ,medicine ,Mortalitat ,Humans ,Human gene mapping ,Seqüència de nucleòtids ,Aged ,Janus Kinases ,B cells ,business.industry ,Gene Expression Profiling ,Gene Amplification ,General Chemistry ,Other subheadings::/therapy [Other subheadings] ,medicine.disease ,Cancer research ,business ,Plasmablastic lymphoma ,Genètica ,IRF4 - Abstract
Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients., Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.
- Published
- 2021
32. Evaluation of FoxP3 Expression in Peripheral T-Cell Lymphoma
- Author
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Hans Konrad Müller-Hermelink, Eva Geissinger, Tina Grieb, Thomas Rüdiger, Sabine Roth, Peter Reimer, Andreas Rosenwald, Marianne Tinguely, Martin Wilhelm, Irina Bonzheim, University of Zurich, and Bonzheim, I
- Subjects
Pathology ,medicine.medical_specialty ,T cell ,Peripheral T-cell lymphoma not otherwise specified ,610 Medicine & health ,chemical and pharmacologic phenomena ,T-Lymphocytes, Regulatory ,T-Lymphocyte Subsets ,10049 Institute of Pathology and Molecular Pathology ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Anaplastic large-cell lymphoma ,Lymph node ,business.industry ,Large-cell lymphoma ,Lymphoma, T-Cell, Peripheral ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,General Medicine ,medicine.disease ,Immunohistochemistry ,Peripheral T-cell lymphoma ,Lymphoma ,2734 Pathology and Forensic Medicine ,medicine.anatomical_structure ,business - Abstract
Peripheral T-cell lymphomas (PTCLs) are biologically heterogeneous and have not been successfully correlated with specific T-cell subsets. We investigated PTCL, not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AILT), and anaplastic large cell lymphoma (ALCL) cases for FoxP3 expression to determine a potential derivation from regulatory T (Treg) cells. One PTCL-NOS case strongly expressed FoxP3 in the neoplastic T cells and showed unusual histomorphologic features with a dense infiltration of the lymph node by immunoblastic T cells and almost no reactive background infiltrate. The patient died shortly after diagnosis, suggesting that biologic properties of Treg cells may have contributed to the rapidly fatal clinical course. All remaining PTCL-NOS and AILT cases showed FoxP3 positivity only in the reactive infiltrate. Among ALCL cases, 4 of 6 ALK+ cases displayed weak and inhomogeneous FoxP3 expression in the tumor cells. FoxP3+ PTCL-NOS presumably derived from bona fide Treg cells occurs but seems rare in the Western population.
- Published
- 2008
33. An Automated Real-Time PCR Assay versus Next-Generation Sequencing in the Detection of BRAF V600 Mutations in Melanoma Tissue Samples.
- Author
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Lenders D, Bonzheim I, Hahn M, Gassenmaier M, Aebischer V, Forschner A, Lenders MM, Flatz L, and Forchhammer S
- Abstract
Background: Next-generation sequencing (NGS) is the most commonly used method for determining BRAF mutational status in patients with advanced melanoma. Automated PCR-based methods, such as the Idylla
TM system, are increasingly used for mutation diagnostics, but it is unclear what impact the choice of diagnostic method has on the management of melanoma., Objectives: To compare the concordance rate of BRAF V600 mutational analysis using IdyllaTM and NGS and to analyze the technical and clinical turnaround time. The clinical relevance is compared by analyzing the impact on the treatment decision., Methods: In this monocentric prospective cohort study, the BRAF mutation status of 51 patients was determined using both methods in parallel., Results: BRAF V600 mutation was detected in 23/51 cases (45%). IdyllaTM showed a 100% concordant result with a faster turnaround time (0.2 days) compared to NGS (12.2 days). In general, less tumor material was required for IdyllaTM than for NGS. Most patients received immunotherapy as a first-line therapy regardless of the BRAF V600 status., Conclusions: IdyllaTM testing proved to be a reliable and rapid alternative to NGS in the determination of BRAF V600 mutation. Although BRAF. status was available earlier, this had no influence on the treatment decision in most cases.- Published
- 2024
- Full Text
- View/download PDF
34. Clonal Hematopoiesis and Bone Marrow Infiltration in Patients With Follicular Helper T-Cell Lymphoma of Angioimmunoblastic Type.
- Author
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Harland L, Borgmann V, Otto F, Overkamp M, Bonzheim I, Fend F, Quintanilla-Martinez L, and Nann D
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Aged, 80 and over, Adult, Immunoblastic Lymphadenopathy genetics, Immunoblastic Lymphadenopathy pathology, Immunoblastic Lymphadenopathy immunology, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, T-Lymphocytes, Helper-Inducer pathology, T-Lymphocytes, Helper-Inducer immunology, High-Throughput Nucleotide Sequencing, DNA Methyltransferase 3A genetics, DNA-Binding Proteins, Dioxygenases, Clonal Hematopoiesis genetics, Bone Marrow pathology, Mutation
- Abstract
Follicular helper T-cell (TFH) lymphoma harbors recurrent mutations of RHOA
G17V , IDH2R172 , TET2, and DNMT3A. TET2 and DNMT3A mutations are the most frequently affected genes in clonal hematopoiesis (CH). The aim of our study was to investigate the frequency of CH in bone marrow biopsies (BMB) of TFH/angioimmunoblastic T-cell lymphoma (TFH-AITL) patients and its association with myeloid neoplasms. A total of 29 BMB from 22 patients with a diagnosis of TFH-AITL were analyzed by next-generation sequencing (NGS) with a custom panel. Morphologically, 5 BMB revealed that TFH-AITL infiltrates of >5% of bone marrow (BM) cellularity confirmed in 4 cases by NGS-based T-cell clonality. IDH2R172 was demonstrated only in 1 (3%) of 29, and RHOAG17V in 2 (7%) of 29 samples. TET2 and DNMT3A were identified in 24 (83%) of 29 and 17 (59%) of 29 BMB, respectively. In the parallel lymph node the frequencies of mutations were 27% (IDH2R172 ), 64% (RHOAG17V ), 86% (TET2), and 50% (DNMT3A). TET2 and/or DNMT3A mutations identical in lymph node and BMB were present in 18 (82%) of 22 patients, regardless of BM infiltration. In 3 cases the CH mutations were detected 13, 41, and 145 months before TFH-AITL diagnosis. Cases with TET2/DNMT3A mutations and BM variant allele frequencies >40% (7/18, 39%) showed lower blood counts. However, only low platelet count was statistically significant (P = .024). Myeloid neoplasms and/or myelodysplastic syndrome-related mutations were identified in 4 cases (4/22; 18%); all with high TET2 variant allele frequencies (>40%; P = .0114). In conclusion, CH is present in 82% of TFH-AITL and can be demonstrated up to 145 months before TFH-AITL diagnosis. NGS T-cell clonality analysis is an excellent tool to confirm TFH-AITL BM infiltration. Concurrent myeloid neoplasms were identified in 18% of the cases and were associated with TET2 mutations with high allelic burden (>40%). We demonstrated that myeloid neoplasms might occur simultaneously or precede the diagnosis of TFH lymphoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
35. mitoBK Ca is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming.
- Author
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Bischof H, Maier S, Koprowski P, Kulawiak B, Burgstaller S, Jasińska J, Serafimov K, Zochowska M, Gross D, Schroth W, Matt L, Juarez Lopez DA, Zhang Y, Bonzheim I, Büttner FA, Fend F, Schwab M, Birkenfeld AL, Malli R, Lämmerhofer M, Bednarczyk P, Szewczyk A, and Lukowski R
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Cell Proliferation, Mitochondria metabolism, Mitochondria genetics, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits metabolism, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits genetics, Mitochondrial Membranes metabolism, Female, Energy Metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms metabolism
- Abstract
Alterations in the function of K
+ channels such as the voltage- and Ca2+ -activated K+ channel of large conductance (BKCa ) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa ). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the 'Warburg effect', thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future., Competing Interests: HB, SM, PK, BK, SB, JJ, KS, MZ, DG, WS, LM, DJ, YZ, IB, FB, FF, MS, AB, RM, ML, PB, AS, RL No competing interests declared, (© 2023, Bischof et al.)- Published
- 2024
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36. Hyper-N-glycosylated SEL1L3 as auto-antigenic B-cell receptor target of primary vitreoretinal lymphomas.
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Elbert M, Neumann F, Kiefer M, Christofyllakis K, Balensiefer B, Kos I, Carbon G, Kaddu-Mulindwa D, Bittenbring JT, Fadle N, Regitz E, Fend F, Bonzheim I, Thurner L, and Bewarder M
- Subjects
- Humans, Glycosylation, Cell Line, Tumor, Retinal Neoplasms genetics, Retinal Neoplasms metabolism, Retinal Neoplasms pathology, Retinal Neoplasms immunology, Autoantigens immunology, Autoantigens metabolism, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse metabolism, Female, Male, Vitreous Body metabolism, Vitreous Body pathology, Middle Aged, Aged, Receptors, Antigen, B-Cell metabolism
- Abstract
Primary vitreoretinal lymphoma (PVRL) is a rare subtype of DLBCL and can progress into primary central nervous system lymphoma (PCNSL). To investigate the role of chronic antigenic stimulation in PVRL, we cloned and expressed B-cell receptors (BCR) from PVRL patients and tested for binding against human auto-antigens. SEL1L3, a protein with multiple glycosylation sites, was identified as the BCR target in 3/20 PVRL cases. SEL1L3 induces proliferation and BCR pathway activation in aggressive lymphoma cell lines. Moreover, SEL1L3 conjugated to a toxin killed exclusively lymphoma cells with respective BCR-reactivity. Western Blot analysis indicates the occurrence of hyper-N-glycosylation of SEL1L3 at aa 527 in PVRL patients with SEL1L3-reactive BCRs. The BCR of a PVRL patient with serum antibodies against SEL1L3 was cloned from a vitreous body biopsy at diagnosis and of a systemic manifestation at relapse. VH4-04*07 was used in both lymphoma manifestations with highly conserved CDR3 regions. Both BCRs showed binding to SEL1L3, suggesting continued dependence of lymphoma cells on antigen stimulation. These results indicate an important role of antigenic stimulation by post-translationally modified auto-antigens in the genesis of PVRL. They also provide the basis for a new treatment approach targeting unique lymphoma BCRs with ultimate specificity., (© 2024. The Author(s).)
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- 2024
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37. Image-guided metabolomics and transcriptomics reveal tumour heterogeneity in luminal A and B human breast cancer beyond glucose tracer uptake.
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Yang Q, Deng S, Preibsch H, Schade TC, Koch A, Berezhnoy G, Zizmare L, Fischer A, Gückel B, Staebler A, Hartkopf AD, Pichler BJ, la Fougère C, Hahn M, Bonzheim I, Nikolaou K, and Trautwein C
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- Humans, Female, Fluorodeoxyglucose F18 metabolism, Gene Expression Profiling, Acetates, Serine, Lipids, Breast Neoplasms diagnostic imaging, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
Background: Breast cancer is a metabolically heterogeneous disease, and although the concept of heterogeneous cancer metabolism is known, its precise role in human breast cancer is yet to be fully elucidated., Methods: We investigated in an explorative approach a cohort of 42 primary mamma carcinoma patients with positron emission tomography/magnetic resonance imaging (PET/MR) prior to surgery, followed by histopathology and molecular diagnosis. From a subset of patients, which showed high metabolic heterogeneity based on tracer uptake and pathology classification, tumour centre and periphery specimen tissue samples were further investigated by a targeted breast cancer gene expression panel and quantitative metabolomics by nuclear magnetic resonance (NMR) spectroscopy. All data were analysed in a combinatory approach., Results: [
18 F]FDG (2-deoxy-2-[fluorine-18]fluoro-d-glucose) tracer uptake confirmed dominance of glucose metabolism in the breast tumour centre, with lower levels in the periphery. Additionally, we observed differences in lipid and proliferation related genes between luminal A and B subtypes in the centre and periphery. Tumour periphery showed elevated acetate levels and enrichment in lipid metabolic pathways genes especially in luminal B. Furthermore, serine was increased in the periphery and higher expression of thymidylate synthase (TYMS) indicated one-carbon metabolism increased in tumour periphery. The overall metabolic activity based on [18 F]FDG uptake of luminal B subtype was higher than that of luminal A and the difference between the periphery and centre increased with tumour grade., Conclusion: Our analysis indicates variations in metabolism among different breast cancer subtypes and sampling locations which details the heterogeneity of the breast tumours. Correlation analysis of [18 F]FDG tracer uptake, transcriptome and tumour metabolites like acetate and serine facilitate the search for new candidates for metabolic tracers and permit distinguishing luminal A and B. This knowledge may help to differentiate subtypes preclinically or to provide patients guide for neoadjuvant therapy and optimised surgical protocols based on individual tumour metabolism., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)- Published
- 2024
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38. Targeted NGS on sequential bone marrow biopsies aids in the evaluation of cytopenias and monocytosis and documents clonal evolution-a proof of principle study.
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Nann D, Rau A, Mahmutovic L, Steinhilber J, Meca V, Federmann B, Vogel W, Bonzheim I, Quintanilla-Martinez L, and Fend F
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- Humans, Mutation, Clonal Evolution genetics, Biopsy, Bone Marrow pathology, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology
- Abstract
Differential diagnosis of clonal versus reactive cytopenia and monocytosis, respectively, frequently presents a diagnostic challenge. With the two recent classifications of myeloid disorders, mutational analysis has gained importance as a diagnostic tool. However, reports on its utility on trephine bone marrow biopsies (BMB) are sparse. The aim of our proof of principle study was to determine the suitability of targeted sequencing for the longitudinal evaluation of cytopenia and monocytosis and demonstration of clonal evolution on sequential BMB. Seventy-seven EDTA-decalcified BMB of 33 patients with peripheral cytopenia and/or monocytosis, including at least one follow-up biopsy/patient, were included. Initial morphological diagnoses were idiopathic cytopenia of undetermined significance (ICUS, 8 cases), MDS (without blast increase, 7 cases), MDS with increased blasts/excess blasts (MDS-IB/EB) (11 cases), and CMML (7 cases). Thirty-one genes relevant for myeloid disorders were examined using two custom AmpliSeq NGS panels. Mutations were found in the initial BMB of 5/8 cases of ICUS, thus changing the diagnosis to clonal cytopenia of unknown significance (CCUS), 5/7 MDS, 10/11 MDS-IB/EB, and 7/7 CMML. Clonal evolution was observed in 14/33 (42%) cases, mostly associated with disease progression. None of the wild-type patients acquired mutations during follow-up. NGS-based mutation profiling is a robust diagnostic tool for BMB and provides valuable additional information, especially for cases with no/minimal dysplasia, and for better risk stratification of MDS. Tracking variant allele frequency and appearance of mutations over time allows for observing clonal evolution or relapse., (© 2023. The Author(s).)
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- 2023
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39. [Molecular diagnostics for vitreoretinal lymphoma].
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Bonzheim I, Salmerón-Villalobos J, Süsskind D, Szurman P, Gekeler F, Spitzer MS, Salaverria I, Campo E, Coupland SE, Quintanilla-Martinez L, and Fend F
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- Humans, Myeloid Differentiation Factor 88 genetics, Pathology, Molecular, Vitreous Body metabolism, Retinal Neoplasms diagnosis, Eye Neoplasms diagnosis, Lymphoma, Large B-Cell, Diffuse diagnosis, Central Nervous System Neoplasms metabolism
- Abstract
Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered a special form of primary diffuse large cell lymphoma (DLBCL) of the CNS (central nervous system) (PCNSL) and arises primary or secondary to PCNSL. According to the cell of origin (COO) classification of DLBCL, PVRL largely belongs to the activated B‑cell (ABC) type of DLBCL. Based on a recently established genetic-biological classification of DLBCL, PCNSL and thus also PVRL belong to a group of DLBCL of the MYD88/CD79B-mutated (MCD) or cluster 5 subtype, which often shows extranodal manifestations and MYD88 and CD79A mutations as well as CDKN2A deletions.PVRL diagnostics is often complicated as it represents a classic masquerade syndrome. Due to the usually limited material with often large numbers of reactive lymphocytes and/or degenerative changes in the cells, the results of diagnostic tests are difficult to interpret. Classic diagnostic tests include cytology on vitreous aspirates, immunocytochemistry, and clonality analysis.New insights into the spectrum of genetic alterations of vitreoretinal lymphomas (VRL) confirm the close relationship to PCNSL and could significantly improve pathological diagnosis. Next-generation sequencing panel-based diagnostics allow VRL diagnosis confirmation with little DNA in almost 100% of patients in cases with insufficient cytological evidence or lack of clonality detection. PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
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- 2023
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40. Fisetin overcomes non-targetability of mutated KRAS induced YB-1 signaling in colorectal cancer cells and improves radiosensitivity by blocking repair of radiation-induced DNA double-strand breaks.
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Khozooei S, Veerappan S, Bonzheim I, Singer S, Gani C, and Toulany M
- Abstract
Background and Purpose: KRAS is frequently mutated, and the Y-box binding protein 1 (YB-1) is overexpressed in colorectal cancer (CRC). Mutant KRAS (KRAS
mut ) stimulates YB-1 through MAPK/RSK and PI3K/AKT, independent of epidermal growth factor receptor (EGFR). The p21-activated kinase (PAK) family is a switch-site upstream of AKT and RSK. The flavonoid compound fisetin inhibits RSK-mediated YB-1 signaling. We sought the most effective molecular targeting approach that interferes with DNA double strand break (DSB) repair and induces radiosensitivity of CRC cells, independent of KRAS mutation status., Materials and Methods: KRAS activity and KRAS mutation were analyzed by Ras-GTP assay and NGS. Effect of dual targeting of RSK and AKT (DT), the effect of fisetin as well as targeting PAK by FRAX486 and EGFR by erlotinib on YB-1 activity was tested by Western blotting after irradiation in vitro and ex vivo. Additionally, the effect of DT and FRAX486 on DSB repair pathways was tested in cells expressing reporter constructs for the DSB repair pathways by flow cytometry analysis. Residual DSBs and clonogenicity were examined by γH2AX- and clonogenic assays, respectively., Results: Erlotinib neither blocked DSB repair nor inhibited YB-1 phosphorylation under KRAS mutation condition in vitro and ex vivo. DT and FRAX486 effectively inhibited YB-1 phosphorylation independent of KRAS mutation status and diminished homologous recombination (HR) and alternative non-homologous end joining (NHEJ) repair. DT and FRAX486 inhibited DSB repair in CaCo2 but not in isogenic KRASG12V cells. Fisetin inhibited YB-1 phosphorylation, blocked DSB repair and increased radiosensitivity, independent of KRAS mutation status., Conclusion: Combination of fisetin with radiotherapy may improve CRC radiation response, regardless of KRASmut status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
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41. A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma.
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van Bladel DAG, Stevens WBC, Kroeze LI, de Groen RAL, de Groot FA, van der Last-Kempkes JLM, Berendsen MR, Rijntjes J, Luijks JACW, Bonzheim I, van der Spek E, Plattel WJ, Pruijt JFM, de Jonge-Peeters SDPWM, Velders GA, Lensen C, van Bladel ER, Federmann B, Hoevenaars BM, Pastorczak A, van der Werff Ten Bosch J, Vermaat JSP, Nooijen PTGA, Hebeda KM, Fend F, Diepstra A, van Krieken JHJM, Groenen PJTA, van den Brand M, and Scheijen B
- Subjects
- Humans, Retrospective Studies, Neoplasm Recurrence, Local, Immunoglobulins, Hodgkin Disease diagnosis, Hodgkin Disease genetics, Hodgkin Disease pathology, Lymphoma, Lymphoma, T-Cell
- Abstract
Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 34 patients (29%) as determined by IG-NGS clonality assessment and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ∼60% of patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based Ig/TCR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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42. UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescents.
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Liebmann A, Admard J, Armeanu-Ebinger S, Wild H, Abele M, Gschwind A, Seibel-Kelemen O, Seitz C, Bonzheim I, Riess O, Demidov G, Sturm M, Schadeck M, Pogoda M, Bien E, Krawczyk M, Jüttner E, Mentzel T, Cesen M, Pfaff E, Kunc M, Forchhammer S, Forschner A, Leiter-Stöppke U, Eigentler TK, Schneider DT, Schroeder C, Ossowski S, and Brecht IB
- Abstract
Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging., Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT)., Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation., Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future., Funding: Found in Acknowledgement., Competing Interests: Declaration of interests Outside of submitted work: IBB: Institutional grant from Biontech. O.R. and C.Sc.: grants: Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe (DKH), European Union (EU), grants to the institution from Illumina and BMS Stiftung Immunonkologie. U.L.S: grants: MSD; support for attending meeting and/or travel: Sun Pharma, Pierre Fabre; participation on a Data Safety Monitoring Board or Advisory Board: MSD, Novartis, Sun Pharma, Almirall, Roche, Sanofi; ADO board member. T.E.: Consulting fees: Bristol-Myers Squibb, MSD, Novartis, Almirall, Hermal, CureVac, Immunocore, Sanofi. S.O.: grants: DFG, Deutsche Luft und Raumfahrt Gesellschaft (DLR), European Union (EU), Bundesministerium für Bildung und Forschung (BMBF), Deutsche Krebshilfe, Bundesministerium für Arbeit und Soziales (BMSA); presentation: Illumina; support for attending meeting and/or travel: Oxford Nanopore Technologies. S.F.: grants: NeraCare, Skyline Dx, Biontech,; speakers honoraria: Kyowa Kirin, Recordati, Takeda Pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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43. Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases.
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Chatziioannou E, Roßner J, Aung TN, Rimm DL, Niessner H, Keim U, Serna-Higuita LM, Bonzheim I, Kuhn Cuellar L, Westphal D, Steininger J, Meier F, Pop OT, Forchhammer S, Flatz L, Eigentler T, Garbe C, Röcken M, Amaral T, and Sinnberg T
- Subjects
- Humans, Prognosis, Lymphocytes, Tumor-Infiltrating pathology, Neoplasm Recurrence, Local pathology, Melanoma, Cutaneous Malignant, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Deep Learning
- Abstract
Background: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma., Methods: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy., Findings: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival., Interpretation: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy., Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript., Competing Interests: Declaration of interests SF received personal fees from Kyowa Kirin and Takeda Pharmaceuticals, institutional grants from NeraCare, SkylineDx, and BioNTech, all outside the submitted work. TA reports institutional grants and personal fees from Novartis, institutional grants from NeraCare, Sanofi, SkylineDx, personal fees from CeCaVa, Pierre Fabre, BMS all outside the submitted work, participate on a data safety monitoring board for Unicancer. DLR reports grants and personal fees from Amgen, Astra Zeneca, Cepheid, Konica—Minolta, Lilly, NextCure personal fees from Cell Signaling Technology, Danaher, Fluidigm, GSK, Merck, Monopteros, NanoString, Odonate, Paige. AI, Regeneron, Roche, Sanofi, Ventana and Verily, royalties from Rarecyte, all outside the submitted work. CG reports grants and personal fees from NeraCare, Novartis, Roche, Sanofi, personal fees from Amgen, BMS, MSD, and Philogen, all outside the submitted work. TE reports personal fees from Novartis, BMS, Almirall Hermal, CureVac, Sanofi, MSD, Pierre Fabre and institutional grants from MSD, Sanofi, BMS, Pfizer, GenenTech, Seagan, Regeneron all outside the submitted work. IB reports having received speaker fees from Bayer, Pfizer, Takeda and AstraZeneca. MR reports grants from AB Science, Abbott, AbbVie, Alcedis, Almirall Hermal, Amgen, Anaptys Bio, Argenx, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CureVac, DelArrivo, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Dynavax Tech, Eli Lilly, Galderma, Genentech, GSK, Hoffmann La Roche, Hokusai, Idera Pharmaceuticals, Ilkos Therapeutic, Immatics biotechnologies, Incyte, Iovance Biotherapeutics, Janssen Cilag, Johnson & Johnson, LEO Pharma, Merck, MSD Sharp &Dohme, Novartis Pharmaceuticals, PellePharm, Pfizer, Philogen, Regeneron Pharmaceuticals, Sanofi Aventis, Schering Plough, Sun Pharma, Technische Universitat Dresden, Topaz Therapeutics, UCB, Universitatsklinik Essen, Universitatklinik Koln, Wilhelm Sander-Stiftung, 4SC. The other authors report no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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44. Detection of circulating cell-free HPV DNA of 13 HPV types for patients with cervical cancer as potential biomarker to monitor therapy response and to detect relapse.
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Mittelstadt S, Kelemen O, Admard J, Gschwind A, Koch A, Wörz S, Oberlechner E, Engler T, Bonzheim I, Staebler A, Weidner N, Stubenrauch F, Iftner T, Riess O, Schroeder C, Kommoss S, and Ossowski S
- Subjects
- Humans, Female, Neoplasm Recurrence, Local, Biomarkers, Chronic Disease, Uterine Cervical Neoplasms, Papillomavirus Infections, Cell-Free Nucleic Acids, Circulating Tumor DNA
- Abstract
Background: HPV-related cervical cancer (CC) is the fourth most frequent cancer in women worldwide. Cell-free tumour DNA is a potent biomarker to detect treatment response, residual disease, and relapse. We investigated the potential use of cell-free circulating HPV-DNA (cfHPV-DNA) in plasma of patients with CC., Methods: cfHPV-DNA levels were measured using a highly sensitive next-generation sequencing-based approach targeting a panel of 13 high-risk HPV types., Results: Sequencing was performed in 69 blood samples collected from 35 patients, of which 26 were treatment-naive when the first liquid biopsy sample was retrieved. cfHPV-DNA was successfully detected in 22/26 (85%) cases. A significant correlation between tumour burden and cfHPV-DNA levels was observed: cfHPV-DNA was detectable in all treatment-naive patients with advanced-stage disease (17/17, FIGO IB3-IVB) and in 5/9 patients with early-stage disease (FIGO IA-IB2). Sequential samples revealed a decrease of cfHPV-DNA levels in 7 patients corresponding treatment response and an increase in a patient with relapse., Conclusions: In this proof-of-concept study we demonstrated the potential of cfHPV-DNA as a biomarker for therapy monitoring in patients with primary and recurrent CC. Our findings facilitate the development of a sensitive and precise, non-invasive, inexpensive, and easily accessible tool in CC diagnosis, therapy monitoring and follow-up., (© 2023. The Author(s).)
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- 2023
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45. Successful treatment of metastatic uveal melanoma with ipilimumab and nivolumab after severe progression under tebentafusp: a case report.
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Reiter S, Schroeder C, Broche J, Sinnberg T, Bonzheim I, Süsskind D, Flatz L, and Forschner A
- Abstract
Metastatic uveal melanoma (UM) is a rare form of melanoma differing from cutaneous melanoma by etiology, prognosis, driver mutations, pattern of metastases and poor response rate to immune checkpoint inhibitors (ICI). Recently, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, tebentafusp, has been approved for the treatment of HLA-A*02:01 metastatic or unresectable UM. While the treatment regime is complex with weekly administrations and close monitoring, the response rate is limited. Only a few data exist on combined ICI in UM after previous progression on tebentafusp. In this case report, we present a patient with metastatic UM who first suffered extensive progression under treatment with tebentafusp but in the following had an excellent response to combined ICI. We discuss possible interactions that could explain responsiveness to ICI after pretreatment with tebentafusp in advanced UM., Competing Interests: AF served as consultant to Immunocore, 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. AF and CS report institutional research grants from BMS Stiftung Immunonkologie. IB received speaker fees from Novartis, Bayer, Pfizer, Takeda and AstraZeneca and honoraria for advisory board participation from BMS and Novartis. 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 © 2023 Reiter, Schroeder, Broche, Sinnberg, Bonzheim, Süsskind, Flatz and Forschner.)
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- 2023
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46. Prevalence of IRF4 rearrangement in large B-cell lymphomas of the Waldeyer's ring in adults.
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Streich S, Frauenfeld L, Otto F, Mankel B, Bonzheim I, Fend F, and Quintanilla-Martinez L
- Subjects
- Child, Humans, B-Lymphocytes pathology, In Situ Hybridization, Fluorescence, Prevalence, Proto-Oncogene Proteins c-bcl-2 genetics, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (B-NHL) in adults. These lymphomas are classified according to gene expression profiling (GEP) into germinal center B-cell (GCB) and activated B-cell type (ABC). Recent studies have suggested new subtypes of large B-cell lymphoma, based on genetic and molecular alterations, among them is large B-cell lymphoma with IRF4-rearrangement (LBCL-IRF4). We used fluorescence in situ hybridization (FISH), GEP (using the DLBCL COO assay by HTG Molecular Inc), and next generation sequencing (NGS) to comprehensively characterize 30 cases of LBCLs located in Waldeyer's ring in adult patients and to identify LBCL-IRF4. FISH revealed breaks of IRF4 in 2/30 cases (6.7%), BCL2 breaks in 6/30 cases (20.0%), and IGH breaks in 13/29 cases (44.8%). GEP classified 14 cases each as GCB or ABC subtype, and 2 cases remained unclassified; this was concordant with the immunohistochemistry (IHC) in 25/30 cases (83.3%). A subgrouping, based on GEP, was performed: group 1 included 14 GCB cases with the most frequent mutations in BCL2 and EZH2 in 6/14 cases (42.8%). The two cases with IRF4 rearrangement were assigned to this group by GEP and showed IRF4 mutations, supporting the diagnosis of LBCL-IRF4. Group 2 included 14 ABC cases; the most frequent mutations were CD79B and MYD88 identified in 5/14 patients (35.7%). Group 3 included 2 unclassifiable cases in which no molecular patterns were detected. Overall, LBCLs of Waldeyer's ring in adult patients are a heterogeneous group, including LBCL-IRF4, which shares several features with cases in the pediatric population., (© 2023. The Author(s).)
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- 2023
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47. TMB and BRAF mutation status are independent predictive factors in high-risk melanoma patients with adjuvant anti-PD-1 therapy.
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Eckardt J, Schroeder C, Martus P, Armeanu-Ebinger S, Kelemen O, Gschwind A, Bonzheim I, Eigentler T, Amaral T, Ossowski S, Rieß O, Flatz L, Garbe C, and Forschner A
- Subjects
- Humans, Proto-Oncogene Proteins B-raf genetics, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Adjuvants, Immunologic, Mutation, Skin Neoplasms pathology, Melanoma drug therapy, Melanoma genetics, Melanoma pathology
- Abstract
Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies., Methods: We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel., Results: The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12-4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19-23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS)., Conclusion: BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy., (© 2022. The Author(s).)
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- 2023
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- View/download PDF
48. FACILITATE: A real-world, multicenter, prospective study investigating the utility of a rapid, fully automated real-time PCR assay versus local reference methods for detecting epidermal growth factor receptor variants in NSCLC.
- Author
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Behnke A, Cayre A, De Maglio G, Giannini G, Habran L, Tarsitano M, Chetta M, Cappellen D, Lespagnol A, Le Naoures C, Massazza G, Destro A, Bonzheim I, Rau A, Battmann A, Kah B, Watkin E, and Hummel M
- Subjects
- Humans, Prospective Studies, Real-Time Polymerase Chain Reaction methods, Mutation, ErbB Receptors genetics, DNA Mutational Analysis methods, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Accurate testing for epidermal growth factor receptor ( EGFR ) variants is essential for informing treatment decisions in non-small cell lung cancer (NSCLC). Automated diagnostic workflows may allow more streamlined initiation of targeted treatments, where appropriate, while comprehensive variant analysis is ongoing. FACILITATE, a real-world, prospective, multicenter, European study, evaluated performance and analytical turnaround time of the Idylla™ EGFR Mutation Test compared with local reference methods. Sixteen sites obtained formalin-fixed paraffin-embedded biopsy samples with ≥ 10% neoplastic cells from patients with NSCLC. Consecutive 5 μm sections from patient samples were tested for clinically relevant NSCLC-associated EGFR variants using the Idylla™ EGFR Mutation Test and local reference methods; performance (concordance) and analytical turnaround time were compared. Between January 2019 and November 2020, 1,474 parallel analyses were conducted. Overall percentage agreement was 97.7% [ n = 1,418; 95% confidence interval (CI): 96.8-98.3], positive agreement, 87.4% ( n = 182; 95% CI: 81.8-91.4) and negative agreement, 99.2% ( n = 1,236; 95% CI: 98.5-99.6). There were 38 (2.6%) discordant cases. Ninety percent of results were returned with an analytical turnaround time of within 1 week using the Idylla™ EGFR Mutation Test versus ∼22 days using reference methods. The Idylla™ EGFR Mutation Test performed well versus local methods and had shorter analytical turnaround time. The Idylla™ EGFR Mutation Test can thus support application of personalized medicine in NSCLC., Competing Interests: IB declares receipt of honoraria from Novartis, Bayer, Pfizer, Takeda, AstraZeneca and BMS. EW declares the receipt of honoraria from AstraZeneca and MSD. MH declares membership in advisory councils or committees for AstraZeneca, Roche, Novartis, Pierre Fabre GDM, Sanofi, MSD and BMS; and receipt of grants or funds from AstraZeneca. Author EW was employed by the company CYPATH. 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 authors declare that this study received funding from AstraZeneca, Cambridge, UK and Biocartis, Mechelen, Belgium. Biocartis were involved in study design, and analysis and interpretation of data. AstraZeneca were not involved in study design or analysis and interpretation of data. The funders were not involved in collection of data. The funders reviewed the manuscript before submission., (Copyright © 2023 Behnke, Cayre, De Maglio, Giannini, Habran, Tarsitano, Chetta, Cappellen, Lespagnol, Le Naoures, Massazza, Destro, Bonzheim, Rau, Battmann, Kah, Watkin and Hummel.)
- Published
- 2023
- Full Text
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49. Germline findings in patients with advanced malignancies screened with paired blood-tumour testing for personalised treatment approaches.
- Author
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Roggia C, Armeanu-Ebinger S, Gschwind A, Seibel-Kelemen O, Hertler S, Faust U, Liebmann A, Haack TB, Neumann M, Bonzheim I, Forschner A, Kopp HG, Herster F, Hartkopf A, Bitzer M, Malek NP, Brecht IB, Ruhm K, Möller Y, Löwenheim H, Ossowski S, Rieß OH, and Schroeder C
- Subjects
- Humans, Precision Medicine, Germ-Line Mutation, Mutation, Genes, BRCA2, Genetic Predisposition to Disease, Genetic Testing methods, Neoplasms diagnosis, Neoplasms genetics, Neoplasms therapy, Hematologic Neoplasms
- Abstract
Background: Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour-normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families., Methods: We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data., Results: We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases., Conclusions: Tumour-normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour-normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2023
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50. Cuprizone feeding induces swollen astrocyte endfeet.
- Author
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Fallier-Becker P, Bonzheim I, and Pfeiffer F
- Subjects
- Animals, Mice, Astrocytes pathology, Mice, Inbred C57BL, Disease Models, Animal, Cuprizone toxicity, Demyelinating Diseases chemically induced, Demyelinating Diseases pathology
- Abstract
The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood-brain barrier (BBB). Here, by analyzing BBB ultrastructure with high-resolution electron microscopy, we report changes at astrocytic endfeet surrounding vessels in the brain parenchyma. Particularly, edema formation around blood vessels and swollen astrocytic endfeet already occurred after feeding low dosages of cuprizone. These findings indicate changes in BBB function that will have an impact on the milieu of the central nervous system (CNS) in the cuprizone model and need to be considered when studying the mechanisms of de- and remyelination., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
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