28 results on '"Diffuse large B-Cell lymphoma"'
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2. Klassifikation der Hodgkin-Lymphome und verwandter Entitäten: Neuigkeiten und offene Fragen
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Hartmann, Sylvia and Fend, Falko
- Published
- 2024
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3. Klassifikation der Hodgkin-Lymphome und verwandter Entitäten: Neuigkeiten und offene Fragen.
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Hartmann, Sylvia and Fend, Falko
- Abstract
Copyright of Die Pathologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2023
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4. Klassifikation aggressiver B-Zell-Lymphome: Neuigkeiten und offene Fragen.
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Rosenwald, Andreas, Menter, Thomas, and Dirnhofer, Stefan
- Abstract
Copyright of Die Pathologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2023
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5. Lymphome und andere hämatologische Neoplasien im Hoden.
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Koch, Karoline, Oschlies, Ilske, and Klapper, Wolfram
- Abstract
Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2022
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6. Die genetische Evolution der in situ follikulären Neoplasie zum t(14;18)-positiven aggressiven B‑Zell-Lymphom.
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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.
- Abstract
Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2021
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7. CAR-T-Zellen zur Behandlung von malignen B-Zell-Lymphomen: Ein neues Therapieprinzip.
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Balke-Want, H. and Borchmann, P.
- Abstract
Copyright of Der Internist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2021
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8. Molekulare Klassifikatoren: Reif für die Klinik?
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Weigert, Oliver and Chapuy, Björn
- Abstract
Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2019
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9. [Lymphomas in children and adolescents].
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Klapper W
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- Adult, Humans, Adolescent, Child, Chromosome Aberrations, Translocation, Genetic, Gene Rearrangement, Burkitt Lymphoma diagnosis, Lymphoma, Large B-Cell, Diffuse diagnosis
- Abstract
Background: Lymphomas in children and adolescents differ from adulthood in relative frequency and variety of entities. In addition, young patients are cared for according to the specific standards of pediatric lymphoma study groups., Objective: To present lymphomas of diagnostic and clinical relevance in the pediatric and adolescent group., Material and Methods: Selective literature research ( http://www.ncbi.nlm.nih.gov ) was combined with clinico-pathological experience of the authors., Results: Children and adolescents are much more likely to suffer from aggressive and precursor cell lymphoma than is the case in adulthood. Unlike adult patients, Burkitt lymphomas and diffuse large B‑cell lymphomas are not treated fundamentally differently. Entities that have been described relatively recently and are particularly common in young patients are high-grade B‑cell lymphoma with 11q aberrations and large-cell B‑cell lymphoma with IRF4 translocations., Conclusion: Lymphoma diagnosis in children and adolescents is characterized by the particular spectrum of diseases that occur at this age. Special knowledge about the clinical relevance of the diagnoses in childhood is helpful in order to enable rapid clinical decision making., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2023
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10. Geriatrisches Assessment bei älteren hämatologischen Patienten.
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Neuendorff, N. R., Maurus, J., Vuong, G. L., Eidam, A., Jordan, B., Müller-Tidow, C., Bauer, J. M., and Jordan, K.
- Abstract
Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2019
- Full Text
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11. Aggressive B‑Zell-Lymphome.
- Author
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Klapper, W., Fend, F., Feller, A., Hansmann, M. L., Möller, P., Stein, H., Rosenwald, A., and Ott, G.
- Abstract
Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2019
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12. Fieber bei monoklonaler Gammopathie und Immunneuropathie - ein differenzialdiagnostischer Sple(e)n.
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Lüscher, Daniel, Diethelm, Markus, Hundsberger, Thomas, and Hitz, Felicitas
- Abstract
We present the case of an 81-year-old woman with fever of unknown origin, a known chronic inflammatory demyelinating polyneuropathy (CIDP) and monoclonal gammopathy of undetermined significance. After prolonged hospitalization, a diffuse large B-cell lymphoma was diagnosed in the spleen. The baseline evaluation and management of patients with a monoclonal gammopathy of undetermined significance are being discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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13. Nachsorge beim diffusen grosszeiligen B-Zell-Lymphom - Evidenz und Empfehlung.
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Vollmer, Kathrin and Mamot, Christoph
- Abstract
Treatment modalities for diffuse large B-cell lymphoma have improved over the last years. Most patients can be cured with immunochemotherapy, and the question of adequate follow-up for early recognition of relapse has emerged. In this review, we illustrate that routine surveillance imaging and laboratory analysis provide a low yield of asymptomatic relapses and fail to improve the prognosis. Relapse is mostly associated with the development of new findings or symptoms and can be clinically detected. Follow-up should be performed in a symptom-orientated manner, should take place to allow early recognition of late toxicities and to facilitate rehabilitation. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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14. [Classification of aggressive B-cell lymphomas : News and open questions].
- Author
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Rosenwald A, Menter T, and Dirnhofer S
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- Humans, Gene Rearrangement, Germinal Center pathology, Chromosome Aberrations, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse diagnosis
- Abstract
The 5th edition of the WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC) show a broad consensus in the categorization of aggressive, large B‑cell lymphomas with expected minor impact only on the daily diagnostic routine. The changes compared to the 2017 revised WHO-HAEM4R are moderate and include updated names of entities, sharpened diagnostic criteria, and upgrades from provisional to definite entities. The definition of the most common aggressive B‑cell lymphoma, diffuse large B‑cell lymphoma (DLBCL), not otherwise specified (NOS), remains unchanged, and both classifications strongly encourage subtyping into germinal center B‑like (GCB) or the activated B‑like (ABC or non-GCB) DLBCL. DLBCL, NOS, should be separated from other large B‑cell lymphomas including large B‑cell lymphoma with IRF4 rearrangement (upgraded to a definite entity in both classifications) and large-cell/high-grade B‑cell lymphomas with 11q aberration. Aggressive B‑cell lymphomas with MYC and BCL2 rearrangements form a molecularly distinct group and are listed as definite entities in both classifications. This is in contrast to the more heterogeneous group of aggressive B‑cell lymphomas with MYC and BCL6 rearrangements that are recognized as a provisional entity in the ICC, while they fall into the DLBCL, NOS, or the HGBL, NOS, groups in the WHO-HAEM5., (© 2023. The Author(s).)
- Published
- 2023
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15. [Classification of Hodgkin lymphoma and related entities : News and open questions].
- Author
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Hartmann S and Fend F
- Subjects
- Humans, Diagnosis, Differential, Hodgkin Disease diagnosis, Lymphoma diagnosis
- Abstract
Two new classifications were recently released: the 5th edition of the WHO classification of hematolymphoid tumors and the International Consensus Classification (ICC) drafted by the Clinical Advisory Committee. In the preparation of both classifications, the previously existing lymphoma categories were reevaluated according to recently obtained data on clinical, morphological, and molecular findings. In this review we summarize the current placements of classic and nodular lymphocyte predominant Hodgkin lymphoma and their relevant differential diagnoses., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2023
- Full Text
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16. [Lymphomas and other hematological neoplasms in the testicles].
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Koch K, Oschlies I, and Klapper W
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- Humans, Male, Testicular Neoplasms diagnosis, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Follicular pathology, Hematologic Neoplasms diagnosis
- Abstract
Background: The testis may be infiltrated by hematological neoplasias. However, only few entities present as primary testicular diseases., Objectives: To present hematological neoplasias in the testis, especially primary testicular hematological diseases., Materials and Methods: Selective literature research ( http://www.ncbi.nlm.nih.gov ) was combined with the clinico-pathological experience of the authors., Results: We present the experience of the lymph node registry Kiel with hematological neoplasias of the testis and develop a staining recommendation. According to our data, the testis is mainly involved by diffuse large B‑cell lymphomas (~70% of cases) followed by precursor cell neoplasias (~20%). Most precursor cell neoplasias are disseminated diseases involving the testis. Primary testicular lymphomas are nearly exclusively diffuse large B‑cell lymphomas that show specific clinical, pathological, and molecular features discriminating them from nodal/disseminated lymphomas. Primary testicular follicular lymphomas, which have been described in the literature, seem to be extremely rare., Conclusion: Primary testicular lymphomas are predominantly diffuse large B‑cell lymphomas. The diagnosis is possible with few immunohistochemical stainings. However, histology cannot replace clinical staging to discriminate primary testicular lymphoma from secondary infiltration by a nodal/disseminated disease., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2022
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17. High dose chemotherapy with autologous stem cell transplantation in diffuse large B-cell lymphoma
- Author
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Popp, Henning, Hoebert, Eckfried, Rabe, Christian, Gorschlueter, Marcus, Strehl, John W., Jha, Vandana, Mey, Ulrich J.M., and Schmidt-Wolf, Ingo G.H.
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diffuse large B-cell lymphoma ,high-dose chemotherapy ,autologous stem cell transplantation ,Medicine - Abstract
Background: High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) plays an important role in the treatment of aggressive non-Hodgkin’s lymphoma (NHL). We report on a retrospective analysis of all patients with diffuse large B-cell lymphoma who were consecutively treated with HDT followed by ASCT at the University Hospital of Bonn, Germany, between 1996 and 2004. Methods: A total of 25 patients were transplanted for biopsy-proven diffuse large B-cell lymphoma (DLBCL). Eight patients received up-front HDT as first-line therapy, four patients received HDT due to incomplete response to conventional induction chemotherapy, and six patients were treated for primary refractory disease. Seven patients had recurrent lymphoma. Results: A complete remission (CR) was achieved in 14 of 25 patients (56%). Estimated 3-year survival for patients treated with upfront HDT, chemosensitive patients with incomplete response to first line therapy, and patients with chemosensitive relapsed disease was 87.5%, 50.0% and 60.0%, respectively. In contrast, no patient with primary refractory disease or relapsed disease lacking chemosensitivity lived longer than 8 months. Chemosensitivity was the only significant prognostic factor for overall survival (OS) in multivariate analysis. Conclusions: Our results confirm that HDT and ASCT is a highly effective therapy in patients with DLBCL leading to long-term survival in a substantial proportion of patients. Patients treated upfront for high-risk disease, incomplete response to conventional first-line therapy, or for chemosensitive relapse have a good prognosis. In contrast, patients with primary chemorefractory disease and patients with relapsed disease lacking chemosensitivity do not benefit from HDT with ASCT.
- Published
- 2007
18. Primäre Lymphome des Gastrointestinaltrakts.
- Author
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Fischbach, W.
- Abstract
Copyright of Der Gastroenterologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2012
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19. Sind primär extranodale diffuse großzellige B-Zell-Lymphome organotypische Erkrankungen?
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Ott, G. and Rosenwald, A.
- Abstract
Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2007
- Full Text
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20. Maligne Non-Hodgkin-Lymphome der B-Zell-Reihe.
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Rosenwald, A., Burek, C., and Ott, G.
- Abstract
Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2006
- Full Text
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21. MALT1 phosphorylation controls activation of T lymphocytes and survival of ABC-DLBCL tumor cells
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Stefanie M. Hauck, Thomas J. O’Neill, Tabea Erdmann, Michael Grau, Hisaaki Shinohara, Kerstin Kutzner, Torben Gehring, Marco Rahm, Regina Feederle, Andrew Flatley, Carina Graß, Isabel Meininger, Katja Lammens, Simone Woods, Ozge Karayel, Georg Lenz, and Daniel Krappmann
- Subjects
0301 basic medicine ,T-Lymphocytes ,Amino Acid Motifs ,Lymphocyte Activation ,Jurkat cells ,General Biochemistry, Genetics and Molecular Biology ,Serine ,03 medical and health sciences ,Jurkat Cells ,Mice ,0302 clinical medicine ,CD28 Antigens ,medicine ,Animals ,Humans ,Phosphorylation ,lcsh:QH301-705.5 ,Cells, Cultured ,Adaptive Immunity ,Antigen Receptor Signaling ,B Cell Lymphomas ,Casein Kinase 1 Alpha ,Cbm Complex ,Immune Response ,Malt1 ,Nf-kappa B ,T Cell Activation ,Chemistry ,T-cell receptor ,breakpoint cluster region ,NF-kappa B ,CD28 ,Casein Kinase Ialpha ,medicine.disease ,B-Cell CLL-Lymphoma 10 Protein ,Cell biology ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,MALT1 ,030104 developmental biology ,HEK293 Cells ,lcsh:Biology (General) ,Guanylate Cyclase ,Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Summary: The CARMA1/CARD11-BCL10-MALT1 (CBM) complex bridges T and B cell antigen receptor (TCR/BCR) ligation to MALT1 protease activation and canonical nuclear factor κB (NF-κB) signaling. Using unbiased mass spectrometry, we discover multiple serine phosphorylation sites in the MALT1 C terminus after T cell activation. Phospho-specific antibodies reveal that CBM-associated MALT1 is transiently hyper-phosphorylated upon TCR/CD28 co-stimulation. We identify a dual role for CK1α as a kinase that is essential for CBM signalosome assembly as well as MALT1 phosphorylation. Although MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical NF-κB signaling in Jurkat and murine CD4 T cells. Moreover, constitutive MALT1 phosphorylation promotes survival of activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) cells addicted to chronic BCR signaling. Thus, MALT1 phosphorylation triggers optimal NF-κB activation in lymphocytes and survival of lymphoma cells. : Gehring et al. identify MALT1 phosphorylation as a process that bridges antigen receptor ligation to downstream signaling pathways in T cells, promotes T lymphocyte activation, and drives survival of B cell lymphoma tumor cells. Keywords: immune response, adaptive immunity, antigen receptor signaling, T cell activation, B cell lymphomas, CBM complex, phosphorylation, NF-kappa B, MALT1, casein kinase 1 alpha
- Published
- 2019
22. [Genetic evolution of in situ follicular neoplasia to t(14;18)-positive aggressive B-cell lymphoma].
- Author
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Vogelsberg A, Steinhilber J, Mankel B, Federmann B, Schmidt J, Montes-Mojarro IA, Hüttl K, Rodriguez-Pinilla M, Baskaran P, Nahnsen S, Piris MA, Ott G, Quintanilla-Martinez L, Bonzheim I, and Fend F
- Subjects
- Evolution, Molecular, Humans, In Situ Hybridization, Fluorescence, Translocation, Genetic genetics, Lymphoma, Follicular genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Background: In situ follicular neoplasia (ISFN) is a t(14;18)(q32;q21)
+ precursor lesion of follicular lymphoma (FL), which in turn can transform into diffuse large B‑cell lymphoma (DLBCL). For DLBCL that arise de novo, no precursor lesion is known. Given the high frequency of the t(14;18) translocation in de novo DLBCL as well, we investigated whether they can also arise from ISFN without FL as an intermediate step., Objectives: To investigate the clonal evolution of ISFN to DLBCL - transformed from FL and de novo., Materials and Methods: Identification of ISFN lesions in patients with DLBCL was performed by BCL2 staining of reactive lymphoid tissues. ISFN and DLBCL were subsequently analyzed by fluorescence in situ hybridization, clonality analyses, sequencing of the t(14;18) breakpoint, and targeted next-generation sequencing., Results: 10 cases with paired ISFN and DLBCL samples were identified, 6 of which were de novo DLBCL and 4 transformed from FL. 3 DLBCL carried MYC-rearrangements in addition to the t(14;18) and were classified as high-grade B‑cell lymphoma (HGBL). The clonal relationship of ISFN and DLBCL/HGBL was confirmed for all cases. CREBBP, KMT2D, EZH2, TNFRSF14, and BCL2 were the genes most frequently mutated, with the distribution of private and shared mutations pointing to 2 different scenarios of clonal evolution. In most cases, DLBCL/HGBL, ISFN, and, if also present, FL had evolved divergently from a common progenitor, whereas linear evolution was less frequent., Conclusion: We show for the first time that t(14;18)+ DLBCL/HGBL can arise directly from ISFN without FL as an intermediate step and that during this progression, divergent evolution is common., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)- Published
- 2021
- Full Text
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23. [CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm].
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Balke-Want H and Borchmann P
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- Child, Humans, Immunotherapy, Adoptive, T-Lymphocytes, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Following the first demonstration of efficacy of anti-CD19-directed chimeric antigen receptor (CAR) T cells in a patient with relapsed chronic lymphocytic leukemia (CLL) in 2011, pivotal studies for this innovative therapy were initially conducted in multiple relapsed or refractory (r/r) childhood and young adult acute B‑cell leukemia and in aggressive adult B‑cell lymphoma. The studies demonstrated efficacy even in chemotherapy-refractory disease, resulting in the first approval of autologous and genetically engineered T cells for the treatment of r/r B‑cell acute lymphoblastic leukemia (B-ALL) in the US for the product tisagenlecleucel (Kymriah®, Novartis) back in 2018. Approval for the treatment of r/r aggressive B‑cell lymphoma followed shortly thereafter for tisagenlecleucel and axicabtagene ciloleucel (Yescarta, Kite/Gilead). This review focuses on the treatment of aggressive B‑cell lymphoma and other CD19 positive B‑cell lymphomas by summarizing the study results of clinically tested CAR T cells, discussing possible resistance mechanisms, and providing an outlook on ongoing studies with new target antigens for the treatment of B‑cell lymphomas.
- Published
- 2021
- Full Text
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24. CME. Diffuses, grosszelliges B-Zell-Lymphom (DLBCL)
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Niklaus Schäfer, Panagiotis Samaras, Ivo Fuchs, Athina Pangalu, Ulf Petrausch, University of Zurich, and Samaras, Panagiotis
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Text mining ,business.industry ,10043 Clinic for Neuroradiology ,10032 Clinic for Oncology and Hematology ,medicine ,Cancer research ,610 Medicine & health ,2700 General Medicine ,General Medicine ,Biology ,medicine.disease ,business ,Diffuse large B-cell lymphoma - Published
- 2015
25. Orale Epstein-Barr-Virus-assoziierte diffuse großzellige B-Zell-Lymphome bei HIV-negativen immunsupprimierten Patienten
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Rhinow, K., Schirmer, I., Loddenkemper, C., Anagnostopoulos, I., Stein, H., and Reichart, P. A.
- Published
- 2006
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26. Funktionelle Validierung von Onkogenen bei molekularen Subtypen von diffusen großzelligen B-Zell Lymphomen (DLBCL)
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Wenzel, Sören-Sebastian
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MCL1 ,immune system diseases ,hemic and lymphatic diseases ,diffuse large B-cell lymphoma ,apoptosis ,NF-κB ,IκBζ - Abstract
Das diffuse großzellige B-Zell Lymphom (DLBCL) stellt mit einem Anteil von ca. 30-40% den häufigsten Lymphom-Subtyp bei Erwachsenen dar. Es ist eine heterogene diagnostische Kategorie, die anhand von Genexpressionsanalysen in zwei vorherrschende molekulare Subtypen unterteilt werden kann: Den Keimzentrums-B-Zell (GCB) Subtyp und den aktivierten B-Zell (ABC) Subtyp. Mehrere Studien konnten zeigen, dass diese molekularen Subtypen aus unterschiedlichen Vorläuferzellen während der B-Zell Entwicklung entstehen, von der Aktivierung bestimmter Signalwege abhängig sind und unterschiedliche klinische Verläufe aufweisen. Die Deregulation bestimmter Onkogene und Signalwege kann zur Entstehung der unterschiedlichen DLBCL-Subtypen beitragen. Allerdings sind viele der zugrunde liegenden molekularen und zellbiologischen Mechanismen immer noch unverstanden. Daher sollten in der vorliegenden Dissertation Subtyp-spezifische Onkogene bei den molekularen DLBCL-Subtypen identifiziert und ihre molekulare Funktion bei der Pathogenese von DLBCL untersucht werden. Bei primären DLBCL-Patienten konnte mittels Genexpressionsanalysen (n = 350; p = 2, 7 x 10-10) und Immunhistochemie (n = 249; p = 0, 001) gezeigt werden, dass ABC DLBCL eine signifikante Überexpression des anti-apoptotischen Proteins MCL1 aufweisen. Die Auswertung von array comparative genomic hybridisation (aCGH) Daten bei DLBCL-Patienten und -Zelllinien zeigte, dass die aberrante MCL1 Expression häufig auf chromosomale Amplifikationen zurückzuführen ist. Zudem konnte nachgewiesen werden, dass die konstitutive Aktivierung des JAK/STAT Signalweges zu einer MCL1 Deregulation bei DLBCL führt. Weitere funktionelle Analysen von MCL1 bei DLBCL-Zelllinien haben gezeigt, dass sowohl die Herunterregulation der MCL1 Expression mittels shRNA, als auch die Behandlung mit dem BH3-Mimetikum Obatoclax nur bei Zelllinien mit einer hohen MCL1 Expression toxisch ist und Apoptose auslöst. Zusätzlich konnte gezeigt werden, dass das Expressionslevel von MCL1 die Sensitivität von DLBCL-Zelllinien gegenüber diversen Chemotherapeutika beeinflusst. Des Weiteren konnte bei der Analyse von Genexpressionsdaten von 350 primären DLBCL-Patienten eine signifikante Überexpression von IκBζ, einem atypischen Mitglied der IκB-Familie, bei ABC DLBCL identifiziert werden (p = 5, 7 x 10-37). Die Herunterregulation von IκBζ mittels shRNA induzierte nur bei ABC DLBCL-Zelllinien und nicht bei GCB DLBCL- Zelllinien Zelltod. Überraschenderweise zeigten Genexpressionsanalysen, dass die Herunterregulation von IκBζ die Expression einer Vielzahl von typischen NF-κB-Zielgenen beeinflusst. Zudem konnte eine Interaktion zwischen IκBζ und den NF-κB-Untereinheiten p50 und p52 festgestellt werden, die auf eine regulatorische Funktion von IκBζ auf den klassischen und alternativen NF-κB- Signalweg deutet. Zusammenfassend unterstreichen die Ergebnisse der vorliegenden Dissertation die funktionelle Bedeutung von MCL1 und IκBζ bei der molekularen Pathogenese von DLBCL. Sowohl der Einfluss von MCL1 auf die Sensitivität von Tumorzellen gegenüber diversen Chemotherapeutika als auch die Schlüsselposition von IκBζ bei der Regulation NF-κB-abhängiger Zielgene zeigen, dass eine spezifische Hemmung ihrer Aktivität einen therapeutischen Nutzen haben kann und sprechen für weitere Evaluationen in zukünftigen Studien., Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30-40% of all malignant lymphoma cases in adults. DLBCL is a heterogeneous diagnostic category and gene expression studies have identified two major molecular subgroups of DLBCL, termed germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL. Further studies revealed that these subgroups arise from different stages of normal B-cell differentiation, utilize distinct oncogenic mechanisms, and differ in their clinical behaviour. Deregulation of certain oncogenes and signaling pathways may contribute to the development of different DLBCL subtypes. However, many of the underlying molecular and biological mechanisms are not yet fully understood. Therefore, the aim of the present study was to identify novel subtype specific oncogenes and to elucidate their molecular function in the pathogenesis of DLBCL. Evaluation of gene expression profiling data from 350 DLBCL patient samples revealed the anti-apoptotic BCL2-Family member MCL1 to be upregulated in ABC compared to GCB DLBCL primary patient samples (p = 2.7 x 10-10). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n = 249; p = 0.001). Analysis of array comparative genomic hybridisation (aCGH) data of DLBCL samples showed that aberrant expression of MCL1 is often caused by chromosomal amplifications. Additionally, constitutive STAT3 signaling was shown as a different mechanism leading to high MCL1 expression. Further analyses revealed that inhibition of MCL1 either by shRNA or treatment with the BH3-mimetic obatoclax induced apoptotic cell death only in MCL1 expressing DLBCL cell lines. Moreover, MCL1 expression levels affected sensitivity of DLBCL cell lines to chemotherapeutic agents commonly used in the treatment of DLBCL patients, indicating that MCL1 contributes to therapy resistance. In addition to these results, gene expression analyses showed that the atypical IκB-family member IκBζ is expressed in the ABC subtype of DLBCL at significant higher levels compared to GCB DLBCL patients (n = 350; p = 5.7 x 10-37). Knockdown of IκBζ using shRNA was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IκBζ knockdown revealed a large number of known NF- κB target genes to be regulated by IκBζ. Further analyses detected a physical interaction of IκBζ with both p50 and p52 NF-κB subunits, indicating that IκBζ regulates a specific set of NF-κB target genes by interacting with components of the classical and alternative NF-κB pathway in ABC DLBCL. Collectively, the results of this study reveal the functional significance of IκBζ and MCL1 in the molecular pathogenesis of DLBCL. Both the effect of MCL1 on the sensitivity towards diverse chemotherapeutic agents as well as the key position of IκBζ in the regulation of NF-κB-dependent target genes suggest that their specific inhibition might be an effective therapeutic approach, and call for further evaluation in future studies.
- Published
- 2014
27. [Aggressive B‑cell lymphomas : Recommendations from the German Panel of Reference Pathologists in the Competence Network on Malignant Lymphomas on diagnostic procedures according to the current WHO classification, update 2017].
- Author
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Klapper W, Fend F, Feller A, Hansmann ML, Möller P, Stein H, Rosenwald A, and Ott G
- Subjects
- Humans, Translocation, Genetic, World Health Organization, Lymphoma, Large B-Cell, Diffuse, Pathologists
- Abstract
The update of the 4th edition of the WHO classification for hematopoietic neoplasms introduces changes in the field of mature aggressive B‑cell lymphomas that are relevant to diagnostic pathologists. In daily practice, the question arises of which analysis should be performed when diagnosing the most common lymphoma entity, diffuse large B‑cell lymphoma. We discuss the importance of the cell of origin, the analysis of MYC translocations, and the delineation of the new WHO entities of high-grade B‑cell lymphomas.
- Published
- 2019
- Full Text
- View/download PDF
28. Discordant Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma
- Author
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Spitzer, Martin Stephan, Kremer, M. (Dr.), Fend, F. (Univ.-Prof. Dr.), and Bernhard, H. (Priv.-Doz. Dr.)
- Subjects
Diskordanter Knochenmarksbefall ,diffus-großzellige B-Zell-Lymphome ,IgH ,Bcl-2 ,microdissection ,hemic and lymphatic diseases ,Medizin ,discordant bone marrow involvement ,Diffuse Large B-Cell Lymphoma ,ddc:610 - Abstract
Diskordanter Befall des Knochenmarks (KM) bei diffus-großzelligen B-Zell-Lymphomen (DLBCL) zeichnet sich durch kleinzellige Infiltrate aus, die eher einem niedrigmalignen Non-Hodgkin-Lymphom entsprechen. In dieser Arbeit wurde zuerst die Häufigkeit dieses Phänomens untersucht. Bei den dabei gefundenen Fällen wurden zur Klärung der klonalen Verwandtschaft vergleichende molekulare Untersuchungen anhand der Immunglobulin-Schwere-Ketten-Gene (IgH) und des Bcl-2-Gens an mikrodissezierten malignen Infiltraten im KM und dem Primärbefund (z. B. Lymphknoten) vorgenommen. Die Ergebnisse wurden in der Zusammenschau mit den immunhistochemischen und durchflußzytometrischen Resultaten sowie den klinischen Verlaufsdaten bewertet. Es konnte gezeigt werden, dass der diskordante Befall des KM bei DLBCL eine heterogene Gruppe von Erkrankungen darstellt: In zwei Drittel der Fälle waren die beiden Tumormanifestationen klonal verwandt, in einem Drittel klonal unverwandt. Discordant bone marrow (BM) involvement in diffuse large B-Cell lymphoma (DLBCL) is characterized by marrow infiltrates predominantly composed of small lymphoid cell infiltrates, cytologically compatible with low-grade non-Hodgkin's lymphoma. As a first step in this study the frequency of this phenomenon was investigated. As a second step the clonal relationship of the retrieved cases was investigated by using immunoglobulin heavy chain gene (IgH), as well as Bcl-2 rearrangements, as molecular markers for a comparative analysis of the microdissected BM infiltrates and the primary tumor site (e. g. lymph node). The molecular results were discussed in the context of immunhistochemistry, flow cytometry and clinical follow-up data. It could be shown that discordant BM infiltrates in DLBCL represent a heterogeneous group of disorders: In two thirds of the cases the two tumor components were clonally related, in one third of the cases they were clonally distinct.
- Published
- 2005
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