41 results on '"Heinz-Wolfram Bernd"'
Search Results
2. Data from Chromosomal Breakpoints Affecting Immunoglobulin Loci Are Recurrent in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma
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Reiner Siebert, Martin L. Hansmann, Ralf Küppers, Harald Stein, Thomas Rüdiger, Reza M. Parwaresch, Peter Möller, Irina B. Kaplanskaya, Georgiy A. Frank, Stefan Gesk, Alexander Claviez, Heinz-Wolfram Bernd, Françoise Berger, Thomas F.E. Barth, Jennifer Riemke, Jorge Höppner, Susanne Grohmann, Roland Schmitz, Christian Bastard, Lana Harder, Evelyne Callet-Bauchu, Anna Sotnikova, Wolfram Klapper, and José I. Martín-Subero
- Abstract
Chromosomal breakpoints affecting immunoglobulin (IG) loci are recurrent in many subtypes of B-cell lymphomas. However, despite the predominant B-cell origin of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL), the presence of chromosomal translocations in IG loci has not yet been systematically explored. Therefore, we have investigated a series of cHL for chromosomal breakpoints in the IGH (n = 230), IGL (n = 139), and IGK (n = 138) loci by interphase cytogenetics. Breakpoints in the IGH, IGL, or IGK locus were observed in the HRS cells of 26 of 149 (17%), 2 of 70, and 1 of 77 evaluable cHLs, respectively. The IG partners could be identified in eight cHLs and involved chromosomal bands 2p16 (REL), 3q27 (BCL6, two cases), 8q24.1 (MYC), 14q24.3, 16p13.1, 17q12, and 19q13.2 (BCL3/RELB). In 65 of 85 (76%) cHLs evaluable for an IGH triple-color probe, the HRS cells showed evidence for a (partial) deletion of the IGH constant region, suggesting the presence of class switch recombination (CSR). Furthermore, analyses with this probe in cases with IGH breakpoints indicated that at least part of them seem to be derived from CSR defects. Our results show that chromosomal breakpoints affecting the IG loci are recurrent in cHL. (Cancer Res 2006; 66(21): 10332-8)
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- 2023
3. Comparative analysis of international prognostic indices in gray-zone lymphoma
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Heinz-Wolfram Bernd, Hanno M Witte, Alfred C. Feller, Arthur Bauer, Hartmut Merz, Niklas Gebauer, and Veronica Bernard
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Oncology ,Cancer Research ,medicine.medical_specialty ,Scoring system ,Concordance ,Gray zone lymphoma ,International Prognostic Index ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Overall survival ,medicine ,Humans ,Retrospective Studies ,business.industry ,Hematology ,Prognosis ,medicine.disease ,Hodgkin Disease ,Progression-Free Survival ,Lymphoma ,Cohort ,Lymphoma, Large B-Cell, Diffuse ,Akaike information criterion ,business - Abstract
Gray-zone lymphoma (GZL) reflects an aggressive B-cell neoplasm with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). The International Prognostic Index (IPI) and its derivatives (R-IPI, NCCN-IPI, and the Hasenclever IPS) have been established for DLBCL or cHL while the most suitable scoring system for GZL remains undetermined. In an exploratory multi-centric cohort of GZL (n = 61), we performed a comparative analysis of prognostic indices with regard to model fit and mutual concordance. The calculation of the corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index) for each scoring system identified the NCCN-IPI to harbor the most convincing prognostic capabilities regarding both overall survival (OS) and progression-free survival (PFS) compared to its enhanced derivatives. The current results affirm the clinical utility of the NCCN-IPI and suggest its preferential use in clinical practice in GZL-patients.
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- 2021
4. Tumour cell characteristics and microenvironment composition correspond to clinical presentation in newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma
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Sylvia Hartmann, Ahmad Sajad Soltani, Katrin Bankov, Julia Bein, Martin‐Leo Hansmann, Andreas Rosenwald, Heinz‐Wolfram Bernd, Alfred Feller, German Ott, Peter Möller, Harald Stein, Wolfram Klapper, Peter Borchmann, Andreas Engert, and Dennis A. Eichenauer
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Tumor Microenvironment ,Humans ,Hematology ,T-Lymphocytes, Helper-Inducer ,Lymph Nodes ,Immunoglobulin D ,Prognosis ,Hodgkin Disease - Abstract
Different studies have characterized the microenvironment and its prognostic impact in classic Hodgkin lymphoma whereas such analyses are pending for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We thus investigated characteristics of tumour cells and microenvironment in NLPHL and evaluated possible correlations with the clinical presentation. Lymph node samples from 152 NLPHL patients who had first-line treatment within the randomized German Hodgkin Study Group HD16-HD18 trials were available and analysed with regard to IgD status and nuclear size of the tumour cells as well as presence of PD1-positive follicular T helper cells and CD163-positive macrophages in the microenvironment. While large tumour cell nuclei and high numbers of PD1-positive follicular T helper cells in the microenvironment were more common in patients presenting with early/intermediate stages than in patients with advanced-stage disease (p 0.0001, unpaired t-test; p = 0.0022, Mann-Whitney test), no differences between risk groups were observed in terms of the IgD status of the tumour cells and the content of CD163-positive macrophages in the microenvironment. PD1-positive follicular T helper cells were present in both cases with typical and variant growth patterns and rosetting around the tumour cells was observed in 96% of patients, indicating an important role of PD1-positive follicular T helper cells in NLPHL.
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- 2022
5. Localized- and advanced-stage follicular lymphomas differ in their gene expression profiles
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Heinz-Wolfram Bernd, Heike Horn, Martin-Leo Hansmann, Klaus Herfarth, Andreas Rosenwald, Alfred C. Feller, Martin Dreyling, Claudia Kalla, Eva Hoster, Wolfram Klapper, Karoline Koch, Stefan Winter, Oliver Weigert, Ellen Leich, Peter Möller, German Ott, Annette M. Staiger, Vindi Jurinovic, Sylvia Hartmann, Harald Stein, Marianne Engelhard, and Wolfgang Hiddemann
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Immunology ,Medizin ,Follicular lymphoma ,Biology ,Logistic regression ,Biochemistry ,Translocation, Genetic ,Cohort Studies ,Young Adult ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Lymphoma, Follicular ,Survival rate ,Aged ,Aged, 80 and over ,Proportional hazards model ,Gene Expression Profiling ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Lymphoma ,Survival Rate ,Gene expression profiling ,Cohort ,Female ,Transcriptome ,Follow-Up Studies - Abstract
The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.
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- 2020
6. Molecular Cytogenetic Profiling Reveals Similarities and Differences Between Localized Nodal and Systemic Follicular Lymphomas
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Heike, Horn, Vindi, Jurinovic, Ellen, Leich, Sabrina, Kalmbach, Julia, Bausinger, Annette M, Staiger, Katrin S, Kurz, Peter, Möller, Heinz-Wolfram, Bernd, Alfred C, Feller, Karoline, Koch, Wolfram, Klapper, Harald, Stein, Martin-Leo, Hansmann, Sylvia, Hartmann, Gabriel, Scheubeck, Martin, Dreyling, Wolfgang, Hiddemann, Klaus, Herfarth, Marianne, Engelhard, Andreas, Rosenwald, Eva, Hoster, and German, Ott
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Hematology - Abstract
Recently, we have developed novel highly promising gene expression (GE) classifiers discriminating localized nodal (LFL) from systemic follicular lymphoma (SFL) with prognostic impact. However, few data are available in LFL especially concerning hotspot genetic alterations that are associated with the pathogenesis and prognosis of SFL. A total of 144 LFL and 527 SFL, enrolled in prospective clinical trials of the German Low Grade Lymphoma Study Group, were analyzed by fluorescence in situ hybridization to detect deletions in chromosomes 1p, 6q, and 17p as well as
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- 2022
7. Integrative genomic and transcriptomic analysis in plasmablastic lymphoma identifies disruption of key regulatory pathways
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Hartmut Merz, Alfred C. Feller, Axel Künstner, Nadine Hertel, Heinz-Wolfram Bernd, Nikolas von Bubnoff, Stephanie Stölting, Niklas Gebauer, Hanno M Witte, Hauke Busch, and Veronica Bernard
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Neuroblastoma RAS viral oncogene homolog ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Lymphoid Neoplasia ,PIM1 ,PDGFRB ,Hematology ,Genomics ,Biology ,medicine.disease ,Transcriptome ,Proto-Oncogene Proteins c-myc ,hemic and lymphatic diseases ,medicine ,biology.protein ,Cancer research ,Plasmablastic Lymphoma ,Bruton's tyrosine kinase ,Humans ,ERBB3 ,Plasmablastic lymphoma ,PI3K/AKT/mTOR pathway ,Signal Transduction - Abstract
Key Points WES coupled with RNA-sequencing of a large PBL cohort reveals genetic drivers of oncogenesis in RTK-RAS, NF-kB, and JAK/STAT signaling.The mutational landscape and SCNV data emphasize the distinctness of EBV+/EBV– PBL from both DLBCL and multiple myeloma., Visual Abstract, Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Targeted-sequencing studies and a single-center whole-exome sequencing (WES) study in HIV-positive patients recently revealed several genes associated with PBL pathogenesis; however, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns, and perturbed pathways in HIV-positive and HIV-negative PBL, we performed WES and transcriptome sequencing (RNA-sequencing) of 33 PBL tumors. Integrative analysis of somatic mutations and gene expression profiles was performed to acquire insights into the divergent genotype–phenotype correlation in Epstein-Barr virus–positive (EBV+) and EBV– PBL. We describe a significant accumulation of mutations in the JAK signal transducer and transcription activator (OSMR, STAT3, PIM1, and SOCS1), as well as receptor tyrosine-kinase RAS (ERBB3, NRAS, PDGFRB, and NTRK) pathways. We provide further evidence of frequent perturbances of NF-κB signaling (NFKB2 and BTK). Induced pathways, identified by RNA-sequencing, closely resemble the mutational profile regarding alterations accentuated in interleukin-6/JAK/STAT signaling, NF-κB activity, and MYC signaling. Moreover, class I major histocompatibility complex–mediated antigen processing and cell cycle regulation were significantly affected by EBV status. An almost exclusive upregulation of phosphatidylinositol 3-kinase/AKT/mTOR signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic mutations in EBV– PBL hint at a specific therapeutically targetable mechanism in PBL subgroups. Our characterization of a mutational and transcriptomic landscape in PBL, distinct from that of diffuse large B-cell lymphoma and multiple myeloma, substantiates the pathobiological independence of PBL in the spectrum of B-cell malignancies and thereby refines the taxonomy for aggressive lymphomas.
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- 2021
8. Performance of international prognostic indices in plasmablastic lymphoma: a comparative evaluation
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Nadine Hertel, Heinz-Wolfram Bernd, Niklas Gebauer, Hauke Busch, Hartmut Merz, Hanno M Witte, Alfred C. Feller, Veronica Bernard, Nikolas von Bubnoff, and Axel Künstner
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Concordance ,Original Article – Clinical Oncology ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Stage (cooking) ,Risk stratification ,Aged ,Retrospective Studies ,Aged, 80 and over ,Univariate analysis ,Framingham Risk Score ,business.industry ,International Agencies ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Lymphoma ,Survival Rate ,Nomograms ,030220 oncology & carcinogenesis ,Cohort ,Plasmablastic Lymphoma ,Female ,business ,IPI ,Plasmablastic lymphoma ,030215 immunology ,Follow-Up Studies - Abstract
Purpose Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell malignancy with a heterogenous clinical and prognostic spectrum, determined by multiple factors, including age, HIV- and MYC-status. While there exist several validated scoring systems for diffuse large B-cell lymphoma, which incorporate basic clinical features (age, lactate dehydrogenase, sites of (extranodal) involvement, stage and performance), none of these have been systematically assessed in PBL. Methods We determined the (age-adjusted; aa)-International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI) in a comprehensive multi-center cohort (n = 78) of PBL patients. Further, all indices were comparatively investigated for model quality and concordance. Results Univariate analysis revealed significant prognostic capabilities for all indices, all of which identified a subgroup with favorable outcome. Discriminatory power between patients with less benign prognosis and especially refractory disease exhibited significant variability. Subsequently, stratified models for each risk score were compared employing corrected Akaike’s information criterion (cAIC) and Harrel’s concordance index (c-index). Here, the NCCN-IPI outperformed both IPI and R-IPI regarding c-index with ambiguous cAIC results, underlining its clinical utility and suggesting it for preferential use in clinical practice. Conclusion Our current observations support the use of the IPI and its enhanced derivatives in PBL patients. There is, however, a distinct requirement for novel prognostic tools to better delineate subgroups at risk for early relapse or refractory disease as well as late relapse. A comprehensive molecular characterization of a clinically annotated cohort of PBL patients is therefore urgently warranted.
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- 2020
9. Clinicopathological characteristics and MYC status determine treatment outcome in plasmablastic lymphoma: a multi-center study of 76 consecutive patients
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Heinz-Wolfram Bernd, Stephanie Stölting, Alfred C. Feller, Hartmut Merz, Nadine Hertel, Niklas Gebauer, Nikolas von Bubnoff, Veronica Bernard, and Hanno M Witte
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Treatment outcome ,Antineoplastic Agents ,lcsh:RC254-282 ,Proto-Oncogene Proteins c-myc ,Internal medicine ,Correspondence ,Genetics research ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,B-cell lymphoma ,business.industry ,Gene Amplification ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,medicine.disease ,Treatment Outcome ,Multi center study ,Plasmablastic Lymphoma ,Female ,business ,Proteasome Inhibitors ,Plasmablastic lymphoma - Published
- 2020
10. MicroRNA Profiling of Low-Grade and Transformed Nodal Marginal Zone Lymphoma Reveals a Similar Signature Pattern Distinct from Diffuse Large B Cell Lymphoma
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Hartmut Merz, Alfred C. Feller, Andrea Senft, Arne Schillert, Christoph Thorns, Veronica Bernard, Niklas Gebauer, and Heinz-Wolfram Bernd
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Biology ,microRNA ,Gene expression ,medicine ,Humans ,RNA, Neoplasm ,Lymph node ,B cell ,Aged ,Retrospective Studies ,Aged, 80 and over ,Regulation of gene expression ,Gene Expression Profiling ,Lymphoma, B-Cell, Marginal Zone ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,MicroRNAs ,medicine.anatomical_structure ,Cancer research ,Female ,Lymph Nodes ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
Background/Aims: As critical post-transcriptional regulators of gene expression, microRNAs are involved in several cellular processes of vital impact including cell growth and apoptosis. Many hematologic malignancies exhibit distinct microRNA signatures. MicroRNA implication in the pathogenesis of nodal marginal zone lymphoma (NMZL), however, remains widely elusive. Methods: Comprehensive morphologic, immunophenotypic and cytogenetic studies were carried out on a cohort of NMZL (n = 30) incorporating indolent as well as transformed MZL. In addition, microRNA signatures were generated, employing a quantitative real-time polymerase chain reaction approach. These were then compared to signatures from cases of diffuse large B cell lymphoma (DLBCL) alongside reactive lymph node controls. Results: While microRNA signatures of low-grade and transformed NMZL did not differ significantly, several microRNAs were differentially expressed between transformed NMZL and DLBCL, hinting at molecularly distinct mechanisms of lymphomagenesis and indicating the biological disparity of transformed NMZL from DLBCL. Conclusion: In the light of the unresolved issue regarding the classification of marginal zone-derived transformed B-cell neoplasms, microRNAs may be a valuable aid in discriminating NMZL from DLBCL. © 2014 S. Karger AG, Basel
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- 2014
11. Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group
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Martin-Leo Hansmann, Heike Horn, German Ott, Thomas F.E. Barth, W Klapper, Sergio Cogliatti, Peter Möller, Sylvia Hartmann, Annette M. Staiger, Lorenz Trümper, Georg Lenz, Dido Lenze, Michael Hummel, Heinz-Wolfram Bernd, David W. Scott, Monika Szczepanowski, Michael Pfreundschuh, Andreas Rosenwald, Harald Stein, Norbert Schmitz, Markus W. Löffler, Marita Ziepert, and Alfred C. Feller
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Disease-Free Survival ,Translocation, Genetic ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Antibodies, Monoclonal, Murine-Derived ,Young Adult ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Germany ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Survival rate ,Cyclophosphamide ,Aged ,Etoposide ,Aged, 80 and over ,business.industry ,Germinal center ,Middle Aged ,BCL6 ,medicine.disease ,Germinal Center ,Non-Hodgkin's lymphoma ,Lymphoma ,Clinical trial ,Survival Rate ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Doxorubicin ,Vincristine ,030220 oncology & carcinogenesis ,Monoclonal ,Proto-Oncogene Proteins c-bcl-6 ,Prednisone ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Rituximab ,Diffuse large B-cell lymphoma - Abstract
Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]–like DLBCL v germinal center B-cell [GCB]–like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.
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- 2017
12. Nodal marginal zone lymphoma: mutation status analyses of CD79A, CD79B, and MYD88 reveal no specific recurrent lesions
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Michelle Gurth, Janina Schemme, Veronica Bernard, Heinz-Wolfram Bernd, and Christoph Thorns
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0301 basic medicine ,Male ,Cancer Research ,Nodal marginal zone lymphoma ,DNA Mutational Analysis ,Biology ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Lymphoid neoplasms ,B cell ,High-Throughput Nucleotide Sequencing ,Hematology ,Lymphoma, B-Cell, Marginal Zone ,CD79B ,CD79A ,medicine.disease ,Lymphoma ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Mutation ,Myeloid Differentiation Factor 88 ,Cancer research ,Female ,Neoplasm Recurrence, Local ,CD79 Antigens - Abstract
Nodal Marginal Zone lymphoma (NMZL) constitutes a rare subtype of B-cell-lymphomas, accounting for less than 2% of all lymphoid neoplasms. The rarity of NMZL as well as its morphological heterogene...
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- 2016
13. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network
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Stephan Stilgenbauer, Andreas Rosenwald, Christoph Loddenkemper, Olivier Hermine, Bertrand Coiffier, Catherine Thieblemont, Johanna Kluin-Nelemans, Wolfgang Hiddemann, Christian Schmidt, Michael Hallek, Michael Pfreundschuh, Françoise Berger, Heinz-Wolfram Bernd, Roswitha Forstpointner, Reda Bouabdallah, Wolfram Klapper, Eva Hoster, Roman Kodet, Lothar Kanz, Nicole Brousse, Martin Dreyling, Thomas F. E. Barth, Sylvia Hartmann, Ursula Vehling-Kaiser, Michael Unterhalt, Vincent Ribrag, Stefano Pileri, Grzegorz Rymkiewicz, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Oncology ,Male ,Cancer Research ,Pathology ,Time Factors ,Biopsy ,Kaplan-Meier Estimate ,Lymphoma, Mantle-Cell ,IMPROVES RESPONSE ,0302 clinical medicine ,International Prognostic Index ,Risk Factors ,Cytology ,CYCLOPHOSPHAMIDE ,Medicine ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,biology ,PROLIFERATION ,Discriminant Analysis ,Middle Aged ,Prognosis ,Immunohistochemistry ,Tumor Burden ,Europe ,030220 oncology & carcinogenesis ,Ki-67 ,SURVIVAL ,Female ,Adult ,medicine.medical_specialty ,DOXORUBICIN ,MCL-NETWORK ,Malignancy ,IMMUNOCHEMOTHERAPY ,Risk Assessment ,VALIDATION ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,Humans ,VINCRISTINE ,Aged ,Cell Proliferation ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,Proportional hazards model ,MIPI ,Retrospective cohort study ,medicine.disease ,Lymphoma ,Ki-67 Antigen ,Multivariate Analysis ,biology.protein ,Mantle cell lymphoma ,business ,030215 immunology - Abstract
Purpose Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Patients and Methods Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. Results The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. Conclusion Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.
- Published
- 2016
14. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL
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Matthias Frank, Markus Loeffler, Michael Pfreundschuh, German Ott, Marita Ziepert, Heinz-Wolfram Bernd, Sergio Cogliatti, Andreas Rosenwald, Michael Hummel, Hans Konrad Müller-Hermelink, Alfred C. Feller, Heike Horn, Christoph Thorns, Lorenz Trümper, Martin-Leo Hansmann, Norbert Schmitz, Thomas F. E. Barth, Wolfram Klapper, Monika Szczepanowski, Peter Möller, Harald Stein, and Dido Lenze
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Male ,Pathology ,Kaplan-Meier Estimate ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,0303 health sciences ,Hematology ,Anatomical pathology ,Middle Aged ,Prognosis ,BCL6 ,Immunohistochemistry ,3. Good health ,Treatment Outcome ,Vincristine ,030220 oncology & carcinogenesis ,Female ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,medicine.drug ,medicine.medical_specialty ,Immunology ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Lymphoma, Large-Cell, Immunoblastic ,Cyclophosphamide ,Aged ,030304 developmental biology ,business.industry ,Gene Expression Profiling ,Large cell ,Cell Biology ,Germinal Center ,medicine.disease ,Lymphoma ,Doxorubicin ,Tissue Array Analysis ,Prednisone ,CD5 ,business ,Diffuse large B-cell lymphoma - Abstract
The survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)–DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.
- Published
- 2010
15. Progressive renal insufficiency, hypercalcaemia, bicytopaenia and a history of breast cancer
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Heinz-Wolfram Bernd, Udo Helmchen, Sebastian Letterer, Florian M. Vogt, Ulrich Lindner, Hendrik Lehnert, and Christian S. Haas
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Transplantation ,Pathology ,medicine.medical_specialty ,Kidney ,bone marrow ,Hypercalcaemia ,business.industry ,Interstitial nephritis ,Case Report ,medicine.disease ,renal insufficiency ,medicine.anatomical_structure ,Breast cancer ,Nephrology ,medicine ,sarcoidosis ,Bone marrow ,Sarcoidosis ,Differential diagnosis ,Nephrocalcinosis ,interstitial nephritis ,business - Abstract
Sarcoidosis can affect all organs and may mimic a variety of other diseases. In the absence of typical pulmonary features, extrapulmonary manifestations may be difficult to diagnose. We describe here the very uncommon case of a patient with mild pulmonal involvement but distinct renal, bone marrow and lymph node sarcoidosis. Treatment with glucocorticoids significantly improved kidney function and normalized serum calcium levels as well as the blood count. This case underscores the importance of sarcoidosis to be considered as a differential diagnosis of renal failure associated with hypercalcaemia and nephrocalcinosis. Bone marrow involvement should always be suspected if mono-, bi- or pancytopaenia coexist.
- Published
- 2010
16. A cytomorphological and immunohistochemical profile of aggressive B-cell lymphoma: high clinical impact of a cumulative immunohistochemical outcome predictor score
- Author
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Andreas Rosenwald, Tiemo Katzenberger, M. Michaela Ott, German Ott, Andreas Lohr, Uwe Mäder, Heinz-Wolfram Bernd, Heike Horn, Hans Konrad Müller-Hermelink, Jörg Kalla, Sylvia Höller, and Philip Went
- Subjects
medicine.medical_specialty ,Pathology ,Histology ,Multivariate analysis ,Chemistry(all) ,Energy Engineering and Power Technology ,Physics and Astronomy(all) ,Pathology and Forensic Medicine ,International Prognostic Index ,Internal medicine ,medicine ,B-cell lymphoma ,Univariate analysis ,Hematology ,business.industry ,Diffuse large B-cell lymphoma ,Prognosis ,medicine.disease ,Immunohistochemistry ,Pollution ,Aggressive B-cell lymphoma ,Regimen ,Fuel Technology ,Chemical Engineering(all) ,Original Article ,business - Abstract
We analyzed morphological and immunohistochemical features in 174 aggressive B-cell lymphomas of nodal and extranodal origin. Morphological features included presence or absence of a follicular component and cytologic criteria according to the Kiel classification, whereas immunohistochemical studies included expression of CD10, BCL-2, BCL-6, IRF4/MUM1, HLA-DR, p53, Ki-67 and the assessment of plasmacytoid differentiation. Patients were treated with a CHOP-like regimen. While the presence or absence of either CD10, BCL-6 and IRF4/MUM1 reactivity or plasmacytoid differentiation did not identify particular cytomorphologic or site-specific subtypes, we found that expression of CD10 and BCL-6, and a low reactivity for IRF4/MUM1 were favourable prognostic indicators. In contrast, BCL-2 expression and presence of a monotypic cytoplasmic immunoglobulin expression was associated with an unfavourable prognosis in univariate analyses. Meta-analysis of these data resulted in the development of a cumulative immunohistochemical outcome predictor score (CIOPS) enabling the recognition of four distinct prognostic groups. Multivariate analysis proved this score to be independent of the international prognostic index. Such a cumulative immunohistochemical scoring approach might provide a valuable alternative in the recognition of defined risk types of aggressive B-cell lymphomas.
- Published
- 2009
17. New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling
- Author
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José I, Martín-Subero, Markus, Kreuz, Marina, Bibikova, Stefan, Bentink, Ole, Ammerpohl, Eliza, Wickham-Garcia, Maciej, Rosolowski, Julia, Richter, Lidia, Lopez-Serra, Esteban, Ballestar, Hilmar, Berger, Xabier, Agirre, Heinz-Wolfram, Bernd, Vincenzo, Calvanese, Sergio B, Cogliatti, Hans G, Drexler, Jian-Bing, Fan, Mario F, Fraga, Martin L, Hansmann, Michael, Hummel, Wolfram, Klapper, Bernhard, Korn, Ralf, Küppers, Roderick A F, Macleod, Peter, Möller, German, Ott, Christiane, Pott, Felipe, Prosper, Andreas, Rosenwald, Carsten, Schwaenen, Dirk, Schübeler, Marc, Seifert, Benjamin, Stürzenhofecker, Michael, Weber, Swen, Wessendorf, Markus, Loeffler, Lorenz, Trümper, Harald, Stein, Rainer, Spang, Manel, Esteller, David, Barker, Dirk, Hasenclever, Reiner, Siebert, Maren, Wehner, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), and for the Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe
- Subjects
Male ,Lymphoma, B-Cell ,Transcription, Genetic ,Immunology ,Biology ,Biochemistry ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Neoplasm Invasiveness ,Epigenetics ,Embryonic Stem Cells ,B cell ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Epigenomics ,Genetics ,0303 health sciences ,Gene Expression Profiling ,Genomics ,Cell Biology ,Hematology ,DNA Methylation ,Hematopoietic Stem Cells ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Female ,Stem cell ,Burkitt's lymphoma ,Diffuse large B-cell lymphoma ,Ciencias de la Salud::Oncología [Materias Investigacion] - Abstract
Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype–specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell–like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.
- Published
- 2009
18. Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials
- Author
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Martin Zimmermann, Monika Szczepanowski, Hilmar Berger, Swen Wessendorf, Peter Møller, Martin-Leo Hansmann, Harald Stein, Wolfram Klapper, Birgit Burkhardt, Maciej Rosolowski, Heinz-Wolfram Bernd, Carsten Schwaenen, Rainer Spang, Reiner Siebert, Michael Hummel, German Ott, Stefan Bentink, Lorenz Trümper, Markus Loeffler, and Alfred Reiter
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Lymphoma, B-Cell ,Adolescent ,Immunology ,In situ hybridization ,Disease ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,030304 developmental biology ,Clinical Trials as Topic ,0303 health sciences ,Hematology ,business.industry ,Gene Expression Profiling ,Age Factors ,Cell Biology ,Middle Aged ,medicine.disease ,Burkitt Lymphoma ,3. Good health ,Lymphoma ,Gene expression profiling ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma ,Comparative genomic hybridization - Abstract
The spectrum of entities, the therapeutic strategy, and the outcome of mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) differs between children and adolescents on the one hand and adult patients on the other. Whereas adult maB-NHLs have been studied in detail, data on molecular profiling of pediatric maB-NHLs are hitherto lacking. We analyzed 65 cases of maB-NHL from patients up to 18 years of age by gene expression profiling, matrix comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and immunohistochemistry. The majority of the analyzed pediatric patients were treated within prospective trials (n = 49). We compared this group to a series of 182 previously published cases of adult maB-NHL. Gene expression profiling reclassified 31% of morphologically defined diffuse large B-cell lymphomas as molecular Burkitt lymphoma (mBL). The subgroups obtained by molecular reclassification did not show any difference in outcome in children treated with the NHL-Berlin-Frankfurt-Muenster (BFM) protocols. No differences were detectable between pediatric and adult mBL with regard to gene expression or chromosomal imbalances. This is the first report on molecular profiling of pediatric B-NHL showing mBL to be much more prominent in children than suggested by morphologic assessment. Based on molecular profiling mBL is a molecularly homogeneous disease across children and adults.
- Published
- 2008
19. Hodgkin's lymphoma as a rare variant of Richter's transformation in chronic lymphocytic leukemia: A case report and review of the literature
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Snjezana Janjetovic, Heinz‑Wolfram Bernd, Walter Fiedler, and Carsten Bokemeyer
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Richter's transformation ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Hairy cell leukemia ,business.industry ,Lymphoblastic lymphoma ,Clinical course ,Cancer ,Articles ,medicine.disease ,Hodgkin's lymphoma ,Lymphoma ,Richter transformation ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,chronic lymphocytic leukemia ,business - Abstract
Richter's transformation induces an aggressive clinical course in chronic lymphocytic leukemia (CLL). In the majority of cases, Richter's transformation manifests itself as a high-grade B-cell non-Hodgkin's lymphoma (B-NHL). However, other histological types, such as classical Hodgkin lymphoma (cHL), lymphoblastic lymphoma, hairy cell leukemia and high-grade T-cell NHL have been described previously. The present study reports a rare case of CLL with transformation into classical Hodgkin's lymphoma (cHL). The common clonal origin of CLL and cHL was documented by immunoglobulin gene rearrangement analysis performed using multiplex polymerase chain reaction. Following a review of the literature, treatment of secondary Hodgkin's lymphoma is discussed, and prognosis is often poor.
- Published
- 2015
20. Chromosomal Breakpoints Affecting Immunoglobulin Loci Are Recurrent in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma
- Author
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Peter Møller, Stefan Gesk, Wolfram Klapper, Heinz-Wolfram Bernd, Christian Bastard, Irina B. Kaplanskaya, Roland Schmitz, Jorge Höppner, José I. Martín-Subero, Reza Parwaresch, Susanne Grohmann, Lana Harder, Thomas Rüdiger, Reiner Siebert, Alexander Claviez, Anna Sotnikova, Martin L. Hansmann, Georgiy A. Frank, Ralf Küppers, Françoise Berger, Harald Stein, Evelyne Callet-Bauchu, Thomas F. E. Barth, and Jennifer Riemke
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Genes, Immunoglobulin Heavy Chain ,Genes, myc ,chemical and pharmacologic phenomena ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Recurrence ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Reed-Sternberg Cells ,In Situ Hybridization, Fluorescence ,Aged ,Genetics ,Chromosome ,Chromosome Breakage ,Middle Aged ,BCL6 ,medicine.disease ,Hodgkin Disease ,Immunoglobulin Class Switching ,Neoplasm Proteins ,Lymphoma ,DNA-Binding Proteins ,Oncology ,Reed–Sternberg cell ,Immunoglobulin class switching ,Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ,Caspases ,Proto-Oncogene Proteins c-bcl-6 ,Immunoglobulin heavy chain ,Female ,Chromosome breakage ,Immunoglobulin Constant Regions - Abstract
Chromosomal breakpoints affecting immunoglobulin (IG) loci are recurrent in many subtypes of B-cell lymphomas. However, despite the predominant B-cell origin of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL), the presence of chromosomal translocations in IG loci has not yet been systematically explored. Therefore, we have investigated a series of cHL for chromosomal breakpoints in the IGH (n = 230), IGL (n = 139), and IGK (n = 138) loci by interphase cytogenetics. Breakpoints in the IGH, IGL, or IGK locus were observed in the HRS cells of 26 of 149 (17%), 2 of 70, and 1 of 77 evaluable cHLs, respectively. The IG partners could be identified in eight cHLs and involved chromosomal bands 2p16 (REL), 3q27 (BCL6, two cases), 8q24.1 (MYC), 14q24.3, 16p13.1, 17q12, and 19q13.2 (BCL3/RELB). In 65 of 85 (76%) cHLs evaluable for an IGH triple-color probe, the HRS cells showed evidence for a (partial) deletion of the IGH constant region, suggesting the presence of class switch recombination (CSR). Furthermore, analyses with this probe in cases with IGH breakpoints indicated that at least part of them seem to be derived from CSR defects. Our results show that chromosomal breakpoints affecting the IG loci are recurrent in cHL. (Cancer Res 2006; 66(21): 10332-8)
- Published
- 2006
21. Wotherspoon criteria combined with B cell clonality analysis by advanced polymerase chain reaction technology discriminates covert gastric marginal zone lymphoma from chronic gastritis
- Author
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A. Marx, Sergio Cogliatti, Heinz Wolfram Bernd, Michael Hummel, A. C. Feller, S. Oeschger, Christoph Loddenkemper, Harald Stein, Thomas F. E. Barth, Peter Møller, M.-L. Hansmann, and H.-H. Wacker
- Subjects
Pathology ,medicine.medical_specialty ,Gene Rearrangement, B-Lymphocyte, Heavy Chain ,Chronic gastritis ,Pilot Projects ,Polymerase Chain Reaction ,Diagnosis, Differential ,Stomach Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,B-cell lymphoma ,B cell ,CD20 ,Genes, Immunoglobulin ,biology ,Gastroenterology ,Reproducibility of Results ,Lymphoma, B-Cell, Marginal Zone ,Gene rearrangement ,Antigens, CD20 ,medicine.disease ,Helicobacter Pylori ,Clone Cells ,Lymphoma ,Lymphatic system ,medicine.anatomical_structure ,Gastritis ,Chronic Disease ,Neoplastic Stem Cells ,biology.protein ,medicine.symptom ,Immunoglobulin Heavy Chains ,Algorithms - Abstract
Background and aims: Gastric mucosa associated lymphoid tissue lymphoma is a well defined B cell lymphoma yet often impossible to distinguish from severe chronic gastritis on morphological grounds alone. Therefore, it was suggested to use the clonality of the immunoglobulin (Ig) heavy chain (H) genes, as detected by polymerase chain reaction (PCR), as a decisive criterion. However, there is controversy as to whether B cell clonality also exists in chronic gastritis, hence rendering this approach futile at present. Methods: An expert panel re-examined the histology and immunohistochemistry of a total of 97 cases of gastric biopsies, including clearcut marginal zone lymphoma, chronic gastritis, and ambiguous cases, applying the Wotherspoon criteria on the basis of haematoxylin-eosin and CD20 immunostainings. In addition, a new and advanced PCR system for detection of clonal IgH gene rearrangements was independently applied in two institutions in each case. Results: The overall IgH clonality assessments of both institutions were in total agreement. Overt lymphoma (Wotherspoon score 5) was clonal in 24/26 cases. Chronic gastritis (Wotherspoon scores 1 and 2) was not clonal in 52/53 cases; the clonal case being Wotherspoon score 2. Of 18 cases with ambiguous histology (Wotherspoon scores 3 and 4) four were clonal. Conclusions: Using advanced PCR technology, clonal gastritis is extremely rare, if it exists at all. Thus B cell clonality in Wotherspoon 3 and 4 cases is regarded as suitable for definitively diagnosing gastric marginal zone lymphoma.
- Published
- 2006
22. Histopathological features and their prognostic impact in nodular lymphocyte-predominant Hodgkin lymphoma--a matched pair analysis from the German Hodgkin Study Group (GHSG)
- Author
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Karoline Koch, Harald Stein, Martin-Leo Hansmann, Peter Möller, Roshanak Bob, Heinz-Wolfram Bernd, Sylvia Hartmann, German Ott, Alfred C. Feller, Dennis A. Eichenauer, Annette Plütschow, Anja Mottok, Wolfram Klapper, Andreas Engert, Sergio Cogliatti, Andreas Rosenwald, and Michael Hummel
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Matched Pair Analysis ,Herpesvirus 4, Human ,Adolescent ,Matched-Pair Analysis ,Lewis X Antigen ,CD15 ,Lymphocyte Activation ,Immunoglobulin D ,Virus ,Inducible T-Cell Co-Stimulator Protein ,Young Adult ,immune system diseases ,Recurrence ,T-Lymphocyte Subsets ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Lymph node ,Neoplasm Staging ,biology ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Fucosyltransferases ,Prognosis ,Hodgkin Disease ,Lymphoma ,Neoplasm Proteins ,medicine.anatomical_structure ,Nodular Lymphocyte Predominant Hodgkin Lymphoma ,biology.protein ,Female ,business ,STAT6 Transcription Factor ,Epithelioid cell - Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.
- Published
- 2014
23. The Clinical Impact of the Cell-of-Origin Classification and the MYC+/BCL2+ Double Expresser Status in DLBCL Treated within Prospective Clinical Trials of the Dshnhl
- Author
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German Ott, Lorenz Truemper, Markus Loeffler, David W. Scott, Thomas F. E. Barth, Annette M. Staiger, Georg Lenz, Sergio Cogliatti, Harald Stein, Michael Pfreundschuh, Heike Horn, Andreas Rosenwald, Michael Hummel, Peter Moeller, Wolfram Klapper, Sylvia Hartmann, Norbert Schmitz, Heinz-Wolfram Bernd, Dido Lenze, Martin-Leo Hansmann, Alfred C. Feller, and Marita Ziepert
- Subjects
Oncology ,medicine.medical_specialty ,Cell of origin ,Immunology ,Bioinformatics ,Biochemistry ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,immune system diseases ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,neoplasms ,business.industry ,Cell Biology ,Hematology ,BCL6 ,Subtyping ,Clinical trial ,030220 oncology & carcinogenesis ,Concomitant ,Immunohistochemistry ,CD5 ,business ,030215 immunology - Abstract
The Lymph2Cx Cell-of-origin (COO) assay enables the identification of molecular GCB and ABC subtypes of diffuse large B-cell lymphomas (DLBCL) using RNA from formalin-fixed paraffin-embedded (FFPE) samples. In order to explore the prognostic power of this COO assay within the frame of prospectively randomized clinical trials for the first time, we retrospectively performed COO analyses in patient samples from two clinical trials (RICOVER-60: n=360 and R-MegaCHOEP: n=92) of the German High Grade Lymphoma Study Group (DSHNHL) using the Nanostring nCounter®-platform. Immunohistochemistry was done for MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1 protein expression, and fluorescence in-situ hybridization was performed for MYC, BCL2 and BCL6 genes with break-apart probes. COO classification was successfully obtained from 414 samples (326/360 (91%) and 88/92 (96%) FFPE samples from the RICOVER60 and R-MegaCHOEP trials, respectively). In the RICOVER-60 study (patients aged > 60 and In RICOVER-60, the ABC-DLBCL group was associated with inferior clinical outcome compared with the GCB subtype (p=0.041, p=0.022 and p=0.034 for EFS, PFS and OS, respectively). A significant survival difference was also seen in CHOP-treated patients. This effect, however, was completely abrogated in R-CHOP treated patients with no significant difference observed in EFS, PFS and OS. This result was confirmed in multivariable analyses adjusted for IPI factors. We found the same results for all RICOVER-60 patients after adjustment for IPI factors (EFS: HR=1.1, PFS: HR=1.2, OS: HR=1.2 for ABC vs. GCB) and after adjustment for IPI factors, bulky disease, gender and age > 70 years. In keeping with this result, no survival differences were observed between ABC-DLBCL and GCB-DLBCL patients in the R-MegaCHOEP trial for EFS, PFS and OS, and this was also confirmed in multivariable analysis (data not shown). In the RICOVER-60 trial, patients with concomitant over-expression of both BCL2 (50-100%) and MYC (40-100%) (MYC+/BCL2+ DE DLBCL) showed significantly inferior survival in all R-CHOP treated patients and especially in the GCB subgroup compared with non-expressers [MYC-/BCL2- DLBCL; MYC-/BCL2+] (p In summary, COO profiling alone failed to identify prognostic subgroups, whereas MYC/BCL2 double expression was highly predictive of poor survival. These data from prospective randomized trials demonstrate that older patients and young high-risk patients show significant differences in molecular profiles and, furthermore, indicate that complete subtyping using different molecular methods will be necessary to predict survival under current standard therapy. Only comprehensive molecular analysis of individual patient samples will allow identification of optimal therapy including new molecules. Disclosures Scott: NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding.
- Published
- 2016
24. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group
- Author
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Wolfgang Hiddemann, Christoph Loddenkemper, Eva Hoster, Thomas E. F. Barth, Martin Dreyling, Wolfram Klapper, Michael Unterhalt, German Ott, Martin-Leo Hansmann, Heinz Wolfram Bernd, and Olaf Determann
- Subjects
Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Lymphoma, Mantle-Cell ,CHOP ,Biochemistry ,immune system diseases ,Germany ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Neoplasm Staging ,Randomized Controlled Trials as Topic ,Chemotherapy ,Hematology ,biology ,business.industry ,Cancer ,Cell Biology ,Antigens, CD20 ,Prognosis ,medicine.disease ,Surgery ,Europe ,Clinical trial ,Ki-67 Antigen ,Treatment Outcome ,Ki-67 ,Relative risk ,biology.protein ,Mantle cell lymphoma ,Immunotherapy ,business ,Biomarkers - Abstract
Clinical outcome of mantle cell lymphoma (MCL) is highly heterogeneous. Tumor cell proliferation as assessed by the Ki-67 index has been shown to yield prognostic information on MCL in many studies using heterogeneously treated patient cohorts. The prognostic value of the Ki-67 index in patients treated with anti-CD20 therapy has not been studied so far. We analyzed the Ki-67 index at primary diagnosis in 249 advanced-stage MCL patients treated within randomized trials. Ki-67 showed high prognostic relevance for overall survival (relative risk 1.27 for 10% higher Ki-67, P < .001), also independently from clinical prognostic factors. The 3 groups with different Ki-67 index of less than 10%, 10% to less than 30%, and 30% or more showed significantly different overall survival in patients treated with CHOP ( P = .001) as well as in patients treated with CHOP in combination with anti-CD20 therapy (R-CHOP, P = .013). Thus, the Ki-67 index remains an important prognostic marker in the era of anti-CD20 therapy. The Euro-pean MCL study is registered at [www.ClinicalTrials.gov][1] as #[NCT00016887][2]. [1]: http://www.ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00016887&atom=%2Fbloodjournal%2F111%2F4%2F2385.atom
- Published
- 2008
25. The prognostic impact of variant histology in nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG)
- Author
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Wolfram Klapper, Heinz-Wolfram Bernd, Sergio Cogliatti, Andreas Rosenwald, Michael Hummel, Sylvia Hartmann, German Ott, Annette Plütschow, Dennis A. Eichenauer, Peter Möller, Karoline Koch, Harald Stein, Martin-Leo Hansmann, Andreas Engert, Roshanak Bob, Anja Mottok, and Alfred C. Feller
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Databases, Factual ,Immunology ,Follicular lymphoma ,Biochemistry ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Germany ,medicine ,Humans ,Stage (cooking) ,Neoplasm Staging ,B-Lymphocytes ,business.industry ,Histology ,Cell Biology ,Hematology ,Odds ratio ,Middle Aged ,medicine.disease ,Prognosis ,Hodgkin Disease ,Lymphoma ,Reed–Sternberg cell ,Multivariate Analysis ,Rituximab ,Education, Medical, Continuing ,Female ,T-Cell/Histiocyte-Rich Large B-Cell Lymphoma ,Neoplasm Recurrence, Local ,business ,medicine.drug ,Follow-Up Studies - Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. The aim of this study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within 9 prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n = 10), typical NLPHL (n = 308), or histopathologic variants (n = 105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. Compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, P = .0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, P = .0009). Variant histology represented an independent prognostic factor (odds ratio = 2.955) in a multivariate model of progression/relapse. A prognostic score, including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender, was derived from this model and allowed the definition of 3 distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome compared with those showing typical histology. The newly developed prognostic score combining histologic and clinical features allows allocating NLPHL patients to defined risk groups.
- Published
- 2013
26. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma
- Author
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Peter Møller, Martin-Leo Hansmann, Michael Pfreundschuh, Harald Stein, Heinz-Wolfram Bernd, Markus Loeffler, Thomas F. E. Barth, Norbert Schmitz, Christopher Schmelter, Claudia Becher, Lorenz Trümper, Alfred C. Feller, Heike Horn, Reiner Siebert, Sergio Cogliatti, Andreas Rosenwald, Michael Hummel, Marita Ziepert, Wolfram Klapper, and German Ott
- Subjects
Male ,Genes, myc ,CHOP ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,0302 clinical medicine ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Multicenter Studies as Topic ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,0303 health sciences ,medicine.diagnostic_test ,Hematology ,Middle Aged ,BCL6 ,Prognosis ,3. Good health ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,Proto-Oncogene Proteins c-bcl-2 ,Vincristine ,030220 oncology & carcinogenesis ,Proto-Oncogene Proteins c-bcl-6 ,Rituximab ,Female ,Lymphoma, Large B-Cell, Diffuse ,medicine.drug ,Immunology ,03 medical and health sciences ,medicine ,Biomarkers, Tumor ,Humans ,Cyclophosphamide ,Survival analysis ,030304 developmental biology ,Aged ,business.industry ,Cell Biology ,medicine.disease ,Survival Analysis ,Lymphoma ,Doxorubicin ,Cancer research ,Prednisone ,business ,Diffuse large B-cell lymphoma ,Fluorescence in situ hybridization - Abstract
MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.
- Published
- 2013
27. Deregulation of a distinct set of microRNAs is associated with transformation of gastritis into MALT lymphoma
- Author
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Christoph Thorns, Silke Szymczak, Heinz-Wolfram Bernd, Andrea Senft, Veronica Bernard, Alfred C. Feller, and Johannes Kuba
- Subjects
Pathology ,medicine.medical_specialty ,Biology ,Pathology and Forensic Medicine ,Malignant transformation ,Helicobacter Infections ,Downregulation and upregulation ,immune system diseases ,hemic and lymphatic diseases ,microRNA ,medicine ,Humans ,Neoplastic transformation ,Molecular Biology ,B cell ,Helicobacter pylori ,MALT lymphoma ,Cell Biology ,General Medicine ,Lymphoma, B-Cell, Marginal Zone ,medicine.disease ,Lymphoma ,MicroRNAs ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Gastritis ,medicine.symptom - Abstract
The mechanisms underlying the transformation from chronic Helicobacter pylori gastritis to gastric extranodal marginal zone lymphoma (MALT lymphoma) are poorly understood. This study aims to identify microRNAs that might be involved in the process of neoplastic transformation. We generated microRNA signatures by RT-PCR in 68 gastric biopsy samples representing normal mucosa, gastritis, suspicious lymphoid infiltrates, and overt MALT lymphoma according to Wotherspoon criteria. Analyses revealed a total of 41 microRNAs that were significantly upregulated (n = 33) or downregulated (n = 8) in succession from normal mucosa to gastritis and to MALT lymphoma. While some of these merely reflect the presence of lymphocytes (e.g. miR-566 and miR-212) or H. pylori infection (e.g. miR-155 and let7f), a distinct set of five microRNAs (miR-150, miR-550, miR-124a, miR-518b and miR-539) was shown to be differentially expressed in gastritis as opposed to MALT lymphoma. This differential expression might therefore indicate a central role of these microRNAs in the process of malignant transformation.
- Published
- 2011
28. BCL6-translocations affect the phenotype of follicular lymphomas only in the absence of t(14;18)IgH/BCL2
- Author
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Wiebke, Gollub, Björn, Stassek, Torge, Huckhagel, Heinz-Wolfram, Bernd, Manuela, Krokowski, Hartmut, Merz, Alfred Christian, Feller, and Christoph, Thorns
- Subjects
Adult ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,Middle Aged ,Immunohistochemistry ,Translocation, Genetic ,DNA-Binding Proteins ,Phenotype ,Proto-Oncogene Proteins c-bcl-2 ,Proto-Oncogene Proteins c-bcl-6 ,Humans ,Chromosomes, Human, Pair 18 ,Immunoglobulin Heavy Chains ,Lymphoma, Follicular ,In Situ Hybridization, Fluorescence ,Aged - Abstract
The translocation t(14;18)IgH/BCL2 is the molecular hallmark of follicular lymphomas (FL). A subset of cases harbours translocations involving the BCL6-gene locus. This study aimed to determine the frequency of BCL2- and BCL6-translocations in FL and to identify morphological and immuno-histochemical features with respect to the presence of BCL2- and BCL6-translocations.Fluorescence-in-situ-hybridisation (FISH) was used to determine the BCL2- and BCL6-translocation status of 102 FL and these were compared to morphological and immunohistochemical parameters.Lymphomas with BCL6- and BCL2-translocations were very similar to t(14;18)-positive lymphomas without BCL6-translocations. In contrast, t(14;18)-negative lymphomas with BCL6-translocations were amongst others of higher grade, less often CD10-positive, involved the bone marrow less frequently and did not infiltrate the lymph node capsule.BCL2- and BCL6-translocations correlate with particular phenotypes of follicular lymphomas. BCL6-translocations seem to affect the phenotype only when they are not accompanied by BCL2-translocations.
- Published
- 2009
29. Basal cell carcinoma with neuroendocrine differentiation arising in a scar: A case report
- Author
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Christoph Thorns, Alfred C. Feller, Heinz-Wolfram Bernd, Manuela Krokowski, Stefan Krueger, and Josef Hoch
- Subjects
Pathology ,medicine.medical_specialty ,Skin Neoplasms ,integumentary system ,business.industry ,fungi ,Dermatology ,General Medicine ,medicine.disease ,Neuroendocrine differentiation ,Cicatrix ,Carcinoma, Basal Cell ,medicine ,Humans ,Immunohistochemistry ,Female ,Basal cell carcinoma ,skin and connective tissue diseases ,business ,Aged - Abstract
Basal cell carcinoma (BCC), the most common cutaneous malignant tumor, may display neuroendocrine differentiation in very rare instances. We here describe a case of a BCC with neuroendocrine differentiation that arose in a scar resulting from a trauma 75 years earlier. Neuroendocrine differentiation was proven by immunohistochemistry and electron microscopy. The simultaneous occurrence of BCC development in a scar and neuroendocrine differentiation is quite rare.
- Published
- 2009
30. MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas
- Author
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Michael Pfreundschuh, Marita Ziepert, Kai O. Wesche, Christoph Thorns, Markus Loeffler, Alfred C. Feller, Wolfram Klapper, Heinz Wolfram Bernd, Hartmut Merz, Kai P. Hoefig, Lila Reiniger, Anja Roehle, Dirk Repsilber, Marlen Thiere, and András Matolcsy
- Subjects
Adult ,Male ,Follicular lymphoma ,Biology ,Article ,immune system diseases ,hemic and lymphatic diseases ,microRNA ,medicine ,Gene silencing ,Humans ,Lymphoma, Follicular ,B cell ,Aged ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Hematology ,Middle Aged ,medicine.disease ,mIRN21 ,Lymphoma ,Gene expression profiling ,MicroRNAs ,medicine.anatomical_structure ,Cancer research ,Female ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
MicroRNAs (miRNA, miR) are negative regulators of gene expression that play an important role in diverse biological processes such as development, cell growth, apoptosis and haematopoiesis, suggesting their association with cancer. Here we analysed the expression signatures of 157 miRNAs in 58 diffuse large B-cell lymphoma (DLBCL), 46 follicular lymphoma (FL) and seven non-neoplastic lymph nodes (LN). Comparison of the possible combinations of DLBCL-, FL- and LN resulted in specific DLBCL- and FL-signatures, which include miRNAs with previously published function in haematopoiesis (MIRN150 and MIRN155) or tumour development (MIRN210, MIRN10A, MIRN17-5P and MIRN145). As compared to LN, some miRNAs are differentially regulated in both lymphoma types (MIRN155, MIRN210, MIRN106A, MIRN149 and MIRN139). Conversely, some miRNAs show lymphoma-specific aberrant expression, such as MIRN9/9*, MIRN301, MIRN338 and MIRN213 in FL and MIRN150, MIRN17-5P, MIRN145, MIRN328 and others in DLBCL. A classification tree was computed using four miRNAs (MIRN330, MIRN17-5P, MIRN106a and MIRN210) to correctly identify 98% of all 111 cases that were analysed in this study. Finally, eight miRNAs were found to correlate with event-free and overall survival in DLBCL including known tumour suppressors (MIRN21, MIRN127 and MIRN34a) and oncogenes (MIRN195 and MIRNLET7G).
- Published
- 2008
31. Preservation of follicle mantle in follicular lymphoma
- Author
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Manuela Krokowski, Heinz-Wolfram Bernd, Alfred C. Feller, and Christoph Thorns
- Subjects
endocrine system ,Cancer Research ,Pathology ,medicine.medical_specialty ,Follicular lymphoma ,Chromosomal translocation ,Hematology ,Biology ,medicine.disease ,Immunohistochemistry ,Lymphoma ,Follicle ,Immunophenotyping ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,Follicular phase ,medicine ,Humans ,Neoplasm Invasiveness ,Lymph Nodes ,Mantle (mollusc) ,Lymphoma, Follicular - Abstract
Follicular lymphoma (FL) is a low-grade lymphoma with a follicular growth pattern, a peculiar immunophenotype, and a characteristic t(14;18) chromosomal translocation involving the bcl2 gene locus ...
- Published
- 2008
32. Sarcoma of follicular dendritic cells with features of sinus lining cells--a new subtype of reticulum cell sarcoma?
- Author
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Jacques Diebold, Hartmut Merz, Agnès Le Tourneau, Heinz-Wolfram Bernd, Christoph Thorns, Alfred C. Feller, Ulrika Schade, and Manuela Krokowski
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,government.form_of_government ,Vesicular Transport Proteins ,Biology ,Pathology and Forensic Medicine ,medicine ,Biomarkers, Tumor ,Humans ,Molecular Biology ,Lymph node ,Histiocyte ,Aged ,Lymphatic Vessels ,Follicular dendritic cells ,Lymphoma, Non-Hodgkin ,Cell Biology ,General Medicine ,Middle Aged ,medicine.disease ,Lymphatic Endothelium ,Lymphatic system ,medicine.anatomical_structure ,Interdigitating dendritic cell sarcoma ,Follicular dendritic cell sarcoma ,government ,Langerhans cell sarcoma ,Female ,Lymph Nodes ,Endothelium, Lymphatic ,Dendritic Cells, Follicular - Abstract
Dendritic cell neoplasms of the World Health Organization classification comprise Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and dendritic cell sarcoma, not otherwise specified. Several studies based on immunohistochemical and ultrastructural analysis tried to further clarify the origin of these neoplasms which are thought to derive from mesenchymal or bone marrow precursors. Lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1) was recently described as a marker for lymphatic endothelium which is expressed on normal liver blood sinusoid lining cells, spleen endothelium, activated tissue macrophages, blood vessels in the lung, endothelial cells of lymphatic sinuses, and in fibroblastic reticular cells in lymph nodes. We present a case of LYVE-1-positive reticulum cell neoplasm in an axillary lymph node. To the best of our knowledge, there has been no report about LYVE-1 expression in histiocytic or dendritic cell neoplasms so far. Due to the assumed specificity of this antibody, we propose designation of this reticulum cell sarcoma as lymphatic sinus lining cell sarcoma which might finally represent another subtype of reticulum cell sarcomas.
- Published
- 2007
33. Tumor sclerosis but not cell proliferation or malignancy grade is a prognostic marker in advanced-stage follicular lymphoma: the German Low Grade Lymphoma Study Group
- Author
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Heinz-Wolfram Bernd, Olaf Determann, Martin-Leo Hansmann, Martin Dreyling, Dirk Janssen, Eva Hoster, Hans-Heinrich Wacker, Peter Møller, Markus Tiemann, Alfred C. Feller, Harald Stein, Wolfgang Hiddemann, Carsten Schrader, Lars Rölver, Wolfram Klapper, German Ott, and Michael Unterhalt
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Follicular lymphoma ,Alpha interferon ,Malignancy ,Risk Assessment ,Statistics, Nonparametric ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Germany ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Humans ,Adverse effect ,Lymphoma, Follicular ,Survival analysis ,Neoplasm Staging ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,Sclerosis ,business.industry ,Proportional hazards model ,Interferon-alpha ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Immunohistochemistry ,Survival Analysis ,Lymphoma ,Female ,business ,Stem Cell Transplantation - Abstract
Purpose Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials. Patients and Methods We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial. Results Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival. Conclusion The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.
- Published
- 2007
34. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling
- Author
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Alfred C. Feller, Peter Lichter, Michael Hummel, Martin-Leo Hansmann, Sergio Cogliatti, Reza Parwaresch, Heinz Wolfram Bernd, Swen Wessendorf, Thomas F. E. Barth, Maciej Rosolowski, Andreas Rosenwald, Christiane Pott, Carsten Schwaenen, Heiko Trautmann, Hilmar Berger, Dirk Hasenclever, Harald Stein, Reiner Siebert, Lana Harder, Monika Szczepanowski, Wolfram Klapper, Dido Lenze, Rainer Spang, Hans Konrad Müller-Hermelink, Markus Loeffler, German Ott, Hans Heinrich Wacker, Michael Kühn, José I. Martín-Subero, Eugenia Haralambieva, Stefan Bentink, Judith Dierlamm, Peter Möller, Lorenz Trümper, and Benjamin Stürzenhofecker
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Oncogene Proteins, Fusion ,Transcription, Genetic ,Genes, myc ,Gene Expression ,Biology ,Translocation, Genetic ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,RNA, Neoplasm ,MYC Gene Rearrangement ,030304 developmental biology ,Oligonucleotide Array Sequence Analysis ,0303 health sciences ,medicine.diagnostic_test ,Genes, Immunoglobulin ,Gene Expression Profiling ,Breakpoint ,Karyotype ,General Medicine ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,Prognosis ,Burkitt Lymphoma ,3. Good health ,Lymphoma ,Genes, bcl-2 ,Gene expression profiling ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,Burkitt's lymphoma ,Algorithms ,Fluorescence in situ hybridization ,Comparative genomic hybridization ,Follow-Up Studies - Abstract
Background The distinction between Burkitt’s lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt’s lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. Methods We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt’s lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt’s lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. Results We used the molecular signature for Burkitt’s lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt’s morphologic appearance. Also, five did not have a detectable IG-myc Burkitt’s translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt’s lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. Conclusions Our molecular definition of Burkitt’s lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt’s lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt’s lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.
- Published
- 2006
35. Tumor Cell Proliferation (Ki-67 Index) Overcomes Cytology and Growth Pattern As Prognostic Factor in Mantle-Cell Lymphoma – Results from Randomized Trials of the European MCL Network
- Author
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Grzegorz Rymkiewicz, Martin Dreyling, Christoph Loddenkemper, Michael Unterhalt, Heinz-Wolfram Bernd, Françoise Berger, Johanna Kluin-Nelemans, Nicole Brousse, Sylvia Hartmann, Stefano Pileri, Andreas Rosenwald, Thomas F. E. Barth, Roman Kodet, Eva Hoster, Wolfram Klapper, Olivier Hermine, and Wolfgang Hiddemann
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,biology ,business.industry ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Blastoid ,biology.organism_classification ,Biochemistry ,Lymphoma ,hemic and lymphatic diseases ,Internal medicine ,Cytology ,Ki-67 ,biology.protein ,Medicine ,Mantle cell lymphoma ,Rituximab ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
On Behalf of the European MCL Pathology Panel Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma with a median overall survival (OS) of 5 years, but clinical course varies considerably. This variability has been partly explained by clinical characteristics forming the MIPI (Hoster et al., JCO 2014), but also biological and histological features such as tumor cell proliferation (Ki-67 index), cytology, or growth pattern (Tiemann et al., BJH 2005). Immuno-chemotherapy induction represents the current standard of care, in younger patients including high-dose cytarabine and followed by autologous stem cell transplantation, whereas older patients benefit from rituximab maintenance (Dreyling et al., Ann Oncol 2013). In 2004, the European MCL Network started two large randomized trials, MCL Younger and MCL Elderly, for previously untreated MCL patients. Histopathological features of diagnostic samples were centrally assessed by the European MCL Pathology Panel. Since MCL is relatively rare, evaluations of prognostic factors were mostly based on smaller, retrospectively collected patient cohorts. We now aimed to comparatively evaluate the prognostic value of Ki-67 index, cytology, and growth pattern using the data of these trials. Methods: The Ki-67 index was counted according to published guidelines (Klapper et al., J Hematopathol 2009). MCL cytology was classified as classic, small-cell (B-CLL-like), pleomorphic (DLBCL-like), or blastic (LB-like) (Vogt and Klapper, Histopathology 2013). MCLs with pleomorphic or blastic cytology were combined to blastoid MCL. The growth pattern was classified as diffuse (≤50% nodular) or non-diffuse (>50% nodular or predominantly mantle-zone pattern). The prognostic relevance of these markers was evaluated with respect to OS, adjusting for MIPI score. Results: Of 1012 trial patients with MCL, Ki-67 index, cytology, or growth pattern were available in 50%, 61%, and 47%, respectively. Reasons for missing information were mainly insufficient material or staining. Median Ki-67 index was 20% (2%-97%). 88% had classic MCL, 2% small-cell, 7% pleomorphic and 3% blastic cytology, summing up to 10% with blastoid MCL. 63% of patients had a diffuse growth pattern. Higher Ki-67 index, blastoid MCL, and diffuse growth were each associated with higher MIPI score. Growth pattern was not clearly associated with Ki-67 index or cytology, whereas pleomorphic (median Ki-67 index 39%, range 7%-90%) or blastic MCL (median 80%, 29%-97%) displayed a substantially higher Ki-67 index compared non-blastoid MCL (median 19%, 2%-95%). In univariable analyses, the adjusted OS hazard ratios for higher Ki-67 index (10% increase), blastoid MCL, or diffuse growth were 1.16 (95% CI 1.09-1.24, p Conclusions: In a large cohort of MCL patients treated in randomized trials according to current guidelines, tumor cell proliferation (Ki-67 index) was a powerful prognostic marker, superior to cytology and growth pattern, and independent of clinical prognostic factors. The Ki-67 index further stratified patients with non-blastoid as well as patients with blastoid MCL into groups with substantially different survival. Thus, standardized assessment of the Ki-67 index (Klapper et al. J Hematopathol 2009) should be routinely performed in clinical practice to allow a more comprehensive individual risk estimation of MCL patients. Further analyses will aim at the biological basis of this prognostic effect. Figure 1: Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 1:. Overall survival according to Ki-67 index (< vs. ≥ 30% from Determann et al., Blood 2008) in patients with non-blastoid (left) or blastoid (right) mantle-cell lymphoma (MCL) Figure 2 Figure 2. Disclosures Dreyling: Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding.
- Published
- 2014
36. Cw high-power IR laser at 2 μm for minimally invasive surgery
- Author
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Verena Ott, Heinz-Wolfram Bernd, Dirk Theisen, Veit Danicke, Robert Keller, and Ralf Brinkmann
- Subjects
Materials science ,business.industry ,medicine.medical_treatment ,chemistry.chemical_element ,Laser ,Ablation ,law.invention ,Core (optical fiber) ,Wavelength ,Thulium ,Optics ,chemistry ,law ,medicine ,Continuous wave ,Laser power scaling ,business ,Laser scalpel - Abstract
The potential of a new continuous wave Thulium YAG laser is investigated for tissue ablation and cutting focusing on applications in minimally invasive surgery. The laser emits at a wavelength of 2.01μm, which is well suited for tissue ablation due to its high absorption by water. The laser power can be tuned up to 60 W output through a 365 μm core diameter quartz fibre. For the ablation studies, the quartz fibre was placed in contact under various pressures (20 to 90mN) to porcine liver under saline solution in vitro at angles varying between 30° to 60°. The influence of different powers (10 to 60W) and cutting velocities (2 to 10mm/s) on the incision depth and coagulation zones of the tissue were investigated. A maximum incision depth of 3.3 mm was found with a power of 60W, a cutting velocity of 2mm/s and a fibre-tissue angle of 45°. The incisions were surrounded by coagulated tissue between 0.4 and 0.8mm in thickness, sometimes with an inner zone of carbonization of 0.2mm on average. In conclusion, the first experiments show that a cw Thulium laser is very well suited for tissue dissection as required in minimally invasive surgery.
- Published
- 2003
37. Application of Newly Developed Tissue-arrays to Study EMMPRIN (CD147) Expression in Malignant Non-Hodgkin Lymphoma
- Author
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Christoph, Thorns, Frank, Noack, Alfred C, Feller, Hartmut, Merz, Winfried, Stöcker, Ewald, Mueller-Kunert, and Heinz-Wolfram, Bernd
- Abstract
Matrix-metalloproteinases (MMP) are involved in a broad spectrum of physiological processes. Moreover, they also play a key role in tumour invasion and metastatic spread. The induction of MMPs is mediated via the extracellular matrix-metalloproteinase inducer (EMMPRIN). EMMPRIN is expressed in a variety of epithelial tumours, but expression in non-Hodgkin lymphomas has not been studied yet.Therefore we studied 201 non-Hodgkin lymphomas (NHL) for EMMPRIN expression by immunohistochemistry using a newly developed tissue microarray (TMA). This new approach to TMA-technology entails the great advantage that areas of interest (for instance with high tumour cell content) are selected by means of serial sections, thus maintaining appropriate samples of each case on the array. The samples were evaluated with regard to the number of positive tumour cells and staining intensity.All specimens on the arrays contained a sufficient amount of tumour cells. Immunohistochemistry yielded satisfactory results in 196 out of 201 cases. EMMPRIN was expressed in a significantly higher number of tumour cells in high-grade NHL compared with low-grade NHL. Furthermore, the staining intensity was significantly stronger in high-grade NHL.We report on a new type of TMA that allows effective parallel analysis of a large number of tissue samples. Our data indicate that the expression of EMMPRIN is strongly associated with a more aggressive lymphoma type. However, additional studies are required to elucidate the role of EMMPRIN in the tumour biology of NHL. Possibly, EMMPRIN could be a new target in the therapy of NHL.
- Published
- 2003
38. The Prognostic Impact Of Gene Rearrangements and Protein Expression Of MYC, BCL2 and BCL6 In Young High-Risk Patients With DLBCL
- Author
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Heinz-Wolfram Bernd, Alfred C. Feller, Wolfram Klapper, Michael Pfreundschuh, Heike Horn, German Ott, Martin Wartenberg, Thomas F. E. Barth, Norbert Schmitz, Marita Ziepert, Lorenz Trümper, Sergio Cogliatti, Martin-Leo Hansmann, Andreas Rosenwald, Michael Hummel, Peter Möller, Harald Stein, Sylvia Hartmann, Markus W. Löffler, and Dido Lenze
- Subjects
Oncology ,medicine.medical_specialty ,Multivariate analysis ,Immunology ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Gene ,Cell Biology ,Hematology ,Gene rearrangement ,medicine.disease ,BCL6 ,3. Good health ,Lymphoma ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Rituximab ,Diffuse large B-cell lymphoma ,030215 immunology ,medicine.drug - Abstract
Purpose A number of retrospective analyses have looked into the prognostic implication of MYC, BCL2 and BCL6 rearrangements and protein expression for MYC, BCL2 and BCL6 in patients with diffuse large B-cell lymphoma (DLBCL). Many of these studies suffer from small patient cohorts and differing or unknown treatment strategies (with or without Rituximab) administered to patients under study. Furthermore, the median age of these patients was relatively high. We for the first time report on the prognostic consequences of MYC, BCL2 and BCL6 alterations in younger (18-60 years) high-risk patients (aaIPI 2 or 3) with DLBCL. Patients and Methods The MegaCHOEP study (Schmitz et al. Lancet Oncology 2012: 13, 1250) randomized patients to 8xCHOEP-14 or sequential high-dose therapy supported by repeated infusions of autologous stem cells. Both treatment arms included 6 infusions of R (375 mg/ sqm). The median patient age was 48 years, and 27% of patients scored an aaIPI of 3. Paraffin-embedded tumor samples from 112 de novo DLBCL were investigated using immunohistochemistry for MYC, BCL2, and BCL6, and fluorescence in-situ hybridisation (FISH) to detect breaks of MYC, BCL2 and BCL6. Results Rearrangements of MYC, BCL2 and BCL6 were detected in 13.6%, 20.7% and 30.9% of DLBCL, respectively. A double or triple hit constellation occurred in 10.8%. Presence of BCL2 breaks (RR=4.7, 95% CI: 1.8-12.2) and MYC breaks (RR=2.4, 95% CI: 0.8-7.5), but not of BCL6 breaks were associated with inferior overall survival in univariate and multivariate analyses adjusted for aaIPI and treatment arm. Protein overexpression of MYC ≥30% (RR=2.4, 95% CI: 0.9-6.5), but not BCL2 (≥60%) or BCL6 (≥30%) indicated inferior overall survival. BCL2 overexpression was associated with inferior EFS (RR=2.2, 95% CI: 0.9-5.5) and PFS (RR=2.8, 95% CI: 1.0-8.2). If the same cutpoint for BCL2 used for a similar analysis in elderly patients treated on the RICOVER-60 trial (Horn et al. Blood 2013) was applied, no differences in EFS or PFS were observed. Conclusion Rearrangements of MYC and BCL2 seem to be relevant prognostic factors also in young high-risk patients. The frequencies of MYC and BCL2 rearrangements are not substantially higher than reported for other, mostly elderly patient groups carrying IPI scores from 0 - 5; it seems unlikely, therefore, that the rearrangements described here (completely) explain the poor prognosis of young, high-risk patients. The prognostic role of BCL2, BCL6, and MYC as well as other biological risk factors must be validated in independent data sets. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
39. [Untitled]
- Author
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Heinz-Wolfram Bernd
- Subjects
General Medicine ,Anatomy ,Developmental Biology - Published
- 2008
40. A chromosomal translocation in cyclin D1–negative/cyclin D2–positive mantle cell lymphoma fuses the CCND2 gene to the IGK locus
- Author
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Wolfram Klapper, Lana Harder, Reiner Siebert, Heinz-Wolfram Bernd, Reza Parwaresch, Inga Nagel, Kai Fu, José I. Martín-Subero, Stefan Gesk, and Dennis D. Weisenburger
- Subjects
CCND2 Gene ,Immunology ,Chromosomal translocation ,Locus (genetics) ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Cyclin D1 ,Cyclin D2 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Cancer research ,Mantle cell lymphoma ,neoplasms ,Gene ,Cyclin - Abstract
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder with distinct pathologic and clinical features. Genetically, the vast majority of MCLs carry the t(11;14)(q13;q32). This characteristic chromosomal abnormality leads to deregulation of the CCND1 gene encoding cyclin D1 at 11q13 through
- Published
- 2006
41. Cell Proliferation (Ki-67) As Prognostic Marker in Mantle Cell Lymphoma
- Author
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Olivier Hermine, Wolfram Klapper, Thomas F. E. Barth, Martin Dreyling, Christoph Loddenkemper, Michael Unterhalt, Heinz-Wolfram Bernd, Andreas Rosenwald, Hanneke C. Kluin-Nelemans, Wolfgang Hiddemann, Eva Hoster, and Sylvia Hartmann
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,biology ,business.industry ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Lymphoma ,Log-rank test ,Autologous stem-cell transplantation ,Interquartile range ,Internal medicine ,Ki-67 ,medicine ,biology.protein ,Mantle cell lymphoma ,business - Abstract
Abstract 2677 Introduction: The percentage of proliferating cells evaluated on diagnostic tumor samples has been shown to be of high prognostic relevance in Mantle Cell Lymphoma (MCL) patients. As MCL is relatively rare, evaluation of proliferation has so far mostly been based on smaller patient cohorts that were retrospectively collected and inhomogenously treated. In 2004, the European MCL Network initiated two large European randomized trials for younger (“MCL Younger” trial) and older (“MCL Elderly” trial) MCL patients, primary results of which have recently been reported (Kluin-Nelemans et al., NEJM 2012, Hermine et al., ASH 2010). We aimed to clarify the prognostic relevance of the proliferation marker Ki-67 using pooled data from these two trials. Patients and Methods: Patients with histologically confirmed and previously untreated MCL of stages II-IV up to 65 years of age were randomly assigned in “MCL Younger” to either 6 cycles R-CHOP followed by myeloablative radio-chemotherapy and autologous stem cell transplantation (ASCT), or 6 cycles alternating R-CHOP/R-DHAP followed by high-dose-Ara-C containing conditioning and ASCT. Patients aged 60 years or older and not eligible for high-dose therapy were randomly assigned in “MCL Elderly” to either 8 cycles of R-CHOP or 6 cycles of R-FC; responding patients were subsequently randomized to either interferon-alpha or rituximab maintenance until progression. Histological diagnosis was confirmed by central review within the European MCL Pathology Panel. The percentage of Ki-67 positive cells was counted on diagnostic lymphoma samples among 2 times 100 cells by the central pathology labs according to published consensus guidelines (Klapper et al., J Hematopathology 2009). The outcome measures were time to treatment failure (TTF) from treatment initiation to stable disease, progression, or death from any cause, and overall survival (OS) from trial registration to death from any cause. We investigated the prognostic value of proliferation as a quantitative marker with regards to TTF and OS in univariable Cox regression and evaluated the previously established cut-off values of 10% and 30% (Determann et al., Blood 2008) using Kaplan-Meier estimates and log rank tests. We also adjusted for clinical prognostic factors (MIPI, Hoster et al., Blood 2008). Results: Counted Ki-67 values were available in 51% (543) of 1057 randomized patients (material not available, 30%; Ki-67 evaluation not possible due to technical reasons, 16%). The origin of tumor tissue was lymph node in 81%, gastrointestinal tract in 12%, bone marrow in 4% and other in 3%. The median proliferation rate was 20% (range, 0–97%; interquartile range, 12–34%) and did not significantly differ between tissue origins. In univariable analysis, a 10% higher proliferation rate was associated with hazard ratios of 1.18 (95% confidence interval, 1.12 to 1.25, p Conclusions: Cell proliferation was confirmed as important biological prognostic marker independent of clinical prognostic factors on a large cohort of MCL patients uniformly treated within clinical trials. Since the evaluation of Ki-67 has been standardized, guidelines (e.g. Dreyling et al., Ann Onc, in press) recommend applying this parameter in clinical routine. Further analyses will focus on the joint correlation of Ki-67, MIPI and minimal residual disease with outcome to potentially allow a more individualized therapeutic approach in MCL patients. On behalf of the European Mantle Cell Lymphoma Network. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2012
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