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Martinleo Hansmann - One of the best experts on this subject based on the ideXlab platform.

  • expression of intracellular signaling molecules in classical and lymphocyte predominance Hodgkin Disease
    Blood, 2004
    Co-Authors: Teresa Marafioti, Michela Pozzobon, Martinleo Hansmann, Georges Delsol, Stefano Pileri, David Y Mason
    Abstract:

    The neoplastic cells in classical Hodgkin Disease (Reed-Sternberg cells) are of B-lymphoid origin, but they lack many markers of this cell lineage, for example, immunoglobulin, CD20, and B-cell–associated transcription factors. In contrast, the neoplastic cells (“L&H” cells) in lymphocyte predominance Hodgkin Disease retain the molecular profile of germinal center B cells. In this paper, we investigated the expression in Hodgkin Disease (45 cases and 3 cell lines) of 5 intracellular signaling molecules found in B cells. The Src family kinase Syk, the B-cell adaptor protein BLNK, and phospholipase C (PLC)–γ2 were consistently absent from Reed-Sternberg cells, whereas 2 other Src kinases (Lyn and Fyn) were heterogeneously expressed in a proportion of cases (12% and 42%, respectively). In contrast, the tumor cells in all cases of lymphocyte predominance Hodgkin Disease were positive for Fyn, Syk, BLNK, and PLC-γ2, and Lyn immunostaining was seen in a minority of biopsies. These results indicate that in Reed-Sternberg cells, the defect in B-cell lineage marker expression includes a spectrum of molecules involved in intracellular signaling, a finding in keeping with recent gene expression profiling studies. Furthermore, the clear difference in expression of signaling proteins between the 2 major subtypes of Hodgkin Disease may be of diagnostic value.

  • evidence that Hodgkin and reed sternberg cells in Hodgkin Disease do not represent cell fusions
    Blood, 2001
    Co-Authors: Martinleo Hansmann, Ralf Kuppers, Andreas Brauninger, Markus Muschen, Verena Distler
    Abstract:

    In most cases, Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin Disease (HD) carry rearranged immunoglobulin (Ig) genes and thus derive from B cells. In rare cases, HRS cells originate from T cells. However, based on the unusual immunophenotype of HRS cells, often showing coexpression of markers typical for different hematopoietic lineages, and the regular detection of numerical chromosomal abnormalities, it has been speculated that HRS cells might represent cell fusions. Five cases of HD with 2 rearranged IgH alleles were analyzed for the presence of additional IgH alleles in germline configuration as a potential footprint of a cell fusion between a B and a non-B cell. Similarly, one case of T-cell-derived HD with biallelic T-cell receptor beta (TCRbeta) rearrangements was studied for the presence of unrearranged TCRbeta alleles. In none of the 6 cases was evidence for additional IgH (or TCRbeta) alleles obtained, strongly arguing against a role of cell fusion in HRS cell generation.

  • molecular single cell analysis of the clonal relationship of small epstein barr virus infected cells and epstein barr virus harboring Hodgkin and reed sternberg cells in Hodgkin Disease
    Blood, 2000
    Co-Authors: Tilmann Spieker, Ralf Kuppers, Andreas Brauninger, Klaus Rajewsky, Julia Kurth, Martinleo Hansmann
    Abstract:

    Epstein-Barr virus (EBV) can be detected in the tumor cells of approximately 40% of cases of classical Hodgkin Disease (cHD). Clonality studies suggest that infection of the neoplastic Hodgkin and Reed/Sternberg (HRS) cells occurs before tumor clone expansion. In EBV-positive cases, variable numbers of EBER-positive small B cells are sometimes also observed that immunohistologically differ from the neoplastic cells by lack of CD30 and latent membrane protein 1 expression. To analyze the clonal relationship between these EBV(+) cells and the HRS cells, single EBV-infected CD30(-) B cells, as well as HRS cells from 3 cases of EBV-positive cHD were micromanipulated, their immunoglobulin gene rearrangements amplified and then compared with each other. In 2 cases, all small EBV-infected cells were clonally unrelated to the HRS cells. In a third case, 2 of 29 small CD30(-) cells were found to carry HRS cell-specific rearrangements. Thus, small CD30(-) EBV-infected B cells in cHD belong to the HRS tumor clone rarely, if at all. In all cases, small clones unrelated to the HRS cell clones were identified among the small EBV(+) CD30(-) cells. The vast majority of small EBV(+) CD30(-) B cells was found to carry somatically mutated V region genes, indicating that in lymph nodes of patients with HD, like in the peripheral blood of healthy individuals, EBV persists in memory B cells.

  • european task force on lymphoma project on lymphocyte predominance Hodgkin Disease histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin Disease with a nodular growth pattern and abundant lymphocytes
    Blood, 2000
    Co-Authors: Ioannis Anagnostopoulos, Martinleo Hansmann, Kaarle Franssila, Martin Harris, Nancy L Harris, Elaine S Jaffe, J Han, J M Van Krieken, Sibrand Poppema, Teresa Marafioti
    Abstract:

    Paraffin blocks and clinical data from 521 patients with lymphocyte predominance Hodgkin Disease (LPHD) diagnosed between 1970 and 1994 were collected from 16 European and United States oncological centers to establish the pathologic and clinical characteristics of a large patient cohort, to determine how frequent T-cell-rich large B-cell lymphoma (TCRLBCL) is among LPHD, and to find differential diagnostic criteria distinguishing between the 2 lymphoma categories. For this purpose, conventionally and immunohistologically stained sections were reviewed by a panel of hematopathologists. The diagnosis of LPHD was confirmed in only 219 of the 388 assessable cases (56.5%). This low confirmation rate was due mainly to the presence of a new variant of classical Hodgkin Disease (CHD), which resembled, in terms of nodular growth and lymphocyte-richness, nodular LPHD and, in terms of the immunophenotype of the tumor cells, CHD and was designated nodular lymphocyte-rich CHD (NLRCHD). The nodules of LRCHD consisted-as in nodular LPHD-predominantly of B cells but differed from those present in LPHD in that they represented expanded mantle zones with atrophic germinal centers. Clinically, patients with LPHD and NLRCHD showed similar Disease characteristics at presentation but differed in the frequency of multiple relapses and prognosis after relapse. Patients with LPHD and NLRCHD clearly differed from patients with CHD with nodular sclerosis or mixed cellularity, as they presented with an earlier Disease stage and infrequent mediastinal involvement. As 97% of the LPHD cases showed a complete or partial nodular growth pattern, their differentiation from TCRLBCL was a rare problem in the present series. (Blood. 2000;96:1889-1899)

  • Hodgkin and reed sternberg cells in lymphocyte predominant Hodgkin Disease represent clonal populations of germinal center derived tumor b cells
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: Andreas Braeuninger, Ralf Kuppers, John G Strickler, H H Wacker, Klaus Rajewsky, Martinleo Hansmann
    Abstract:

    Among the four subtypes of Hodgkin Disease (HD), lymphocyte-predominant (LP) HD is now generally considered as a separate entity. The B cell nature of the typical Hodgkin and Reed–Sternberg (HRS) cells and their variants (L and H, lymphocytic and histiocytic cells) in LP HD has long been suspected, but the question of whether these cells represent a true tumor clone is unclear. We previously demonstrated clonal Ig gene rearrangements in one case of LP HD. In the present study, five cases of LP HD were analyzed by micromanipulation of single HRS cells from frozen tissue sections and DNA amplification of rearranged Ig heavy chain genes from those cells. Clonal V gene rearrangements harboring somatic mutations were detected in each case. In three cases ongoing somatic mutation was evident. This shows that HRS cells in LP HD are a clonal tumor population derived from germinal center B cells. The pattern of somatic mutation indicates that HRS cells in LP HD are selected for antibody expression. This, and the presence of ongoing mutation discriminates LP from classical HD.

Ama Z S Rohatiner - One of the best experts on this subject based on the ideXlab platform.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    Results A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100 000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracylines (SMR = 14.8, 95% CI = 4.8 to 34.5). Conclusions The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    BACKGROUND: Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin Disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction. METHODS: We followed a cohort of 7033 Hodgkin Disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided. RESULTS: A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5). CONCLUSIONS: The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

Anthony J Swerdlow - One of the best experts on this subject based on the ideXlab platform.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    Results A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100 000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracylines (SMR = 14.8, 95% CI = 4.8 to 34.5). Conclusions The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    BACKGROUND: Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin Disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction. METHODS: We followed a cohort of 7033 Hodgkin Disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided. RESULTS: A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5). CONCLUSIONS: The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

Ralf Kuppers - One of the best experts on this subject based on the ideXlab platform.

  • evidence that Hodgkin and reed sternberg cells in Hodgkin Disease do not represent cell fusions
    Blood, 2001
    Co-Authors: Martinleo Hansmann, Ralf Kuppers, Andreas Brauninger, Markus Muschen, Verena Distler
    Abstract:

    In most cases, Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin Disease (HD) carry rearranged immunoglobulin (Ig) genes and thus derive from B cells. In rare cases, HRS cells originate from T cells. However, based on the unusual immunophenotype of HRS cells, often showing coexpression of markers typical for different hematopoietic lineages, and the regular detection of numerical chromosomal abnormalities, it has been speculated that HRS cells might represent cell fusions. Five cases of HD with 2 rearranged IgH alleles were analyzed for the presence of additional IgH alleles in germline configuration as a potential footprint of a cell fusion between a B and a non-B cell. Similarly, one case of T-cell-derived HD with biallelic T-cell receptor beta (TCRbeta) rearrangements was studied for the presence of unrearranged TCRbeta alleles. In none of the 6 cases was evidence for additional IgH (or TCRbeta) alleles obtained, strongly arguing against a role of cell fusion in HRS cell generation.

  • molecular single cell analysis of the clonal relationship of small epstein barr virus infected cells and epstein barr virus harboring Hodgkin and reed sternberg cells in Hodgkin Disease
    Blood, 2000
    Co-Authors: Tilmann Spieker, Ralf Kuppers, Andreas Brauninger, Klaus Rajewsky, Julia Kurth, Martinleo Hansmann
    Abstract:

    Epstein-Barr virus (EBV) can be detected in the tumor cells of approximately 40% of cases of classical Hodgkin Disease (cHD). Clonality studies suggest that infection of the neoplastic Hodgkin and Reed/Sternberg (HRS) cells occurs before tumor clone expansion. In EBV-positive cases, variable numbers of EBER-positive small B cells are sometimes also observed that immunohistologically differ from the neoplastic cells by lack of CD30 and latent membrane protein 1 expression. To analyze the clonal relationship between these EBV(+) cells and the HRS cells, single EBV-infected CD30(-) B cells, as well as HRS cells from 3 cases of EBV-positive cHD were micromanipulated, their immunoglobulin gene rearrangements amplified and then compared with each other. In 2 cases, all small EBV-infected cells were clonally unrelated to the HRS cells. In a third case, 2 of 29 small CD30(-) cells were found to carry HRS cell-specific rearrangements. Thus, small CD30(-) EBV-infected B cells in cHD belong to the HRS tumor clone rarely, if at all. In all cases, small clones unrelated to the HRS cell clones were identified among the small EBV(+) CD30(-) cells. The vast majority of small EBV(+) CD30(-) B cells was found to carry somatically mutated V region genes, indicating that in lymph nodes of patients with HD, like in the peripheral blood of healthy individuals, EBV persists in memory B cells.

  • Hodgkin and reed sternberg cells in lymphocyte predominant Hodgkin Disease represent clonal populations of germinal center derived tumor b cells
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: Andreas Braeuninger, Ralf Kuppers, John G Strickler, H H Wacker, Klaus Rajewsky, Martinleo Hansmann
    Abstract:

    Among the four subtypes of Hodgkin Disease (HD), lymphocyte-predominant (LP) HD is now generally considered as a separate entity. The B cell nature of the typical Hodgkin and Reed–Sternberg (HRS) cells and their variants (L and H, lymphocytic and histiocytic cells) in LP HD has long been suspected, but the question of whether these cells represent a true tumor clone is unclear. We previously demonstrated clonal Ig gene rearrangements in one case of LP HD. In the present study, five cases of LP HD were analyzed by micromanipulation of single HRS cells from frozen tissue sections and DNA amplification of rearranged Ig heavy chain genes from those cells. Clonal V gene rearrangements harboring somatic mutations were detected in each case. In three cases ongoing somatic mutation was evident. This shows that HRS cells in LP HD are a clonal tumor population derived from germinal center B cells. The pattern of somatic mutation indicates that HRS cells in LP HD are selected for antibody expression. This, and the presence of ongoing mutation discriminates LP from classical HD.

  • Hodgkin Disease Hodgkin and reed sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from b cells at various stages of development
    Proceedings of the National Academy of Sciences of the United States of America, 1994
    Co-Authors: Ralf Kuppers, Klaus Rajewsky, Min Zhao, Gunther Simons, Ralf Laumann, Robert L Fischer, Martinleo Hansmann
    Abstract:

    Hodgkin Disease (HD) is characterized by a small number of putative malignant cells [Hodgkin and Reed-Sternberg (HRS) cells] among a background of lymphocytes and histiocytes. The lineage of HRS cells is still elusive and a clonal origin of these rare cells has not formally been demonstrated. We isolated HRS cells by micromanipulation from histological sections of three cases of Hodgkin lymphoma (each representing a distinct subtype of the Disease) and analyzed individual cells for immunoglobulin variable (V) gene rearrangements by PCR. In each of the three cases a single heavy-chain V (VH) (and in one case, in addition, a kappa light-chain) gene rearrangement was amplified from the HRS cells, identifying these cells as members of a single clone. A potentially functional VH rearrangement was obtained from a case of nodular sclerosis HD. Somatic mutations and intraclonal diversity in the VH genes indicate a germinal center B-cell origin of the HRS cells in a case of lymphocyte-predominant HD, whereas in a case of mixed-cellularity HD the sequence analysis revealed only nonfunctional V gene rearrangements, suggesting a pre-B-cell origin. This indicates that HRS cells can originate from B-lineage cells at various stages of development.

Craig D Higgins - One of the best experts on this subject based on the ideXlab platform.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    Results A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100 000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracylines (SMR = 14.8, 95% CI = 4.8 to 34.5). Conclusions The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.

  • myocardial infarction mortality risk after treatment for Hodgkin Disease a collaborative british cohort study
    Journal of the National Cancer Institute, 2007
    Co-Authors: Anthony J Swerdlow, Craig D Higgins, Paul A Smith, David Cunningham, B W Hancock, A Horwich, Peter Hoskin, Andrew Lister, John Radford, Ama Z S Rohatiner
    Abstract:

    BACKGROUND: Myocardial infarction is a major cause of excess long-term mortality in survivors of Hodgkin Disease, but limited information exists on the effects of specific chemotherapy regimens used to treat these patients on their risk of death from myocardial infarction. METHODS: We followed a cohort of 7033 Hodgkin Disease patients who were treated in Britain from November 1, 1967, through September 30, 2000, and compared their risk of myocardial infarction mortality with that in the general population of England and Wales. All statistical tests were two-sided. RESULTS: A total of 166 deaths from myocardial infarction occurred in the cohort, statistically significantly more than expected (standardized mortality ratio [SMR] = 2.5, 95% confidence interval [CI] = 2.1 to 2.9), with an absolute excess risk of 125.8 per 100,000 person-years. Standardized mortality ratios decreased sharply with older age at first treatment, but absolute excess risks of death from myocardial infarction increased with older age up to age 65 years at first treatment. The statistically significantly increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks were increased statistically significantly and independently for patients who had been treated with supradiaphragmatic radiotherapy, anthracyclines, or vincristine. Risk was particularly high for patients treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (SMR = 9.5, 95% CI = 3.5 to 20.6). Risk at 20 or more years after first treatment was particularly great for patients who had received supradiaphragmatic radiotherapy and vincristine without anthracyclines (SMR = 14.8, 95% CI = 4.8 to 34.5). CONCLUSIONS: The risk of death from myocardial infarction after treatment for Hodgkin Disease remains high for at least 25 years. The increased risks are related to supradiaphragmatic radiotherapy but may also be related to anthracycline and vincristine treatment.