310 results on '"Dybkaer K"'
Search Results
2. Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium
- Author
-
Deng, L, Xu-Monette, Z Y, Loghavi, S, Manyam, G C, Xia, Y, Visco, C, Huh, J, Zhang, L, Zhai, Q, Wang, Y, Qiu, L, Dybkær, K, Chiu, A, Perry, A M, Zhang, S, Tzankov, A, Rao, H, Abramson, J, Sohani, A R, Xu, M, Hsi, E D, Zhu, J, Ponzoni, M, Wang, S, Li, Ling, Zhang, M, Ferreri, A J M, Parsons, B M, Li, Y, Piris, M A, Medeiros, L J, and Young, K H
- Published
- 2016
- Full Text
- View/download PDF
3. Permeability and flow modelling of diatomaceous shales in the Danish North Sea
- Author
-
Proestakis, Ermis, Thomas, Marcus Anders Jonathan Gordon, Weibel, Rikke, Amour, Frédéric, Dybkær, K., Hajiabadi, Mohammad Reza, Meireles, Leonardo Teixeira Pinto, Fabricius, Ida Lykke, Nick, H., Rasmussen, E. S., Proestakis, Ermis, Thomas, Marcus Anders Jonathan Gordon, Weibel, Rikke, Amour, Frédéric, Dybkær, K., Hajiabadi, Mohammad Reza, Meireles, Leonardo Teixeira Pinto, Fabricius, Ida Lykke, Nick, H., and Rasmussen, E. S.
- Published
- 2022
4. Permeability and flow modelling of diatomaceous shales in the Danish North Sea
- Author
-
Ermis Proestakis, Marcus Anders Jonathan Gordon Thomas, Rikke Weibel, Frédéric Amour, Dybkær, K., Mohammad Reza Hajiabadi, Leonardo Teixeira Pinto Meireles, Ida Lykke Fabricius, Nick, H., and Rasmussen, E. S.
- Published
- 2022
5. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study
- Author
-
Visco, C, Li, Y, Xu-Monette, Z Y, Miranda, R N, Green, T M, Li, Y, Tzankov, A, Wen, W, Liu, W-m, Kahl, B S, d'Amore, E S G, Montes-Moreno, S, Dybkær, K, Chiu, A, Tam, W, Orazi, A, Zu, Y, Bhagat, G, Winter, J N, Wang, H-Y, O'Neill, S, Dunphy, C H, Hsi, E D, Zhao, X F, Go, R S, Choi, W W L, Zhou, F, Czader, M, Tong, J, Zhao, X, van Krieken, J H, Huang, Q, Ai, W, Etzell, J, Ponzoni, M, Ferreri, A J M, Piris, M A, Møller, M B, Bueso-Ramos, C E, Medeiros, L J, Wu, L, and Young, K H
- Published
- 2012
- Full Text
- View/download PDF
6. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies
- Author
-
Iqbal, J, Kucuk, C, deLeeuw, R J, Srivastava, G, Tam, W, Geng, H, Klinkebiel, D, Christman, J K, Patel, K, Cao, K, Shen, L, Dybkaer, K, Tsui, I F L, Ali, H, Shimizu, N, Au, W Y, Lam, W L, and Chan, W C
- Published
- 2009
- Full Text
- View/download PDF
7. Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma
- Author
-
Frei, E, Visco, C, Xu-Monette, Z Y, Dirnhofer, S, Dybkær, K, Orazi, A, Bhagat, G, Hsi, E D, van Krieken, J H, Ponzoni, M, Go, R S, Piris, M A, Møller, M B, Young, K H, and Tzankov, A
- Published
- 2013
- Full Text
- View/download PDF
8. In Silico Analysis of Global Gene Expression in Myeloma CCL: In Search of Stem Cell Genes: B553
- Author
-
Johnsen, H E, Urup, T, Hoejfeldt, A D, Fogd, K B, Bergkvist, K S, Madsen, L H, Lehmann, K, Dybkaer, K, Caraux, A, Klein, B, and Jensen, A M
- Published
- 2009
9. The European Myeloma Stem Cell Network (MSCNET): B552
- Author
-
Johnsen, H E, Schmitz, A, Fogd, K B, Andersen, H, Vanderkerken, K, Valckenborgh, K, Sonneveld, E V, Duin, M V, Orfao, A, Sanz, R G, Paiva, B, Sahota, S, Pietras, D J, Weston-Bell, N, Babbage, G, Bos, N A, Fuhler, G, Klein, B, Caraux, A, Hose, D, Seckinger, A, Niklas, Z, Pfeifer, S, Schreder, M, Andres, M P, San Miguel, J, Almeida, J, Hoejfeldt, A, Hansen, A L, Dybkaer, K, Bøgsted, M, Urup, T, and Pilgaard, L
- Published
- 2009
10. A Novel Chemosensitivity Index for Chemotherapy Correlates to Resistance and Refractoriness: B551
- Author
-
Johnsen, H E, Sonneveld, P, Duin, M V, Knudsen, S, Dahlgaard, J, Bøgsted, M, Hoejfeldt, A D, Dybkaer, K, and Jensen, A M
- Published
- 2009
11. Erratum: Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study
- Author
-
Visco, C, Li, Y, Xu-Monette, Z Y, Miranda, R N, Green, T M, Li, Y, Tzankov, A, Wen, W, Liu, W-m, Kahl, B S, d'Amore, E S G, Montes-Moreno, S, Dybkær, K, Chiu, A, Tam, W, Orazi, A, Zu, Y, Bhagat, G, Winter, J N, Wang, H-Y, O'Neill, S, Dunphy, C H, Hsi, E D, Zhao, X F, Go, R S, Choi, W W L, Zhou, F, Czader, M, Tong, J, Zhao, X, van Krieken, J H, Huang, Q, Ai, W, Etzell, J, Ponzoni, M, Ferreri, A J M, Piris, M A, Møller, M B, Bueso-Ramos, C E, Medeiros, L J, Wu, L, and Young, K H
- Published
- 2014
- Full Text
- View/download PDF
12. AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma.
- Author
-
Wang, Jinfen, Xu-Monette, Z.Y., Jabbar, K.J., Manyam, G.C., Tzankov, A., Visco, C., Montes-Moreno, S., Dybkær, K., Bhagat, G., Hsi, E.D., Krieken, J.H. van, Ponzoni, M., Ferreri, A.J., Wang, S., Møller, M.B., Piris, M.A., Medeiros, L.J., Li, Y., Young, K.H., Wang, Jinfen, Xu-Monette, Z.Y., Jabbar, K.J., Manyam, G.C., Tzankov, A., Visco, C., Montes-Moreno, S., Dybkær, K., Bhagat, G., Hsi, E.D., Krieken, J.H. van, Ponzoni, M., Ferreri, A.J., Wang, S., Møller, M.B., Piris, M.A., Medeiros, L.J., Li, Y., and Young, K.H.
- Abstract
Contains fulltext : 177844.pdf (Publisher’s version ) (Open Access)
- Published
- 2017
13. Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma
- Author
-
Xia, Y., Xu-Monette, Z.Y., Tzankov, A., Li, X., Manyam, G.C., Murty, V., Bhagat, G., Zhang, S., Pasqualucci, L., Visco, C., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Winter, J.N., Piris, M.A., Westin, J., Fowler, N., Miranda, R.N., Ok, C.Y., Li, Y., Li, J., Medeiros, L.J., Young, K.H., Xia, Y., Xu-Monette, Z.Y., Tzankov, A., Li, X., Manyam, G.C., Murty, V., Bhagat, G., Zhang, S., Pasqualucci, L., Visco, C., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Winter, J.N., Piris, M.A., Westin, J., Fowler, N., Miranda, R.N., Ok, C.Y., Li, Y., Li, J., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 173033.pdf (Publisher’s version ) (Open Access), PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.
- Published
- 2017
14. Prevalence and clinical implications of cyclin D1 expression in diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program
- Author
-
Ok CY, Xu Monette ZY, Tzankov A, O'Malley DP, Montes Moreno S, Visco C, Møller MB, Dybkaer K, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Han van Krieken J, Farnen JP, Piris MA, Winter JN, Medeiros LJ, Young KH, PONZONI , MAURILIO, Ok, Cy, Xu Monette, Zy, Tzankov, A, O'Malley, Dp, Montes Moreno, S, Visco, C, Møller, Mb, Dybkaer, K, Orazi, A, Zu, Y, Bhagat, G, Richards, Kl, Hsi, Ed, Han van Krieken, J, Ponzoni, Maurilio, Farnen, Jp, Piris, Ma, Winter, Jn, Medeiros, Lj, and Young, Kh
- Published
- 2014
15. Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy
- Author
-
Yao, Z, primary, Deng, L, additional, Xu-Monette, Z Y, additional, Manyam, G C, additional, Jain, P, additional, Tzankov, A, additional, Visco, C, additional, Bhagat, G, additional, Wang, J, additional, Dybkaer, K, additional, Tam, W, additional, Hsi, E D, additional, van Krieken, J H, additional, Ponzoni, M, additional, Ferreri, A J M, additional, Møller, M B, additional, Winter, J N, additional, Piris, M A, additional, Fayad, L, additional, Liu, Y, additional, Song, Y, additional, Orlowski, R Z, additional, Kantarjian, H, additional, Medeiros, L J, additional, Li, Y, additional, Cortes, J, additional, and Young, K H, additional
- Published
- 2017
- Full Text
- View/download PDF
16. Global myeloma research clusters, output, and citations: A bibliometric mapping and clustering analysis
- Author
-
Andersen, J.P. Bøgsted, M. Dybkær, K. Mellqvist, U.-H. Morgan, G.J. Goldschmidt, H. Dimopoulos, M.A. Einsele, H. San Miguel, J. Palumbo, A. Sonneveld, P. Johnsen, H.E.
- Abstract
Background: International collaborative research is a mechanism for improving the development of dis-ease- specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings: We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and coauthorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (>90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. Conclusion and Perspective: Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care. © 2015 Andersen et al.
- Published
- 2015
17. p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function
- Author
-
Xu-Monette, Z.Y., Zhang, S., Li, X., Manyam, G.C., Wang, X.X., Xia, Y., Visco, C., Tzankov, A., Zhang, L., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Parsons, B.M., Winter, J.N., Piris, M.A., Medeiros, L.J., Young, K.H., Xu-Monette, Z.Y., Zhang, S., Li, X., Manyam, G.C., Wang, X.X., Xia, Y., Visco, C., Tzankov, A., Zhang, L., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Parsons, B.M., Winter, J.N., Piris, M.A., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 171992.pdf (publisher's version ) (Open Access), The role of p53 family member p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell-like DLBCL patients with wide- type TP53. The prognostic impact in germinal-center-B-cell-like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.
- Published
- 2016
18. Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma
- Author
-
Xu-Monette, Z.Y., Li, L, Byrd, J.C., Jabbar, K.J., Manyam, G.C., Winde, C. Maria de, Brand, M. van den, Tzankov, A., Visco, C., Wang, J, Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Winter, J.N., Wang, M., Hagemeister, F.B., Piris, M.A., Krieken, J.H. van, Medeiros, L.J., Li, Y., Spriel, A.B. van, Young, K.H., Xu-Monette, Z.Y., Li, L, Byrd, J.C., Jabbar, K.J., Manyam, G.C., Winde, C. Maria de, Brand, M. van den, Tzankov, A., Visco, C., Wang, J, Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Winter, J.N., Wang, M., Hagemeister, F.B., Piris, M.A., Krieken, J.H. van, Medeiros, L.J., Li, Y., Spriel, A.B. van, and Young, K.H.
- Abstract
Contains fulltext : 171804.pdf (publisher's version ) (Closed access), CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in approximately 60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-kappaBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.
- Published
- 2016
19. Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma
- Author
-
Ye, Q., Xu-Monette, Z.Y., Tzankov, A., Deng, L., Wang, X., Manyam, G.C., Visco, C., Montes-Moreno, S., Zhang, L., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Piris, M.A., Winter, J.N., Medeiros, L.J., Hu, S., Young, K.H., Ye, Q., Xu-Monette, Z.Y., Tzankov, A., Deng, L., Wang, X., Manyam, G.C., Visco, C., Montes-Moreno, S., Zhang, L., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Piris, M.A., Winter, J.N., Medeiros, L.J., Hu, S., and Young, K.H.
- Abstract
Contains fulltext : 171272.pdf (publisher's version ) (Open Access), Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors.
- Published
- 2016
20. Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma
- Author
-
Xu-Monette, Z.Y., Deng, Q., Manyam, G.C., Tzankov, A., Li, L, Xia, Y., Wang, X.X., Zou, D., Visco, C., Dybkaer, K., Li, J., Zhang, L., Liang, H., Montes-Moreno, S., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Wang, S.A., Miranda, R.N., Piris, M.A., Winter, J.N., Medeiros, L.J., Li, Y., Young, K.H., Xu-Monette, Z.Y., Deng, Q., Manyam, G.C., Tzankov, A., Li, L, Xia, Y., Wang, X.X., Zou, D., Visco, C., Dybkaer, K., Li, J., Zhang, L., Liang, H., Montes-Moreno, S., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Wang, S.A., Miranda, R.N., Piris, M.A., Winter, J.N., Medeiros, L.J., Li, Y., and Young, K.H.
- Abstract
Contains fulltext : 172126.pdf (publisher's version ) (Closed access), PURPOSE: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. EXPERIMENTAL DESIGN: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients. RESULTS: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts. CONCLUSIONS: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. (c)2016 AACR.
- Published
- 2016
21. The myeloma stem cell concept, revisited: From phenomenology to operational terms
- Author
-
Johnsen, H.E. (Hans), Bøgsted, M. (Martin), Schmitz, A., Bødker, J.S. (Julie Støve), El-Galaly, T.C. (Tarec Christoffer), Johansen, P. (Preben), Valent, P. (Peter), Zojer, N. (Niklas), Valckenborgh, E. (Els) van, Vanderkerken, K. (Karin), Duin, M. (Mark) van, Sonneveld, P. (Pieter), Perez-Andres, M., Orfao, A. (Alberto), Dybkær, K. (Karen), Johnsen, H.E. (Hans), Bøgsted, M. (Martin), Schmitz, A., Bødker, J.S. (Julie Støve), El-Galaly, T.C. (Tarec Christoffer), Johansen, P. (Preben), Valent, P. (Peter), Zojer, N. (Niklas), Valckenborgh, E. (Els) van, Vanderkerken, K. (Karin), Duin, M. (Mark) van, Sonneveld, P. (Pieter), Perez-Andres, M., Orfao, A. (Alberto), and Dybkær, K. (Karen)
- Abstract
The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19–/CD45low/–/CD38high/CD138+ malignant plasma cell, but not the CD19+/CD38low/–memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment. Using a new approach, analysis of c-DNA libraries from CD19+/CD27+/CD38–single cells has identified clonotypic memory B cell, suggested to be the cell of origin. This is consistent with multiple myeloma being a multistep hierarchical process before or during clinical presentation. We anticipate that further characterization will require single cell geno-and phenotyping combined with clonogenic assays. To implement such technologies, we propose a revision of the concept of a myeloma stem cell by including operational in vitro assays to describe the cellular components of origin, initiation, maintenance, and evolution of multiple myeloma. These terms are in accordance with recent (2012) consensus statements on the definitions, assays, and nomenclature of cancer stem cells, which is technically precise without completely abolishing established terminology. We expect that this operational model will be useful for future reporting of parameters used to identify and characterize the multiple myeloma stem cells. We strongly recommend that these parameters include validated standard technologies, reproducible assays, and, most importantly, supervised prospective sampling of selected biomaterial which reflects clinical stages, disease spectrum, and therapeutic outcome. This framework is key to the characterization of the cellular architecture of multiple myeloma and its use in preci
- Published
- 2016
- Full Text
- View/download PDF
22. The myeloma stem cell concept, revisited: from phenomenology to operational terms
- Author
-
Johnsen, H. E., primary, Bogsted, M., additional, Schmitz, A., additional, Bodker, J. S., additional, El-Galaly, T. C., additional, Johansen, P., additional, Valent, P., additional, Zojer, N., additional, Van Valckenborgh, E., additional, Vanderkerken, K., additional, van Duin, M., additional, Sonneveld, P., additional, Perez-Andres, M., additional, Orfao, A., additional, and Dybkaer, K., additional
- Published
- 2016
- Full Text
- View/download PDF
23. Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma
- Author
-
Xia, Y, primary, Xu-Monette, Z Y, additional, Tzankov, A, additional, Li, X, additional, Manyam, G C, additional, Murty, V, additional, Bhagat, G, additional, Zhang, S, additional, Pasqualucci, L, additional, Visco, C, additional, Dybkaer, K, additional, Chiu, A, additional, Orazi, A, additional, Zu, Y, additional, Richards, K L, additional, Hsi, E D, additional, Choi, W W L, additional, van Krieken, J H, additional, Huh, J, additional, Ponzoni, M, additional, Ferreri, A J M, additional, Møller, M B, additional, Parsons, B M, additional, Winter, J N, additional, Piris, M A, additional, Westin, J, additional, Fowler, N, additional, Miranda, R N, additional, Ok, C Y, additional, Li, Y, additional, Li, J, additional, Medeiros, L J, additional, and Young, K H, additional
- Published
- 2016
- Full Text
- View/download PDF
24. Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP
- Author
-
Xu-Monette, Z.Y., Dabaja, B.S., Wang, X., Tu, M., Manyam, G.C., Tzankov, A., Xia, Y., Zhang, L., Sun, R., Visco, C., Dybkaer, K., Yin, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Zhao, X., Winter, J.N., Piris, M.A., McDonnell, T.J., Miranda, R.N., Li, Y., Medeiros, L.J., Young, K.H., Xu-Monette, Z.Y., Dabaja, B.S., Wang, X., Tu, M., Manyam, G.C., Tzankov, A., Xia, Y., Zhang, L., Sun, R., Visco, C., Dybkaer, K., Yin, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Parsons, B.M., Zhao, X., Winter, J.N., Piris, M.A., McDonnell, T.J., Miranda, R.N., Li, Y., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 152029.pdf (publisher's version ) (Closed access), MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc(high)Bcl-2(high) DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict
- Published
- 2015
25. Age cutoff for Epstein-Barr virus-positive diffuse large B-cell lymphoma--is it necessary?
- Author
-
Ok, C.Y., Ye, Q., Li, L, Manyam, G.C., Deng, L., Goswami, R.R., Wang, X., Montes-Moreno, S., Visco, C., Tzankov, A., Dybkaer, K., Zhang, L., Abramson, J., Sohani, A.R., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhang, S., Parsons, B.M., Xu, M., Moller, M.B., Winter, J.N., Piris, M.A., Xu-Monette, Z.Y., Medeiros, L.J., Young, K.H., Ok, C.Y., Ye, Q., Li, L, Manyam, G.C., Deng, L., Goswami, R.R., Wang, X., Montes-Moreno, S., Visco, C., Tzankov, A., Dybkaer, K., Zhang, L., Abramson, J., Sohani, A.R., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhang, S., Parsons, B.M., Xu, M., Moller, M.B., Winter, J.N., Piris, M.A., Xu-Monette, Z.Y., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 153699.pdf (publisher's version ) (Open Access), Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are =50 years of age and compared this patient group to patients who are >50 years. In patients who are =50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG>/=2). Comparing EBV+ DLBCL patients in =50 years versus >50 years, both groups had similar clinicopathologic, immunophenotypic and genetic features. Gene expression profiling, microRNA profiling and treatment outcome of the younger patients with EBV+ DLBCL was not distinctive from tumors in older patients. Based on our data, we suggest that the arbitrary age cutoff for EBV+ DLBCL is unnecessary and should be eliminated in the WHO lymphoma classification scheme.
- Published
- 2015
26. Clinical and biological significance of de novo CD5+ diffuse large B-cell lymphoma in Western countries
- Author
-
Xu-Monette, Z.Y., Tu, M., Jabbar, K.J., Cao, X., Tzankov, A., Visco, C., Cai, Q., Montes-Moreno, S., An, Y., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Farnen, J.P., Winter, J.N., Piris, M.A., Miranda, R.N., Medeiros, L.J., Young, K.H., Xu-Monette, Z.Y., Tu, M., Jabbar, K.J., Cao, X., Tzankov, A., Visco, C., Cai, Q., Montes-Moreno, S., An, Y., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Farnen, J.P., Winter, J.N., Piris, M.A., Miranda, R.N., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 154770.pdf (publisher's version ) (Open Access), CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5+ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5+ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell-like subtype, Bcl-2 overexpression, and STAT3 and NF-kappaB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5- DLBCL patients, which was independent of Bcl-2, STAT3, NF-kappaB and the International Prognostic Index. Interestingly, SSBP2 expression abolished the prognostic significance of CD5 expression, suggesting a tumor-suppressor role of SSBP2 for CD5 signaling. Gene-expression profiling demonstrated that B-cell receptor signaling dysfunction and microenvironment alterations are the important mechanisms underlying the clinical impact of CD5 expression. This study shows the distinctive clinical and biological features of CD5+ DLBCL patients in Western countries and underscores important pathways with therapeutic implications.
- Published
- 2015
27. Evaluation of NF-kappaB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions
- Author
-
Ok, C.Y., Xu-Monette, Z.Y., Li, L, Manyam, G.C., Montes-Moreno, S., Tzankov, A., Visco, C., Dybkaer, K., Routbort, M.J., Zhang, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Rao, H., Moller, M.B., Winter, J.N., Piris, M.A., Wang, S.A., Medeiros, L.J., Young, K.H., Ok, C.Y., Xu-Monette, Z.Y., Li, L, Manyam, G.C., Montes-Moreno, S., Tzankov, A., Visco, C., Dybkaer, K., Routbort, M.J., Zhang, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Rao, H., Moller, M.B., Winter, J.N., Piris, M.A., Wang, S.A., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 155215.pdf (publisher's version ) (Closed access), Nuclear factor-kappaB (NF-kappaB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-kappaB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-kappaB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-kappaB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P=0.0170), singular expression of the remaining NF-kappaB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P=0.0307 and P=0.0247). When cases were stratified into GCB- and ABC-DLBCL, p52 or p52/RELB dimer expression status was associated with better OS and PFS (P=0.0134 and P=0.0124) only within the GCB subtype. However, multivariate analysis did not show p52 expression to be an independent prognostic factor. Beneficial effect of p52 in GCB-DLBC appears to be its positive correlation with CD30 and negative correlation with BCL2 expression. Gene expression profiling (GEP) showed that p52(+) GCB-DLBCL was distinct from p52(-) GCB-DLBCL. Collectively, our data suggest that DLBCL patients with p52 expression might not benefit from therapy targeting the NF-kappaB pathway.
- Published
- 2015
28. Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma
- Author
-
Chen, J., Xu-Monette, Z.Y., Deng, L., Shen, Q., Manyam, G.C., Martinez-Lopez, A., Zhang, L., Montes-Moreno, S., Visco, C., Tzankov, A., Yin, L., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Farnen, J.P., Winter, J.N., Piris, M.A., Pham, L., Young, K.H., Chen, J., Xu-Monette, Z.Y., Deng, L., Shen, Q., Manyam, G.C., Martinez-Lopez, A., Zhang, L., Montes-Moreno, S., Visco, C., Tzankov, A., Yin, L., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Zhao, X., Moller, M.B., Farnen, J.P., Winter, J.N., Piris, M.A., Pham, L., and Young, K.H.
- Abstract
Contains fulltext : 155086.pdf (publisher's version ) (Open Access), Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4+ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4+ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of =2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4+ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4+ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4+ associated poor prognosis.
- Published
- 2015
29. Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma
- Author
-
Li, L, Xu-Monette, Z.Y., Ok, C.Y., Tzankov, A., Manyam, G.C., Sun, R., Visco, C., Zhang, M., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Wang, J, Parsons, B.M., Winter, J.N., Piris, M.A., Pham, L.V., Medeiros, L.J., Young, K.H., Li, L, Xu-Monette, Z.Y., Ok, C.Y., Tzankov, A., Manyam, G.C., Sun, R., Visco, C., Zhang, M., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Moller, M.B., Wang, J, Parsons, B.M., Winter, J.N., Piris, M.A., Pham, L.V., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 153743.pdf (publisher's version ) (Closed access), Dysregulated NF-kappaB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-kappaB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-kappaB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2- activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-kappaB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.
- Published
- 2015
30. Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy
- Author
-
Liu, Z., Xu-Monette, Z.Y., Cao, X., Manyam, G.C., Wang, X., Tzankov, A., Xia, Y., Li, X., Visco, C., Sun, R., Zhang, L., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Piris, M.A., Winter, J.N., O'Malley, D.P., Medeiros, L.J., Young, K.H., Liu, Z., Xu-Monette, Z.Y., Cao, X., Manyam, G.C., Wang, X., Tzankov, A., Xia, Y., Li, X., Visco, C., Sun, R., Zhang, L., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Ponzoni, M., Ferreri, A.J., Parsons, B.M., Moller, M.B., Piris, M.A., Winter, J.N., O'Malley, D.P., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 153740.pdf (publisher's version ) (Closed access), Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in >/=2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.
- Published
- 2015
31. Global myeloma research clusters, output, and citations: A bibliometric mapping and clustering analysis
- Author
-
Andersen, J.P. (Jens Peter), Bøgsted, M. (Martin), Dybkær, K. (Karen), Mellqvist, U.H. (U. H.), Morgan, G. (Gareth), Goldschmidt, H. (Hartmut), Dimopoulos, M.A. (Meletios), Einsele, H. (Hermann), San Miguel, J. (Jesús), Palumbo, A. (Antonio), Sonneveld, P. (Pieter), Johnsen, H.E. (Hans), Andersen, J.P. (Jens Peter), Bøgsted, M. (Martin), Dybkær, K. (Karen), Mellqvist, U.H. (U. H.), Morgan, G. (Gareth), Goldschmidt, H. (Hartmut), Dimopoulos, M.A. (Meletios), Einsele, H. (Hermann), San Miguel, J. (Jesús), Palumbo, A. (Antonio), Sonneveld, P. (Pieter), and Johnsen, H.E. (Hans)
- Abstract
Background: International collaborative research is a mechanism for improving the development of dis-ease- specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings: We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and coauthorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43
- Published
- 2015
- Full Text
- View/download PDF
32. Global Myeloma Research Clusters, Output, and Citations: A Bibliometric Mapping and Clustering Analysis
- Author
-
Andersen, JP, Bogsted, M, Dybkaer, K, Mellqvist, UH, Morgan, GJ, Goldschmidt, H, Dimopoulos, MA, Einsele, H, San Miguel, J, Palumbo, A, Sonneveld, Pieter, Johnsen, HE, Andersen, JP, Bogsted, M, Dybkaer, K, Mellqvist, UH, Morgan, GJ, Goldschmidt, H, Dimopoulos, MA, Einsele, H, San Miguel, J, Palumbo, A, Sonneveld, Pieter, and Johnsen, HE
- Abstract
Background International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (> 90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. Conclusion and Perspective Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care.
- Published
- 2015
33. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study
- Author
-
Visco, C., van Krieken, J. H., Ai, W., Piris, M. A., O'Neill, S., Go, R. S., Dybkaer, K., Miranda, R. N., Ponzoni, M., Chiu, A., Choi, W. W., Zu, Y., Tai, Y. C., Wang, H.-Y., Tzankov, A., Ferreri, A. J., Huang, Q., Dunphy, C. H., Li, Y., His, E. D., Liu, W.-m., Bhagat, G., Dirnhofer, S., d'Amore, E. S. G., Montes-Moreno, S., Zhao, X., Orazi, A., Kahl, B. S., Winter, J. N., Xu-Monette, Z. Y., and Zhao, X. F.
- Subjects
immune system diseases ,hemic and lymphatic diseases - Abstract
Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. We analyzed Bcl-2 protein expression, and BCL2 and MYC gene abnormalities by interphase fluorescence in situ hybridization in 327 patients with de novo disease treated with rituximab-CHOP. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma. The prognostic relevance of isolated MYC rearrangements was weaker than that of BCL2 isolated translocations, but was probably limited by the rarity of the rearrangements. Seven of eight patients with double hit lymphoma had the germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P=0.0002), and their outcome was similar to that of patients with the activated B-cell subtype (P=0.30), but not as bad as the outcome of patients with double hit lymphoma (P
- Published
- 2013
- Full Text
- View/download PDF
34. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study
- Author
-
Xu-Monette, Z Y, Dybkær, K, Dunphy, C H, Tzankov, A, Wang, H-Y, Hsi, E D, Zhou, F, Miranda, R N, Green, T M, d'Amore, E S G, Bhagat, G, van Krieken, J H, Montes-Moreno, S, Wen, W, Kahl, B S, Zu, Y, O'Neill, S, Go, R S, Czader, M, Chiu, A, Choi, W W L, Zhao, X F, Orazi, A, Visco, C, Zhao, X, Huang, Q, Li, Y, Liu, W-m, Tam, W, Tong, J, and Winter, J N
- Subjects
immune system diseases ,hemic and lymphatic diseases - Abstract
Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development - namely germinal center B-cell-like and activated B-cell-like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1, and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B-cells. Cutoffs for each marker were obtained using receiver operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1, and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
- Published
- 2012
- Full Text
- View/download PDF
35. Multiple Myeloma Subtyping That Associates Normal B-Cell Subset Phenotypes, do Correlate to Disease Stage and Prognosis - Indication of Reversible Phenotypic Plasticity as a Hallmark
- Author
-
Johnsen, H.E., primary, Bødker, J.S., additional, Schmitz, A., additional, Falgreen, S., additional, Perez-Andres, M., additional, Samur, M.K., additional, Davies, F., additional, Pawlyn, C., additional, Kaiser, M., additional, Johnson, D., additional, Bertsch, U., additional, Broijl, A., additional, van Duin, M., additional, Shah, R., additional, Kjeldsen, M.K., additional, Bergkvist, K.S., additional, Bilgrau, A.E., additional, Johansen, P., additional, El-Galaly, T.C., additional, Samworth, R., additional, Sonneveld, P., additional, Goldschmidt, H., additional, Morgan, G.J., additional, Orfao, A., additional, Munshi, N., additional, Dybkær, K., additional, and Bøgsted, M., additional
- Published
- 2015
- Full Text
- View/download PDF
36. Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium
- Author
-
Deng, L, primary, Xu-Monette, Z Y, additional, Loghavi, S, additional, Manyam, G C, additional, Xia, Y, additional, Visco, C, additional, Huh, J, additional, Zhang, L, additional, Zhai, Q, additional, Wang, Y, additional, Qiu, L, additional, Dybkær, K, additional, Chiu, A, additional, Perry, A M, additional, Zhang, S, additional, Tzankov, A, additional, Rao, H, additional, Abramson, J, additional, Sohani, A R, additional, Xu, M, additional, Hsi, E D, additional, Zhu, J, additional, Ponzoni, M, additional, Wang, S, additional, Li, Ling, additional, Zhang, M, additional, Ferreri, A J M, additional, Parsons, B M, additional, Li, Y, additional, Piris, M A, additional, Medeiros, L J, additional, and Young, K H, additional
- Published
- 2015
- Full Text
- View/download PDF
37. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP
- Author
-
Tzankov, A., Xu-Monette, Z.Y., Gerhard, M., Visco, C., Dirnhofer, S., Gisin, N., Dybkaer, K., Orazi, A., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Ponzoni, M., Ferreri, A.J., Ye, Q., Winter, J.N., Farnen, J.P., Piris, M.A., Moller, M.B., You, M.J., McDonnell, T., Medeiros, L.J., Young, K.H., Tzankov, A., Xu-Monette, Z.Y., Gerhard, M., Visco, C., Dirnhofer, S., Gisin, N., Dybkaer, K., Orazi, A., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Ponzoni, M., Ferreri, A.J., Ye, Q., Winter, J.N., Farnen, J.P., Piris, M.A., Moller, M.B., You, M.J., McDonnell, T., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 136658.pdf (publisher's version ) (Closed access), In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.
- Published
- 2014
38. Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma
- Author
-
Ok, C.Y., Chen, J., Xu-Monette, Z.Y., Tzankov, A., Manyam, G.C., Li, L., Visco, C., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Zhao, X., Ponzoni, M., Ferreri, A.J., Bertoni, F., Farnen, J.P., Moller, M.B., Piris, M.A., Winter, J.N., Medeiros, L.J., Young, K.H., Ok, C.Y., Chen, J., Xu-Monette, Z.Y., Tzankov, A., Manyam, G.C., Li, L., Visco, C., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huh, J., Zhao, X., Ponzoni, M., Ferreri, A.J., Bertoni, F., Farnen, J.P., Moller, M.B., Piris, M.A., Winter, J.N., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 139215.pdf (publisher's version ) (Closed access), PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited. EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations. RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL. CONCLUSIONS: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113-23. (c)2014 AACR.
- Published
- 2014
39. 409: Transcription factors with differential transcription start sites during B-cell differentiation in normal tissues and diffuse large B-cell lymphoma
- Author
-
Bødker, J., primary, Kjeldsen, M.K., additional, Kloster, M.B., additional, Rodrigo-Domingo, M., additional, Bilgrau, A.E., additional, Johansen, P., additional, Schmitz, A., additional, Johnsen, H.E., additional, Bøgsted, M., additional, and Dybkær, K., additional
- Published
- 2014
- Full Text
- View/download PDF
40. Single nucleotide variation in the TP53 3' untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program
- Author
-
Li, Y., Gordon, M.W., Xu-Monette, Z.Y., Visco, C., Tzankov, A., Zou, D., Qiu, L., Montes-Moreno, S., Dybkaer, K., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huang, Q., Ai, W., Ponzoni, M., Ferreri, A.J., Winter, J.N., Go, R.S., Piris, M.A., Moller, M.B., Wu, L., Wang, M., Ramos, K.S., Medeiros, L.J., Young, K.H., Li, Y., Gordon, M.W., Xu-Monette, Z.Y., Visco, C., Tzankov, A., Zou, D., Qiu, L., Montes-Moreno, S., Dybkaer, K., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huang, Q., Ai, W., Ponzoni, M., Ferreri, A.J., Winter, J.N., Go, R.S., Piris, M.A., Moller, M.B., Wu, L., Wang, M., Ramos, K.S., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 185425.pdf (publisher's version ) (Closed access), We identified multiple single nucleotide variants (SNVs) in the TP53 3' untranslated region (3'UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 3'UTR SNVs had a better 5-year survival rate than patients carrying a wild-type CDS and the reference 3'UTR, yet there is no statistically significance difference in overall survival (OS). In contrast, 3'UTR variation predicted poorer OS for patients with a mutant TP53 CDS. We then sequenced TP53 3'UTR in 247 additional DLBCL patients as a validation set. Altogether, we identified 187 novel SNVs; 36 occurred at least twice. Most of the newly identified 3'UTR SNVs were located at sites that are complementary to seed sequences of microRNAs (miRNAs) that are predicted or experimentally known to target TP53. Three SNVs disrupt the seed match between miR-125b and the TP53 3'UTR, thereby impeding suppression of p53 by this miRNA. In addition, a germline SNV (rs78378222) located in the TP53 polyadenylation signal resulted in downregulation of both p53 messenger RNA and protein levels and reduction of cellular apoptosis. This study is the first to demonstrate the prognostic value of the TP53 3'UTR in cancer.
- Published
- 2013
41. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program
- Author
-
Hu, S., Xu-Monette, Z.Y., Tzankov, A., Green, T., Wu, L., Balasubramanyam, A., Liu, W.M., Visco, C., Li, Y., Miranda, R.N., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Zhao, X., Krieken, J.H.J.M. van, Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Zhou, F., Slack, G.W., Gascoyne, R.D., Tu, M., Variakojis, D., Chen, W., Go, R.S., Piris, M.A., Moller, M.B., Medeiros, L.J., Young, K.H., Hu, S., Xu-Monette, Z.Y., Tzankov, A., Green, T., Wu, L., Balasubramanyam, A., Liu, W.M., Visco, C., Li, Y., Miranda, R.N., Montes-Moreno, S., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Zhao, X., Krieken, J.H.J.M. van, Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Zhou, F., Slack, G.W., Gascoyne, R.D., Tu, M., Variakojis, D., Chen, W., Go, R.S., Piris, M.A., Moller, M.B., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 118768.pdf (publisher's version ) (Closed access), Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.
- Published
- 2013
42. Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma
- Author
-
Frei, E., Visco, C., Xu-Monette, Z.Y., Dirnhofer, S., Dybkaer, K., Orazi, A., Bhagat, G., Hsi, E.D., Krieken, J.H.J.M. van, Ponzoni, M., Go, R.S., Piris, M.A., Moller, M.B., Young, K.H., Tzankov, A., Frei, E., Visco, C., Xu-Monette, Z.Y., Dirnhofer, S., Dybkaer, K., Orazi, A., Bhagat, G., Hsi, E.D., Krieken, J.H.J.M. van, Ponzoni, M., Go, R.S., Piris, M.A., Moller, M.B., Young, K.H., and Tzankov, A.
- Abstract
Item does not contain fulltext, BACKGROUND: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. METHODS: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. RESULTS: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. CONCLUSIONS: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.
- Published
- 2013
43. MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program
- Author
-
Xu-Monette, Z.Y., Moller, M.B., Tzankov, A., Montes-Moreno, S., Hu, W., Manyam, G.C., Kristensen, L., Fan, L., Visco, C., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Wu, L., Zhao, X., Bueso-Ramos, C.E., Wang, S.A., Go, R.S., Li, Y., Winter, J.N., Piris, M.A., Medeiros, L.J., Young, K.H., Xu-Monette, Z.Y., Moller, M.B., Tzankov, A., Montes-Moreno, S., Hu, W., Manyam, G.C., Kristensen, L., Fan, L., Visco, C., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Bhagat, G., Richards, K.L., Hsi, E.D., Choi, W.W., Krieken, J.H.J.M. van, Huang, Q., Huh, J., Ai, W., Ponzoni, M., Ferreri, A.J., Wu, L., Zhao, X., Bueso-Ramos, C.E., Wang, S.A., Go, R.S., Li, Y., Winter, J.N., Piris, M.A., Medeiros, L.J., and Young, K.H.
- Abstract
Contains fulltext : 125629.pdf (publisher's version ) (Closed access), MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction.
- Published
- 2013
44. Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy
- Author
-
Yao, Z, Deng, L, Xu-Monette, Z Y, Manyam, G C, Jain, P, Tzankov, A, Visco, C, Bhagat, G, Wang, J, Dybkaer, K, Tam, W, Hsi, E D, van Krieken, J H, Ponzoni, M, Ferreri, A J M, Møller, M B, Winter, J N, Piris, M A, Fayad, L, Liu, Y, Song, Y, Orlowski, R Z, Kantarjian, H, Medeiros, L J, Li, Y, Cortes, J, and Young, K H
- Abstract
In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I–II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.
- Published
- 2018
- Full Text
- View/download PDF
45. Single site polymorphisms and alternative splicing of the human CD13 gene-different splicing frequencies among patients with acute myeloid leukaemia and healthy individuals
- Author
-
Dybkaer, K., Kristensen, Jørgen Schøler, and Pedersen, Finn Skou
- Published
- 2001
46. Single site polymorphisms and alternative splicing of the human CD13 gene--different splicing frequencies among patients with acute myeloid leukaemia and healthy individuals
- Author
-
Dybkaer, K, Kristensen, J S, and Pedersen, F S
- Subjects
Male ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Molecular Sequence Data ,Antigens, CD13 ,Exons ,Middle Aged ,Polymorphism, Single Nucleotide ,Alternative Splicing ,Leukemia, Myeloid ,Case-Control Studies ,Acute Disease ,Humans ,Female ,Amino Acid Sequence - Abstract
Udgivelsesdato: 2001-Mar
- Published
- 2001
47. Stromal-mediated down-regulation of CD13 in bone marrow cells originating from acute myeloid leukemia patients
- Author
-
Dybkaer, K., Olesen, G., Pedersen, Finn Skou, and Kristensen, Jørgen Schøler
- Published
- 2001
48. Stromal-mediated down-regulation of CD13 in bone marrow cells originating from acute myeloid leukemia patients
- Author
-
Dybkaer, K, Olesen, G, Pedersen, F S, and Kristensen, J S
- Subjects
Male ,Transcription, Genetic ,Antigens, CD13 ,Antigens, Differentiation, Myelomonocytic ,Mice ,Antigens, CD ,Bone Marrow ,Animals ,Humans ,Cell Lineage ,Myeloid Cells ,RNA, Messenger ,RNA, Neoplasm ,Promoter Regions, Genetic ,Cells, Cultured ,Gene Expression Regulation, Leukemic ,Middle Aged ,Coculture Techniques ,Neoplasm Proteins ,Mice, Inbred C57BL ,Leukemia, Myeloid ,Organ Specificity ,Acute Disease ,Neoplastic Stem Cells ,Female ,Stromal Cells ,Poly A - Abstract
Udgivelsesdato: 2001-Mar
- Published
- 2001
49. Stroma mediated down-regulation of CD13 in patients with acute myeloid leukemia
- Author
-
Dybkær, K., Olesen, G., Pedersen, F.S., and Kristensen, J.S
- Published
- 2001
50. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study
- Author
-
Visco, C., Li, Y., Xu-Monette, Z.Y., Miranda, R.N., Green, T.M., Tzankov, A., Wen, W., Liu, W.M., Kahl, B.S., d'Amore, E.S., Montes-Moreno, S., Dybkaer, K., Chiu, A., Tam, W., Orazi, A., Zu, Y., Bhagat, G., Winter, J.N., Wang, H.Y., O'Neill, S., Dunphy, C.H., Hsi, E.D., Zhao, X.F., Go, R.S., Choi, W.W., Zhou, F., Czader, M., Tong, J., Krieken, J.H. van, Huang, Q., Ai, W., Etzell, J., Ponzoni, M., Ferreri, A.J., Piris, M.A., Moller, M.B., Bueso-Ramos, C.E., Medeiros, L.J., Wu, L., Young, K.H., Visco, C., Li, Y., Xu-Monette, Z.Y., Miranda, R.N., Green, T.M., Tzankov, A., Wen, W., Liu, W.M., Kahl, B.S., d'Amore, E.S., Montes-Moreno, S., Dybkaer, K., Chiu, A., Tam, W., Orazi, A., Zu, Y., Bhagat, G., Winter, J.N., Wang, H.Y., O'Neill, S., Dunphy, C.H., Hsi, E.D., Zhao, X.F., Go, R.S., Choi, W.W., Zhou, F., Czader, M., Tong, J., Krieken, J.H. van, Huang, Q., Ai, W., Etzell, J., Ponzoni, M., Ferreri, A.J., Piris, M.A., Moller, M.B., Bueso-Ramos, C.E., Medeiros, L.J., Wu, L., and Young, K.H.
- Abstract
Contains fulltext : 110658.pdf (publisher's version ) (Closed access)
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.