Clinical outcome in diffuse large B-cell lymphoma is dependent on the relationship between different cell-cycle regulator proteins.

Sanchez, Emily; Chacón, Ignacio Fernández; Plaza, M.M.S.; Muñoz, Elkin; Cruz, M A; Martinez, B.; López, L. Humanes; Martínez-Montero, J C; Orradre, J L; Saez, A I; Garcia, Joseph F.; Ma, Ping

doi:10.1200/jco.1998.16.5.1931

Cited by 92 publications

(96 citation statements)

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“…Overall analysis showed that an extended overall survival (OS) time is associated with low growth fraction, low expression of p53 and MDM2 proteins and high Rb expression. In contrast with this finding, higher disease-free survival (DFS) time is mainly associated with low bcl2 expression (Slymen et al, 1990;Yamanaka et al, 1992;Miller et al, 1994;Piris et al, 1994;Martin et al, 1995;Hermine et al, 1996;Hill et al, 1996;Kramer et al, 1996;Gascoyne et al, 1997;Grogan et al, 1988;Sánchez et al, 1998) Earlier studies in non-Hodgkins lymphomas (NHLs) pointed to the presence of a small group of DLBCL characterized by an unusually high level of p27 KIP1 expression (Sánchez-Beato et al, 1997;Quintanilla-Martinez et al, 1998), in which the opposing relationship between p27 KIP1 and MIB1 expression seemed to be lost. The main purpose of this work was to analyse the expression of this protein in greater depth, and to determine the clinical relevance of p27 KIP1 expression in this lymphoma type.…”

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p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

et al. 1999

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Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27 KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27 KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27 KIP1 staining. We analysed p27 KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27 KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27 KIP1 was found in lymphomas of this type. The overall correlation between p27 KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27 KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27 KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27 KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins. © 1999 Cancer Research Campaign

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“…A cut-off point of 20% of positive cells was used, as a previous study showed that this point discriminated between groups presenting different clinical behaviour. Categories were therefore classified as equal to or less than 20%, or greater than 20% (Sánchez et al, 1998).…”

Section: Quantitative Studiesmentioning

confidence: 99%

p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

et al. 1999

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“…16,23,[27][28][29][30][31][32][33][34][35] However, some studies have found that bcl-2 expression is associated with a significantly worse overall survival, 3,[36][37][38][39][40][41][42] or event-free survival. [29][30][31]36,37 The discrepancies related to bcl-2 expression and prognosis may be related to the underlying subgroups of DLBCL. Within the nongerminal center B-cell-like subgroup of DLBCL, bcl-2 expression is associated with a significantly worse overall survival and event-free survival, whereas bcl-2 expression is not predictive of survival within the germinal center B-cell-like subgroup.…”

Section: Discussionmentioning

confidence: 99%

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma

et al. 2005

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We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-b), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P ¼ 0.025) or PKC-b (P ¼ 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-b had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P ¼ 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-b was an independent predictor of poor overall survival (P ¼ 0.035). Cyclin D2 and PKC-b expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.

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“…Although numerous promising cellular targets and assays have been identified, such as p53 [9,20], p16 INK4A [21], bcl-2 [22,23], bcl-6 [23,24], and gene expression profiling [25,26], none of these have gained the level of acceptance required to be routinely used for risk stratification in trials and other clinical settings. Until such biology-based markers have been validated and standardized, clinical factors will continue to be the foundation of prognosis assessment in DLBCL.…”

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confidence: 99%

Factors predicting long‐term survival in low‐risk diffuse large B‐cell lymphoma

Møller¹,

Pedersen²,

Christensen³

2003

American J Hematol

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The International Prognostic Index (IPI) is widely used for risk stratification of patients with diffuse large B-cell lymphoma (DLBCL). However, even among patients with low-risk disease, according to the IPI a substantial proportion of patients ultimately succumb to their disease. Using mature population-based data from the Danish Lymphoma Group, we analyzed if prognostic clinical pretreatment factors could be identified in patients with lowrisk DLBCL. One hundred seventy-seven patients, all with a prognostic profile as favorable as possible according to the IPI and treated with anthracycline-based combination chemotherapy (92%) or loco-regional radiotherapy/surgery (8%) with curative intent were included. The median age was 50 years and 170 achieved complete remission. The median follow-up time was 11 years. Twenty-six patients relapsed, with a median time to relapse of 12.1 months. Overall survival at 5 years and 10 years was 85% and 75%, respectively. Stage II was associated with poor response to treatment (P = 0.044). In a multivariate analysis, Stage II (P = 0.001) and age >50 years (P = 0.043) were independently associated with poor outcome. Patients without these adverse factors had an excellent prognosis, with a survival at 5 and 15 years of 90% and 80%, respectively. In contrast, patients with both adverse factors had poor outcome, with survival at 5 and 15 years of 70% and 29%, respectively (P < 0.001). The present data suggest that risk stratification of DLBCL patients with a favorable IPI score can be improved by the simple use of two clinical pretreatment factors. Am. J.

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Clinical outcome in diffuse large B-cell lymphoma is dependent on the relationship between different cell-cycle regulator proteins.

Cited by 92 publications

References 22 publications

p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma

Factors predicting long‐term survival in low‐risk diffuse large B‐cell lymphoma

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