Prognostic implications of caspase-3 expression in patients with diffuse large B-cell lymphoma (DLBCL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17500-17500 ◽  
Author(s):  
W. H. Elsawy ◽  
M. Abdel Kader ◽  
A. Elfar ◽  
A. Gharib ◽  
S. Eltrhony ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Poor Prognosis ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Serum Lactate Dehydrogenase ◽  
Large B Cell Lymphoma ◽  
Large B Cell

17500 Background: Caspase-3 activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase-2 and caspase-3. The following study was designed to evaluate the correlation between Caspase-3 and the clinical outcome in patients with diffuse large B-cell lymphoma. Methods: Caspase-3 was determined by both immunohistochemistry and by quantitative reverse-transcription PCR in 49 previously untreated patients with diffuse large B-cell lymphoma. Results: Caspase-3 was positive in 69.4% of the patients by immunostaining and Tumor cells displayed a diffuse cytosolic expression in 51% of patients. The median value of Caspase-3mRNA within the group by quantitative PCR was 1. Caspase-3mRNA level was μ1 in 28 patients and <1 in 21 patients. Caspase-3 expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.02), and the International Prognostic Index (P = 0.0001). Patients with Caspase-3-positive immunostaining had a significantly higher complete response rate to chemotherapy and a longer overall survival than Caspase-3-negative patients. Also, patients with tumor cells expressing diffuse cytosolic immunostaining for caspase-3 had a poor prognosis when compared with those expressing a punctate staining (P > 0.0004 log-rank). A low caspase-3 mRNA expression by quantitative RT-PCR was also associated with a poor prognosis, although this was not statistically significant. In addition, patients with a high TUNEL positivity had a low survival probability (P > 0.02). Conclusions: Our results suggest that Caspase-3 activation or its lack may be a powerful independent predictor of response and survival in previously untreated diffuse large B-cell lymphomas. No significant financial relationships to disclose.

scholarly journals Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1350-1358 ◽  
Author(s):  
Ash A. Alizadeh ◽  
Andrew J. Gentles ◽  
Alvaro J. Alencar ◽  
Chih Long Liu ◽  
Holbrook E. Kohrt ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Single Gene ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractSeveral gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the “germinal center B cell–like” subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of “cell-of-origin” classification, “stromal signatures,” IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

Prediction of Survival In Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes Reflecting Tumor and Microenvironment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2006-2006
Author(s):  
Ash A. Alizadeh ◽  
Andrew J. Gentles ◽  
Alvaro J. Alencar ◽  
Holbrook E Kohrt ◽  
Roch Houot ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Single Gene ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2006 Background: Several gene expression signatures predict survival in diffuse large B cell lymphoma (DLBCL), but the lack of practical methods for genome scale analysis has limited translation to clinical practice. Methods: We examined the power of individual genes to predict survival across different therapeutic eras. In studying 787 patients with DLBCL, we built and validated a simple model employing one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). We validated models in an independent cohort using diagnostic formalin-fixed specimens. Results: We verified expression of LMO2 as an independent predictor of survival and ‘Germinal Center B-cell’ subtype. We identified expression of TNFRSF9 from the tumor microenvironment, as the best in bivariate combination with LMO2. We studied distribution of TNFRSF9 tissue expression in 95 patients. A model integrating these two genes (TGS) was independent of ‘cell of origin’ classification, ‘stromal signatures’, IPI, and added to the predictive power of the IPI. This bivariate model and a composite score integrating the IPI (TGS-IPI) performed well in three independent cohorts of 545 previously described patients. Both models robustly stratified outcomes in a simple assay of routine specimens from 147 newly diagnosed patients as depicted. Conclusion: Measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL. A simple test integrating these two genes with the IPI can readily be used to select patients of different risk groups for clinical trials. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3305
Author(s):  
Bogyeong Han ◽  
Sehui Kim ◽  
Jiwon Koh ◽  
Jeemin Yim ◽  
Cheol Lee ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
Cell Phenotype ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marrow involvement (p = 0.001), high IPI (p = 0.017), CD10 expression (p = 0.006), poor performance status (p = 0.028), and elevated LDH levels (p < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients.

scholarly journals Molecular Heterogeneity in Localized Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Qin ◽  
Di Fu ◽  
Qing Shi ◽  
Lei Dong ◽  
Hongmei Yi ◽  
...  
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Serum Lactate Dehydrogenase ◽  
Molecular Characteristics ◽  
Molecular Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Large B Cell

The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network–International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-β signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase &gt;3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.

Primary Mediastinal Large B-Cell Lymphoma: A Clinicopathologic Study of 43 Patients From the Nebraska Lymphoma Study Group

1999 ◽  
Vol 17 (3) ◽  
pp. 784-784 ◽  
Author(s):  
Ashraf A. Abou-Elella ◽  
Dennis D. Weisenburger ◽  
Julie M. Vose ◽  
Jeffrey P. Kollath ◽  
James C. Lynch ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Serum Lactate Dehydrogenase ◽  
Control Group ◽  
Female Ratio ◽  
Large B Cell Lymphoma ◽  
Large B Cell

PURPOSE: To investigate whether primary mediastinal large B-cell lymphoma (PMLBL) is a distinct clinicopathologic entity with a more aggressive course than other diffuse large B-cell lymphomas (DLBL). MATERIALS AND METHODS: All patients with CD20-positive DLBL who presented with a mediastinal mass measuring at least 5.0 cm and were treated with curative intent were identified. A control group of 352 patients with nonmediastinal DLBL was selected for comparison. RESULTS: The 43 patients with PMLBL had a male to female ratio of 20:23 and a median age of 42 years. Stage I/II disease was present in 58% of the patients, with only 9% having bone marrow involvement. A complete remission was achieved in 63% of the patients, and the 5-year overall and failure-free survivals were 46% and 38%, respectively. Among the clinical variables, an elevated serum lactate dehydrogenase level, a low performance score, more than one extranodal site, and an intermediate or high International Prognostic Index score were predictive of poor survival. When compared with the DLBL group, a younger median age was the only clinical feature that was significantly different in the PMLBL group. CONCLUSION: The clinical features of PMLBL do not appear to be significantly different from those of nonmediastinal DLBL. Although the younger age of onset, slight female predominance, mediastinal location, and size of the mass may justify the recognition of PMLBL as a clinical syndrome, additional evidence is needed to define it as a distinct disease entity.

CD5 Expression Is a Predictive Factor for Poor Prognosis among Biomarkers in Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab Plus CHOP Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3447-3447
Author(s):  
Daisuke Ennishi ◽  
Masahiro Yokoyama ◽  
Kengo Takeuchi ◽  
Hiroaki Asai ◽  
Yuko Mishima ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Initial Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Several biomarkers indicating poor prognosis have been reassessed in patients with diffuse large B-cell lymphoma (DLBCL) treated by rituximab combination chemotherapy. However, no studies have investigated the outcome by combining these biomarkers for rituximab treatment. In addition, no large studies have reassessed the outcome of patients with CD5-positive DLBCL treated by rituximab. To determine the most influential biomarkers, we reassessed and investigated the predictive value of three biomarkers, namely Bcl-2 expression, GC phenotype and CD5 expression, in DLBCL patients treated with rituximab in combination with CHOP as an initial therapy. Methods: A total of 121 patients with CD20-positive DLBCL receiving RCHOP at our institute between April 2002 and October 2005 were enrolled in the study. To classify the samples into immunohistochemically defined GC or non-GC phenotypes, we used a previously described algorithm using expression of CD10, Bcl-6, and MUM1 (Hans et al. Blood, 2004). For examination of the CD5 expression, we defined the cases as CD5-positive if CD5 expression was detected by immunohistochemical and flow cytometric analyses. We also assessed the outcome of patients according to International Prognostic Index (IPI). Results: Expression of Bcl-2 was detected in 79 of the 121 (65%) patients, while CD5 expression was positive in 11 patients (9%). Overall, 48 of the 121 (40%) patients expressed a non-GC phenotype. CD5-positive patients displayed a significantly poorer progression-free survival (PFS) and overall survival (OS) than CD5-negative patients (2-year PFS, 18% vs. 73%, P<0.001; OS, 45% vs. 91%, P=0.001). However, there were no significant differences in PFS and OS according to Bcl-2 expression (PFS, 76% vs. 91%, P=0.08; OS, 77% vs. 97%, P=0.06) or GC phenotype (PFS, 70% vs. 90%, P=0.08; OS, 77% vs. 91%, P=0.12). In contrast, the differences between high or high-intermediate and low or low-intermediate of IPI for PFS and OS were significant (2-year PFS, 52% vs. 91%, P=0.001; OS, 64% vs. 92%, P=0.01). Multivariate analysis revealed that CD5 expression and the IPI were significant prognostic factors for PFS and OS (RR: PFS, 13.57 and 9.65, respectively; OS, 18.15 and 10.72, respectively) (Table 1). Conclusion: These results demonstrated that CD5 expression was the most influential prognostic factor among the biomarkers examined and associated with a very poor outcome, even after rituximab treatment. To confirm this conclusion, further large studies of CD5-positive DLBCL patients are required. Cox’s hazard regression analysis of PFS and OS Variable RR 95% CI P RR indicates relative risk; CI, confidence interval; GC phenotype, non-GC type worse; and IPI, higher IPI worse PFS CD5 13.57 4.260–42.947 <0.001 BCL2 2.00 0.518–7.761 0.314 GC phenotype 2.59 0.851–7.857 0.094 IPI 0 to2 or 3 to 5 9.65 2.911–31.987 <0.001 OS CD5 18.15 3.023–109.029 0.002 BCL2 1.29 0.240–6.966 0.764 GC phenotype 1.43 0.367–5.573 0.606 IPI 0 to2 or 3 to 5 10.72 1.945–59.085 0.006

scholarly journals Elevated M-MDSCs in Circulation Are Indicative of Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients

2021 ◽  
Vol 10 (8) ◽  
pp. 1768
Author(s):  
Zhitao Wang ◽  
Rui Jiang ◽  
Qian Li ◽  
Huiping Wang ◽  
Qianshan Tao ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Suppressor Cells ◽  
B Cell Lymphoma ◽  
Pathological Process ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Accumulation Mechanism ◽  
Large B Cell

Myeloid-derived suppressor cells (MDSCs) are defined as negative regulators that suppress the immune response through a variety of mechanisms, which usually cluster in cancer, inflammation, and autoimmune diseases. This study aims to investigate the correlation between M-MDSCs and the clinical features of diffuse large B-cell lymphoma (DLBCL) patients, as well as the possible accumulation mechanism of M-MDSCs. The level of M-MDSCs is significantly increased in newly diagnosed and relapsed DLBCL patients. Regarding newly diagnosed DLBCL patients, the frequency of M-MDSCs is positively correlated with tumor progression and negatively correlated with overall survival (OS). More importantly, the level of M-MDSCs can be defined as a biomarker for a poor prognosis in DLBCL patients. Additionally, interleukin-35 (IL-35) mediates the accumulation of M-MDSCs in DLBCL patients. Anti-IL-35 treatment significantly reduces levels of M-MDSCs in Ly8 tumor-bearing mice. Thus, M-MDSCs are involved in the pathological process of DLBCL. Targeting M-MDSCs may be a promising therapeutic strategy for the treatment of DLBCL patients.

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