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Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma
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Eileen Wedge Jakob Werner Hansen Christian Garde Fazila Asmar Dorte Tholstrup Søren Sommer Kristensen Helga D. Munch‐Petersen Elisabeth Ralfkiaer Peter Brown Kirsten Grønbæk Lasse Sommer Kristensen 《American journal of hematology》2017,92(7):689-694
Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell‐free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite‐treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03‐55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80‐50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene‐specific methylation data. This analysis shows that global hypomethylation co‐occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker. 相似文献
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Hedström G Berglund M Molin D Fischer M Nilsson G Thunberg U Book M Sundström C Rosenquist R Roos G Erlanson M Amini RM Enblad G 《British journal of haematology》2007,138(1):68-71
Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome. 相似文献
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《British journal of haematology》2017,177(1):95-105
The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL ). A hundred and eighty‐eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT 3) level with low or normal serum free tetraiodothyronine (FT 4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression‐free survival (PFS ) and overall survival (OS ). Receiver‐operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI ) and low T3 syndrome. Twenty‐four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS , especially for those with IPI 0−2, extranodal sites ≤1 and stage III−IV. Synchronously low FT 3 and FT 4 had poorer survival outcome compared to only low FT 3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL . Low T3 syndrome was found to be a strong prognostic predictor in DLBCL . 相似文献
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The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional assessment tool that is a significant prognostic factor for various cancers. However, the role of the GNRI in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. To address this issue, we retrospectively analyzed a total of 476 patients with newly diagnosed de novo DLBCL. We defined the best cutoff value of the GNRI as 96.8 using a receiver operating characteristic curve. Patients with a GNRI <?96.8 had significantly lower overall survival (OS) and progression-free survival (PFS) than those with a GNRI ≥?96.8 (5-year OS, 61.2 vs. 84.4%, P?<?0.001; 5-year PFS, 53.7 vs. 75.8%, P?<?0.001). Multivariate analysis showed that performance status, Ann Arbor stage, serum lactate dehydrogenase, and GNRI were independent prognostic factors for OS. Among patients with high-intermediate and high-risk by National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), the 5-year OS was significantly lower in patients with a GNRI <?96.8 than in those with a GNRI ≥?96.8 (high-intermediate risk, 59.5 vs. 75.2%, P?=?0.006; high risk, 37.4 vs. 64.9%, P?=?0.033). In the present study, we demonstrated that the GNRI was an independent prognostic factor in DLBCL patients. The GNRI could identify a population of poor-risk patients among those with high-intermediate and high-risk by NCCN-IPI. 相似文献
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Olarte I Martinez A Ramos-Peñafiel C Castellanos-Sinco H Zamora J Collazo-Jaloma J Gutiérrez M Gutiérrez-Kobeh L Chavez-Olmos P Manzanilla H Garrido-Guerrero E Ordoñez-Razo RM Miranda EI 《Hematology (Amsterdam, Netherlands)》2011,16(6):368-372
This study evaluates the prognostic value of MAGE-A3 expression in 28 diffuse large B-cell lymphoma (DLBCL) patients. A significant association was observed between MAGE-A3 expressions, assessed by quantitative real-time RT-polymerase chain reaction (PCR), with advanced stages of disease (P < 0.05). Elevated serum lactate dehydrogenase (LDH) levels and International Prognostic Index (IPI) score were significantly higher in MAGE-A3-positive patients (P = 0.025 and P = 0.004, respectively). Expression of MAGE-A3 was associated with poor response to treatment and a significantly shorter overall survival (P < 0.001). Our data address new information in the association of MAGE-A3 expression and poor prognosis in DLBCL patients. 相似文献
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Wing ?C.?Chan 《International journal of hematology》2010,92(2):219-230
Substantial additional insight has been obtained in the past decade regarding the pathogenesis of diffuse large B cell lymphoma
(DLBCL). Distinct subtypes of DLBCL have been defined by gene expression profiling (GEP) and they differ not only in GE profiles
but also in the pattern of genetic abnormalities. The ability to correlate corresponding genetic and GEP data markedly facilitates
the identification of target genes in regions with copy number abnormalities. Oncogenic pathways are often differentially
activated in these different subtypes of DLBCL, suggesting that therapy should be targeted according to these differences.
The tumor microenvironment plays a significant role in determining outcome and may be a novel target for therapy. The role
of microRNA in lymphomagenesis is increasingly being recognized and mutation of key genes has been demonstrated to drive the
activation of the NF-κB pathway and B cell receptor signaling. The pace of discovery will be even more rapid in the near future
with the convergence of data from multiple complementary genome-wide studies and technological innovations including the rapid
advance in the technology of high-throughput sequencing. 相似文献
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In this report we describe a rare case of primary hepatic diffuse large B cell lymphoma in a 67-year-old man who presented with abdominal pain, deteriorated liver function, elevated lactate dehydrogenase. He was found to have diffuse nodular intrahepatic space-occupying lesion with normal α-fetoprotein and carcino-embryogenic antigen. The final diagnosis was made by percutaneous biopsy of the liver as the clinical manifestation not consistent with common liver diseases. The patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) without surgical resection with a favorable response. However, serious complication was occurred after 4 cycles of chemotherapy, and the patient finally died of concurrent acute respiratory distress syndrome. 相似文献
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Rearrangement of the BCL6 locus at 3q27 is an independent poor prognostic factor in nodal diffuse large B-cell lymphoma 总被引:8,自引:0,他引:8
Barrans SL O'Connor SJ Evans PA Davies FE Owen RG Haynes AP Morgan GJ Jack AS 《British journal of haematology》2002,117(2):322-332
Diffuse large B-cell lymphomas (DLBCL) are a heterogeneous group of tumours, varying in clinical features, immunophenotype and cytogenetics. The aim of this study was to investigate the prognostic significance of BCL6 gene rearrangement at the 3q27 locus in patients with primary nodal disease, and to examine interrelationships with immunophenotype and International Prognostic Index (IPI). We have developed a fluorescent in situ hybridization (FISH)-based technique for the retrospective analysis of the effect of BCL6 gene rearrangements on survival, using nuclei extracted from paraffin-embedded tissue. FISH results were obtained in 111 presentation cases of nodal DLBCL. The IPI was calculated and each case was stained immunocytochemically for BCL6, BCL2 and CD10. 3q27 rearrangements were detected in 25% of cases. BCL2 protein and a germinal centre (GC) phenotype (defined as CD10+, BCL6+) were expressed in 56% and 41% of cases respectively. In multivariate analysis, rearrangement of 3q27 and BCL2 expression and the absence of a GC phenotype were associated with a poor prognosis. These factors can be used in conjunction with the IPI to improve risk stratification in nodal DLBCL. 相似文献
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Ranger AM Zha J Harada H Datta SR Danial NN Gilmore AP Kutok JL Le Beau MM Greenberg ME Korsmeyer SJ 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(16):9324-9329
The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage. 相似文献
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Qingqing Cai Jason Westin Kai Fu Madhav Desai Liang Zhang Huiqiang Huang Wenqi Jiang Rong Liang Zhengzi Qian Richard E. Champlin Michael Wang 《Annals of hematology》2014,93(4):541-556
Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in the world. Clinically, biologically, and pathologically, DLBCL is a heterogeneous entity with a range of potential outcomes. Immunochemotherapy regimens, consisting of the chimeric monoclonal anti-CD20 antibody rituximab in combination with chemotherapy, have improved the outcomes. Relapsed DLBCL is generally treated with salvage immunochemotherapy followed by high-dose therapy and autologous stem cell transplantation; however, DLBCL is not yet curable in up to a third of patients. The real promise for cure lies in novel agents and their rational combinations. The improved understanding of DLBCL subtypes and gene expression profiling has led to the identification of targeted drugs that may allow for subtype specific therapy. We have summarized the existing data on the prognostic factors and the treatment of DLBCL, including the use of novel agents such as lenalidomide, carfilzomib, and ibrutinib. We also share our thoughts on the direction of future clinical trials. 相似文献
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Kobayashi Y Miura K Hojo A Hatta Y Tanaka T Kurita D Iriyama N Kobayashi S Takeuchi J 《Journal of cancer research and clinical oncology》2011,137(7):1079-1084