Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

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.     

Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma

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.     

Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma

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 .     

Geriatric nutritional risk index as a prognostic factor in patients with diffuse large B cell lymphoma

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.     

MAGE-A3 expression is an adverse prognostic factor in diffuse large B-cell lymphoma

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.     

Pathogenesis of diffuse large B cell lymphoma

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.     

Primary hepatic diffuse large B cell lymphoma: A case report: Primary hepatic diffuse large B cell lymphoma

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.     

Rearrangement of the BCL6 locus at 3q27 is an independent poor prognostic factor in nodal diffuse large B-cell lymphoma

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.     

Bad-deficient mice develop diffuse large B cell lymphoma

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.     

Accelerated therapeutic progress in diffuse large B cell lymphoma

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.     

Charlson Comorbidity Index is an independent prognostic factor among elderly patients with diffuse large B-cell lymphoma

Purpose

The clinical outcome for elderly patients with diffuse large B-cell lymphoma (DLBCL) has improved. However, the management of elderly patients with cancer is frequently complicated by their coexisting disorders. The aim of this study was to evaluate the correlation between comorbid medical status and clinical outcome among elderly patients with DLBCL.

Methods

We retrospectively analyzed all patients over 65?years old with newly diagnosed DLBCL from 2001 to 2008 in our institution. To assess their comorbid medical status, we calculated Charlson Comorbidity Index (CCI) of each patient without considering primary disease and then divided them into low CCI (0 or 1) or high CCI group (2 or more).

Results

A total of 80 patients from age of 66?C90?years (median 73?years) were analyzed. Seventy-two patients (90%) were treated with cyclophosphamide-, doxorubicin-, vincristine-, and prednisone (CHOP)-based chemotherapy, and 14 patients (18%) were assigned to high CCI. The overall survival (OS) rate at 3?years for all patients was 70%, with significant difference between good and poor risk patients in revised International Prognostic Index (IPI) (90 vs. 45%, P?P?=?0.0045). In addition, high CCI group was significantly inferior to low CCI group for overall response rate (93 vs. 64% P?=?0.0158) and 3-year OS (85 vs. 55% P?=?0.0026), respectively.

Conclusions

Among elderly DLBCL, high CCI was independently associated with worse outcome. Novel discrete strategies for these deteriorated patients are therefore warranted.