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Endogenous BFL1 expression renders diffuse large B-cell lymphoma (DLBCL) cells insensitive to B-cell lymphoma 2 (BCL2) and/or MCL1 inhibitors. Considering the difficulties in developing a direct BFL1 inhibitor, we intended to inhibit histone deacetylase (HDAC) to mitigate the biological role of BFL1 by modulating WT1 and NOXA. Cells expressing high BFL1 exhibited enhanced sensitivity to pan-HDAC inhibitor compared to low BFL1 expressing cells, mainly attributable to the difference in the amount of apoptosis. HDAC inhibitors decreased BFL1 and WT1 expressions while increasing NOXA levels. The BFL1 knockdown experiment demonstrated that HDAC inhibitor's sensitivity depends on the BFL1 expression in DLBCL cells. Furthermore, we found that the specific HDAC class was expected to play a critical role in BFL1 inhibition by comparing the effects of several HDAC inhibitors. Thus, our study provides a rationale for using HDAC inhibitors to induce apoptosis in DLBCL patients using BFL1 as a predictive biomarker. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated feasibility and substantial benefit of direct-acting antivirals (DAAs) administration during or after first-line immune-chemotherapy (I-CT) in patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphomas (DLBCL). However, data on DAAs used during or after salvage treatments are still lacking. In this study we assessed clinical and virological outcome in 11 patients with relapsed (n = 7) or refractory (n = 4) HCV-positive DLBCL. DAAs were given either concurrently (n = 3) or subsequent (n = 8) to salvage I-CT. Most patients (10 of 11) received sofosbuvir-based regimens. All patients completed their planned courses of DAAs and achieved sustained virological response. DAAs were well tolerated, with no grade ≥2 adverse events. At a median follow-up of 3.6 years four patients died (4-year OS: 76%). In conclusion, we provide evidence that DAAs in HCV-positive relapsed/refractory DLBCL are extremely safe and effective, suggesting that they should be used if HCV eradication was not instituted before. [ABSTRACT FROM AUTHOR]

This study aimed to investigate and compare exosomal miR-155, let-7g and let-7i levels as a noninvasive biomarker among patients with refractory/relapsed or responsive DLBCL after R-CHOP treatment and patients receiving R-CHOP. Plasma was collected and exosomes were isolated from plasma. Exosomes confirmed by zeta-seizer, electron microscope, and western blot. Exosomes concentration was investigated by BCA assay. MiR-155, let-7g and let-7i levels were evaluated in plasma-derived exosomes by real-time PCR. Plasma IFN-γ and IL-4 level were measured by ELISA assay. We observed the significant increase in the exosomal miR-155 levels (p =.002) and exosomes concentration (p =.001) in refractory/relapsed patients compared to responsive patients and patients receiving R-CHOP. No association was not observed between exosomal miR-155 levels and IPI and disease stage. The significant decrease in IFN-γ levels was observed in patients receiving R-CHOP compared to refractory/relapsed or responsive patients (p=.001). Therefore, exosomal miR-155 might be useful as potential prognostic biomarkers to predict response to treatment in DLBCL patients. [ABSTRACT FROM AUTHOR]

Molecular studies have shown metformin to have a promising effect in lymphoma; however, there is lack of studies translating this effect into clinical settings. This was a case-control study to assess the clinical effect of metformin in diabetic diffuse large B-cell lymphoma (DLBCL) patients. Case subjects were diabetic on metformin with a new diagnosis of DLBCL. A total of 24 case subjects were identified, and for each case a control was matched. Outcomes of this study were to assess overall response rate, complete remission rate, progression free survival, and overall survival between the two groups. There was a significant increase in overall response rate, complete remission rate, and improved progression free survival in the metformin group compared to the control group, however, no significant overall survival difference was observed. Metformin use might be associated with an improved response rates and progression-free survival in diabetic DLBCL patients. [ABSTRACT FROM PUBLISHER]

The role of consolidative radiotherapy (RT) in patients ≥60 years old with DLBCL in the rituximab era is controversial. We examined the impact on disease control and overall survival by the addition of consolidative RT after completion of chemotherapy, while adjusting for known adverse risk factors. Retrospective chart review from 2004 to 2012 of 83 consecutive patients ≥60 years old with DLBCL treated in the rituximab era, 68 of which had a complete response to chemotherapy, was performed. Amongst patients with a complete response, consolidative RT use was associated with 100% 5-year local control, improved progression-free survival (p = 0.047), and a trend for overall survival (p = .098) on multivariate analysis. Amongst all patients, the use of consolidative RT was associated with improved overall survival (p = 0.03). The use of consolidative RT should be considered for patients ≥60 years old independent of stage and response to chemotherapy. [ABSTRACT FROM AUTHOR]

The National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI) is an enhanced prognostic tool that has identified some specific extranodal sites as a poor prognostic factor. We retrospectively analyzed 148 Taiwanese patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimens from January 2001 to December 2010 at the Tri-Service General Hospital. In univarate analysis, ≥ 2 extranodal involved sites had no significant prognostic relevance ( p = 0.108), although extranodal involvement of the lung/pleura, liver, lower urinary tract or bone marrow was a statistically significant poor prognostic factor ( p < 0.001). In multivariate analysis, specific extranodal sites had a stronger predictive value for poor prognosis (relative risk 3.654, 95% confidence interval 1.514-8.815, p = 0.004) compared with the number of extranodal sites involved. This finding suggests that specific extranodal involved sites have prognostic value in the R era. [ABSTRACT FROM AUTHOR]

In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diffuse large B-cell lymphoma (DLBCL) identified by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classified as frail. Frail patients had a median age of 78 years, stage III-IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2-3 in 53%. Treatment consisted of several different regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2-3 ( p = 0.005) and the presence of respiratory comorbidity ( p = 0.044) were the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fit patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confidence interval 1.48-3.78; p < 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma (NHL) in the United States, and two-thirds of these patients will present with advanced stage (stage III-IV) disease. Although radiation therapy (RT) alone was the first curative therapy for limited stage DLBCL, the advancement of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with the addition of the anti-CD20 antibody rituximab became the cornerstone of current management. The role of consolidative RT as part of first-line therapy in the management of patients with advanced stage DLBCL remains unclear, and represents an area of controversy with considerable differences in patterns of practice across different institutions. Emerging data now challenge the National Comprehensive Cancer Network (NCCN) guidelines, and give support to the use of consolidative RT in patients with advanced stage DLBCL. This review summarizes the major studies as reflected in our current practice and provides further insight into future directions for randomized trials which would help better define the role of consolidative RT in such a cohort. [ABSTRACT FROM AUTHOR]

There have been two major developments over the last decade that has led to improvements in outcome and longer survival for patients with diffuse large B-cell lymphoma (DLBCL). These developments have been firstly to increase the dose of active cytotoxic drugs and shorten the time between cycles, resulting in dose-dense and/or dose-intense regimens and secondly the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy. Both strategies have been associated with higher response rates, lower relapse rates, longer event-free survival (EFS) and improved overall survival (OS), particularly in better prognostic groups. A combination of dose-dense and dose-intense chemotherapy regimens plus rituximab is currently being tested to confirm that the use of both approaches confers survival advantage. High-risk, poorer-prognosis DLBCL remains a challenge, and new treatment strategies are required for these patients. Improvements in outcome may potentially be achieved through a greater understanding of the genetic abnormalities specifically associated with poorer-prognosis disease, and factors that lead to unresponsiveness to chemotherapy. The role of radiotherapy is currently less clearly defined than at anytime in the management of DLBCL and the current evidence for using radiotherapy in this disease is therefore rigorously reviewed. [ABSTRACT FROM AUTHOR]