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High‐dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is widely used in patients with diffuse large B‐cell lymphoma. HDCT/ASCT is associated with increased morbidity in elderly/unfit patients. We retrospectively evaluated the use of reduced intensity conditioning in DLBCL patients. Our study included 146 patients aged 60 years and older treated at our institution between 2005 and 2019; 86 patients received standard intensity conditioning (SI group) with BEAM or TEAM (BCNU or thiotepa, etoposide, cytarabine, melphalan). Sixty patients received reduced intensity high‐dose conditioning (RI group) with BM (BCNU, melphalan, 43.3%), TM (thiotepa, melphalan, 16.7%), BCNU or busulfan thiotepa (38.4%), or bendamustine melphalan (1.7%). Median follow‐up was 62.4 months. We observed comparable toxicities in the SI and RI groups. The cumulative incidence of relapse at 3 years was higher in the RI group (30.8% vs. 23.4%, p = 0.034). There was no difference in nonrelapse mortality (NRM). In univariate analyses, SI vs. RI conditioning resulted in superior progression‐free survival (PFS) (HR 1.80 CI 1.11–2.92, p = 0.017) but not in superior overall survival (OS) (HR 1.48 CI 0.86–2.56, p = 0.152). On multivariate analysis, we observed no difference in PFS (HR 0.74 CI 0.40–1.38, p = 0.345) and a trend toward better OS with RI conditioning (HR 0.45 CI 0.22–0.94, p = 0.032). Age 60–69 versus ≥ 70 years and remission prior to ASCT were the only factors predicting better PFS. Factors associated with better OS were RI conditioning, age 60–69 versus ≥ 70 years, ECOG 0 versus ≥ 1 performance status, bulky disease, and prior lines 1 versus ≥ 2. In conclusion, RI conditioning prior to ASCT may be feasible in elderly patients and led to a comparable outcome when corrected for several significant confounders. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions Accurate prevalence estimates of diffuse large B‐cell lymphoma (DLBCL) are important for numerous purposes including orphan drug designation. A key criterion for orphan drug designation is a disease prevalence of less than 5/10,000 persons. The objective is to apply and compare different methods of prevalence assessment.In the present nationwide Danish cohort study, the prevalence of DLBCL was assessed using different methodologies, including register‐based and formula‐based approaches.The prevalence calculations were based on 9,492 patients diagnosed with DLBCL since year 2000. Incidence increased and survival improved in the period, resulting in higher prevalence of DLBCL. In year 2023, the 2‐,3‐,5‐,10‐, and 20‐year prevalences were 1.53, 2.19, 3.45, 6.08, and 8.80 per 10,000 adults using the register‐based approach. The formula‐based approach was generally accurate when using restricted mean survival. However, when using median survival, the total prevalence was estimated at 8.1 per 10,000 adults. Furthermore, when extrapolating the median survival from the 5‐year survival under constant hazard assumption as done in some orphan drug designation reports, the prevalence was estimated at 6.6 per 10,000 adults.In conclusion, the estimated DLBCL prevalences are sensitive to the applied method. DLBCL would disqualify from orphan drug designation in some of the mentioned scenarios. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion Diffuse large B‐cell lymphoma (DLBCL) exhibits striking clinical and biological heterogeneity. Recent studies have identified new subgroups within germinal center B‐cell like (GCB) DLBCL, associated with inferior prognosis, irrespective of MYC and BCL2 translocations. We explored the existence of such a DLBCL high‐risk subgroup, based on multilevel aberrations, especially focusing on MYC and BCL2.Tissue samples from 111 DLBCL patients were sequenced with a 90‐gene lymphoma panel, followed by integrative analyses combining sequencing data, immunohistochemistry, fluorescent in situ hybridization, and clinical data.We identified a high‐risk subgroup in DLBCL defined by: dual immunohistochemical MYC and BCL2 expression (DEL), concurrent MYC and BCL2 translocations (DHL‐BCL2), mutations in MYC, CXCR4, or both, and/or BCL2 amplification. The high‐risk subgroup constituted 41% of the cohort and included DHL‐BCL2, DEL, a GCB subgroup likely representing the recently described GCB subgroups, and a subset of non‐GCB patients. In multivariate analysis, high‐risk features provided independent predictive value from age and IPI. The 5‐year overall survival was 36% in high‐risk patients, compared to 76% in non‐high‐risk patients.We identified a distinct high‐risk DLBCL subgroup, characterized by MYC and BCL2 aberrations, beyond conventional DHL‐BCL2 and DEL, and irrespective of cell‐of‐origin, thereby expanding the poor‐prognosis group. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R‐CHOP (R‐CHOP‐14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R‐CHOP‐14 and R‐miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80–91). Despite higher CR rates with R‐CHOP‐14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R‐CHOP‐14 and R‐miniCHOP regarding overall survival (OS) (p =.88, HR 0.94, 95% CI = 0.47–1.90) and progression‐free survival (PFS) (p =.26, HR 0.66, 95% CI = 0.32–1.36). At a median follow‐up of 40 months, the 2‐year OS rates were 56% with R‐CHOP‐14 and 53% with R‐miniCHOP. Two‐year PFS rates were 46% for R‐CHOP‐14 and 50% for R‐mini‐CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p =.72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R‐miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most frequent lymphoma. MIC‐A and MIC‐B are the natural ligands for NKG2D, a receptor expressed in NK cells. MIC‐A soluble isoforms (sMICA) have been described in different malignancies. Objectives: To analyze lymphocyte subsets and sMIC‐A in germinal center DLBCL. Materials and Methods: sMICA, sMICB, and peripheral blood lymphocyte subsets (CD4+, CD8+, NK, NKT, γδ T cells, and dendritic cells) were analyzed in 59 patients and 60 healthy donors. Results: Patients had decreased numbers of type 1 and type 2 dendritic cells, NK, iNKT, CD4 T, and CD8 T cells, and higher levels of sMIC‐A. The 2‐year PFS for high IPI scores and high sMIC‐A was 24% and 28%, respectively. The 2‐year OS for high IPI scores and high sMIC‐A was 42% and 33%. The 2‐year PFS and OS for patients not achieving response to treatment were 0% and 10%, respectively. The MICPI score (one point each for high IPI score and high sMIC‐A) showed that those patients summing two points had worse PSF and OS. Conclusions: Patients with DLBCL have decreased numbers of peripheral lymphocyte subsets and high levels of sMIC‐A. The addition of sMIC‐A to IPI could improve its prognostic relevance. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high‐risk r/r DLBCL with one prior line of therapy. The successful development of CAR T‐cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B‐cell lymphoma subtypes. However, CAR T‐cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T‐cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR‐T cell therapy for B‐cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment. [ABSTRACT FROM AUTHOR]

Background: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high‐risk mature B‐cell non‐Hodgkin lymphoma (B‐NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. Methods: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single‐arm multicenter trial. Results: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B‐cell lymphoma, and aggressive mature B‐NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow‐up period was 47.5 months. Three‐year event‐free survival and overall survival were 97.7% (95% confidence interval, 84.9–99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B‐cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non‐hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre‐phase treatment, with a frequency of 54.5%. Conclusion: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high‐risk mature B‐NHL was observed in Japan. [ABSTRACT FROM AUTHOR]

Objectives: The treatment of relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency‐approved chimeric antigen receptor T‐cell (CAR‐T) therapies (axicabtagene ciloleucel [axi‐cel], lisocabtagene maraleucel [liso‐cel], tisagenlecleucel [tisa‐cel]) for the third‐line onwards (3+L), and targeted therapies (polatuzumab vedotin–bendamustine–rituximab [pola‐BR], tafasitamab–lenalidomide [Tafa‐L]) for the second‐line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost‐effectiveness of transplant‐ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach. Methods: A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine–rituximab (BR), rituximab–gemcitabine–oxaliplatin (R‐GemOx), axi‐cel, liso‐cel, tisa‐cel, pola‐BR, and Tafa‐L. First‐year treatment costs (drug and medical services costs) were calculated. Results were merged on two‐dimensional graphs illustrating 2L and 3+L EFs. Results: Second‐line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa‐L (45.7, €104 541), 3+L EF is formed by R‐GemOx (12.0, €29 080), Tafa‐L (15.5, €104 541), and axi‐cel (18.69, €308 516). These interventions build the respective cost‐effectiveness thresholds for novel interventions. Conclusions: Using the EF approach, the currently most cost‐effective interventions (based on cost‐effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL) have poor outcomes and few treatment options. We report the preliminary results of the efficacy and safety of PD‐1 monoclonal antibody (mab) plus Rituximab for r/r DLBCL. Methods: In this single‐center, single‐arm phase 2 and retrospective study, r/r DLBCL patients received PD‐1 mab and Rituximab every 3 weeks. Immunohistochemistry, fluorescence in situ hybridization, and probe capture‐based high‐resolution sequencing were performed. Efficacy, safety and prognostic factors were analyzed. Results: Between October 16th, 2018, and July 10th, 2022, 36 patients (10 patients in retrospective study and 26 patients in phase 2 study) were enrolled and received at least one dose of PD‐1 mab combined with Rituximab. The objective response rate was 52.8%. The median progression free survival (PFS) and overall survival was 2.8 and 19.6 months, respectively. The median duration of response was 18.7 months. Rare grade 3 or 4 treatment related adverse events were observed. B2M mutations correlated with a significantly poor PFS (p =.013) and OS (p =.009) in DLBCL patients treated with this regimen. Conclusion: PD‐1 mab combined with Rituximab could be a potential treatment option for r/r DLBCL with manageable safety profile. [ABSTRACT FROM AUTHOR]

Introduction: The prognosis of diffuse large B‐cell lymphoma (DLBCL) patients with refractory or multiply relapsed (R/R) disease is disappointing. Pixantrone is currently approved as third or fourth line regimen, with encouraging results, even if long‐term follow‐up data are limited. Methods: In this post‐hoc analysis of our observational study, we retrospectively investigated disease outcome and clinical characteristics of 16 R/R DLBCL patients who achieved a complete response with pixantrone. Results: Pixantrone was administered as third or fourth line in 12/16 (75%) and 4/16 (25%) cases. After a median follow‐up of 24 months, 14/16 patients (87.5%) were alive (causes of death were progressive disease and secondary acute myeloid leukemia, one case each). Median progression‐free survival was 23.8 months, median duration of response was 17.8 months and median overall survival (OS) was not reached (2‐years OS was 84%). A significant proportion of patients achieved a long‐lasting response >12 months (7/16 cases). Response to prior therapy did not influence long‐term remission after pixantrone. Conclusion: In this real‐life experience, pixantrone demonstrated long‐term efficacy in a cohort of R/R DLBCL cases who had previously received at least two prior regimens; many of whom had characteristics associated with poor prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Dose‐adjusted EPOCH and rituximab (DA‐EPOCH‐R) is a regimen used for the treatment of high‐risk diffuse large B‐cell lymphoma (DLBCL) designed to overcome resistance to standard R‐CHOP by combining prolonged exposure of lymphoma cells to cytotoxic agents and dose‐adjustment based on toxicity. Data on outcomes of older patients are scarce. Patients and Methods: We collected data on patients with newly diagnosed high‐risk DLBCL older than 60 years treated with DA‐EPOCH‐R. High‐risk patients were defined by the age‐adjusted international prognostic index score 2 or 3. Results: A total of 120 patients were included. Median age was 69 years (range 60–82). Response rate was 74%; with 59% complete responses. Dose of DA‐EPOCH‐R was escalated in 50 patients (42%). Three‐year progression‐free survival (PFS) and overall survival (OS) was 53% and 58%, respectively, with treatment‐related mortality (TRM) of 13%. In univariate analysis, favorable prognostic factors were performance status (PS) (0–2 vs. 3–4), age (<70 vs. ≥70 years), and center. In multivariate analysis, PS and center retained prognostic significance. Patients with PS 0–2 had 3‐year PFS and OS of 58% and 64%, respectively, with TRM of 6%. Conclusion: DA‐EPOCH‐R is efficacious in sufficiently fit older high‐risk DLBCL patients. Patients with poor PS have unacceptable toxicity and require less intensive therapy. [ABSTRACT FROM AUTHOR]

Comprehensive insights are lacking into why patients with hematological malignancies (HMs) receive no cancer-directed treatment. We evaluated socio-demographic and cancer-related characteristics, decision-making rationales, and overall survival in patients with three common HMs-diffuse large B-cell lymphoma (DLBCL), symptomatic multiple myeloma (MM), and acute myeloid leukemia (AML)-who do not receive cancer-directed treatment, using the nationwide Netherlands Cancer Registry. A total of 26 945 patients diagnosed with DLBCL (47%), symptomatic MM (29%), or AML (25%) between 2014 and 2021 were included. About 16% of the patients did not receive cancer-directed treatment, ranging from 26% in AML to 15% in DLBCL and 10% in MM. The primary reason for not receiving cancer-directed treatment in all three HMs was related to physical condition. The second main reason was patient/family choice in DLBCL and MM, whereas in AML it was rapid disease progression. In female patients, patient/family choice was a more prevalent reason for not receiving cancer-directed treatment than in male patients. Patients with a lower socio-economic position more often did not receive cancer-directed treatment. Median OS varied by reason for not receiving cancer-directed treatment, with the shortest OS in patients experiencing rapid disease progression or death before treatment initiation (0·4 to 0·6 months)., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Both peripherally inserted central catheters (PICCs) and implanted port catheters (PORTs) are commonly used for the delivery of immunochemotherapy. We compared the safety of the two types of devices in a homogeneous and monocentric population of diffuse large B‐cell lymphoma (DLBCL) patients who were treated with first‐line immunochemotherapy by evaluating the numbers of catheter‐related venous thromboses (VTs) and infections that occurred in the six months after implantation according to the type of device. Methods: Using a propensity score, the adjusted relative risk (ARR) between the type of catheter and the occurrence of catheter‐related complications (infection and/or VT) of interest was retrospectively determined. Results: 479 patients were enrolled (266 PORTs/213 PICCs), and 26 VTs (5.4%) and 30 infections (6.3%) were identified in the period following PICC/PORT implantation. The adjusted relative risk (ARR) of catheter‐related complications (infection and/or VT) according to the type of device was 2.6 (95% CI =1.3–5.9, p =.0075). This risk increase associated with the PICC device was significant for both infections (ARR = 3.2; 95% CI = 1.3–10.9) and thrombosis (ARR = 4; 95% CI = 1.5–11.6). Conclusion: Our study supports the preferential use of PORTs for the first line of treatment for DLBCL patients. [ABSTRACT FROM AUTHOR]

Introduction: Pixantrone is a novel aza‐anthracenedione with antineoplastic activity, currently approved for multiply relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), even if real‐life data are limited. Methods: We investigated pixantrone efficacy and safety in clinical practice, as 3rd or 4th line therapy. We retrospectively analyzed a cohort of 37 R/R DLBCL patients managed in 8 Tuscan onco‐hematological centers. Pixantrone, 50 mg/m2, was administered on days 1, 8, 15 of a 28 days cycle for up to 6 cycles. Response to therapy was evaluated according to the Lugano 2014 classification. Results: Pixantrone was administered as 3rd or 4th line in 24/37 (64.9%) and 13/37 (35.1%) cases. Overall response rate and CR rate were 43.2% and 32.4%. After a median follow‐up of 6 months, 17/37 patients (46%) were alive, the main cause of death was progressive disease (14/37 cases, 37.9%). Median PFS was 3 months, median DOR was 17.9 months, and median OS was 9.7 months. A significant proportion of patients achieved a long‐lasting response >12 months (8/37 cases). IPI>2 showed a trend toward inferior PFS. Conclusion: In this real‐life setting, pixantrone demonstrated appreciable efficacy in a population with poor prognosis; in a small proportion of cases, it can be associated with long‐term remission. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B cell lymphoma (DLBCL) is an aggressive disease. The first‐line treatment is well defined in young patients; however, in oldest old patients treatment remains unclear. Objectives: To investigate the impact of therapeutics management and geriatric evaluation on survival in aged patients with DLBCL. Methods: We performed a systematic review of PubMed and COCHRANE databases of published report on elderly patients (median age 80 and above) with DLBCL, from January 2002 to January 2020. Results: We included 32 studies (6 prospective and 26 retrospective). Patients treated with anthracyclines‐containing chemoimmunotherapy had a 2‐year overall survival (OS) of 59%–74.3% in prospective studies and 48.1–64.6% in retrospective studies. With less intensive treatment without anthracyclines, 2‐year OS was 28%–53%. Without specific treatment, median OS was 2 months. History of falls and severe comorbidities were associated with a decreased survival. Conclusions: Chemoimmunotherapy with anthracyclines increases survival in selected very elderly patients in comparison with less intensive regimen. Geriatric assessment, in particular altered mobility disorders and severe comorbidities, is predictive of survival and should be associated with the therapeutic decision. More comparative studies are needed to guide the management of frailer patients. [ABSTRACT FROM AUTHOR]

Introduction: Hypoalbuminemia is a known adverse prognostic factor in lymphomas. Yet, it is unknown if axicabtagene ciloleucel (axi‐cel) overcomes the adverse prognostic impact of hypoalbuminemia in relapsed/refractory large B‐cell lymphoma. Methods: We conducted a retrospective analysis across three Mayo Clinic centers to assess the relationship of hypoalbuminemia (defined as a serum albumin (SA) levels ≤ 3.5 g/dL) on outcomes of patients treated with axi‐cel. Results: This analysis included 81 patients. Two patients had no available SA levels preceding axi‐cel infusion. Eighteen patients (22.8%) had hypoalbuminemia with a median SA of 3.3 g/dL. Patients with normal SA had a statistically higher ORR than those without hypoalbuminemia (P =.018). There was no difference in 1‐year PFS and OS between the group with hypoalbuminemia and the group with normal SA levels (48% vs 49%, P =.81) and (74% vs 73%, P =.97), respectively. There was no difference in the severity or median duration of cytokine release syndrome or neurotoxicity between the two groups. Conclusion: Notwithstanding the limitations related to the relatively small sample size, axi‐cel therapy appears to overcome the adverse effect of hypoalbuminemia on OS and PFS. Large multicenter clinical studies are certainly needed to validate these findings. [ABSTRACT FROM AUTHOR]

We conducted a retrospective study to analyze the prognostic factors impacting the overall survival (OS) and progression‐free survival (PFS) of diffuse large B‐cell lymphoma (DLBCL) patients undergoing first‐line therapy and admitted to intensive care unit (ICU) compared to a control cohort who did not required ICU admission. Between January 1, 2008, and December 31, 2018, 828 patients were diagnosed with DLBCL at our institution, including 72 patients who were required ICU admission during disease course. Among them, forty‐five patients undergoing homogeneous first‐line therapy with /R‐CHOP‐like regimen and ICU‐admitted were selected for the present analysis. Control "non‐ICU" DLBCL patients were matched by age, IPI score and treatment received. The median age at ICU admission was 65 years, 97.8% of patients displayed advanced‐stage disease (III/IV), and 84.4% had a high IPI score (3‐5). The main reasons for ICU admission were acute respiratory failure (40.0%) and septic shock (33.3%). The ICU mortality rate was 33.3%. The 2‐year PFS was lower in ICU survivors patients than in non‐ICU patients: 31.7% (95% CI 18.5‐54.1) vs 60.8% (95% CI 51.2‐72.1, P =.00049). Admission to the ICU is an event that clearly impacts the outcomes of patients with DLBCL, until 2 years after the event. ICU prognosis seems mainly related to critical patient severity at admission rather than lymphoma‐related prognostic factors (IPIs), suggesting that ICU admission criteria should not be based only on the lymphoma prognosis. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R‐mini‐CYVE) in patients with relapsed or refractory B‐cell non–Hodgkin's lymphoma (NHL). Methods: We included pretreated adult patients with B‐cell NHL who were ineligible for high‐dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. Results: Between 2013 and 2019, 56 patients with diffuse large B‐cell lymphoma (n = 45, 80%) and indolent B‐cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36‐88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R‐mini‐CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression‐free survival and overall survival times were 5.7 (95% CI: 0.5‐10.9) and 14.7 (95% CI: 3.5‐25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non‐haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine‐related neurotoxicity (5%). Conclusion: R‐mini‐CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B‐cell NHL who were ineligible for HDT. [ABSTRACT FROM AUTHOR]

Purpose: Previous published data showed an impact of single‐nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B‐cell lymphoma (DLBCL). Patients and Methods: We investigated the role of four VEGF‐A and two VEGFR‐2 gene polymorphisms on the outcome of 273 patients with diffuse large B‐cell lymphoma who were treated with R‐CHOP within a prospective, randomized trial of the German High‐Grade Non‐Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single‐nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control. Results: There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed. Conclusion: Single‐nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL. [ABSTRACT FROM AUTHOR]

Objective: In diffuse large B‐cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R‐CHOP regimen. Methods: The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide‐containing high‐dose regimen (n = 37) and etoposide‐containing frontline treatment (n = 69, R‐CHOEP) were studied using immunohistochemical thioredoxin‐1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin. Results: Thioredoxin‐1 knockdown sensitised DLBCL cells to doxorubicin (P <.0001) but decreased etoposide‐induced cell death (P <.00001). In DLBCL patients who received etoposide‐containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5‐year overall survival (46% vs 76%, P =.026) and disease‐specific survival (68% vs 90%, P =.026). Conclusions: Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R‐CHOP immunochemotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Diffuse large B‐cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%‐40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high‐risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor‐related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. Methods: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R‐CHOP (n = 1327). Results: Five‐years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R‐TS), identifying four different risk groups, with 5‐years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. Conclusions: (a) All variables of the original TS retain an independent prognostic role, and R‐TS remains predictive in the rituximab era; (b) R‐TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets. [ABSTRACT FROM AUTHOR]

Objective: Diffuse large B‐cell lymphoma (DLBCL) can be classified as germinal center B cell–like (GCB) or activated B cell–like (ABC)/non‐GCB based on cell‐of‐origin (COO) classification. This study evaluated the prognostic significance of COO classification in 250 patients diagnosed with de novo DLBCL who received R‐CHOP therapy. We also assessed whether the genomic status of MYC, BCL2, or MYC/BCL2 double expression (DE) could provide additional prognostic information for DLBCL patients. Methods: The clinicopathologic features and outcome of patients with GCB DLBCL were compared to patients with non‐GCB DLBCL using Fisher's exact test. The prognostic significance of COO, MYC‐R, and MYC/BCL2 DE were studied using multivariate Cox proportional hazard analysis. Results: There were 162 men and 88 women with a median age of 62 years (range, 18‐86). Forty‐five of 250 (18%) cases harbored MYC rearrangement (R). The frequency of MYC‐R was much higher in GCB than in non‐GCB tumors (40/165, 24% vs 5/85, 6%) (P =.0001). MYC/BCL2 DE was observed in 53 of 125 (42%) cases. COO classification failed to predict overall survival (OS) in DLBCL patients, either those patients with MYC‐R were included (P =.10) or not (P =.27). In contrast, MYC‐R and MYC/BCL2 DE significantly correlated with inferior OS (P =.0001 and P =.001, respectively). In multivariate analysis, MYC‐R and MYC/BCL2 DE were still independent prognostic factors in DLBCL patients. Conclusions: MYC‐R and MYC/BCL2 DE are independent prognostic factors for DLBCL patients treated with R‐CHOP. In this cohort, COO classification failed to stratify patient outcome. [ABSTRACT FROM AUTHOR]

Objectives: R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard therapy for patients with previously untreated diffuse large B‐cell lymphomas (DLBCL). Dose‐dense two‐weekly 'R‐CHOP‐14' was not superior over three‐weekly 'R‐CHOP‐21' in randomised clinical trials (RCTs). We present real‐world data on effectiveness of R‐CHOP‐14 and R‐CHOP‐21 in patients with DLBCL treated in German routine practice. Methods: We identified 582 patients with DLBCL treated with R‐CHOP‐14 or R‐CHOP‐21 in 92 sites from the prospective clinical cohort study Tumour Registry Lymphatic Neoplasms. Patients' schedules were classified by (a) length of the initial first cycle and (b) length of cycles 1‐4. Results: About 55% of patients received R‐CHOP‐21, 45% R‐CHOP‐14, in median 6 cycles. 51% and 55% of patients, respectively, were able to continue their initial R‐CHOP‐14 and R‐CHOP‐21 schedule. While most characteristics between the patient cohorts were similar, patients receiving R‐CHOP‐21 presented slightly more often with tumour stage I and lower IPI risk. 3‐year overall survival of patients with R‐CHOP‐14 and R‐CHOP‐21 did not differ: 84% vs 84% (first cycle), 87% vs 89% (cycles 1‐4). Conclusions: Patients with DLBCL in Germany are slightly more likely to receive R‐CHOP‐21 than R‐CHOP‐14. Both schedules are similarly effective in routine practice confirming the results from RCTs. [ABSTRACT FROM AUTHOR]

Background: Causality between hepatitis B virus (HBV) infection and diffuse large B‐cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression‐free survival (PFS) in patients with both HBV infection and DLBCL. Methods: In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co‐infection were excluded from this study. We retrospectively analyzed patients' demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti‐HBs, HBeAg, anti‐HBe, and HBV‐DNA) on OS and PFS. Results: The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first‐line therapy, 24 patients (70%) were treated with R‐CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti‐HBe positive patients had a statistically significant better OS and PFS compared with anti‐HBe negative group (both P < .0001). Viremia with HBV‐DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001). Conclusion: High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL. [ABSTRACT FROM AUTHOR]

Objective: Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME). Methods: We used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL. Results: Incidence of EBV‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV‐neg DLBCL (P = 0.018). EBV‐pos tissues had similar expression of T‐cell genes compared to EBV‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 "M2" macrophage score. Conclusion: In EBV‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL. [ABSTRACT FROM AUTHOR]

Purpose: Sinonasal tract diffuse large B‐cell lymphoma (SNT‐DLBCL), a rare extranodal lymphoma, is not well characterized. We performed a population‐based study to determine cell‐of‐origin, clinical presentation and impact of rituximab (R) and central nervous system (CNS) directed chemotherapy on survival. Patients and methods: Patients with SNT‐DLBCL were identified from pathology databases. Clinical information was collected and outcomes between different treatment modalities evaluated. Results: Thirty‐two percent of the patients had germinal centre B‐cell phenotype. Forty‐six patients were treated with curative intent using CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP‐like chemotherapy, 21 (46%) before and 25 (54%) in the R‐era. Additionally, 24 (52%) received CNS‐directed chemotherapy. Addition of R to chemotherapy reduced the risk of progression (RR = 0.368, 95% CI 0.138‐0.976, P = 0.045) and death (RR = 0.245, 95% CI 0.068‐0.883, P = 0.032), and translated into better survival (5‐year PFS, 67% vs 38%, P = 0.037; 5‐year OS, 81% vs 48%, P = 0.020). CNS‐directed chemotherapy reduced the risk of progression (RR = 0.404, 95% CI 0.159‐1.029, P = 0.057) and death (RR = 0.298, 95% CI 0.093‐0.950, P = 0.041), and translated into favorable survival (5‐year PFS, 67% vs 32%, P = 0.050; 5‐year OS 82% vs 43%, P = 0.030). Conclusion: Patients with SNT‐DLBCL benefit from rituximab and CNS‐directed chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives: The GMALL‐B‐ALL/NHL2002 protocol is effective in Burkitt lymphoma/leukemia (BL). Its role in other aggressive lymphomas and in patients with simultaneous central nervous system (CNS) and peripheral involvement is unclear. Methods: This is a retrospective outcome analysis in 76 patients with BL (n = 26), B‐lymphoblastic lymphoma (B‐LBL; n = 3), diffuse large B‐cell lymphoma (DLBCL; n = 31), mantle cell lymphoma (MCL; n = 6), transformed B‐cell non‐Hodgkin lymphomas (tB‐NHL; n = 7), and T‐cell NHL (T‐NHL; n = 3) treated with the GMALL‐B‐ALL/NHL2002 protocol. Results: 73.1% of scheduled chemotherapy cycles were administered. Treatment was discontinued in 38 patients (50.0%) due to progression (n = 14), toxicities (n = 11), scheduled treatment change (n = 6), and unknown reasons (n = 7). All BL/B‐LBL patients were treated first‐line, and at a median follow‐up of 124.7 months, median progression‐free survival was not reached. In DLBCL, median PFS was 68.4 months in first‐line treated patients and 3.7 months in relapsed/refractory patients. CNS involvement was present in 10 non‐BL/B‐LBL cases and did not have a negative impact on survival in first‐line treated patients but was fatal in all relapsed/refractory patients. Conclusion: This study confirmed the activity of the GMALL‐B‐ALL/NHL2002 protocol in BL/B‐LBL. It was also effective in first‐line treated non‐BL/B‐LBL lymphomas with and without simultaneous CNS‐/peripheral involvement, but ineffective in relapsed/refractory disease. [ABSTRACT FROM AUTHOR]

Introduction: PI3K inhibitors are evaluated for relapsed and refractory Diffuse large B-cell lymphoma (DLBCL) patients. Objective: As rituximab has shown to influence B-cell receptor (BCR) signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib. Methods: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib. Results: Rituximab and to a lesser extent obinutuzumab monotherapy resulted in a temporary upregulation of p-Akt, p42/44, and p38 signaling pathways. Idelalisib reduced p-Akt expression. Rituximab antagonized the p-Akt downregula-tion at early time points, while obinutuzumab did not interfere with idelalisib's effects. In cell growth analysis, early antagonism could also be detected. Conclusion: The combination of idelalisib with CD antibodies shows an initial antagonism of rituximab but not obinutuzumab in downregulation of PI3K-signaling targets. [ABSTRACT FROM AUTHOR]

Objective: Many salvage therapies have been proposed for relapsed/refractory (R/R) diffuse large B-cell lymphomas or for consolidation in the case of suboptimal response. Radiotherapy (RT) is one modality of salvage therapy, but its place is currently not well defined. Method: This study reports a retrospective review of patients receiving unplanned radiotherapy for R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL), or as consolidation therapy after second-line chemotherapy, treated in our hospital. Results: Fifty-one patients with a median age of 53.5 years [19-89] were selected. The histologic type was DLBCL in 35 cases (68%), PMBCL in 8 cases (16%), and secondary transformed NHL in 8 cases (16%). Median aaIPI was 1 [0-4], and 17 patients (33%) had a high tumor burden (bulky disease). Sixteen patients (31%) were irradiated for a response considered to be insufficient, 18 patients (36%) were refractory, and 17 patients (33%) had relapsed. Patients were irradiated with a median dose of 40 Gy [15-44], 29 (57%) by a conformal 3D technique and 22 (43%) by tomotherapy. With a median follow-up of 36 months [1.0-127.8] after irradiation, 5-year progression-free survival (PFS) and overall survival (OS) were 62% and 72%, respectively. In multivariate analysis, adverse factors associated with PFS and OS in our cohort were age >70 years (HR = 5.06, P = .02) and post-RT relapse (HR = 12.24, P = .002), whereas favorable factors were number of lines of chemotherapy <3 (HR = 0.02, P = .03) and bulky disease (HR = 0.02, P = .009). Conclusion: Due to its low toxicity and ease of use, radiotherapy should therefore remain an available option in patients with R/R DLBCL or as consolidation therapy in patients with high-risk disease, mostly in patients with chemo-sensitive disease or bulky disease. [ABSTRACT FROM AUTHOR]

Background: During the treatment of diffuse large B-cell lymphoma (DLBCL) patients, treatment-related toxicities are higher in the initial phase of treatment (First cycle effect). Toxicities can be tumor lysis syndrome, deterioration in performance status, febrile neutropenia, and rarely mortality. Prephase treatment before definitive chemotherapy is used in European countries to alleviate these toxicities. Methods: This was a non-randomized study carried out with the aim to evaluate the role of prephase treatment given prior to definitive chemotherapy in newly diagnosed DLBCL patients. Patients were divided into 2 cohorts "prephase cohort" and "non-prephase cohort." Prephase cohort received prephase treatment consisting of vincristine (1 mg) on -6th day and prednisolone 100 mg daily for 7 days (-6th day to day 0). Prephase treatment was followed by CHOP/R-CHOP chemotherapy on day 1. Non-prephase cohort received chemotherapy without prephase. Both groups were followed up for 30 days post-first cycle chemotherapy. Results: A total of 100 patients with DLBCL (50 in each cohort) were enrolled. There was a significant improvement in performance status of the patients who received prephase. A majority of 92% patients attained ECOG performance status of either 0 or 1 before starting chemotherapy in the prephase cohort. Febrile neutropenia was lower (16%) in the prephase cohort as compared with the non-prephase cohort (34%; P = .037). Conclusion: Prephase treatment prior to definitive chemotherapy (CHOP ± Rituximab) improves the performance status and decreases first cycle effect in DLBCL patients. [ABSTRACT FROM AUTHOR]

Objective To examine the influence of anxiety, depression and unmet supportive care needs on future quality of life (QoL) in multiple myeloma ( MM) and diffuse large B-cell lymphoma ( DLBCL) patients. Methods Multiple myeloma and DLBCL patients recruited through the population-based Victorian Cancer Registry. Data were collected through two telephone interviews: (T1) on average 7 months postdiagnosis, (T2) average 8 months later. QoL was examined at T2 using the Functional Assessment of Cancer Therapy ( FACT-G) scale. The Hospital Anxiety and Depression Scale measured anxiety and depression, and the Supportive Care Needs Survey measured unmet needs at T1. Multivariate linear regression examined associations between QoL subscales (physical, emotional, social and functional well-being and overall QoL) and T1 anxiety, depression and unmet needs. Results Except physical well-being, all other QoL subscales and overall QoL were significantly associated with T1 anxiety. All QoL subscales and overall QoL were significantly associated with T1 depression. Only patient care needs were associated with physical and social well-being and overall QoL. Conclusion Anxiety, depression and patient care unmet needs during treatment are associated with diminished physical and emotional well-being in the following months. Psychological distress and unmet supportive care needs experienced during treatment should be addressed to maximise future QoL. [ABSTRACT FROM AUTHOR]

Objectives CD5-positive ( CD5+) diffuse large B-cell lymphoma ( DLBCL) represents 5%-10% of all DLBCL cases, which has been associated with a poorer prognosis in patients treated with R- CHOP. Prognostic impact of CD5 expression in patients with DLBCL treated with R- EPOCH has not been evaluated. Methods We studied 130 patients with de novo DLBCL who received frontline R- EPOCH therapy. The clinicopathologic features and overall survival ( OS) were compared between patients with CD5+ and CD5- DLBCL. MYC, BCL2, and BCL6 rearrangements were examined by fluorescent in situ hybridization. Results Sixteen (12.3%) of 130 DLBCLs were CD5+. Most clinicopathologic features including cell of origin and frequency of MYC, BCL2, and BCL6 rearrangements were similar between CD5+ and CD5− groups. Patients with CD5+ DLBCL, however, showed higher rate of central nervous system relapse (33.3% vs 15.6%; P<.01) and a higher Ki67 proliferative index compared with CD5- patients. The median OS was significantly worse in CD5+ than CD5- patients (28.13 months vs not reached, P=.006). CD5 expression was an independent prognostic factor for OS in multivariate analysis. Conclusions R- EPOCH therapy does not seem to impact the known poorer prognosis of patients with de novo CD5+ DLBCL, and CD5 expression was still an independent prognostic factor in R- EPOCH-treated patients with DLBCL. [ABSTRACT FROM AUTHOR]

Objective The impact of body mass index ( BMI) and body surface area ( BSA) on survival in diffuse large B-cell lymphoma ( DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients. Patients and methods A total of 653 R- CHOP(-like)-treated DLBCL patients were included in this retrospective cohort study. Patients, baseline clinicopathologic characteristics and treatment information were retrieved from the Danish Lymphoma Registry. Anthropometric measures were obtained from chemotherapy prescription charts. Results Underweight ( BMI <18.5 kg/m2) was associated with significantly worse progression-free survival ( PFS) for male patients only in sex-stratified analyses ( HR 3.92, 95% CI: 1.57-9.75, P = 0.003, for males; HR 1.65, 95% CI: 0.90-3.02, P = 0.107, for females). In multivariate analyses, underweight was associated with worse PFS for both sexes ( HR 5.34, 95% CI: 2.07-13.79, P = 0.001, for males; HR 2.14, 95% CI: 1.12-4.08, P = 0.021, for females). Similar results were obtained in analyses of overall survival. In crude analyses, BSA <1.8 m2 was associated with worse PFS for men and women ( HR 1.65, 95% CI: 1.03-2.65, P = 0.039, for men; HR 1.62, 95% CI: 1.03-2.56, P = 0.037, for women). In multivariate analyses, however, these associations diminished. Conclusions Our study demonstrates that underweight DLBCL patients have worse outcomes following R- CHOP as compared to normal as well as overweight patients. [ABSTRACT FROM AUTHOR]

Objective and methods The aim of this study was to investigate the effect of season of diagnosis on the outcome of patients with diffuse large B-cell lymphoma ( DLBCL) and Hodgkin lymphoma ( HL). In this study, we included curatively treated DLBCL ( n = 5875) and HL ( n = 1693) patients, diagnosed between 2000 and 2011, based on data from the Swedish Lymphoma Register. Results Overall survival was significantly better for patients diagnosed with DLBCL during the summer months, but not for patients diagnosed with HL. The difference remained in a multivariable analysis adjusted for age, stage, performance status, number of extra nodal sites and year of diagnosis ( HR 1.08; 95% CI 1.02-1.14, P = 0.0069). When analyzing the DLBCL patients according to gender in the multivariable model, the effect of season was shown to be restricted to male patients ( HR = 1.09, 95% CI 1.01-1.17, P = 0.0269. Conclusions In summary, season of diagnosis was shown to have impact on overall survival in male patients with DLBCL. Possible explanations of our results are the higher vitamin D level during the summer months, the effects of sunlight on the circadian rhythm and the immune system, or the lower risk of infectious disease during the summer. Further investigations are needed to explore these hypotheses. [ABSTRACT FROM AUTHOR]

Central nervous system ( CNS) involvement with diffuse large B-cell lymphoma ( DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks. [ABSTRACT FROM AUTHOR]

Objective DLBCL is a heterogeneous disease with 40% of patients presenting as refractory/relapsing disease following R- CHOP treatment. Few recent studies investigating CD30 expression in DLBCL reported various prognostic effects. This study aimed to evaluate CD30 expression and its correlation with MYC rearrangement and to clarify its prognostic significance in DLBCL. Methods In 98 patients with de novo DLBCL, we studied CD30 expression by immunohistochemistry using different cutoff values (>0%, ≥20%, and ≥40% lymphoma cells, respectively) and correlated with the corresponding MYC rearrangement status by FISH. Results The clinicopathologic features were very similar between the CD30+ and CD30- groups. The only major difference was that CD30 expression was nearly exclusively seen in cases without MYC rearrangement. CD30 expression was not predictive of overall survival irrespective of therapy regimens, cell of origin, or MYC rearrangement status ( P > 0.05). In the 27 patients receiving aggressive regimens, CD30 expression was associated with better OS ( P = 0.008) when all patients were included while the survival advantage was lost ( P = 0.21) if MYC rearranged cases were excluded. Conclusions CD30 expression was not associated with prognosis in our cohort of de novo DLBCL, including in patients who received aggressive chemotherapy. CD30 expression and MYC rearrangement were mutually exclusive in de novo DLBCL. [ABSTRACT FROM AUTHOR]

Central nervous system ( CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma ( DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma ( PCNSL), secondary CNS lymphoma ( sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement ( P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL. [ABSTRACT FROM AUTHOR]

Background: The treatment strategy for diffuse large B-cell lymphoma (DLBCL) in elderly patients is problematic. Although several researchers have reported the effectiveness of comprehensive geriatric assessment (CGA) and the futility of curative treatment in 'unfit' patients with DLBCL, these propositions are not firmly established. Patients and methods: We conducted a retrospective analysis using a database. Patients with DLBCL were eligible if ≧ 60 yr old. CGA stratification was performed using medical records. Results: One hundred and 35 patients were identified. Anthracycline-based chemotherapy with curative intent was performed in 115 (85%) patients. According to CGA, 82 (61%) patients were classified as 'fit'. Their 1-yr overall survival (OS) was significantly better than that of 'unfit' patients [91.3% vs. 53.8%, P < 0.001]. Patients classified as 'unfit' treated with curative intent had a significantly better 1-yr OS when compared with those receiving palliative measures [66.1% vs. 19.0%, P < 0.001]. Conclusions: CGA is an effective tool for predicting outcomes in older patients with DLBCL. The patients treated with curative intent had significantly better outcomes compared with those receiving palliation, irrespective of CGA stratification. Curative treatment should be considered even for 'unfit' patients. [ABSTRACT FROM AUTHOR]

Background: Anemia is frequently identified at the time of diagnosis in patients with diffuse large B-cell lymphoma (DLBCL); however, studies addressing the prognostic significance of this important clinical parameter are lacking. Methods: In this dual-center study of patients with DLBCL (n = 556) treated with rituximab-containing regimens, we evaluated the prognostic relevance of anemia at diagnosis in a training set (n = 211) and validated our findings in a second independent patient cohort (n = 345). Using Kaplan- Meier curves as well as univariate and multivariate Cox regression models, we analyzed the impact of anemia on 5-year overall survival (OS) and 5-year disease-free survival (DFS) alongside established prognostic indicators including age, tumor stage, the revised International Prognostic Index (R-IPI), and the recently published NCCN-IPI. The influence of anemia on the predictive accuracy of IPI, R-IPI, and NCCNIPI prognosis scores was subsequently determined using the Harrell's concordance index. Results: Anemia was an independent predictor of impaired OS and DFS at 5 years in both DLBCL patient cohorts (P < 0.001, log-rank test). In multivariate analysis, hemoglobin level was also a strong and independent prognostic indicator in patients stratified according to R-IPI or NCCN-IPI score. In survival analysis, the estimated concordance index, using IPI, R-IPI, and NCCN-IPI stratification measures (0.69, 0.64, and 0.70, respectively), improved to 0.70, 0.68, and 0.73, respectively, when anemia was also considered. Conclusion: In this study, we have demonstrated that anemia at the time of diagnosis is an independent predictor of impaired clinical outcome in DLBCL. Furthermore, consideration of hemoglobin levels may improve the accuracy of recently established prognostic tools in lymphoma. Our data encourage further evaluation of the prognostic utility of this readily accessible biological parameter in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Objectives Diffuse large B-cell lymphoma ( DLBCL) is an aggressive subtype of non-Hodgkin lymphoma ( NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study ( GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. Methods To evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. Results Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 × 10−10). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 × 10−6), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). Conclusions Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to determine the prognostic value of whole-body maximum standardized uptake value ( SUVmax), whole-body metabolic tumor volume ( MTV), and whole-body total lesion glycolysis ( TLG) at pretreatment 18F-fluoro-2-deoxy- d-glucose positron emission tomography/computed tomography ( FDG- PET/ CT) in patients with newly diagnosed diffuse large B-cell lymphoma ( DLBCL). Materials and Methods Seventy-three patients with newly diagnosed DLBCL who had undergone FDG- PET/ CT before rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R- CHOP) immunochemotherapy were retrospectively included. All FDG-avid lesions in each patient were segmented using semi-automated software to calculate whole-body SUVmax, whole-body MTV, and whole-body TLG values. Cox regression analyses were used to determine the associations of whole-body SUVmax, whole-body MTV, whole-body TLG, and dichotomized National Comprehensive Cancer Network International Prognostic Index ( NCCN- IPI) risk group (low risk vs. high risk) with progression-free survival ( PFS) and overall survival ( OS). Results On univariate Cox regression analysis, only the NCCN- IPI was a significant predictor of PFS ( P = 0.024), and only the NCCN- IPI and whole-body MTV were significant predictors of OS ( P = 0.039 and P = 0.043, respectively). In the multivariate Cox proportional hazards model, only the NCCN- IPI remained an independent predictive factor of PFS ( P = 0.024) and OS ( P = 0.039). Conclusion Whole-body SUVmax, whole-body MTV, and whole-body TLG do not provide any prognostic information in DLBCL beyond that which can already be obtained by the NCCN- IPI. Therefore, the NCCN- IPI remains the most important prognostic tool in this disease. [ABSTRACT FROM AUTHOR]

This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R- CHOP21 in very elderly patients with DLBCL. A prospective, multi-institutional phase II trial was conducted on patients with previously untreated CD20+ DLBCL who were older than 70 yr. Patients were treated with four cycles of R- CHOP21 followed by weekly consolidation with rituximab (375mg/m2, four times infusion) ( NCT01181999). We also compared the clinical outcomes with an historical case-matched control group treated conventionally with six cycles of R- CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013 . The median age was 76 yr (range: 70-89). Forty-one of the 51 patients completed the planned rituximab consolidation (R-consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow-up of 20.3 months, 2-yr progression-free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R- CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL. [ABSTRACT FROM AUTHOR]

Objectives Inherited chromosomally integrated human herpesvirus-6 (ci HHV-6) is characterised by the complete HHV-6 genome integration into the host germ line genome and is vertically transmitted with a Mendelian inheritance. By now, the only relationship between ci HHV-6 and diseases seems to be with angina pectoris. Methods We report a case of an 82-year-old man diagnosed with diffuse large B-cell lymphoma ( DLBCL) on October 2014. To substantiate the suspicion of ci HHV-6, we analysed peripheral blood mononuclear cells, bone marrow biopsy and pleural effusion-derived mesothelial cells with PCR, RT- PCR and FISH. Results Virological routine screening by PCR showed the absence of HHV-8 and EBV infections, while the presence of HHV-6 DNA (ie, U22, U42 and U94 HHV-6 genes), with a viral load of about 1.0 genome per cell, strongly suggests ci HHV-6. The RT- PCR showed the positivity only for the immediate-early U94, at low levels of transcription (100±15 transcripts/1 μg RNA). FISH analysis reported a case of inherited ci HHV-6 in 17p chromosome region and, for the first time, in a marker chromosome. Conclusions This is the first case of inherited ci HHV-6 in a marker chromosome, possibly elucidating the role of this abnormality in the biology of DLBCL. [ABSTRACT FROM AUTHOR]

Introduction The murine double minute 2 ( MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 ( SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. Patients and methods In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Results Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival ( P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients ( P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aa IPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Conclusion Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma ( DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment. [ABSTRACT FROM AUTHOR]

Primary testicular non-Hodgkin lymphoma ( NHL) is a rare entity with the most common histologic subtype consisting of diffuse large B-cell lymphoma ( DLBCL). Patients with primary testicular lymphoma ( PTL) have a poor prognosis and a higher propensity for relapse. Also rare are composite lymphomas ( CL) defined as two or more morphologically and phenotypically distinct lymphomas coexisting in a single organ or tissue. Here we present the first reported case of primary testicular composite lymphoma consisting of DLBCL and mantle cell lymphoma ( MCL). [ABSTRACT FROM AUTHOR]

Objectives A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte/monocyte ratio ( LMR) at diagnosis of diffuse large B-cell lymphoma ( DLBCL). Here, we investigated the significance of LMR in DLBCL patients in relation to advanced age. Methods We examined the prognostic impact of LMR in 603 DLBCL treated with rituximab plus CHOP, using the receiver operating characteristic curve analysis for optimal cut-off values, and performed a subgroup analysis according to age. Results In elderly groups (age ≥ 70), absolute monocyte count was significantly increased, whereas LMR was significantly decreased compared to younger groups. Patients under 70 yr of age with LMR <3.04 had significantly lower overall survival ( OS) and progression-free survival ( PFS) compared to those with LMR ≥3.04 ( P < 0.001 for both). However, in elderly patients (age ≥ 70), there was no significant difference in OS between patients' LMR levels using the 3.04 cut-off value ( P = 0.059). Therefore, a new LMR cut-off value of 2.36 was selected in elderly patients, having observed that elderly patients with LMR <2.36 had significantly lower OS compared to those with LMR ≥2.36 ( P = 0.021). In multivariate analysis, LMR remained a significant prognostic factor for OS ( P = 0.004) or PFS ( P < 0.001). Conclusions We suggest the use of a different cut-off value of LMR in elderly patients to distinguish high-risk from low-risk groups. [ABSTRACT FROM AUTHOR]

Background Expression patterns of micro RNAs in serum are involved in potentially non-invasive biomarkers for various diseases. The purpose of this study is to examine the expression of miR-21 in serum of patients with diffuse large B-cell lymphoma ( DLBCL) and to validate the significance of miR-21 in early diagnosis, genotyping, treatment options as well as its prognosis estimates of Chinese DLBCL. Methods miR-21 expression was detected by fluorescent quantity polymerase chain reaction ( qPCR) in 9 DLBCL cell lines (OCI-Ly1, OCI-Ly3, OCI-Ly4, OCI-Ly7, OCI-Ly8, OCI-Ly10, OCI-Ly18, OCI-Ly19, and HBL), as well as in tumor tissue and serum samples from patients with DLBCL (germinal center B-cell-like ( GCB) DLBCL 32; activated B-cell-like ( ABC) DLBCL 30) and 50 healthy subjects. Results Expression of miR-21 was increased in DLBCL cell lines. Compared with the miR-21 expression of GCB subgroup ( OCI-Ly1, OCI-Ly4, OCI-Ly7, OCI-Ly8, OCI-Ly18, OCI-Ly19), ABC subgroup ( OCI-Ly3, OCI-Ly10, and HBL) has higher expression ( t = 11.18, P < 0.01). Circulating miR-21 level in sera from patients with DLBCLwas associated with matched tumor tissue ( r2 = 0.931, P < 0.0001). Consistent with the in vitro, miR-21 expression levels in serum of patients with DLBCL [21.38(10.26-45.21)] were higher than those in serum of control cases [1.87(1.05-3.97); U = 168, P = 0.000]. Moreover, miR-21 expression levels in serum of patients with subgroup ABC [28.68(14.92~98.44)] were higher than that of patients with subgroup GCB [18.3(7.32~33.46); U = 336, P = 0.043]. miR-21 expression in serum of DLBCL with stage I and II were higher than those in stage III and IV ( U = 62, P = 0.013 in GCB type; U = 53, P = 0.014 in ABC type). Compared with relapse-free survival in patients with DLBCL, high expression of miR-21 was associated with well prognosis ( U = 259, P = 0.035). Conclusion miR-21 expressed in the serum of patients with DLBCL from Chinese was associated with clinical stage, molecular subgroup, and prognosis estimates. miR-21 may be served as a biomarker in early diagnosis, genotyping, treatment options, and prognosis estimating of Chinese DLBCL. [ABSTRACT FROM AUTHOR]

Objectives The tumor microenvironment, including tumor-infiltrating lymphocytes and myeloid-derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear. Methods We evaluated the prognostic impact of the absolute lymphocyte count ( ALC), absolute monocyte count ( AMC), and lymphocyte/monocyte ratio ( LMR) in 359 diffuse large B-cell lymphoma ( DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone ( R- CHOP). Results The median follow-up time of the surviving patients was 58 months. Low ALC and an elevated AMC were both associated with poor survival rates. Receiver operating characteristic curve analysis showed that LMR was the best predictor of survival, with 4.0 as the cutoff point. Patients with LMR ≤4.0 were more likely to have an aggressive tumor, and this was associated with poor treatment responses. Patients with LMR ≤4.0 at diagnosis had significantly poorer overall survival ( OS) and progression-free survival ( PFS) than those with LMR >4.0. Multivariate analysis, which included prognostic factors of the International Prognostic Index, showed LMR ≤4.0 to be an independent predictor for the OS (hazard ratio [ HR], 2.507; 95% confidence interval [ CI], 1.255-5.007; P = 0.009) and PFS ( HR, 2.063; 95% CI, 1.249-3.408; P = 0.005). Conclusions The LMR at diagnosis, as a simple index which reflects host systemic immunity, predicts clinical outcomes in DLBCL patients treated with R- CHOP. [ABSTRACT FROM AUTHOR]

In large B-cell lymphoma ( LBCL) MYC- and MYC/ BCL2 double-hit ( DH) translocations have been associated with inferior survival. We hypothesised that the negative prognostic impact of MYC translocation was determined by an immunoglobulin MYC translocation partner gene ( IG- MYC), as opposed to a non-immunoglobulin partner gene (non IG- MYC). In a prospective, unselected cohort of 237 LBCL patients MYC and BCL2 translocations were identified by Flourescent in situ hybridisation ( FISH) with split probes. MYC translocation partner gene was identified by IGH/ MYC fusion probes and/or kappa/lambda split probes. Clinical data were collected from patient files. MYC translocation was identified in 28/225 patients. IG- MYC translocation partner gene was identified in 12/24 patients. DH translocation was identified in 23/228 patients. IG- MYC translocation partner gene was identified in 9/19 DH patients. Neither MYC-nor DH translocation showed correlation with survival. However, MYC translocation with IG- MYC translocation partner gene was associated with worse OS compared with both MYC translocation with non IG- MYC translocation partner gene ( P = 0.02) as well as absence of MYC translocation ( P = 0.03). In patients with DH a similar, however, stronger correlation was seen ( P = 0.003 and P = 0.0004 respectively). MYC - or DH translocation with non IG- MYC translocation partner gene was not associated with worse overall survival ( P = 0.2 and P = 0.3 respectively). Most patients received Rituximab (86%) and CHOP/ CHOP-like chemotherapy regimes (81%). We suggest that prognostic stratification of LBCL patients by MYC and/or DH translocations should include identification of MYC translocation partner gene because approximately half of the cases harbour non IG- MYC translocation partner genes with no or minor influence on survival. [ABSTRACT FROM AUTHOR]

Objectives The use of new drugs has improved the treatment of multiple myeloma and diffuse large B-cell lymphoma ( DLBCL). Nevertheless, over time many patients relapse and develop resistance to treatment, and efforts are needed to overcome drug resistance. The widely used malaria drug artesunate has been reported to have antitumor activity, and we aimed to test the effects of artesunate on a panel of myeloma and lymphoma cells. Methods Myeloma and DLBCL cell lines were treated with artesunate in vitro. The effects of artesunate treatment were evaluated using ATP content measurements for proliferation and annexin V/propidium iodide labeling for apoptosis. Western blotting was used to look for artesunate-induced protein changes. In addition, we measured artesunate effects on patient myeloma cells in the presence of bone marrow stromal cells. Results Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with downregulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 μ m. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 μ m. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment. Conclusion Our findings indicate that artesunate is a potential drug for treatment of multiple myeloma and DLBCL at doses of the same order as currently in use for treatment of malaria without serious adverse effects. [ABSTRACT FROM AUTHOR]