Follicular lymphoma.

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.

Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies.

We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B-cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r=0·24-0·46, P<0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P<0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P<0·001) in FL. In AML and HL, response to first line therapy was lower in patients with low serum selenium, but selenium was no longer predictive of response when other variables were entered into a multivariate model. Low selenium was also associated with a worse overall survival in FL [Hazard Ratio (HR) 2·3, 95% confidence interval (CI) 1·4, 4·0] and a trend to a worse overall survival in AML (HR 1·43, 95% CI 0·96, 2·13) by univariate Cox regression analysis, but not by multivariate analysis. In conclusion, low serum selenium is associated with a worse outcome in patients with haematological malignancies, but is not independently predictive, suggesting that it reflects other factors.

Chemosensitization of B-cell lymphomas by methylseleninic acid involves nuclear factor-kappaB inhibition and the rapid generation of other selenium species.

Although recent reports suggest that selenium can modulate the activity of cytotoxic drugs, the mechanism underlying this activity remains unclear. This has been investigated using a panel of human B-cell lymphoma cell lines. The cytotoxic effects of chemotherapeutic agents (e.g., doxorubicin, etoposide, 4-hydroperoxycyclophosphamide, melphalan, and 1-beta-d-arabinofuranosylcytosine) were increased by up to 2.5-fold when combined with minimally toxic concentrations (EC(5-10)) of the organic selenium compound, methylseleninic acid (MSA). DNA strand breaks were identified using comet assays, but the measured genotoxic activity of the combinations did not explain the observed synergistic effects in cell death. However, minimally toxic (EC(10)) concentrations of MSA induced a 50% decrease in nuclear factor-kappaB (NF-kappaB) activity after an exposure of 5 h, similar to that obtained with the specific NF-kappaB inhibitor, BAY 11-7082. Combinations of BAY 11-7082 with these cytotoxic drugs also resulted in synergism, suggesting that the chemosensitizing activity of MSA is mediated, at least in part, by its effects on NF-kappaB. Basal intracellular selenium concentration was higher in a MSA-sensitive cell line. After exposure to MSA, methylselenocysteine and selenomethionine were identified as the main intracellular species generated. Volatile selenium species, trapped using solid-phase microextraction fibers, were identified as dimethylselenide and dimethyldiselenide. These volatile species are thought to be the most biologically active forms of selenium. Taken together, these results show that the NF-kappaB pathway is one target for MSA underlying the interaction between MSA and chemotherapy. These data encourage the further clinical development of selenium as a potential modulator of cytotoxic drug activity in B-cell lymphomas.

Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin's lymphoma.

PURPOSE: This study was undertaken to test the hypothesis that serum selenium concentration at presentation correlates with dose delivery, first treatment response, and overall survival in patients with aggressive B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: The patients presented between July 1986 and March 1999 and received anthracycline-based chemotherapy, radiotherapy, or both. The total selenium content was retrospectively analyzed in 100 sera, frozen at presentation, using inductively coupled plasma mass spectrometry. RESULTS: The serum selenium concentration ranged from 0.33 to 1.51 micromol/L (mean, 0.92 micromol/L; United Kingdom adult reference range, 1.07 to 1.88 micromol/L). Serum selenium concentration correlated closely with performance status but with no other clinical variable. Multivariate analysis revealed that increased dose delivery, summarized by an area under the curve, correlated positively with younger age (P <.001), advanced stage (P =.001), and higher serum selenium concentration (P =.032). Selenium level also correlated positively with response (odds ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.90; P =.011) and achievement of long-term remission after first treatment (log-rank test, 4.38; P =.036). On multivariate analysis, selenium concentration was positively predictive of overall survival (hazard ratio [HR], 0.76 for 0.2 micromol/L increase; 95% CI, 0.60 to 0.95; P =.018), whereas age indicated negative borderline significance (HR, 1.09; 95% CI, 0.99 to 1.18; P =.066). CONCLUSION: Serum selenium concentration at presentation is a prognostic factor, predicting positively for dose delivery, treatment response, and long-term survival in aggressive non-Hodgkin's lymphoma. Unlike most existing prognostic factors in aggressive non-Hodgkin's lymphoma, selenium supplementation may offer a novel therapeutic strategy in this frequently curable malignancy.