BackgroundDiffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL.Methodology/Principal FindingsIn the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75NTR/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab.Conclusions/SignificanceCollectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.

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Secondary Progressive multiple sclerosis (SPMS) is a common form of MS with few approved and effective therapies. Previous studies of therapeutic plasma exchange (PLEX) in SPMS have reported mixed results. The purpose of this study was to evaluate long-term efficacy and safety of PLEX in SPMS. We retrospectively analyzed 25 years of PLEX therapy in SPMS to identify improvements in disease progression and disability as well as potential predictors of therapeutic success. Using 271 patients, we show a significant improvement in Expanded Disability Status Scale (EDSS) lasting for at least three years following a course of PLEX. Furthermore, disability remained significantly improved or stabilized for seven years post-PLEX. Patients with continued and measureable disability worsening in the previous three years are more apt to improve with PLEX. A small number of patients (N=42) for whom PLEX was considered but denied by their insurance carriers, and who therefore received other treatments, were also followed over the 25 year period. Progression of disability in this group was significantly worse when compared with PLEX group. No major problems occurred during 8709 PLEX procedures. Peripheral vascular access (venous or arterial) was utilized to avoid complications related to central line placement.Because of the paucity of beneficial therapeutic interventions in SPMS and the relative safety and efficacy of long-term PLEX, this therapy should be considered in this form of MS.