The potential therapeutic role of selenium in diffuse large B-cell lymphoma

PhDThe clinical background to this work confirms the very poor outcome of patients with recurrent diffuse large B-cell lymphoma (DLBCL) and highlights the need for better therapies. One such potential option would be to add selenium (Se) to conventional chemotherapy. Previous work has demonstrated the ability of non-toxic concentrations of Se to sensitise DLBCL cell lines to chemotherapy and to protect normal cells from chemotherapy-induced toxicity. The aims of this study were therefore to identify mechanisms of Se action and potential biomarkers of Se activity. The form of Se used was methylseleninic acid (MSA), a precursor of methylselenol, which is the metabolite thought to be responsible for the anti-tumour effects of organic Se compounds. DLBCL cell lines differed in their sensitivity to MSA, which may relate to differences in intracellular glutathione depletion by MSA. MSA sensitivity, however, was not related to the induction of DNA damage or to the p53 status of lymphoma cell lines. Although cytotoxic concentrations of MSA induced apoptosis, chemo-sensitising concentrations did not enhance apoptosis or alter pro-apoptotic pathways. MSA induced endoplasmic reticulum (ER) stress in a concentration-dependent manner, however, in an MSA-resistant cell line, this led to autophagy and cell survival. Thus, ER stress induction is not a mechanism of chemo-sensitisation. MSA inhibited HDAC activity in DLBCL cell lines but only in a cell-based assay, suggesting that a metabolite of MSA is responsible for this effect. In addition, MSA inhibited the hypoxia-induced induction of HIF-1α in DLBCL cell lines. Peripheral blood mononuclear cells (PBMCs) were relatively resistant to MSA and this was associated with increased expression of two pro-survival proteins, GRP78 and NF-κB. In addition, the metabolism of MSA differed between PBMCs and DLBCL cell lines, suggesting that methylselenol is formed more efficiently in the latter. In contrast, keratinocytes and fibroblasts were relatively sensitive to MSA, but MSA was unable to protect keratinocytes from the toxicity of chemotherapeutic agents. These results differ 3 from those obtained in DLBCL cell lines in which MSA enhances the activity of chemotherapeutic agents. Combining MSA and bortezomib in mantle cell lymphoma cell lines unexpectedly resulted in an antagonistic interaction. This was associated with the induction of ER stress and autophagy and increased expression of two pro-survival proteins, Bcl-2 and Mcl-1. A proteomics approach identified novel protein changes induced by chemo-sensitising concentrations of MSA in two DLBCL cell lines. Several potential biomarkers of Se activity were identified; GRP78, NF-κB, vascular endothelial growth factor and acetylated histone H3. In conclusion, Se in the form of MSA affects many intracellular pathways in DLBCL cell lines, such that it has not been possible to identify a single unifying mechanism of Se action. However, differences have been observed between PBMCs and DLBCL cell lines and this work has identified novel protein changes and mechanisms of Se actionKatherine Priestly Trust Fund Medical reseach Counci

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

Introduction: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicentre observational study evaluating bendamustine toxicity in real-world practice. Methods: Patients receiving at least one dose of bendamustine (B) +/- rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details and grade 3-5 adverse events (AEs) were analysed. Results: 323 patients were enrolled from 9 NHS hospitals. Most patients (96%) received BR and 46% R maintenance. 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%), and the relative risk highest during maintenance (54%), induction (34%) and follow-up (28%). Toxicity led to permanent treatment discontinuation in 13% of patients, and 2.8% died of bendamustine-related infections (n=5), myelodysplastic syndrome (n=3), and cardiac disease (n=1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor pre-induction PS, poor pre-maintenance PS, abnormal pre-induction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3/10 opportunistic infections occurred despite prophylaxis. Conclusion: In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to trial populations of younger, fitter patients. Poor PS, mantle cell histology and maintenance rituximab were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death warranting extended antimicrobial prophylaxis and infectious surveillance, especially in maintenance-treated patients

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Outpatient management of steroid-induced hyperglycaemia and steroid-induced diabetes in people with lymphoproliferative disorders treated with intermittent high dose steroids

High dose steroids (HDS) are used in the treatment of haematological malignancies. The reported risk of steroid-induced diabetes (SID) is high. However, screening is not consistently performed. We implemented a protocol for detection and management of SID and steroid-induced hyperglycamia (SIH) in haematology outpatients receiving HDS. Eighty-three people were diagnosed with a lymphoproliferative disorder, of whom 6 had known Type 2 diabetes. Fifty-three people without known diabetes were screened by HbA1c and random venous plasma glucose. All patients (n = 34) subsequently prescribed HDS checked capillary blood glucose (CBG) pre-breakfast and pre-evening meal. Treatment algorithms used initiation and/or dose titration of gliclazide or human NPH insulin, aiming for pre-meal CBG 5–11 mmol/l. Type 2 diabetes was identified in 4/53 people screened (7.5%). Of 34 people treated with HDS, 17 (44%) developed SIH/SID. All 7 people with Type 2 diabetes developed SIH and 3 required insulin. Of 27 people without known diabetes, 8 (30%) developed SID and 1 required insulin. Pre-treatment HbA1c was higher in people who developed SID compared to those that did not (p = 0.002). This is the first report of a SID/SIH detection and treatment protocol for use in people with lymphoproliferative disorders receiving intermittent HDS, demonstrating its feasibility and safety