Abstract Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) occurs at diverse anatomic sites and is closely associated with several distinct chronic inflammatory ...disorders. Both the acquired genetic abnormalities and active chronic immunological responses play a critical role in the development of MALT lymphoma, interestingly by dysregulating similar molecular mechanisms. The three translocations seen in MALT lymphoma, namely t(14;18)(q32;q21)/ IGH-MALT1, t(1;14)(p22;q32)/ BCL10-IGH, and t(11;18)(q21;q21)/ BIRC3 ( API2 ) -MALT1 are capable of activating both canonical and non-canonical NF-κB pathways. TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes its negative regulation to several signalling including BCR and TLR, which activate the canonical NF-κB pathway. Similarly, the immunological responses also activate the canonical NF-κB pathway via surface antigen receptor and TLR, and the non-canonical NF-κB pathway by T-cell help and BAFFR. There is also emerging evidence indicating oncogenic cooperation between the above genetic changes and immunological stimulation in the pathogenesis of MALT lymphoma.
Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B ...cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes.
In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II–IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 to a maximum of 2 mg total dose intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1–5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m2 intravenously or 1·6 mg/m2 subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing.
Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0–32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0–74·7 vs 74·3%, 69·3–78·7; hazard ratio 0·86, 95% CI 0·65–1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 87·1% of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths.
This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival.
Janssen-Cilag, Bloodwise, and Cancer Research UK.
Summary Background More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis ...represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. Methods Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5–6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov , number NCT00395200. Findings We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×106 cells per kg bodyweight (range 1·1–2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3–4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change −0·02 logMAR units, 95% CI −0·03 to −0·01; p=0·003) and visual evoked response latency (−1·33 ms, −2·44 to −0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm2 , 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. Interpretation Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. Funding Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.
Background and Aim
Additional simethicone (SIM) can improve adequate bowel preparation and adenoma detection rate (ADR). However, there is no consensus on the optimal dose of SIM. In this study, we ...compared the adequate bowel preparation rate with supplementation of split‐dose 2 L polyethylene glycol (PEG) with low‐dose SIM (200 mg) versus high‐dose SIM (1200 mg).
Methods
This was a prospective, randomized, observer‐blinded trial involving consecutive subjects undergoing colonoscopy. The primary outcome was adequate bowel preparation as assessed by Boston Bowel Preparation Scale (BBPS) score.
Results
Four hundred subjects were randomly allocated to low‐dose SIM or high‐dose SIM group. Baseline characteristics were comparable in the two groups (P > 0.05). No significant between‐group differences were observed with respect to total bubble scale (BS) (8.49 ± 1.00 vs 8.39 ± 1.10, P = 0.07), total BBPS score (8.70 ± 0.81 vs 8.29 ± 1.18, P = 0.98), ADR (33.68% vs 31.79%, P = 0.69) or withdrawal time (13 range, 10–16 min vs 13 10–15 min, P = 0.96). The intubation time in low‐dose SIM group was significantly shorter than that in high‐dose SIM group (8 (4–16) min vs 10 6–17 min, P = 0.04). In addition, BS scores as well as diminutive ADR in right colon were superior in the low‐dose SIM group (2.68 ± 0.59 vs 2.52 ± 0.73, P = 0.03 and 54.29% vs 30.30%, P = 0.046, respectively).
Conclusion
Addition of low‐dose SIM to split‐dose 2 L PEG was as effective as addition of high‐dose SIM with respect to adequate bowel preparation, ADR and patient tolerance. However, low‐dose SIM was superior with respect to intubation time, right colon BS scores, right colon diminutive ADR and cost savings.
During the long-term operation of solid oxide electrolysis cell (SOEC), the coarsening and depletion of the Ni phase of the electrode are found to decrease the cell performance and limit cell ...durability. In this study, a comprehensive numerical study is conducted to quantitatively evaluate the degradation process in the fuel electrode of SOEC. The phase-field model is adopted to track the Ni phase migration process and generate the electrode structures with Ni depletion. An electrode model based on the lattice Boltzmann method is then used to evaluate the electrochemical performance of the fuel electrode. It is found that the maximum width of the Ni depletion region can reach 3–4 μm. The Ni depletion will aggravate the coarsening of the Ni phase. The corresponding electrochemical evaluation also shows that the randomly distributed ionic particles in the porous fuel electrode lengthens the ion transport path and increases the electrode ohmic overpotential. The Ni depletion also increases the activation overpotential loss due to the reduction of the active reaction sites. The severe Ni depletion can increase the total overpotential by up to 52.8% compared to the initial state. Besides, increasing the wettability of the Ni phase can effectively suppress the reduction of active reaction sites due to Ni coarsening.
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•An integrated model for quantifying the Ni migration of SOEC is established.•The effects of Ni depletion on performance degradation are clarified.•The severe Ni depletion can increase the total overpotential by up to 52.8%.
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