Overall survival in the UK in mycosis fungoides or Sézary syndrome cutaneous T-cell lymphoma: comparative effectiveness of mogamulizumab versus current standard of care.

Aim: Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with patients with previously treated advanced mycosis fungoides/Sézary syndrome (MF/SS) in real-world setting. Design, setting & participants: Data were from the Hospital Episode Statistics database (all patients in NHS secondary care system in 2009-2019). Patients were selected according to trial inclusion criteria, then trial and HES samples were matched on selected variables with significant imbalance. Outcomes: The analysis indicated significant improvement in OS for mogamulizumab treatment compared with UK clinical practice (hazard ratio: 0.36, 95% CI: 0.24, 0.53). Conclusion: Results suggest an OS advantage for patients with advanced MF/SS treated with mogamulizumab in MAVORIC trial compared with UK clinical practice.

Cost-utility analysis of mogamulizumab in advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma.

Aim: This study assessed the cost-utility of mogamulizumab, a novel monoclonal antibody, versus established clinical management (ECM) in UK patients in previously treated advanced mycosis fungoides (MF)/Sézary syndrome (SS). Materials & methods: Lifetime partitioned survival model based on overall survival, next treatment-free survival and the use of allogeneic stem cell transplant was developed. Inputs were from the pivotal MAVORIC trial, real-world evidence and published literature. Extensive sensitivity analyses were conducted. Results: Discounted incremental quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio were 3.08, £86,998 and £28,233. Results were most sensitive to the survival extrapolations, utilities and costs after loss of disease control. Conclusion: Mogamulizumab is a cost-effective alternative to ECM in UK patients with previously treated advanced MF/SS.

Adjusting for treatment crossover in the MAVORIC trial: survival in advanced mycosis fungoides and Sézary syndrome.

Background: Relative overall survival (OS) estimates reported in the MAVORIC trial are potentially confounded by a high proportion of patients randomized to vorinostat switching to mogamulizumab; furthermore, vorinostat is not used in clinical practice in the UK. Methods: Three methods were considered for crossover adjustment. Survival post-crossover adjustment was compared with data from the Hospital Episode Statistics (HES) to contextualize estimates. Results: Following adjustment, the OS hazard ratio for mogamulizumab versus vorinostat was 0.42 (95% CI: 0.18, 0.98) using the method considered most appropriate based on an assessment of assumptions and comparison with HES. Conclusions: OS of mogamulizumab relative to vorinostat may be underestimated in MAVORIC due to the presence of crossover. The HES database was used to validate this adjustment.

Health state utilities associated with caring for an individual with cutaneous T-cell lymphoma (CTCL).

AIM: Cutaneous T-cell Lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma characterized by skin lesions, which can negatively impact the quality of life of both patients and their caregivers. The Decision Support Unit (DSU) at the National Institute for Health and Care Excellence (NICE) in the UK recently outlined a rationale for the inclusion of caregiver burden in economic evaluations. This study aimed to estimate utilities for health states associated with being a caregiver for an individual with CTCL at different stages of treatment. MATERIALS AND METHODS: A targeted literature review and interviews with CTCL specialists informed the development of health state vignettes describing the experience caring for an individual with CTCL. The vignettes were evaluated in interviews with the UK general population using a visual analogue scale (VAS), the time trade-off (TTO) method and the EQ-5D-5L. RESULTS: Four vignettes were developed describing the caregiver experience for an individual with CTCL on i) second line treatment, ii) third line treatment, iii) end of life care, iv) a post-patient death. One hundred interviews were conducted to evaluate the health state vignettes. The pattern of results was similar across the evaluation methods: second line treatment (VAS: 39.2, TTO = 0.52, EQ-5D-5L: 0.56), third line treatment (VAS: 31.1, TTO = 0.39, EQ-5D-5L: 0.37), end of life care (VAS: 28.2, TTO = 0.37, EQ-5D-5L: 0.31) and post-patient death (VAS: 41.2, TTO = 0.63, EQ-5D-5L: 0.59). Limitations and conclusions: These findings highlight the substantial burden of caring for an individual with CTCL and the importance of including caregiver burden in the health technology assessment review process. A limitation is the hypothetical vignette approach, which meant the TTO participants did not have experience of caring for individuals with CTCL, but were imagining this state. There is also the possibility that they may also be considering the patient experience when responding to the questions.

Modulation of eIF5A1 expression alters xylem abundance in Arabidopsis thaliana.

Eukaryotic translation initiation factor 5A (eIF5A) is thought to facilitate protein synthesis by participating in the nuclear export of specific mRNAs. In Arabidopsis, there are three isoforms of eIF5A. One of them, AteIF5A1, has been shown to be expressed in vascular tissue, specifically developing vessel members, using GUS as a reporter. In order to determine whether AteIF5A1 plays a role in xylem formation, its full-length cDNA was constitutively over-expressed in transgenic Arabidopsis plants. Microscopic analysis revealed that the cross-sectional area of the xylem in the main inflorescence stems of transgenic plants was 1.9-fold higher than those of corresponding inflorescence stems of wild-type plants. In wild-type stems, the primary xylem typically comprised six cell layers and was approximately 105 mum thick, but increased to 9-11 cell layers, 140-155 mum thick, in transgenic stems. Similarly, the secondary xylem increased from six cell layers, approximately 70 mum thick, in control stems to approximately 9 cell layers, 95-105 mum thick, in transgenic stems. Moreover, constitutive down-regulation of AteIF5A1 using antisense technology resulted in the major suppression of xylem formation compared with control plants, and the antisense transgenic plants were also stunted. These data collectively indicate that eIF5A1 plays a role in xylogenesis.

Regulation and execution of molecular disassembly and catabolism during senescence.

Senescence is a highly orchestrated developmental stage in the life cycle of plants. The onset of senescence is tightly controlled by signaling cascades that initiate changes in gene expression and the synthesis of new proteins. This complement of new proteins includes hydrolytic enzymes capable of executing catabolism of macromolecules, which in turn sets in motion disassembly of membrane molecular matrices, leading to loss of cell function and, ultimately, complete breakdown of cellular ultrastructure. A distinguishing feature of senescence that sets it apart from other types of programmed cell death is the recovery of carbon and nitrogen from the dying tissue and their translocation to growing parts of the plant such as developing seeds. For this to be accomplished, the initiation of senescence and its execution have to be meticulously regulated. For example, the initiation of membrane disassembly has to be intricately linked with the recruitment of nutrients because their ensuing translocation out of the senescing tissue requires functional membranes. Molecular mechanisms underlying this linkage and its integration with the catabolism of macromolecules in senescing tissues are addressed.

Characterization of a plastid triacylglycerol lipase from Arabidopsis.

Full-length cDNA corresponding to Arabidopsis (Arabidopsis thaliana) gene At2g31690, which has been annotated in GenBank as a putative triacylglycerol (TAG) lipase, was obtained by reverse transcription-polymerase chain reaction using RNA from senescing rosette leaves of Arabidopsis as a template. The cognate protein was found to contain the lipase active site sequence, and corresponding recombinant protein proved capable of deesterifying TAG. In vitro chloroplast import assays indicated that the lipase is targeted to chloroplasts. This was confirmed by confocal microscopy of rosette leaf tissue treated with fluorescein isocyanate-labeled, lipase-specific antibody, which revealed that lipase protein colocalizes with plastoglobular neutral lipids. Western-blot analysis indicated that the lipase is expressed in roots, inflorescence stems, flowers, siliques, and leaves and that it is strongly up-regulated in senescing rosette leaf tissue. Transgenic plants with suppressed lipase protein levels were obtained by expressing At2g31690 cDNA in antisense orientation under the regulation of a constitutive promoter. Transgenic plants bolted and flowered at the same time as wild-type plants, but were severely stunted and exhibited delayed rosette senescence. Moreover, the stunted growth phenotype correlated with irregular chloroplast morphology. The chloroplasts of transgenic plants were structurally deformed, had reduced abundance of thylakoids that were abnormally stacked, and contained more plastoglobular neutral lipids than chloroplasts of wild-type plants. These observations collectively indicate that this TAG lipase plays a role in maintaining the structural integrity of chloroplasts, possibly by mobilizing the fatty acids of plastoglobular TAG.

Seat inclinations affect the function of children with cerebral palsy: a review of the effect of different seat inclines.

PURPOSE: An evaluation of the current research evaluating the impact of seat inclinations upon postural control, muscle activity and upper extremity function in children with cerebral palsy. METHOD: A literature review searching 13 electronic databases was undertaken. Inclusion criteria were applied to abstracts found; full text research articles were retrieved and a critical review of the eligible articles completed. RESULTS: Ten studies were reviewed which investigated the effect of seat inclinations. Improved postural control and a reduction in pathological movements were achieved in anterior tilt; reduced postural sway was evident for children with spastic cerebral palsy sitting on anterior incline, and increased sway for those with hypotonia; extensor thrust was evoked when in posterior incline; and there was evidence of improved arm and hand function whilst seated in the functional sitting position as opposed a posterior seat incline. CONCLUSIONS: (i) The current literature is inconclusive, however there are indications that neutral and anterior seat inclines do positively affect function for children with cerebral palsy; (ii) Individual assessment of seating ability and need is advocated for these children rather than the adoption of a universal seat incline.