Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in patients with non-Hodgkin's lymphoma in the United Kingdom (UK)

Introduction: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for prevention of febrile neutropenia (FN) following chemotherapy for non-Hodgkin’s lymphoma (NHL) in the United Kingdom (UK). Methods: A mathematical model was constructed simulating the experience of patients with NHL undergoing chemotherapy. Three strategies were modelled: primary prophylaxis (G-CSFs administered in all cycles); secondary prophylaxis (G-CSFs administered in all cycles following an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim; lenograstim and pegfilgrastim. Costs were taken from UK databases and utility values from published sources with the base case analysis using list prices for G-CSFs and a willingness to pay (WTP) threshold of £20,000 per QALY gained. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. Results: In the base-case analysis the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 22%, secondary prophylaxis with pegfilgrastim for baseline FN risk 8-22%, and no G-CSFs for baseline FN risk less than 8%. Using a WTP threshold of £30,000, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 16%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. Conclusions: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on underlying FN risk level, patient age, and G-CSF price

Consistency between direct trial evidence and Bayesian Mixed Treatment Comparison: Is head-to-head evidence always more reliable?

Objectives: This study aims to highlight the benefits of Bayesian mixed treatment comparison (MTC), within a case study of the efficacy of three treatments (pegfilgrastim, filgrastim and lenograstim) for the prevention of febrile neutropenia (FN) following chemotherapy. Methods: Two published meta-analyses have assessed the relative efficacy of the three treatments based on head-to-head trials. In the present study, all the trials from these meta-analyses were synthesised within a single network in a Bayesian MTC. Following a systematic review, the evidence base was then updated to include further recently-published trials. The metaanalyses and MTC were re-analysed using the updated evidence base. Results: Using data from the previously-published meta-analyses only, the relative risk of FN for pegfilgrastim vs. no treatment was estimated at 0.08 (95% confidence interval: 0.03, 0.18) from the head-to-head trial and 0.27 (95% credible interval: 0.12, 0.60) from the MTC, reflecting strong inconsistency between the results of the direct and indirect methodologies. When subsequently-published head-to-head trials were included, the meta-analysis estimate increased to 0.29 (95% confidence interval: 0.15, 0.55), while the MTC gave a relative risk of 0.34 (95% credible interval: 0.23, 0.54). The initial MTC results were therefore a better predictor of subsequent study results than was the direct trial. The MTC was also able to estimate the probability that there were clinically significant difference in efficacy between the treatments. Conclusions: Bayesian MTC provides clinically relevant information, including a measure of the consistency of direct and indirect evidence. Where inconsistency exists, it should not always be assumed that the direct evidence is more appropriate

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis: systematic review and mixed method treatment comparison

Background This study assesses the efficacy of three granulocyte colony-stimulating factors (G-CSFs; pegfilgrastim, filgrastim and lenograstim) in preventing febrile neutropenia (FN). Methods A systematic review was undertaken. Head-to-head studies were combined using direct meta-analyses. In addition, an indirect Bayesian mixed treatment comparison (MTC) was undertaken to facilitate comparison between G-CSFs where there were no direct trials, and to allow data from all trials to be synthesised into a coherent set of results. Results The review identified the following studies comparing G-CSF prophylaxis to no primary G-CSF prophylaxis: 5 studies of pegfilgrastim, 9 studies of filgrastim and 5 studies of lenograstim. In addition, 5 studies were identified comparing pegfilgrastim to filgrastim. The two synthesis methods (meta-analysis and MTC) demonstrated that all three G-CSFs significantly reduced FN rate. Pegfilgrastim reduced FN rate to a greater extent than filgrastim (significantly in the head-to-head meta-analysis and in the MTC of all studies, and not quite significantly when the MTC was restricted to RCTs only). In the absence of direct trials, the MTC gave an 80-86% probability that pegfilgrastim is superior to lenograstim in preventing FN, and a 71-72% probability that lenograstim is superior to filgrastim. Conclusions Prophylaxis with G-CSFs significantly reduces FN rate. A head-to-head meta-analysis shows pegfilgrastim to be significantly superior to filgrastim in preventing FN events, while an MTC demonstrates that pegfilgrastim is likely to be superior to lenograstim

Consistency between direct trial evidence and Bayesian Mixed Treatment Comparison: Is head-to-head evidence always more reliable?

Objectives This study aims to highlight the benefits of Bayesian mixed treatment comparison (MTC), within a case study of the efficacy of three treatments (pegfilgrastim, filgrastim and lenograstim) for the prevention of febrile neutropenia (FN) following chemotherapy. Methods Two published meta-analyses have assessed the relative efficacy of the three treatments based on head-to-head trials. In the present study, all the trials from these meta-analyses were synthesised within a single network in a Bayesian MTC. Following a systematic review, the evidence base was then updated to include further recently-published trials. The metaanalyses and MTC were re-analysed using the updated evidence base. Results Using data from the previously-published meta-analyses only, the relative risk of FN for pegfilgrastim vs. no treatment was estimated at 0.08 (95% confidence interval: 0.03, 0.18) from the head-to-head trial and 0.27 (95% credible interval: 0.12, 0.60) from the MTC, reflecting strong inconsistency between the results of the direct and indirect methodologies. When subsequently-published head-to-head trials were included, the meta-analysis estimate increased to 0.29 (95% confidence interval: 0.15, 0.55), while the MTC gave a relative risk of 0.34 (95% credible interval: 0.23, 0.54). The initial MTC results were therefore a better predictor of subsequent study results than was the direct trial. The MTC was also able to estimate the probability that there were clinically significant difference in efficacy between the treatments. Conclusions Bayesian MTC provides clinically relevant information, including a measure of the consistency of direct and indirect evidence. Where inconsistency exists, it should not always be assumed that the direct evidence is more appropriate

Granulocyte colony-stimulating factors for prevention of febrile neutropenia following chemotherapy: systematic review and meta-analysis

Background: Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. Methods: A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in preventing FN in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. Results: Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 – 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 – 0.69) for filgrastim, and 0.62 (95% CI: 0.44 – 0.88) for lenograstim. Five studies compared pegfilgrastim with filgrastim; FN incidence was significantly lower for pegfilgrastim than filgrastim, with relative risk 0.66 (95% CI: 0.44 – 0.98). Conclusions: Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim

Active-site protonation states in an Acyl-Enzyme intermediate of a Class A β-Lactamase with a Monobactam Substrate

The monobactam antibiotic aztreonam is used to treat cystic fibrosis patients with chronic pulmonary infections colonized by Pseudomonas aeruginosa strains expressing CTX-M extended-spectrum β-lactamases. The protonation states of active-site residues that are responsible for hydrolysis have been determined previously for the apo form of a CTX-M β-lactamase but not for a monobactam acyl-enzyme intermediate. Here we used neutron and high-resolution X-ray crystallography to probe the mechanism by which CTX-M extended-spectrum β-lactamases hydrolyze monobactam antibiotics. In these first reported structures of a class A β-lactamase in an acyl-enzyme complex with aztreonam, we directly observed most of the hydrogen atoms (as deuterium) within the active site. Although Lys 234 is fully protonated in the acyl intermediate, we found that Lys 73 is neutral. These findings are consistent with Lys 73 being able to serve as a general base during the acylation part of the catalytic mechanism, as previously proposed

Comparison of case note review methods for evaluating quality and safety in health care

Objectives: To determine which of two methods of case note review – holistic (implicit) and criterion-based (explicit) – provides the most useful and reliable information for quality and safety of care, and the level of agreement within and between groups of health-care professionals when they use the two methods to review the same record. To explore the process–outcome relationship between holistic and criterion-based quality-of-care measures and hospital-level outcome indicators. © 2010 Crown Copyrigh

Raman spectroscopy study of NaxCoO2 and superconducting NaxCoO2.yH2O

The Raman spectra of the parent compound NaxCoO2 (x=0.75) and the superconducting oxyhydrates NaxCoO2.yH2O with different superconducting temperatures (Tc) have been measured. Five Raman active phonons around 195 cm-1 (E1g), 482 cm-1, 522 cm-1, 616 cm-1 (3E2g), 663 cm-1 (A1g) appear in all spectra. These spectra change systematically along with the intercalation of H2O and superconducting properties. In particular, the Raman active phonons (A1g and E1g) involving the oxygen motions within the Co-O layers show up monotonous decrease in frequency along with superconducting temperature Tc. The fundamental properties and alternations of other active Raman phonons in the superconducting materials have also been discussed.Comment: 16 pages, 4 figures, 2 table

Single stranded fully Modified-Phosphorothioate oligonucleotides can induce structured nuclear inclusions, alter nuclear protein localization and disturb the transcriptome In Vitro

Oligonucleotides and nucleic acid analogues that alter gene expression are now showing therapeutic promise in human disease. Whilst the modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, such modifications may also confer unexpected physicochemical and biological properties. Gapmer mixed-modified and DNA oligonucleotides on a phosphorothioate backbone can bind non-specifically to intracellular proteins to form a variety of toxic inclusions, driven by the phosphorothioate linkages, but also influenced by the oligonucleotide sequence. Recently, the non-antisense or other off-target effects of 2′ O- fully modified phosphorothioate linkage oligonucleotides are becoming better understood. Here, we report chemistry-specific effects of oligonucleotides composed of modified or unmodified bases, with phosphorothioate linkages, on subnuclear organelles and show altered distribution of nuclear proteins, the appearance of highly stable and strikingly structured nuclear inclusions, and disturbed RNA processing in primary human fibroblasts and other cultured cells. Phosphodiester, phosphorodiamidate morpholino oligomers, and annealed complimentary phosphorothioate oligomer duplexes elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of transfected fibroblasts exhibiting such disruption. Our data add to the growing body of evidence of off-target effects of some phosphorothioate nucleic acid drugs in primary cells and suggest alternative approaches to mitigate these effects

Magnetic resonance for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis

Introduction Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients. Methods Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard. Results Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78–96%; range 65–100%) and mean specificity 90% (95% CI: 75–96%; range 54–100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61–100%) and mean specificity 96% (95% CI: 72–100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78–94%) and mean specificity 73% (95% CI: 63–81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38–86%) and specificity 100% (95% CI: 69–100%). Conclusions USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group