Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Phase transition in malonic acid: An infrared study

Malonic acid is shown to undergo an interesting phase transition at 360 K when the two non-equivalent cyclic hydrogen-bonded dimers present in the low-temperature phase become equivalent.

Liquid phase oxidation of propionaldehyde: Kinetics of initiation step

A method of determining the rate of the initiation reaction in the liquid phase oxidation of propionaldehyde is described.

High frequency fire alters C:N:P stoichiometry in forest litter

Fire is a major driver of ecosystem change and can disproportionately affect the cycling of different nutrients. Thus, a stoichiometric approach to investigate the relationships between nutrient availability and microbial resource use during decomposition is likely to provide insight into the effects of fire on ecosystem functioning. We conducted a field litter bag experiment to investigate the long-term impact of repeated fire on the stoichiometry of leaf litter C, N and P pools, and nutrient-acquiring enzyme activities during decomposition in a wet sclerophyll eucalypt forest in Queensland, Australia. Fire frequency treatments have been maintained since 1972, including burning every two years (2yrB), burning every four years (4yrB) and no burning (NB). C:N ratios in freshly fallen litter were 29-42% higher and C:P ratios were 6-25% lower for 2yrB than NB during decomposition, with correspondingly lower 2yrB N:P ratios (27-32) than for NB (34-49). Trends in litter soluble and microbial N:P ratios were similar to the overall litter N:P ratios across fire treatments. Consistent with these, the ratio of activities for N-acquiring to P-acquiring enzymes in litter was higher for 2yrB than NB while 4yrB was generally intermediate between 2yrB and NB. Decomposition rates of freshly fallen litter were significantly lower for 2yrB (72±2% mass remaining at the end of experiment) than for 4yrB (59±3%) and NB (62±3%), a difference that may be related to effects of N limitation, lower moisture content, and/or litter C quality. Results for older mixed-age litter were similar to those for freshly fallen litter although treatment differences were less pronounced. Overall, these findings show that frequent fire (2yrB) decoupled N and P cycling, as manifested in litter C:N:P stoichiometry and in microbial biomass N:P ratio and enzymatic activities. These data indicate that fire induced a transient shift to N-limited ecosystem conditions during the post-fire recovery phase. This article is protected by copyright. All rights reserved.

Control by glyphosate and its alternatives of glyphosate-susceptible and glyphosate-resistant Echinochloa colona in the fallow phase of crop rotations in subtropical Australia

Echinochloa colona is the most common grass weed of summer fallows in the grain-cropping systems of the subtropical region of Australia. Glyphosate is the most commonly used herbicide for summer grass control in fallows in this region. The world's first population of glyphosate-resistant E. colona was confirmed in Australia in 2007 and, since then, >70 populations have been confirmed to be resistant in the subtropical region. The efficacy of alternative herbicides on glyphosate-susceptible populations was evaluated in three field experiments and on both glyphosate-susceptible and glyphosate-resistant populations in two pot experiments. The treatments were knockdown and pre-emergence herbicides that were applied as a single application (alone or in a mixture) or as part of a sequential application to weeds at different growth stages. Glyphosate at 720 g ai ha−1 provided good control of small glyphosate-susceptible plants (pre- to early tillering), but was not always effective on larger susceptible plants. Paraquat was effective and the most reliable when applied at 500 g ai ha−1 on small plants, irrespective of the glyphosate resistance status. The sequential application of glyphosate followed by paraquat provided 96–100% control across all experiments, irrespective of the growth stage, and the addition of metolachlor and metolachlor + atrazine to glyphosate or paraquat significantly reduced subsequent emergence. Herbicide treatments have been identified that provide excellent control of small E. colona plants, irrespective of their glyphosate resistance status. These tactics of knockdown herbicides, sequential applications and pre-emergence herbicides should be incorporated into an integrated weed management strategy in order to greatly improve E. colona control, reduce seed production by the sprayed survivors and to minimize the risk of the further development of glyphosate resistance.

A phase space approach to generalized Hamilton–Jacobi theory

Generalizations of H–J theory have been discussed before in the literature. The present approach differs from others in that it employs geometrical ideas on phase space and classical transformation theory to derive the basic equations. The relation between constants of motion and symmetries of the generalized H–J equations is then clarified. Journal of Mathematical Physics is copyrighted by The American Institute of Physics.

Controlling Pythium in Ginger: Phase 2

The fungal disease Pythium Soft Rot is regarded by the ginger industry as their most serious disease threat. This project was developed to further investigate the factors contributing to the persistence and spread of Pythium Soft Rot on ginger farms and to identify measures for their control. The study demonstrated that the pathogen capable of causing Pythium Soft Rot in ginger was spread in contaminated ‘seed’, soil and water and that it can be managed through a combination of strategies that rely on early detection, reducing pathogen levels in soils, preventing water logging and restricting movement of contaminated ‘seed’, soil and water. However, in order to have an effective level of control, all strategies need to be integrated in an effective manner.

Structural phase transition study of the morphotropic phase boundary compositions of Na0.5Bi0.5TiO3-PbTiO3

Neutron, synchrotron x-ray powder diffraction and dielectric studies have been performed for morphotropic phase boundary (MPB) compositions of the (1 - x )Na1/2Bi1/2TiO3-xPbTiO(3) system. At room temperature, the MPB compositions (0.10 < x <= 0.15) consist of a mixture of rhombohedral (space group R3c) and tetragonal ( space group P4mm) structures with the fraction of tetragonal phase increasing with increasing PbTiO3 content. On heating, while the rhombohedral phase just outside the MPB region, i.e. x = 0.10, transforms directly to a cubic phase, the rhombohedral phase of the MPB compositions transforms gradually to a tetragonal phase, until interrupted by a rhombohedral-cubic phase transition. The correspondence of the dielectric anomalies with the structural transitions of the different compositions has been examined and compared with earlier reports.

Computational studies on new chemical species in the gas-phase and the solid-state.

There is intense activity in the area of theoretical chemistry of gold. It is now possible to predict new molecular species, and more recently, solids by combining relativistic methodology with isoelectronic thinking. In this thesis we predict a series of solid sheet-type crystals for Group-11 cyanides, MCN (M=Cu, Ag, Au), and Group-2 and 12 carbides MC2 (M=Be-Ba, Zn-Hg). The idea of sheets is then extended to nanostrips which can be bent to nanorings. The bending energies and deformation frequencies can be systematized by treating these molecules as an elastic bodies. In these species Au atoms act as an 'intermolecular glue'. Further suggested molecular species are the new uncongested aurocarbons, and the neutral Au_nHg_m clusters. Many of the suggested species are expected to be stabilized by aurophilic interactions. We also estimate the MP2 basis-set limit of the aurophilicity for the model compounds [ClAuPH_3]_2 and [P(AuPH_3)_4]^+. Beside investigating the size of the basis-set applied, our research confirms that the 19-VE TZVP+2f level, used a decade ago, already produced 74 % of the present aurophilic attraction energy for the [ClAuPH_3]_2 dimer. Likewise we verify the preferred C4v structure for the [P(AuPH_3)_4]^+ cation at the MP2 level. We also perform the first calculation on model aurophilic systems using the SCS-MP2 method and compare the results to high-accuracy CCSD(T) ones. The recently obtained high-resolution microwave spectra on MCN molecules (M=Cu, Ag, Au) provide an excellent testing ground for quantum chemistry. MP2 or CCSD(T) calculations, correlating all 19 valence electrons of Au and including BSSE and SO corrections, are able to give bond lengths to 0.6 pm, or better. Our calculated vibrational frequencies are expected to be better than the currently available experimental estimates. Qualitative evidence for multiple Au-C bonding in triatomic AuCN is also found.

Association between feline immunodeficiency virus (FIV) plasma viral RNA load, concentration of acute phase proteins and disease severity

Veterinarians have few tools to predict the rate of disease progression in FIV-infected cats. In contrast, in HIV infection, plasma viral RNA load and acute phase protein concentrations are commonly used as predictors of disease progression. This study evaluated these predictors in cats naturally infected with FIV. In older cats (>5 years), log10 FIV RNA load was higher in the terminal stages of disease compared to the asymptomatic stage. There was a significant association between log10 FIV RNA load and both log10 serum amyloid A concentration and age in unwell FIV-infected cats. This study suggests that viral RNA load and serum amyloid A warrant further investigation as predictors of disease status and prognosis in FIV-infected cats.

Kinetics of vapour phase oxidation of furfural on vanadium catalyst

Vapour phase oxidation of furfural over vanadium pentoxide catalyst was studied using an isothermal flow reactor in the temperature range of 220–280°C. Maleic anhydride and carbon dioxide are found to be formed from furfural by a parallel reaction scheme. The following rate equation based on the two-stage redox mechanism—the substance to be oxidized reduces the catalyst which in turn is reoxidized by oxygen from the feed—is found to explain the data satisfactorily.The reoxidation of the reduced catalyst was found to be the rate controlling step.

Mechanism of vapour phase oxidation of anthracene over cobalt molybdate catalyst

Vapour phase oxidation of anthracene over cobalt molybdate catalyst was investigated in an isothermal flow reactor in the temperature range of 280—340°C. Fifteen different models based on redox, Langmuir—Hinshelwood and Rideal mechanisms were tested in order to elucidate the mechanism of the above reaction. These models were compared on the basis of three criteria and were finally discriminated employing the non-intrinsic parameter method. Two-stage redox mechanism was found to explain the data satisfactorily.

Barium hexaferrite (M-phase) exhibiting superstructure

Barium hexaferrite (M-phase) prepared by the flux method is found to exhibit \checkmark 3 \ut \times \checkmark 3 \ut superstructure similar to barium hexaaluminate.

Impact of nitrification inhibitor (DMPP) on soil nitrous oxide emissions from an intensive broccoli production system in sub-tropical Australia

Vegetable cropping systems are often characterised by high inputs of nitrogen fertiliser. Elevated emissions of nitrous oxide (N2O) can be expected as a consequence. In order to mitigate N2O emissions from fertilised agricultural fields, the use of nitrification inhibitors, in combination with ammonium based fertilisers, has been promoted. However, no data is currently available on the use of nitrification inhibitors in sub-tropical vegetable systems. A field experiment was conducted to investigate the effect of the nitrification inhibitor 3,4-dimethylpyrazole phosphate (DMPP) on N2O emissions and yield from broccoli production in sub-tropical Australia. Soil N2O fluxes were monitored continuously (3 h sampling frequency) with fully automated, pneumatically operated measuring chambers linked to a sampling control system and a gas chromatograph. Cumulative N2O emissions over the 5 month observation period amounted to 298 g-N/ha, 324 g-N/ha, 411 g-N/ha and 463 g-N/ha in the conventional fertiliser (CONV), the DMPP treatment (DMPP), the DMMP treatment with a 10% reduced fertiliser rate (DMPP-red) and the zero fertiliser (0N), respectively. The temporal variation of N2O fluxes showed only low emissions over the broccoli cropping phase, but significantly elevated emissions were observed in all treatments following broccoli residues being incorporated into the soil. Overall 70–90% of the total emissions occurred in this 5 weeks fallow phase. There was a significant inhibition effect of DMPP on N2O emissions and soil mineral N content over the broccoli cropping phase where the application of DMPP reduced N2O emissions by 75% compared to the standard practice. However, there was no statistical difference between the treatments during the fallow phase or when the whole season was considered. This study shows that DMPP has the potential to reduce N2O emissions from intensive vegetable systems, but also highlights the importance of post-harvest emissions from incorporated vegetable residues. N2O mitigation strategies in vegetable systems need to target these post-harvest emissions and a better evaluation of the effect of nitrification inhibitors over the fallow phase is needed.