Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

A simple analog controller for single-phase half-bridge rectifier and its application to transformerless UPS

A simple, low-cost, constant frequency, analog controller is proposed for the front-end half-bridge rectifier of a single-phase transformerless UPS system to maintain near unity power factor at the input and zero dc-offset voltage at the output. The controller generates the required gating pulses by comparing the input current with a periodic, bipolar, linear carrier without sensing the input voltage. Two voltage controllers and a single integrator with reset are used to generate the required carrier. All the necessary control operations can be performed without using any PLL, multiplier and/or divider. The controller can be fabricated as a single integrated circuit. The control concept is validated through simulation and also experimentally on an 800W half-bridge rectifier. Experimental results are presented for ac-dc application, and also for ac-dc-ac UPS application with both sinusoidal and nonlinear loads. The simulation and experimental results agree well.

A Proportional plus Multiresonant Controller for Three-Phase Four-Wire High-Frequency Link Inverter

A new solution for unbalanced and nonlinear loads in terms of power circuit topology and controller structure is proposed in this paper. A three-phase four-wire high-frequency ac-link inverter is adopted to cater to such loads. Use of high-frequency transformer results in compact and light-weight systems. The fourth wire is taken out from the midpoint of the isolation transformer in order to avoid the necessity of an extra leg. This makes the converter suitable for unbalanced loads and eliminates the requirements of bulky capacitor in half-bridge inverter. The closed-loop control is carried out in stationary reference frame using proportional + multiresonant controller (three separate resonant controller for fundamental, fifth and seventh harmonic components). The limitations on improving steady-state response of harmonic resonance controllers is investigated and mitigated using a lead-lag compensator. The proposed voltage controller is used along with an inner current loop to ensure excellent performance of the power converter. Simulation studies and experimental results with 1 kVA prototype under nonlinear and unbalanced loading conditions validate the proposed scheme.

Non-Linear vibration of an elastic string

Equations proposed in previous work on the non-linear motion of a string show a basic disagreement, which is here traced to an assumption about the longitudinal displacement u. It is shown that it is neither necessary nor justifiable to assume that u is zero; and also that the velocity of propagation of u disturbances in a string is different from that in an infinite medium, although this difference is usually negligible. After formulating the exact equations of motion for the string, a systematic procedure is described for obtaining approximations to these equations to any order, making only the assumption that the strain in the material of the string is small. The lowest order equations in this scheme are non-linear, and are used to describe the response of a string near resonance. Finally, it is shown that in the absence of damping, planar motion of a string is always unstable at sufficiently high amplitudes, the critical amplitude falling to zero at the natural frequency and its subharmonics. The effect of slight damping on this instability is also discussed.

Application of ultraspherical polynomials to non-linear autonomous systems

This paper deals with the approximate solutions of non-linear autonomous systems by the application of ultraspherical polynomials. From the differential equations for amplitude and phase, set up by the method of variation of parameters, the approximate solutions are obtained by a generalized averaging technique based on the ultraspherical polynomial expansions. The method is illustrated with examples and the results are compared with the digital and analog computer solutions. There is a close agreement between the analytical and exact results.

Annealing response of the intermetallic alloy Ti-22Al-25Nb

A hot rolled two-phase Ti-22Al-25Nb (at.%) alloy containing the orthorhombic (O) and beta(B2) phases was subjected to thermal treatment under different conditions. The experiment was aimed to examine the recrystallization response of the beta(B2) phase (static and dynamic) to microstructure and crystallographic texture evolution using scanning electron microscopy coupled with electron backscattered diffraction (SEM-EBSD). Specimens rolled in the two-phase (O + beta(B2)) region consisted of highly deformed beta(B2) grains. The texture was close to that of the typical bcc deformation texture with a few additional texture components. A subsequent heat treatment of these rolled specimens in single beta(B2) phase region was characterized by static recrystallized beta(B2) grains with the final texture partly inherited from as-rolled material. In contrast, specimens rolled in the single beta(B2) region produced beta(B2) grains with the texture similar to that of completely dynamic recrystallized one. (C) 2010 Elsevier Ltd. All rights reserved.

Simple kinetic sensor to structural transitions

Driven nonequilibrium structural phase transformation has been probed using time-varying resistance fluctuations or noise. We demonstrate that the non-Gaussian component (NGC) of noise obtained by evaluating the higher-order statistics of fluctuations, serves as a simple kinetic detector of these phase transitions. Using the Martensite transformation in free-standing wires of nickel-titanium binary alloys as a prototype, we observe clear deviations from the Gaussian background in the transformation zone, indicative of the long-range correlations in the system as the phase transforms. The viability of non-Gaussian statistics as a robust probe to structural phase transition was also confirmed by comparing the results from differential scanning calorimetry measurements. We further studied the response of the NGC to the modifications in the microstructure on repeated thermal cycling, as well as the variations in the temperature-drive rate, and explained the results using established simplistic models based on the different competing time scales. Our experiments (i) suggest an alternative method to estimate the transformation temperature scales with high accuracy and (ii) establish a connection between the material-specific evolution of microstructure to the statistics of its linear response. Since the method depends on an in-built long-range correlation during transformation, it could be portable to other structural transitions, as well as to materials of different physical origin and size.

Worst inputs and a bound on the highest peak statistics of a class of non-linear systems

A method is developed by which the input leading to the highest possible response in an interval of time can be determined for a class of non-linear systems. The input, if deterministic, is constrained to have a known finite energy (or norm) in the interval under consideration. In the case of random inputs, the energy is constrained to have a known probability distribution function. The approach has applications when a system has to be put to maximum advantage by getting the largest possible output or when a system has to be designed to the highest maximum response with only the input energy or the energy distribution known. The method is also useful in arriving at a bound on the highest peak distribution of the response, when the excitation is a known random process.As an illustration the Duffing oscillator has been analysed and some numerical results have also been presented.

Stress induced phase transition in monomolecular perfluroalkylsilane film self assembled on aluminium surface

We control the stiffnesses of two dual double cantelevers placed in series to control penetration into a perflurooctyltrichlorosilane monolayer self assembled on aluminium and silicon substrates. The top cantilever which carries the probe is displaced with respect to the bottom cantilever which carries the substrate, the difference in displacement recorded using capacitors gives penetration. We further modulate the input displacement sinusoidally to deconvolute the viscoelastic properties of the monolayer. When the intervention is limited to the terminal end of the molecule there is a strong viscous response in consonance with the ability of the molecule to dissipate energy by the generation of gauche defects freely. When the intervention reaches the backbone, at a contact mean pressure of 0.2GPa the damping disappears abruptly and the molecule registers a steep rise in elastic modulus and relaxation time constant, with increasing contact pressure. We offer a physical explanation of the process and describe this change as due to a phase transition from a liquid like to a solid like state.

Construction and use of linear regression models for processor performance analysis

Processor architects have a challenging task of evaluating a large design space consisting of several interacting parameters and optimizations. In order to assist architects in making crucial design decisions, we build linear regression models that relate Processor performance to micro-architecture parameters, using simulation based experiments. We obtain good approximate models using an iterative process in which Akaike's information criteria is used to extract a good linear model from a small set of simulations, and limited further simulation is guided by the model using D-optimal experimental designs. The iterative process is repeated until desired error bounds are achieved. We used this procedure to establish the relationship of the CPI performance response to 26 key micro-architectural parameters using a detailed cycle-by-cycle superscalar processor simulator The resulting models provide a significance ordering on all micro-architectural parameters and their interactions, and explain the performance variations of micro-architectural techniques.

Rare earth exchanged (Ce3+, La3+ and RE3+) H-Y zeolites as solid acid catalysts for the synthesis of linear alkyl benzenes

Rare earth exchanged H–Y zeolites were prepared by simple ion exchange methods at 353 K and have been characterized using different physicochemical techniques. A strong peak around 58 ppm in the 27Al{1H} MAS NMR spectra of these zeolites suggests a tetrahedral coordination for the framework aluminium. Small peak at or near 0 ppm is due to hexa-coordinated extra-framework aluminium and a shoulder peak near 30 ppm is a penta-coordinated aluminium species; [Al(OH)4]−. The vapor-phase benzene alkylation with 1-decene and 1-dodecene was investigated with these catalytic systems. Under the reaction conditions of 448 K, benzene/olefin molar ratio of 20 and time on stream 3 h, the most efficient catalyst was CeH–Y which showed more than 70% of olefin conversion with 48.5% 2-phenyldecane and 46.8%, 2-phenyldodecane selectivities with 1-decene and 1-dodecene respectively.

New type of high field electrooptic response in nematics

We have made concurrent measurements of ionic current and optical transmission between crossed polarisers on several nematics with positive dielectric anisotropy under the action of applied low frequency (< 1KHz) square wave voltages. When the field E is low, the measured current is linear in E and there is no electrooptic response. Beyond some value of the field (E(0)similar to 100 esu), the current becomes independent of the field (phenomenon of limiting current). Further an electrooptic signal is measured at twice the frequency of the applied voltage, which exhibits a peak as a function of the field. The width of the peak is 3 to 4 times the value of E-0, and the signal level at the peak decreases as the frequency is increased. These measurements have been made on three highly polar compounds with cyano end groups. Careful observations do not show any evidence of electrohydrodynamic instabilities in the sample. It is argued that the observations can be understood if at the onset of the phenomenon of the limiting current, a strong electric field gradient is established near one of the electrodes due to the sweeping of an ionic species with high mobility. The field gradient produces a flexoelectric deformation of the director field, which in turn gives rise to the electrooptic effect. At higher fields, the stabilising dielectric torque takes over to suppress this instability.

Nonlinear intrinsic instability of solid propellant combustion including gas-phase thermal inertia

The problem of homogeneous solid propellant combustion instability is studied with a one-dimensional flame model, including the effects of gas-phase thermal inertia and nonlinearity. Computational results presented in this paper show nonlinear instabilities inherent in the equations, due to which periodic burning is found even under steady ambient conditions such as pressure. The stability boundary is obtained in terms of Denison-Baum parameters. It is found that inclusion of gas-phase thermal inertia stabilizes the combustion. Also, the effect of a distributed heat release in the gas phase, compared to the flame sheet model, is to destabilize the burning. Direct calculations for finite amplitude pressure disturbances show that two distinct resonant modes exist, the first one near the natural frequency as obtained from intrinsic instability analysis and a second mode occurring at a much higher driving frequency. It is found that er rn in the low frequency region, the response of the propellant is significantly affected by the specific type of gas-phase chemical heat-release model employed. Examination of frequency response function reveals that the role of gas-phase thermal inertia is to stabilize the burning near the first resonant mode. Calculations made for different amplitudes of driving pressure show that the mean burning rate decreases with increasing amplitude. Also, with an increase in the driving amplitude, higher harmonics are generated in the burning rate.

Two-dimensional NMR spectroscopy of connected transitions by linear combination of flip angle dependent cosy: An alternative scheme for E.COSY

An alternative pulse scheme which simplifies and improves the recently proposed P.E.COSY experiment is suggested for the retention of connected or unconnected transitions in a coupled spin system. An important feature of the proposed pulse scheme is the improved phase characteristics of the diagonal peaks. A comparison of various experiments designed for this purpose, namely COSY-45, E.COSY, P.E.COSY and the present scheme (A.E.COSY), is also presented. The suppression of unconnected transitions and the measurement of scalar coupling constants and their relative signs are illustrated from A.E.COSY spectra of 2,3-dibromopropionic acid and 2-(2-thienyl)pyridine.

Experimental studies and phase field modeling of microstructure evolution during solidification with electromagnetic stirring

Thixocasting requires manufacturing of billets with non-dendritic microstructure. Aluminum alloy A356 billets were produced by rheocasting in a mould placed inside a linear electromagnetic stirrer. Subsequent heat treatment was used to produce a transition from rosette to globular microstructure. The current and the duration of stirring were explored as control parameters. Simultaneous induction heating of the billet during stirring was quantified using experimentally determined thermal profiles. The effect of processing parameters on the dendrite fragmentation was discussed. Corresponding computational modeling of the process was performed using phase-field modeling of alloy solidification in order to gain insight into the process of morphological changes of a solid during this process. A non-isothermal alloy solidification model was used for simulations. The morphological evolution under such imposed thermal cycles was simulated and compared with experimentally determined one. Suitable scaling using the thermosolutal diffusion distances was used to overcome computational difficulties in quantitative comparison at system scale. The results were interpreted in the light of existing theories of microstructure refinement and globularisation.