Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

Far field subwavelength source resolution using Phase Conjugating Lens Assisted With Evanescent-to-Propagating Spectrum Conversion

The imaging properties of a phase conjugating lens operating in the far field zone of the imaged source and augmented with scatterers positioned in the source near field region are theoretically studied in this paper. The phase conjugating lens consists of a double sided 2D assembly of straight wire elements, individually interconnected through phase conjugation operators. The scattering elements are straight wire segments which are loaded with lumped impedance loads at their centers. We analytically and numerically analyze all stages of the imaging process; i) evanescent-to-propagating spectrum conversion; ii) focusing properties of infinite or finite sized phase conjugating lens; iii) source reconstruction upon propagating-to-evanescent spectrum conversion. We show that the resolution that can be achieved depends critically on the separation distance between the imaged source and scattering arrangement, as well as on the topology of the scatterers used. Imaged focal widths of up to one-seventh wavelength are demonstrated. The results obtained indicate the possibility of such an arrangement as a potential practical means for realising using conventional materials devices for fine feature extraction by electromagnetic lensing at distances remotely located from the source objects under investigation

Finite difference time domain modeling of phase grating diffusion

In this paper, a method for modeling diffusion caused by non-smooth boundary surfaces in simulations of room acoustics using finite difference time domain (FDTD) technique is investigated. The proposed approach adopts the well-known theory of phase grating diffusers to efficiently model sound scattering from rough surfaces. The variation of diffuser well-depths is attained by nesting allpass filters within the reflection filters from which the digital impedance filters used in the boundary implementation are obtained. The presented technique is appropriate for modeling diffusion at high frequencies caused by small surface roughness and generally diffusers that have narrow wells and infinitely thin separators. The diffusion coefficient was measured with numerical experiments for a range of fractional Brownian diffusers.

A geometric analysis of the effects of noise on Berry phase

In this work we describe the effect of classical and quantum noise on the Berry phase. It is not a topical review article but rather an overview of our work in this field aiming at giving a simple pictorial intuition of our results.

Structural phase transitions in low-dimensional ion crystals

A chain of singly charged particles, confined by a harmonic potential, exhibits a sudden transition to a zigzag configuration when the radial potential reaches a critical value, depending on the particle number. This structural change is a phase transition of second order, whose order parameter is the crystal displacement from the chain axis. We study analytically the transition using Landau theory and find full agreement with numerical predictions by Schiffer [Phys. Rev. Lett. 70, 818 (1993)] and Piacente [Phys. Rev. B 69, 045324 (2004)]. Our theory allows us to determine analytically the system's behavior at the transition point.

Berry phase in open quantum systems: a quantum Langevin equation approach

The evolution of a two level system with a slowly varying Hamiltonian, modeled as a spin 1/2 in a slowly varying magnetic field, and interacting with a quantum environment, modeled as a bath of harmonic oscillators is analyzed using a quantum Langevin approach. This allows to easily obtain the dissipation time and the correction to the Berry phase in the case of an adiabatic cyclic evolution.

Phase diagram of spin-1 bosons on one-dimensional lattices

Spinor Bose condensates loaded in optical lattices have a rich phase diagram characterized by different magnetic order. Here we apply the density matrix renormalization group to accurately determine the phase diagram for spin-1 bosons loaded on a one-dimensional lattice. The Mott lobes present an even or odd asymmetry associated to the boson filling. We show that for odd fillings the insulating phase is always in a dimerized state. The results obtained in this work are also relevant for the determination of the ground state phase diagram of the S=1 Heisenberg model with biquadratic interaction.