Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

Background: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. Patients and methods: Eighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. Results: In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P <0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P <0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P <0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10-15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). Conclusions: Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Comment on ``Measurement of the 3^3He mass diffusion coefficient in superfluid 4^4He over the 0.45--0.95 K temperature range

The role of 3He-3He collisions in our diffusion experiment is addressed and shown to not be relevant to the measurement of 3He diffusion against phonons in superfluid helium.Comment: Two pages, in Europhysics Letters forma

Neutron Beam Effects on Spin Exchange Polarized He-3

We have observed depolarization effects when high intensity cold neutron beams are incident on alkali-metal-spin-exchange polarized He-3 cells used as neutron spin filters. This was first observed as a reduction of the maximum attainable He-3 polarization and was attributed to a decrease of alkali-metal polarization, which led us to directly measure alkali-metal polarization and spin relaxation over a range of neutron fluxes at LANSCE and ILL. The data reveal a new alkali-metal spin-relaxation mechanism that approximately scales as the square root of the neutron capture-flux density incident on the cell. This is consistent with an effect proportional to the recombination-limited ion concentration, but is much larger than expected from earlier work.Comment: submitted to Physical Review Letter

Measurement of the 3He mass diffusion coefficient in superfluid 4He over the 0.45-0.95 K temperature range

We have measured the mass diffusion coefficient D of 3He in superfluid 4He at temperatures lower than were previously possible. The experimental technique utilizes scintillation light produced when neutron react with 3He nuclei, and allows measurement of the 3He density integrated along the trajectory of a well-defined neutron beam. By measuring the change in 3He density near a heater as a function of applied heat current, we are able to infer values of D with 20% accuracy. At temperatures below 0.7 K and for concentrations of order 10^{-4} we find D=(2.0+2.4-1.2)T^-(6.5 -/+ 1.2) cm^2/s, in agreement with a theoretical approximation.Comment: 8 pages, 5 figures. Submitted to Europhysics Letters and prepared in that journal's forma

Effect of granularity on the insulator-superconductor transition in ultrathin Bi films

We have studied the insulator-superconductor transition (IST) by tuning the thickness in quench-condensed $Bi$ films. The resistive transitions of the superconducting films are smooth and can be considered to represent "homogeneous" films. The observation of an IST very close to the quantum resistance for pairs, $R_{\Box}^N \sim h/4e^2$ on several substrates supports this idea. The relevant length scales here are the localization length, and the coherence length. However, at the transition, the localization length is much higher than the superconducting coherence length, contrary to expectation for a "homogeneous" transition. This suggests the invalidity of a purely fermionic model for the transition. Furthermore, the current-voltage characteristics of the superconducting films are hysteretic, and show the films to be granular. The relevant energy scales here are the Josephson coupling energy and the charging energy. However, Josephson coupling energies ($E_J$) and the charging energies ($E_c$) at the IST, they are found to obey the relation $E_J < E_c$. This is again contrary to expectation, for the IST in a granular or inhomogeneous, system. Hence, a purely bosonic picture of the transition is also inconsistent with our observations. We conclude that the IST observed in our experiments may be either an intermediate case between the fermioinc and bosonic mechanisms, or in a regime of charge and vortex dynamics for which a quantitative analysis has not yet been done.Comment: accepted in Physical Review

European Medicines Agency review of ixazomib (Ninlaro) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy

On 21 November 2016, the European Commission issued a marketing authorisation valid throughout the European Union for ixazomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Ixazomib was evaluated in one, randomised, double-blind, phase III study comparing ixazomib plus lenalidomide and dexamethasone (n=360; ixazomib arm) versus placebo plus lenalidomide and dexamethasone (n=362; placebo arm) in adult patients with relapsed and/or refractory multiple myeloma who had received at least one prior therapy. The median progression-free survival (PFS) in the intent-to-treat population was 20.6 months in patients treated with ixazomib compared with 14.7 months for patients in the placebo arm (stratified HR=0.742, 95% CI 0.587 to 0.939, stratified p-value=0.012). The most frequently reported adverse reactions (≥20%) within the ixazomib and placebo arms were diarrhoea (42% vs 36%), constipation (34% vs 25%), thrombocytopaenia (28% vs 14%), peripheral neuropathy (28% vs 21%), nausea (26% vs 21%), peripheral oedema (25% vs 18%), vomiting (22% vs 11%) and back pain (21% vs 16%). The scientific review concluded that the gain in PFS of 5.9 months observed with ixazomib was considered clinically meaningful. Concerning the possible uncertainty about the magnitude of the effect, this uncertainty was acceptable given the favourable toxicity profile, and considering that ixazomib is the first agent to allow oral triple combination therapy in this patient population which represents a therapeutic innovation in terms of convenience for patients. Therefore, the benefit-risk for ixazomib in combination with lenalidomide and dexamethasone was considered positive, although the efficacy evidence was not as comprehensive as normally required

Search for Parity Violation in 93Nb Neutron Resonances

A new search has been performed for parity violation in the compound nuclear states of 94Nb by measuring the helicity dependence of the neutron total cross section. Transmission measurements on a thick niobium target were performed by the time-of-flight method at the Manuel Lujan Neutron Scattering Center with a longitudinally polarized neutron beam in the energy range 32 to 1000 eV. A total of 18 p-wave resonances in 93Nb were studied with none exhibiting a statistically significant parity-violating longitudinal asymmetry. An upper limit of 1.0×10-7 eV (95% confidence level) was obtained for the weak spreading widthΓw in 93Nb

Coulomb blockade in one-dimensional arrays of high conductance tunnel junctions

Properties of one-dimensional (1D) arrays of low Ohmic tunnel junctions (i.e. junctions with resistances comparable to, or less than, the quantum resistance $R_{\rm q}\equiv h/e^2\approx 25.8$ k$\Omega$) have been studied experimentally and theoretically. Our experimental data demonstrate that -- in agreement with previous results on single- and double-junction systems -- Coulomb blockade effects survive even in the strong tunneling regime and are still clearly visible for junction resistances as low as 1 k$\Omega$. We have developed a quasiclassical theory of electron transport in junction arrays in the strong tunneling regime. Good agreement between the predictions of this theory and the experimental data has been observed. We also show that, due to both heating effects and a relatively large correction to the linear relation between the half-width of the conductance dip around zero bias voltage, $V_{1/2}$, and the measured electronic temperature, such arrays are inferior to those conventionally used in the Coulomb Blockade Thermometry (CBT). Still, the desired correction to the half-width, $\Delta V_{1/2}$, can be determined rather easily and it is proportional to the magnitude of the conductance dip around zero bias voltage, $\Delta G$. The constant of proportionality is a function of the ratio of the junction and quantum resistances, $R/R_{\rm q}$, and it is a pure strong tunneling effect.Comment: LaTeX file + five postscript figure