Integrating novel agents into multiple myeloma treatment - current status in Switzerland and treatment recommendations.

The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.

Adverse reactions to biologic agents and their medical management.

Biologic agents have substantially advanced the treatment of immunological disorders, including chronic inflammatory and autoimmune diseases. However, these drugs are often associated with adverse events (AEs), including allergic, immunological and other unwanted reactions. AEs can affect almost any organ or system in the body and can occur immediately, within minutes to hours, or with a delay of several days or more after initiation of biologic therapy. Although some AEs are a direct consequence of the functional inhibition of biologic-agent-targeted antigens, the pathogenesis of other AEs results from a drug-induced imbalance of the immune system, intermediary factors and cofactors, a complexity that complicates their prediction. Herein, we review the AEs associated with biologic therapy most relevant to rheumatic and immunological diseases, and discuss their underlying pathogenesis. We also include our recommendations for the medical management of such AEs. Increased understanding and improved risk management of AEs induced by biologic agents will enable better use of these versatile immune-response modifiers.

The extraordinarily bright optical afterglow of GRB 991208 and its host galaxy

Observations of the extraordinarily bright optical afterglow (OA) of GRB 991208 started 2.1 d after the event. The flux decay constant of the OA in the R-band is -2.30 +/- 0.07 up to 5 d, which is very likely due to the jet effect, and after that it is followed by a much steeper decay with constant -3.2 +/- 0.2, the fastest one ever seen in a GRB OA. A negative detection in several all-sky films taken simultaneously to the event implies either a previous additional break prior to 2 d after the occurrence of the GRB (as expected from the jet effect). The existence of a second break might indicate a steepening in the electron spectrum or the superposition of two events. Once the afterglow emission vanished, contribution of a bright underlying SN is found, but the light curve is not sufficiently well sampled to rule out a dust echo explanation. Our determination of z = 0.706 indicates that GRB 991208 is at 3.7 Gpc, implying an isotropic energy release of 1.15 x 10E53 erg which may be relaxed by beaming by a factor > 100. Precise astrometry indicates that the GRB coincides within 0.2' with the host galaxy, thus given support to a massive star origin. The absolute magnitude is M_B = -18.2, well below the knee of the galaxy luminosity function and we derive a star-forming rate of 11.5 +/- 7.1 Mo/yr. The quasi-simultaneous broad-band photometric spectral energy distribution of the afterglow is determined 3.5 day after the burst (Dec 12.0) implying a cooling frequency below the optical band, i.e. supporting a jet model with p = -2.30 as the index of the power-law electron distribution.

Optical nebulosities associated with IRAS sources in dense cloud cores

I, H¿ and [SII] CCD images of the regions around 4 young IRAS sources embedded in the dense molecular cloud cores CB 6, CB 39, AFGL 5142, and L 1251 are presented. Reflection nebulosities are found in all 4 regions. Herbig-Haro objects are detected in AFGL 5142 and L 1251. In both cases, the HH objects are new discoveries.

Optical counterpart of galactic plane variable radio sources

We present I-band deep CCD exposures of the fields of galactic plane radio variables. An optical counterpart, based on positional coincidence, has been found for 15 of the 27 observed program objects. The Johnson I magnitude of the sources identified is in the range 18-21.

Simultaneous Optical Recording in Multiple Cells by Digital Holographic Microscopy of Chloride Current Associated to Activation of the Ligand-Gated Chloride Channel GABA(A) Receptor.

Chloride channels represent a group of targets for major clinical indications. However, molecular screening for chloride channel modulators has proven to be difficult and time-consuming as approaches essentially rely on the use of fluorescent dyes or invasive patch-clamp techniques which do not lend themselves to the screening of large sets of compounds. To address this problem, we have developed a non-invasive optical method, based on digital holographic microcopy (DHM), allowing monitoring of ion channel activity without using any electrode or fluorescent dye. To illustrate this approach, GABA(A) mediated chloride currents have been monitored with DHM. Practically, we show that DHM can non-invasively provide the quantitative determination of transmembrane chloride fluxes mediated by the activation of chloride channels associated with GABA(A) receptors. Indeed through an original algorithm, chloride currents elicited by application of appropriate agonists of the GABA(A) receptor can be derived from the quantitative phase signal recorded with DHM. Finally, chloride currents can be determined and pharmacologically characterized non-invasively simultaneously on a large cellular sampling by DHM.

Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: is it feasible?

BACKGROUND: The increasing use of erythropoietins with long half-lives and the tendency to lengthen the administration interval to monthly injections call for raising awareness on the pharmacokinetics and risks of new erythropoietin stimulating agents (ESA). Their pharmacodynamic complexity and individual variability limit the possibility of attaining comprehensive clinical experience. In order to help physicians acquiring prescription abilities, we have built a prescription computer model to be used both as a simulator and education tool. METHODS: The pharmacokinetic computer model was developed using Visual Basic on Excel and tested with 3 different ESA half-lives (24, 48 and 138 hours) and 2 administration intervals (weekly vs. monthly). Two groups of 25 nephrologists were exposed to the six randomised combinations of half-life and administration interval. They were asked to achieve and maintain, as precisely as possible, the haemoglobin target of 11-12 g/dL in a simulated naïve patient. Each simulation was repeated twice, with or without randomly generated bleeding episodes. RESULTS: The simulation using an ESA with a half-life of 138 hours, administered monthly, compared to the other combinations of half-lives and administration intervals, showed an overshooting tendency (percentages of Hb values > 13 g/dL 15.8 ± 18.3 vs. 6.9 ± 12.2; P < 0.01), which was quickly corrected with experience. The prescription ability appeared to be optimal with a 24 hour half-life and weekly administration (ability score indexing values in the target 1.52 ± 0.70 vs. 1.24 ± 0.37; P < 0.05). The monthly prescription interval, as suggested in the literature, was accompanied by less therapeutic adjustments (4.9 ± 2.2 vs. 8.2 ± 4.9; P < 0.001); a direct correlation between haemoglobin variability and number of therapy modifications was found (P < 0.01). CONCLUSIONS: Computer-based simulations can be a useful tool for improving ESA prescription abilities among nephrologists by raising awareness about the pharmacokinetic characteristics of the various ESAs and recognizing the factors that influence haemoglobin variability.

Organometallic anticancer agents that interfere with cellular energy processes: a subtle approach to inducing cancer cell death.

Two hybrid compounds comprising an antimetastatic ruthenium-arene fragment tethered to an indazole-3-carboxylic acid derivative that inhibits aerobic glycolysis in cancer cells have been prepared and evaluated in a variety of cancer cell lines, including highly relevant human glioblastoma cells, with an apparent synergistic action between the two components observed.

Optical response of Cu3Ge thin films

We report an investigation on the optical properties of Cu3Ge thin films displaying very high conductivity, with thickness ranging from 200 to 2000 Å, deposited on Ge substrates. Reflectance, transmittance, and ellipsometric spectroscopy measurements were performed at room temperature in the 0.01-6.0, 0.01-0.6, and 1.4-5.0 eV energy range, respectively. The complex dielectric function, the optical conductivity, the energy-loss function, and the effective charge density were obtained over the whole spectral range. The low-energy free-carrier response was well fitted by using the classical Drude-Lorentz dielectric function. A simple two-band model allowed the resulting optical parameters to be interpreted coherently with those previously obtained from transport measurements, hence yielding the densities and the effective masses of electrons and holes.

Optical-geometrical effects on the photoluminescence spectra of Si nanocrystals embedded in SiO2

We demonstrate that thickness, optical constants, and details of the multilayer stack, together with the detection setting, strongly influence the photoluminescence spectra of Si nanocrystals embedded in SiO2. Due to multiple reflections of the visible light against the opaque silicon substrate, an interference pattern is built inside the oxide layer, which is responsible for the modifications in the measured spectra. This interference effect is complicated by the depth dependence of (i) the intensity of the excitation laser and (ii) the concentration of the emitting nanocrystals. These variations can give rise to apparent features in the recorded spectra, such as peak shifts, satellite shoulders, and even splittings, which can be mistaken as intrinsic material features. Thus, they can give rise to an erroneous attribution of optical bands or estimate of the average particle size, while they are only optical-geometrical artifacts. We have analyzed these effects as a function of material composition (Si excess fraction) and thickness, and also evaluated how the geometry of the detection setup affects the measurements. To correct the experimental photoluminescence spectra and extract the true spectral shape of the emission from Si nanocrystals, we have developed an algorithm based on a modulation function, which depends on both the multilayer sequence and the experimental configuration. This procedure can be easily extended to other heterogeneous systems.

Linear and nonlinear optical properties of Si nanocrystals in SiO2 deposited by plasma-enhanced chemical-vapor deposition

Linear and nonlinear optical properties of silicon suboxide SiOx films deposited by plasma-enhanced chemical-vapor deposition have been studied for different Si excesses up to 24¿at.¿%. The layers have been fully characterized with respect to their atomic composition and the structure of the Si precipitates. Linear refractive index and extinction coefficient have been determined in the whole visible range, enabling to estimate the optical bandgap as a function of the Si nanocrystal size. Nonlinear optical properties have been evaluated by the z-scan technique for two different excitations: at 0.80¿eV in the nanosecond regime and at 1.50¿eV in the femtosecond regime. Under nanosecond excitation conditions, the nonlinear process is ruled by thermal effects, showing large values of both nonlinear refractive index (n2 ~ ¿10¿8¿cm2/W) and nonlinear absorption coefficient (ß ~ 10¿6¿cm/W). Under femtosecond excitation conditions, a smaller nonlinear refractive index is found (n2 ~ 10¿12¿cm2/W), typical of nonlinearities arising from electronic response. The contribution per nanocrystal to the electronic third-order nonlinear susceptibility increases as the size of the Si nanoparticles is reduced, due to the appearance of electronic transitions between discrete levels induced by quantum confinement.