Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial.

AIM: To evaluate the activity and safety of the PD-1 antibody pembrolizumab in adult patients with advanced osteosarcoma. MATERIAL AND METHODS: The study was a single-arm, open-label, phase 2 trial in patients with unresectable, relapsed osteosarcoma. The primary endpoint was clinical benefit rate (CBR) at 18 weeks of treatment, defined as complete response, partial response, or stable disease using RECIST v1.1. The trial had a Simon´s two-stage design, and ≥ 3 of 12 patients with clinical benefit in stage 1 were required to proceed to stage 2. The trial is registered with ClinicalTrials.gov, number NCT03013127. NanoString analysis was performed to explore tumor gene expression signatures and pathways. RESULTS: Twelve patients were enrolled and received study treatment. No patients had clinical benefit at 18 weeks of treatment, and patient enrollment was stopped after completion of stage 1. Estimated median progression-free survival was 1.7 months (95% CI 1.2-2.2). At time of data cut-off, 11 patients were deceased due to osteosarcoma. Median overall survival was 6.6 months (95% CI 3.8-9.3). No treatment-related deaths or drug-related grade 3 or 4 adverse events were observed. PD-L1 expression was positive in one of 11 evaluable tumor samples, and the positive sample was from a patient with a mixed treatment response. CONCLUSION: In this phase 2 study in advanced osteosarcoma, pembrolizumab was well-tolerated but did not show clinically significant antitumor activity. Future trials with immunomodulatory agents in osteosarcoma should explore combination strategies in patients selected based on molecular profiles associated with response.

Novel method to determine recursive filtration and noise reduction in fluoroscopic imaging - a comparison of four different vendors.

PURPOSE: This study attempted to develop a method to measure the applied recursive filtration and to determine the noise reduction of four different fluoroscopic systems. The study also attempted to elucidate the importance of considering the recursive filter for quality control tests concerning signal-to-noise ratio (SNR) or image quality. The vendor's settings for recursive filtration factor (ß) are, unfortunately, often not available. Hence, a method to determine the recursive filtration and associated noise reduction would be useful. METHOD: The recursive filter was determined by using a single fluoroscopic series and the method presented in this study. The theoretical noise reduction based on the choice of ß was presented. In addition, the corresponding noise reduction, evaluated as the ratio of the standard deviation of the pixel value between a series with ß equal to zero (recursive filtration off) and ß > 0, was determined for different pulse rates given by pulses per second (pps), doses (mAs) and recursive filter. The images were acquired using clinically relevant radiation quality and quantity. RESULTS: The presented method to measure the recursive filter exhibited high accuracy (1.08%) and precision (1.48%). The recursive filtration and noise reduction were measured for several settings for each vendor. The recursive filtration settings and associated recursive filtration factors for four different vendors were presented. CONCLUSIONS: This study presented an accurate method to determine applied recursive filtration, which was easy to determine. Hence, for all quality control purposes, including noise evaluation, it was possible to consider the essential noise reduction given by the settings for recursive filtration. It was also possible to compare the recursive filtration settings and associated recursive filtration within and between vendors.

Carbon nanocones: wall structure and morphology.

Large-scale production of conical carbon nanostructures is possible through pyrolysis of hydrocarbons in a plasma torch process. The resulting carbon cones occur in five distinctly different forms, and disc-shaped particles are produced as well. The structure and properties of these carbon cones and discs have been relatively little explored until now. Here we characterize the structure of these particles using transmission electron microscopy, synchrotron x-ray and electron diffraction. The carbon nanocones are found to exhibit several interesting structural features; instead of having a uniform cross-section, the walls consist of a relatively thin inner graphite-like layer with a non-crystalline envelope, where the amount of the latter can be modified significantly by annealing. The cones appear with a well-defined faceting along the cone edge, demonstrating strict long-range atomic ordering; they also present occasional examples of symmetry breaking, such as two apexes appearing in the same carbon nanocone.

A Scandinavian Point of View: Caring for Patients With Sarcoma Across Boundaries.

Sarcomas are rare connective tissue malignancies. Patients and their families often experience many challenging problems during the cancer journey. Professionals working in this complex landscape need to collaborate to optimize patient outcomes.

Hydrophilic carotenoids: surface properties and aggregation of an astaxanthin-lysine conjugate, a rigid, long-chain, highly unsaturated and highly water-soluble tetracationic bolaamphiphile.

The surface and aggregation properties of a synthetic, highly water-soluble carotenoid, the tetracationic astaxanthin-lysine conjugate (Asly), have been examined through measurements of surface tension, optical absorption and dynamic light scattering. The following parameters were determined: critical aggregation concentration c(M), surface concentration Gamma, molecular area a(m), free energy of adsorption and aggregation (DeltaG(ad) degrees and DeltaG(M) degrees , respectively), and the aggregate size r(H). The compound forms true monomolecular solutions in water below c(M); aggregates emerge only at rather high concentrations (> or =2.18 mM).

Transient molecular electro-optics Cartesian rotation vector versus Eulerian angles.

Comparing the Euler angles, the classical choice of generalized coordinates describing the three rotational degrees of freedom of a rigid body, and the Cartesian rotation vector, we show that they both have their advantages and disadvantages in kinetic theory and Brownian dynamics analysis of molecular electro-optics. The Eulerian angles often yield relatively simple, yet singular, equations of motion, while their counterparts expressed in terms of Cartesian rotation vector are non-singular but more complex. In a special case, we show that the generalized force associated with the Cartesian rotation vector equals the torque. In addition, we introduce a new graphical approach to qualitatively track how changes in the Eulerian angles affect the Cartesian rotation vector.

Hydrophilic carotenoids: surface properties and aqueous aggregation of a rigid, long-chain, highly unsaturated dianionic bolaamphiphile with a carotenoid spacer.

The water dispersibility of astaxanthin was greatly enhanced by converting it to a disodium disuccinate salt. This carotenoid salt behaved as a bolaamphiphile in water; dynamic light scattering (DLS) revealed the formation of stable aggregates with an average hydrodynamic radius close to 1 microm. Larger aggregates were observed in solutions of increased osmolarity. Absorption spectra demonstrated that the aggregates could withstand the addition of 20% acetonitrile before disintegrating to monomers. The physicochemical properties of this astaxanthin derivative in solution were comprehensively studied by measuring surface tension, critical aggregate concentration, surface concentration, molecule area, free energy of adsorption and micellation, adsorption-aggregate energy relationship, and equilibrium constants, and then compared with similar compounds reported previously in the literature.

Hydrophilic carotenoids: surface properties and aggregation behavior of a highly unsaturated carotenoid lysophospholipid.

The water dispersibility of a hydrophobic carotenoid has been greatly enhanced by using it as the acyl part in the synthesis of a highly unsaturated lysophospholipid. Dynamic light scattering has revealed the formation of stable aggregates with an average hydrodynamic radius of a few nanometers, and absorption spectra show that the aggregates can withstand the addition of ethanol or acetonitrile until the volume fraction of water falls below 70 and 62%, respectively. The properties of the carotenoid phospholipids have been characterized by determining surface tension, critical micelle concentration, surface concentration, molecular area, free energy of adsorption and micellation, adsorption-micellar energy relationship, and equilibrium constants.

Hydrophilic carotenoids: facile syntheses of carotenoid oxime hydrochlorides as long-chain, highly unsaturated cationic (bola)amphiphiles.

Stable cationic carotenoid aggregates - predominantly of the J-type - develop when the hydrochlorides of carotenoid aldoximes and ketoximes are exposed to water. The oxime hydrochlorides are obtained by simple syntheses from commercially available food color carotenoids. Bluish-purple, unstable transient compounds were observed during hydrochlorination performed at liquid nitrogen temperature.

Physical and chemical modifications of collagen gels: impact on diffusion.

The extracellular matrix (ECM) represents a major barrier for delivery of therapeutic drugs, and the transport is determined by the ECM composition, structure, and distribution. Because of the high interstitial fluid pressure in tumors, diffusion becomes the main transport mechanism through ECM. The purpose of this work was to study the impact of the structure of the collagen network on diffusion, by studying to what extent the orientation and chemical modification of the collagen network influenced diffusion. Collagen gels with a concentration of 0.2-2.0% that is comparable with the amount of collagen in the tumor ECM were used as a model system for ECM. Collagen gels were aligned in a low-strength magnetic field and geometrical confinement, and chemically modified by adding decorin or hyaluronan. Diffusion of dextran 2-MDa molecules in the collagen gels was measured using fluorescence recovery after photobleaching. Alignment of the collagen fibers in our gels was found to have no impact on the diffusion coefficient. Adding decorin reduced the diameter of the collagen fibers, but no effect on diffusion was observed. Hyaluronan also reduced the fiber diameter, and high concentration of hyaluronan (2.5 mg/ml) increased the diffusion coefficient. The results indicate that the structure of the collagen network is not a major factor in determining the diffusion through the ECM. Rather, increasing the concentration of collagen was found to reduce the diffusion coefficient. Concentration of the collagen network is more important than the structure in determining the diffusion coefficient.

Studies on the mechanism of the Carr-Price blue colour reaction.

The reaction of retinoids (retinol, retinyl acetate and anhydroretinol) with Brønsted acids was studied as a model system for the Carr-Price reaction. The anhydroretinylic cation was characterised by VIS and 2D NMR spectroscopy, including an estimate of the charge distribution and region of bond inversion, observed in a mixture of identified E/Z isomers. Products obtained by quenching with NaOMe-MeOH were identified by HPLC and MS. The classical Carr-Price reaction between retinol (vitamin A) and the Lewis acid SbCl(3) in saturated chloroform solution was reinvestigated by VIS, NMR, EPR, dynamic light scattering and chemical quenching. Whereas product instability and failure to provide informative NMR spectra indicated a radical cation, EPR results excluded free-radical species. Dynamic light scattering experiments, in comparison with model systems, revealed strong aggregation for the Carr-Price complex, rationalizing the low stability, NMR problems and dimerisation observed by chemical quenching. The VIS data support structural similarity of the blue Carr-Price product with the delocalized anhydroretinylic cation, and a detailed structure of the antimony complex is evaluated.

Characterization of thermally sensitive interactions in aqueous mixtures of hydrophobically modified hydroxyethylcellulose and cyclodextrins.

Effects of beta-cyclodextrin (beta-CD) or hydroxypropyl-beta-cyclodextrin (HP-beta-CD) addition and temperature on thermodynamic, rheological, and structural features of semidilute solutions of hydroxyethylcellulose (HEC) and its hydrophobically modified analogue (HM-HEC) are reported. Differential scanning calorimetric (DSC) measurements revealed a thermally induced crystal melting transition of beta-CD at high concentrations in solutions of HEC and HM-HEC. No transition with HP-beta-CD was observed in aqueous solution. Viscosity results indicated that at a cosolute concentration of 2 mm, the beta-CD units are threaded onto hydrophobic tails of HM-HEC (C16 groups) to form columnar structures. This arrangement is more effective in the encapsulation of the hydrophobic chains than the monomer hydrophobic deactivation accomplished by the HP-beta-CD units. At cosolute concentrations above 8 mm, no further decoupling of the hydrophobic interactions occurs for any of the cosolutes. Small-angle neutron scattering (SANS) experiments on HM-HEC/beta-CD mixtures suggest that the large-scale association structures in HM-HEC/D(2)O solutions are reduced upon addition of beta-CD, and an interesting temperature effect is observed at 2 mm beta-CD addition. At high beta-CD concentrations and low temperatures, the formation of large beta-CD clusters or crystallites generates cross-links in the HEC and HM-HEC networks, resulting in a viscosity enhancement of several orders of magnitude. This strong temperature effect is not reflected in the structural features probed by SANS.

Solution properties of chitin in alkali.

The solution properties of alpha-chitin dissolved in 2.77 M NaOH are discussed. Chitin samples in the weight-average molecular weight range 0.1 x 10(6) g/mol to 1.2 x 10(6) g/mol were prepared by heterogeneous acid hydrolysis of chitin. Dilute solution properties were measured by viscometry and light scattering. From dynamic light scattering data, relative similar size distributions of the chitin samples were obtained, except for the most degraded sample, which contained aggregates. Second virial coefficients in the range 1 to 2 x 10(-3) mL.mol.g(-2) indicated that 2.77 M NaOH is a good solvent to chitin. The Mark-Houwink-Sakurada equation and the relationship between the z-average radius of gyration (Rg) and the weight-average molecular weight (Mw) were determined to be [eta] = 0.10Mw0.68 (mL.g(-1)) and Rg = 0.17Mw0.46 (nm), respectively, suggesting a random-coil structure for the chitin molecules in alkali conditions. These random-coil structures have Kuhn lengths in the range 23-26 nm.