LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial.

BACKGROUND: Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary. METHODS: In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety. RESULTS: A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B. CONCLUSIONS: AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.

Manufacturing of Open-Cell Aluminium Foams: Comparing the Sponge Replication Technique and Its Combination with the Freezing Method.

The manufacturing of aluminium foams with a total porosity of 87% using the sponge replication method and a combination of the sponge replication and freezing technique is presented. Foams with different cell counts were prepared from polyurethane (PU) templates with a pore count per inch (ppi) of 10, 20 and 30; consolidation of the foams was performed in an argon atmosphere at 650 °C. The additional freezing steps resulted in lamellar pores in the foam struts. The formation of lamellar pores increased the specific surface area by a factor of 1.9 compared to foams prepared by the sponge replication method without freezing steps. The formation of additional lamellar pores improved the mechanical properties but reduced the thermal conductivity of the foams. Varying the pore cell sizes of the PU template showed that-compared to foams with dense struts-the highest increase (~7 times) in the specific surface area was observed in foams made from 10 ppi PU templates. The effect of the cell size on the mechanical and thermal properties of aluminium foams was also investigated.

Refractory Metal Coated Alumina Foams as Support Material for Stem Cell and Fibroblasts Cultivation.

Ceramics are widely used as implant materials; however, they are brittle and may emit particles when used in these applications. To overcome this disadvantage, alumina foams, which represent a 3D cellular structure comparable to that of human trabecular bone structures, were sputter coated with platinum, tantalum or titanium and modified with fibronectin or collagen type I, components of the extracellular matrix (ECM). To proof the cell material interaction, the unmodified and modified materials were cultured with (a) mesenchymal stem cells being a perfect indicator for biocompatibility and releasing important cytokines of the stem cell niche and (b) with fibroblasts characterized as mediators of inflammation and therefore an important cellular component of the foreign body reaction and inflammation after implantation. To optimize and compare the influence of metal surfaces on cellular behavior, planar glass substrates have been used. Identified biocompatible metal surface of platinum, titanium and tantalum were sputtered on ceramic foams modified with the above-mentioned ECM components to investigate cellular behavior in a 3D environment. The cellular alumina support was characterized with respect to its cellular/porous structure and niche accessibility and coating thickness of the refractory metals; the average cell size was 2.3 mm, the average size of the cell windows was 1.8 mm, and the total foam porosity was 91.4%. The Pt, Ti and Ta coatings were completely dense covering the entire alumina foam surface. The metals titanium and tantalum were colonized very well by the stem cells without a coating of ECM components, whereas the fibroblasts preferred components of the ECM on the alumina foam surface.

Open-Cellular Alumina Foams with Hierarchical Strut Porosity by Ice Templating: A Thickening Agent Study.

Alumina replica foams were manufactured by the Schwartzwalder sponge replication technique and were provided with an additional strut porosity by a freeze-drying/ice-templating step prior to thermal processing. A variety of thickeners in combination with different alumina solid loads in the dispersion used for polyurethane foam template coating were studied. An additional strut porosity as generated by freeze-drying was found to be in the order of ~20%, and the spacings between the strut pores generated by ice-templating were in the range between 20 µm and 32 µm. In spite of the lamellar strut pore structure and a total porosity exceeding 90%, the compressive strength was found to be up to 1.3 MPa. Combining the replica process with freeze-drying proves to be a suitable method to enhance foams with respect to their surface area accessible for active coatings while preserving the advantageous flow properties of the cellular structure. A two-to-threefold object surface-to-object volume ratio of 55 to 77 mm-1 was achieved for samples with 30 vol% solid load compared to 26 mm-1 for non-freeze-dried samples. The freeze-drying technique allows the control of the proportion and properties of the introduced pores in an uncomplicated and predictable way by adjusting the process parameters. Nevertheless, the present article demonstrates that a suitable thickener in the dispersion used for the Schwartzwalder process is inevitable to obtain ceramic foams with sufficient mechanical strength due to the necessarily increased water content of the ceramic dispersion used for foam manufacturing.

Polymer Derived Ceramics from Si, B, SiB6, and Mo5SiB2 Filler-Loaded Perhydropolysilazane Precursors as Protective and Functional Coatings for Refractory Metal Alloys.

Oxidation barrier coatings on the base of a perhydropolysilazane precursor with different amounts of Si, B, SiB6 and Mo5SiB2 (T2) fillers for the oxidation protection of Mo-Si-B alloys were developed. The influence of different filler compositions as well as the influence of pyrolysis conditions (temperature and atmosphere) was studied. The coating slurries were examined with respect to their rheological behavior, which allows optimization of the coating slurry. Dilatometry studies show that the coefficient of thermal expansion of the composites can be matched to refractory, especially molybdenum alloy based, substrates by varying the content and the composition of the filler. The pyrolyzed coating systems offer a low porosity, which is one of the key parameters to a high oxidation protection capability.

Cellular Nickel-Yttria/Zirconia (Ni-YSZ) Cermet Foams: Manufacturing, Microstructure and Properties.

Open-celled ceramic composite foams were prepared from NiO and yttria-stabilized zirconia (YSZ) powders by the polymer sponge replication (Schwartzwalder) technique using the respective aqueous dispersions. Mechanically stable NiO-YSZ foams with an average porosity of 93 vol.% were obtained. After chemical reduction of the NiO phase with hydrogen, cellular Ni-YSZ cermet structures were obtained. They are characterized by an electric conductivity up to 19∙103 S∙m-1 which can be adjusted by both, the Ni volume fraction, and the sintering/reduction procedure. The NiO-YSZ ceramic foams, as well as the cellular Ni-YSZ cermets prepared therefrom, were characterized with respect to their microstructure by scanning electron microscopy, confocal Raman microscopy and X-ray diffraction with Rietveld analysis. In addition, the compressive strength, the electric conductivity and the thermal conductivity were determined. The collected data were then correlated to the sample microstructure and porosity and were also applied for modelling of the mechanical and electric properties of the bulk Ni-YSZ strut material.

Acoustic metamaterial capsule for reduction of stage machinery noise.

Noise mitigation of stage machinery can be quite demanding and requires innovative solutions. In this work, an acoustic metamaterial capsule is proposed to reduce the noise emission of several stage machinery drive trains, while still allowing the ventilation required for cooling. The metamaterial capsule consists of c-shape meta-atoms, which have a simple structure that facilitates manufacturing. Two different metamaterial capsules are designed, simulated, manufactured, and experimentally validated that utilize an ultra-sparse and air-permeable reflective meta-grating. Both designs demonstrate transmission loss peaks that effectively suppress gear mesh noise or other narrow band noise sources. The ventilation by natural convection was numerically verified, and was shown to give adequate cooling, whereas a conventional sound capsule would lead to overheating. The noise spectra of three common stage machinery drive trains are numerically modelled, enabling one to design meta-gratings and determine their noise suppression performance. The results fulfill the stringent stage machinery noise limits, highlighting the benefit of using metamaterial capsules of simple c-shape structure.

Open-Cell Aluminum Foams by the Sponge Replication Technique.

Open-cell aluminum foams were manufactured by a sponge replication technique having a total porosity of ~90%. The influence of the thermal processing conditions such as atmosphere and temperature on the cellular structure, phase composition porosity, thermal conductivity, and compressive strength of the foams was studied. It was found that the thermal processing of aluminum foams in Ar at temperatures up to 800 °C led to aluminum foams with a reduced strut porosity, a lower amount of aluminum oxide, a higher thermal conductivity, and a higher compression strength, compared to foams thermally processed in air. These results were explained by the lower amount of aluminum oxide after thermal processing of the foams.

Tailored Oxidation Barrier Coatings for Mo-Hf-B and Mo-Zr-B Alloys.

The cyclic oxidation response of Mo-14Hf-23B and Mo-14.8Zr-26B (compositions in at. %) was investigated in air at 800 °C, which is a critical temperature for Mo-based alloys because of the pesting phenomenon. Rapid oxidation was observed for the unprotected samples, and an oxidation protection coating was developed based on a preceramic polymer with silicon and boron as particulate fillers. Cyclic oxidation tests of the coated samples showed excellent oxidation protection: no Mo, Hf or Zr oxides were found after testing and a small mass gain in the initial stage of oxidation indicated the formation of a glassy protection layer on the alloys surfaces after exposure to air at 800 °C.

Refitting of Zirconia Toughening into Open-Cellular Alumina Foams by Infiltration with Zirconyl Nitrate.

The present work describes the combination of the well-established dispersion infiltration of the hollow struts in reticulated porous ceramics (RPCs) and the salt solution infiltration of the remaining strut porosity. This approach is applied on alumina foams, which are loaded subsequently with a dispersion of sub-micrometer alumina particles and a ZrO(NO3)2 solution. The zirconyl nitrate is converted into a ZrO2 transformation toughening phase during the final sintering step. As a consequence of the complex microstructure evolution during the consecutive infiltration cycles, the reinforcement phase concentrates selectively at the weak spots of RPC structures-namely, the hollow strut cavities and longitudinal cracks along the struts. As a consequence, a severe improvement of the compressive strength is observed: The average compressive strength, normalized to a porosity of 91.6 vol.%, is 1.47 MPa for the Al2O3/ZrO2 infiltrated foams, which is an improvement by 40% with respect to alumina-only loaded foams (1.05 MPa) or by 206% compared to uninfiltrated alumina RPCs (0.48 MPa). The compressive strength results are correlated to infiltration parameters and the properties of the infiltration fluids, for example the rheological behavior and the size of the Zr solute species in the respective ZrO(NO3)2 solution.

Mechanical and Surface-Chemical Properties of Polymer Derived Ceramic Replica Foams.

Polymer derived ceramic foams were prepared with the replica method using filler free and filler loaded polysiloxane containing slurries for the impregnation of open celled polyurethane foams. A significant change in mechanical strength, porosity and surface energy, i.e., wettability after thermal treatment between 130 °C (crosslinking) and 1000 °C (pyrolysis) in argon atmosphere was observed. While low-temperature pyrolyzed foams are elastic and hydrophobic, foams pyrolyzed at high temperatures are brittle and hydrophilic, and they possess higher compression strength. Changes of these properties were correlated with the polymer-to-ceramic transformation.

Final Results of a Non-Interventional Study Evaluating the Quality of Life in Second-line Treatment of Metastatic Renal Cell Carcinoma With Everolimus: The EVERPRO Study.

BACKGROUND: This study assessed the quality of life (QoL) and the implication of time effort of everolimus treatment in patients with metastatic renal cell carcinoma (mRCC). METHODS: Adult patients with mRCC were eligible for everolimus treatment after first-line vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors or bevacizumab therapy. The primary end-point, QoL, was assessed by means of the NCCN-FACT FKSI-19 questionnaire. RESULTS: In total, 202 patients (24% of female patients; median age, 71 years) were evaluable for QoL analyses. The median treatment duration was 4.4 months (95% CI, 3.8-5.3) and the median time to progression was 6 months (95% CI, 5.4-7.5). The median FKSI-19 total score remained stable during treatment (52.0 at therapy start, 55.0 at observation end). The median time effort spent on total therapy was 20 hours per patient. Most of the patients stated to have "no limitations," "a little" or "moderate" limitations in their daily, social, and professional lives. Two months after the start of treatment, 65 patients reported none or a little time burden due to therapy. CONCLUSIONS: QoL was maintained during the everolimus therapy and limitations as well as time effort were acceptable for most of the patients. The study supports previous findings on switching mode of action after anti-VEGFR-targeted therapy to a mammalian target of rapamycin inhibitor.

Changes in Treatment Reality and Survival of Patients With Advanced Clear Cell Renal Cell Carcinoma - Analyses From the German Clinical RCC-Registry.

INTRODUCTION: Because the treatment landscape for metastatic renal cell carcinoma (mRCC) has evolved dramatically over the past decade, data on patients' treatment and outcomes in routine practice, so called "real-world data," are important to complement clinical trial data. We present choice of systemic first-/second-line treatments, number and sequences of treatment lines, and survival of patients with clear cell mRCC. PATIENTS AND METHODS: A total of 1085 patients with clear cell mRCC who were recruited at the start of first-line treatment into the prospective German clinical cohort study (RCC-Registry) by 122 sites between December 2007 and May 2017 were analyzed. RESULTS: The choice of first-/second-line treatment and changes over time reflect the chronologic approval of different targeted agents: from mainly tyrosine kinase inhibitors (TKIs), to TKIs/mechanistic target of rapamycin inhibitors, to now TKIs/mechanistic target of rapamycin inhibitors/checkpoint inhibitor. The median first-line overall survival ranged from 7.2 months (95% confidence interval [CI], 4.8-10.9 months) in high MSKCC (Memorial Sloan Kettering Cancer Center) risk to 36.7 months (95% CI, 27.9-43.0 months) in low-risk patients. For trial-ineligible routine patients meeting common exclusion criteria of clinical trials, the median overall survival was 14.6 months (95% CI, 11.5-18.0 months) compared with 26.2 months (95% CI, 22.1-31.5 months) for potentially trial-eligible patients. CONCLUSION: This is the first prospective long-term cohort study showing changes in treatment reality and survival of routine patients with clear cell mRCC. Newly approved treatments are quickly applied in routine care. Patients with unfavorable prognosis, including trial-ineligible patients, have inferior outcomes. Survival times of potentially trial-eligible patients are similar to those reported from clinical trials.

Efficacy of non-pharmacological interventions for procedural pain relief in adults undergoing burn wound care: A systematic review and meta-analysis of randomized controlled trials.

The aim of the present meta-analysis was to investigate the efficacy of non-pharmacological interventions for procedural pain relief in adults undergoing burn wound care compared to standard care alone or an attention control. Through a comprehensive literature search in various electronic databases 21 eligible randomized controlled trials (RCTs) were included, comprising a total of 660 patients. Random effects meta-analyses revealed significant positive treatment effects on pain outcomes, Hedges' g=0.58, 95% CI [0.33; 0.84]. Heterogeneity of study effects was substantial, I2=72%. Effects were significantly larger for comparisons against treatment as usual (TAU), g=0.69, CI 95% [0.40; 0.98] than for comparisons against attention control groups, g=0.21 [-0.11; 0.54], p<0.001. Distraction interventions, particularly those using virtual reality, and hypnosis revealed the largest effects on pain relief. Non-pharmacological interventions further resulted in a significant small, homogeneous effect on anxiety reduction, g=0.36 [0.20; 0.52]. In summary, benefits of non-pharmacological interventions on procedural pain relief and reduction of mental distress were demonstrated. Results have been proven to be free of publication bias. However, further high quality trials are needed to strengthen the promising evidence.

Improving the Strength of ZTA Foams with Different Strategies: Immersion Infiltration and Recoating.

The combination of high strength and toughness, excellent wear resistance and moderate density makes zirconia-toughened alumina (ZTA) a favorable ceramic, and the foam version of it may also exhibit excellent properties. Here, ZTA foams were prepared by the polymer sponge replication method. We developed an immersion infiltration approach with simple equipment and operations to fill the hollow struts in as-prepared ZTA foams, and also adopted a multiple recoating method (up to four cycles) to strengthen them. The solid load of the slurry imposed a significant influence on the properties of the ZTA foams. Immersion infiltration gave ZTA foams an improvement of 1.5 MPa in compressive strength to 2.6 MPa at 87% porosity, only resulting in a moderate reduction of porosity (2-3%). The Weibull modulus of the infiltrated foams was in the range of 6-9. The recoating method generated an increase in compression strength to 3.3-11.4 MPa with the reduced porosity of 58-83%. The recoating cycle dependency of porosity and compression strength is nearly linear. The immersion infiltration strategy is comparable to the industrially-established recoating method and can be applied to other reticulated porous ceramics (RPCs).

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BACKGROUND: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. METHODS: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. RESULTS: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. CONCLUSIONS: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).

Chaotic vibrations of the duffing system with fractional damping.

We examined the Duffing system with a fractional damping term. Calculating the basins of attraction, we demonstrate a broad spectrum of non-linear behaviour connected with sensitivity to the initial conditions and chaos. To quantify dynamical response of the system, we propose the statistical 0-1 test as well as the maximal Lyapunov exponent; the application of the latter encounter a few difficulties because of the memory effect due to the fractional derivative. The results are confirmed by bifurcation diagrams, phase portraits, and Poincaré sections.

Clinical pharmacokinetics of thalidomide.

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200 mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (C(max)) of 1-2 mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC( infinity )) of 18 mg. h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state C(max) (C(ss)(max)) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with C(ss)(max) of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400 mg. Because of the low solubility of thalidomide, C(max) is less than proportional to dose, and t(max) is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function.

A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects.

Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(C(max)) and ln[(AUC(0-infinity))], respectively. There was a marginal but statistically significant 1-hour increase in t(max) in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased ( approximately 14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean t(max) for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.