Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.

BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

First synthesis of silicon nanocrystals in amorphous silicon nitride from a preceramic polymer.

We report the first synthesis of silicon nanocrystals embedded in a silicon nitride matrix through a direct pyrolysis of a preceramic polymer (perhydropolysilazane). Structural analysis carried out by XRD, XPS, Raman and TEM reveals the formation of silicon quantum dots and correlates the microstructures with the annealing temperature. The photoluminescence of the nanocomposites was investigated by both linear and nonlinear measurements. Furthermore we demonstrate an enhanced chemical resistance of the nitride matrix, compared to the typical oxide one, in both strongly acidic and basic environments. The proposed synthesis via polymer pyrolysis is a striking innovation potentially allowing a mass-scale production nitride embedded Si nanocrystals.

Theranostic gold-magnetite hybrid nanoparticles for MRI-guided radiosensitization.

The main limitation of drug-enhanced radiotherapy concerns the difficulty to evaluate the effectiveness of cancer targeting after drug administration hindering the standardization of therapies based on current radiosensitizing compounds. The challenge regards the development of systems able to combine imaging and radiotherapy enhancement in order to perform highly reliable cancer theragnosis. For these reasons, gold-magnetite hybrid nanoparticles (H-NPs) are proposed as innovative theranostic nanotools for imaging-guided radiosensitization in cancer treatment. In this work we propose a novel method for the synthesis of hydrophilic and superparamagnetic Tween20-stabilized gold-magnetite H-NPs. Morphology and chemical composition of nanoparticles were assessed by transmission electron microscopy, x-ray diffraction analysis and ion-coupled plasma optical emission spectroscopy. Colloidal stability and magnetic properties of nanoparticles were determined by dynamic light scattering and magnetometry. The potentialities of H-NPs for magnetic resonance imaging were studied using a human 4T-MRI scanner. Nanoparticles were proven to induce concentration-dependent contrast enhancement in T2*-weighted MR-images. The cytotoxicity, the cellular uptake and the radiosensitization activity of H-NPs were investigated in human osteosarcoma MG63 cell cultures and murine 3T3 fibroblasts, using specific bioassays and laser scanning confocal microscopy. H-NPs did not exhibit significant toxicity and were demonstrated to be internalized by cells. A significant x-ray enhancement at specific H-NPs exposure concentrations was evidenced on MG63 cell line.

Adult ECG criteria for left ventricular hypertrophy in young competitive athletes.

Time-tested data indicate that ECG diagnosis of left ventricular hypertrophy in young athletes is challenging due to low sensitivity of the commonly used criteria. We sought to establish whether adult ECG criteria can be appropriate to make diagnosis of both common and uncommon patterns of left ventricular hypertrophy in young trained athletes. A total of 122 athletes, ages 16.2±3.8 years, training at least 5 h per week, were studied with Sokolow-Lyon voltage, Romhilt-Estes, Cornell voltage, Cornell Product, Perugia and Framingham scores. Garson Criteria were also investigated in athletes under 16. Participants were divided into 2 groups based on the presence (group-A, n=56) or absence (group-B, n=66) of at least one positive ECG score. Test performance was calculated with respect to accurate echocardiographic diagnosis of left ventricular hypertrophy. There were no inter-group differences regarding physical characteristics and training burden. 9 athletes from group-A (16%) and 2 from group-B (3%) were found to have left ventricular hypertrophy, likely to be pathological in 2 cases from group-A. Criteria gathering both QRS voltages and ST-T anomalies, like Perugia-score, best identified this subgroup and should be preferred to those based on QRS voltage analysis alone.

Multifunctional branched gold-carbon nanotube hybrid for cell imaging and drug delivery.

Branched gold nanoparticles were grown on oxidized multiwalled carbon nanotubes by one-step reduction of gold chloride in water. The carbon nanotube/gold hybrids were used for the delivery of the anticancer drug doxorubicin hydrochloride into A549 lung cancer cell line. Doxorubicin (Dox) can be adsorbed in high quantity on both inner and outer surfaces of oxidized carbon nanotubes by π-π stacking interactions between doxorubicin aromatic groups and carbon nanotube (CNT) backbone. Carbon nanotube/gold hybrids display a broad absorption band in the red and near-infrared regions allowing their use for imaging applications. In vitro cellular tests showed that the nanostructures can efficiently transport and deliver doxorubicin inside the cells.

Poststroke shoulder pain in subacute patients and its correlation with upper limb recovery after robotic or conventional treatment: A secondary analysis of a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Poststroke shoulder pain is a common complication. We aimed to investigate the prevalence of poststroke shoulder pain, with attention to the neuropathic component, and the relationship between poststroke shoulder pain and upper limb improvement in motor function, strength, disability, and quality of life after upper limb rehabilitation. METHODS: This is a secondary analysis of a multicenter randomized controlled trial to compare upper limb conventional or robotic rehabilitation on 224 patients enrolled in eight rehabilitation centers. We assessed poststroke shoulder pain (using the Numerical Rating Scale and the Douleur Neuropathique 4), and upper limb motor function, strength, disability, and quality of life at baseline (T0), after 30 rehabilitation sessions (T1), and three months after the end of rehabilitation (T2). RESULTS: A moderate/severe poststroke shoulder pain was reported by 28.9% of patients, while 19.6% of them showed a neuropathic component. At T0, the intensity of pain was higher in women and in patients with neglect syndrome, positively correlated with the time since stroke and disability and negatively correlated with motor function, strength, and the physical aspects of the quality of life.Moderate/severe pain and neuropathic component significantly reduced after both treatments and this reduction was maintained at T2. Finally, the intensity of pain at baseline was negatively correlated with the improvement of upper limb motor function. CONCLUSIONS: Poststroke shoulder pain negatively impact on motor performance, strength, disability, and physical aspects of the quality of life as well as on upper limb motor recovery; however, it can be reduced after a robotic or a conventional rehabilitation. Therefore, we suggest considering poststroke shoulder pain when planning the rehabilitation intervention.

Graphene oxide nanocomposite magnetic microbeads for the remediation of positively charged aromatic compounds.

Integrating graphene as an inorganic nanostructure within a hydrogel matrix enables the creation of a unique hybrid composite combining the peculiar chemical and physical properties of graphene with the high porosity and stability of hydrogels as for example agarose gel. As a consequence, the resulting material forms a double-network system providing advantages deriving from both the components. In this study, we present the synthesis of novel magnetic porous agarose-based graphene oxide microbeads for the adsorption and separation of positively charged aromatic molecules. The hydrogel-based graphene oxide beads revealed an ultrafast adsorption kinetics for positively charged aromatic dyes. We tested this material for the purification of fluorescent-tagged biomolecules. In addition, reduced graphene oxide microbeads were decorated with palladium nanoparticles, showing a high catalytic activity towards the reduction of dyes by sodium borohydride. Our results show that magnetic agarose based graphene microbeads with enhanced physical-chemical properties can be used for several biochemical applications.

Aerobic exercise and non-alcoholic fatty liver disease: a case report.

Non-alcoholic steatosis (non-alcoholic fatty liver disease [NAFLD]), now considered a metabolic pathway to advanced liver disease, cirrhosis and hepatocellular carcinoma, can also be explained by physical inactivity and increased dietary fat intake. No established treatment exists for this potentially serious disorder. The authors present the case of a 29-year-old man with NALFD who followed a restricted diet and practiced aerobic exercise for 16 weeks. Outcome after a combination therapy of aerobic exercise and diet was good, suggesting that treatment with a restricted diet and physical exercise can improve blood biochemical values in patients with NAFLD. Moderate-intensity aerobic exercise may help to normalize liver enzyme values and the quality of life of patients with fatty liver diseases.

The influence of metal nanoparticle size distribution in photoelectron spectroscopy.

We present an innovative approach to characterize small metal nanoclusters embedded in an amorphous carbon matrix. A simple mathematical relation linking binding energy shifts to the mean nanoparticle (NP) dimensions allows determination of the distribution of NP sizes by fitting the Au 4f X-ray photoemission spectrum. The NP size distributions obtained using our method are compared with those obtained from X-ray diffraction spectra.

Palladium nanoparticle functionalized graphene xerogel for catalytic dye reduction.

We report a method to synthesize a palladium-functionalized porous graphene xerogel structure. A graphene xerogel nanocomposite with a three-dimensional microstructure was obtained by chemical reduction of an aqueous dispersion of graphene oxide at mild temperature. After the graphene hydrogel has been placed in a K2PdCl4 solution, the spontaneous redox reaction between the reduced graphene and Pd2+ takes place, leading to the formation of nanohybrid materials consisting of a graphene porous matrix decorated with Pd nanoparticles. The final porosity of the material was tuned through drying the graphene hydrogel by solvent evaporation. The palladium functionalized porous graphene xerogels were successfully used for the catalytic reduction of Rhodamine 6G.

Plasma assisted surface treatments of biomaterials.

The biocompatibility of an implant depends upon the material it is composed of, in addition to the prosthetic device's morphology, mechanical and surface properties. Properties as porosity and pore size should allow, when required, cells penetration and proliferation. Stiffness and strength, that depend on the bulk characteristics of the material, should match the mechanical requirements of the prosthetic applications. Surface properties should allow integration in the surrounding tissues by activating proper communication pathways with the surrounding cells. Bulk and surface properties are not interconnected, and for instance a bone prosthesis could possess the necessary stiffness and strength for the application omitting out prerequisite surface properties essential for the osteointegration. In this case, surface treatment is mandatory and can be accomplished using various techniques such as applying coatings to the prosthesis, ion beams, chemical grafting or modification, low temperature plasma, or a combination of the aforementioned. Low temperature plasma-based techniques have gained increasing consensus for the surface modification of biomaterials for being effective and competitive compared to other ways to introduce surface functionalities. In this paper we review plasma processing techniques and describe potentialities and applications of plasma to tailor the interface of biomaterials.

Unusual pleural effusion from vulvar squamous cell carcinoma: report of a case and review of the literature.

Vulvar tumors are not very common and account for about 4% of all cancers affecting the female genital organs. Frequently, malignant neoplasia of this site have squamous phenotype and the rare cases of metastasization are reported in the locoregional lymph nodes and in the surrounding organs. We report a case of metastasization of a vulvar squamous cell carcinoma in an unusual place such as the parietal pleura, in a relapsing patient that was submitted to a surgical vulvectomy the previous year.

The binding of bilirubin to albumin. A study using spin-labelled bilirubin.

Binding between human serum albumin and a spin-labelled derivative of bilirubin was investigated by circular dichroism, fluorescence quenching, electron spin resonance and visible spectroscopy. The orders of magnitude of the binding constants obtained by flurorescence quenching and electron spin resonance spectroscopies were 10(7) and 10(3) 1 . mol-1, respectively. These data suggest that most spin-labelled bilirubin interacts with human serum albumin at the side not holding the spin-labelled side-arm. CD measurements showed the presence of at least two sites, associated with opposite Cotton effects. It is worthy of note that the Cotton sign of the first site is inverted with respect to the corresponding one of bilirubin. CD measurements on mixed systems (spin-labelled bilirubin/human serum albumin/bilirubin) were also performed. The decomposition of the ternary curves shows that the rotatory power of bilirubin bound to human serum albumin is higher in the ternary system than in the binary (bilirubin/human serum albumin). The corresponding CD measurements for the binding between spin-labelled bilirubin and bovine serum albumin are also reported and discussed.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Role of chemical interactions in bacterial adhesion to polymer surfaces.

Development of biomaterial-related infections is attracting an increasing interest due to the significant percentage of implant failure in the hospital care. Recent literature puts in evidence the dependence of the infection risk on the different biomaterials used, because of the different interactions between material surface and micro-organisms. Despite this, the mechanisms underlying the adhesion of bacteria to the biomaterial surface are still unclear. Aim of this work is to study the initial events of the processes responsible for the bacterial adhesion on polymers in order to prevent the development of bacterial infections and the consequent failure and replacement of biomedical devices. Electrostatic and Lifshitz-van der Waals forces are usually considered responsible for the interactions at the biomaterial interface. A new term that involves Lewis acid-base interactions is here introduced to better describe the bacterial adhesion to the polymer surface. Two requirements are needed to test this hypothesis: the development of an ideal polymeric surface in terms of chemical and morphological properties and the choice of a specific bacterial strain to be utilized as "probe". Experiments were worked out using an Escherichia coli (Gram-) strain that represent one of the principal isolates from infected biomaterial implants and its adhesion was investigated on polymers having different acid/basic character. The findings indicate that the bacterial adhesion is influenced by the chemical properties of the polymeric surface. These results may be interpreted taking into account a mechanism in which the acid/base (Lewis) interaction plays an important role.

Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy.

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2 (TxA2), we tested whether TxA2 plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2 exposure from postnatal days 5-14) was associated with increased TxB2 generation and was significantly prevented by TxA2 synthase inhibitor CGS-12970 (10 mg x kg(-1) x day(-1)) or TxA2-receptor antagonist CGS-22652 (10 mg x kg(-1) x day(-1)). TxA2 mimetics U-46619 (EC50 50 nM) and I-BOP (EC50 5 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2 formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2 in vasoobliteration of OIR and unveil a so far unknown function for TxA2 in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2 might participate in other ischemic neurovascular injuries.

Aryl and triterpenic glycosides from Margyricarpus setosus.

Investigation of aerial parts of Margyricarpus setosus afforded three new aryl glycosides, beta-hydroxyphenylethyl-O-alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside, benzyl-O-alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside, 4-methoxybenzyl-O-alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside, and three new triterpene glycosides, tormentic acid 3 beta-O-beta-D-quinovopyranoside, tormentic acid 3 beta-O-beta-D-fucopyranoside and tormentic acid 3 beta-O-alpha-L-rhamnopyranoside. Twelve known compounds were also found, among them beta-hydroxy-3',4'-dimethoxyphenylethyl glucoside and beta-hydroxy-3',4'-dimethoxyphenylethyl rutinoside, which were obtained previously by partial synthesis, were isolated for the first time from a natural source. The structures of the new compounds were elucidated on the basis of chemical and spectral data.

Studies on the constituents of Cyclanthera pedata fruits: isolation and structure elucidation of new triterpenoid saponins.

The isolation of nine triterpenoid saponins (1-9), among them six new natural compounds (1-6), from the MeOH extract of the fruits of Cyclanthera pedata is reported. All of the structures were elucidated by spectroscopic methods, including the concerted application of one-dimensional (1)H-(1)H total correlation spectroscopy, (1)H-(1)H nuclear Overhauser effect spectroscopy), and (13)C-(13)C DEPT-NMR and two-dimensional NMR techniques (double-quantum filtered correlated spectroscopy, rotating-frame Overhauser enhancement spectroscopy, heteronuclear single quantum coherence, and heteronuclear multiple bond correlation). A comparative study of seeds and fruits has been also carried out.

Beat-to-beat measurement and analysis of the R-T interval in 24 h ECG Holter recordings.

This study assesses the feasibility of beat-to-beat measurement of the R-T interval in Holter ECG recordings. The low sampling rate of the Holter system was increased by a specific interpolating filter, and the precision and accuracy of two T-wave fiducial point (T-wave maximum: Tm, T-wave end: Te) detection algorithms were compared. The results of the validation tests show better performance of the Tm measurement procedure in the presence of high noise levels. The overall process for the beat-to-beat R-T interval measurement was then tested on ECG Holter recordings collected during free and controlled respiration. Finally, the R-Tm and the corresponding R-R intervals were measured on 24 h ECG recordings of healthy subjects and the spectral analysis was applied to the constructed series. Both R-R and R-Tm spectra show two main frequency components (low-frequency approximately 0.1 Hz, high-frequency approximately 0.25 Hz) changing in their power ratios continuously throughout the 24 h period. The method described seems to provide a dynamic index of the sympatho-vagal balance at the ventricle that can be useful for a deeper understanding of ventricular repolarisation duration variability.

Improved late potential analysis in frequency domain.

This work presents a technique to improve the identification of late potentials (LP) in patients affected by greater arrhythmogenic right ventricular disease (GARVD). Several authors have documented the correlation between GARVD and LP by means of time domain analysis. Moreover, the high incidence of bundle branch block in patients affected by GARVD suggests LP analysis in the frequency domain be performed. The method of spectral mapping of the ECG with Fourier transform was adopted. This consists in dividing the ST segment into 25 subsegments and estimating their frequency components by means of the fast Fourier transform. Recently, it was documented that this technique suffers from poor reproducibility of results. Low reproducibility is the consequence of an improper localization of the analysed QRS segments. An algorithm to increase the QRS end point identification reproducibility is proposed. An optimal QRS filter was adopted as well as a technique based on the Hilbert transform. This technique allowed the reliability of the normality factor estimates to be improved. The computed normality factors on the XYZ leads and on the vector magnitude were used to classify patients and healthy subjects; 28 patients affected by greater arrhythmogenic right ventricular disease and 35 healthy subjects were analysed in the study. High sensitivity was obtained with respect to GARVD and clinical sustained ventricular tachycardia by means of a cluster analysis technique. By applying the technique proposed in this paper the identification of LP in GARVD was increased from 47% to 88%, when clinical sustained ventricular tachycardia was documented, whereas in patients affected by GARVD but not prone to sustained ventricular tachycardia LP identification increases from 18% to 64%.