Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

Abstract Introduction Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively. Conclusions Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy

Cell Behaviour of the Biomimetic Modifications on a New TiHfNb Alloy Developed for Orthopaedic Applications

The field of cellular behaviour and the biomimetic modifications on inorganic materials destined for biomedical applications shows a remarkable increase in scientific studies and, therefore, this is reflected in the investment priorities and the fundamental effort of the global research community in this area. The essential purpose of this study is to assessment the cellular behaviour of a novel TiHfNb alloy with biomimetic modification. For the mimic surface, the samples were initially bioactive with oxygen plasma or with piranha, then the following samples were biofunctionalized with APTES + maleimide and finally different surface peptide sequences were immobilized (RGD, FHRRIKA, PHSRN or 50/50 mixtures of RGD / FHRRIKA or RGD / PHSRN). To evaluate the biomimetic modification, adhesion and cell proliferation studies were carried out. Different techniques for chemical characterization were used, including: X-ray photoelectron spectroscopy (XPS), contact angle (CA), immunofluorescence, scanning electron microscope (SEM) and lactate dehydrogenase (LDH). With respect to the different peptide sequences used, the results indicated that the samples with RGD and the mixture exhibited more extended cells on the surface. © Published under licence by IOP Publishing Ltd.Peer reviewe

The phase problem in crystallography

The candidate's early work in the area of direct methods in crystallography was mainly concerned with pulling together strands of development that were going on in various parts of the world and incorporating them in his computer package MITHRIL. At the same time he began investigations of his own into the application of quartets by which the power of the earlier direct methods could be extended. It is his work in the last decade that has been his greatest contribution to crystallography. He was early in the field in the application of the maximum entropy method, a method that had been previously used by astronomers for some time in improving noisy images. Maximum entropy was introduced into crystallography via a massive paper by Professor G Bricogne with extravagant claims for what it could achieve. It quickly became clear that these extreme claims were unfounded and, to some extent, disillusionment set in with respect to the method. However, maximum entropy was actually a useful concept with a great deal to offer but this required careful and painstaking work to reveal. It is in effectively applying the maximum entropy idea in a variety of crystallographic situations that Professor Gilmore has made his seminal contributions. What is so impressive is the range of applications to which he has applied the method and the ingenuity of the applications. Through its use he has contributed in the studies involving powders, proteins and electron diffraction data from bulk and surface studies. The candidate has established a leading world position in the application of the maximum entropy method and would be the first to be approached by anyone seeking advice in this field. He has brought credit to the University of Glasgow and I recommend without any qualification that he should be awarded the degree of Doctor of Science. (author)SIGLEAvailable from British Library Document Supply Centre-DSC:DXN035638 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Comparative study of surface chemical composition and oxide layer modification upon oxygen plasma cleaning and piranha etching on a novel low elastic modulus Ti25Nb21Hf alloy

Metals are widely employed for many biological artificial replacements, and it is known that the quality and the physical/chemical properties of the surface are crucial for the success of the implant. Therefore, control over surface implant materials and their elastic moduli may be crucial to avoid undesired effects. In this study, surface modification upon cleaning and activation of a low elastic modulus Ti alloy (Ti25Hf21Nb) was investigated. Two different methods, oxygen plasma (OP) cleaning and piranha (PI) solution, were studied and compared. Both surface treatments were effective for organic contaminant removal and to increase the Ti-oxide layer thickness rather than other metal-oxides present at the surface, which is beneficial for biocompatibility of the material. Furthermore, both techniques drastically increased hydrophilicity and introduced oxidation and hydroxylation (OH)-functional groups at the surface that may be beneficial for further chemical modifications. However, these treatments did not alter the surface roughness and bulk material properties. The surfaces were fully characterized in terms of surface roughness, wettability, oxide layer composition, and hydroxyl surface density through analytical techniques (interferometry, X-ray photoelectron spectroscopy (XPS), contact angle, and zinc complexation). These findings provide essential information when planning surface modifications for cleanliness, oxide layer thickness, and surface hydroxyl density, as control over these factors is essential for many applications, especially in biomaterials.Peer Reviewe

Study on the use of 3-aminopropyltriethoxysilane and 3-chloropropyltriethoxysilane to surface biochemical modification of a novel low elastic modulus Ti-Nb-Hf alloy

A biocompatible new titanium alloy Ti-16Hf-25Nb with low elastic modulus (45 GPa) and the use of short bioadhesive peptides derived from the extracellular matrix have been studied. In terms of cell adhesion, a comparative study with mixtures of short peptides as RGD (Arg-Gly-Asp)/PHSRN (Pro-His-Ser-Arg-Asn) and RGD (Arg-Gly-Asp)/FHRRIKA (Phe-His-Arg-Arg-Ile-Lys-Ala) have been carried out with rat mesenchymal cells. The effect of these mixtures of short peptides have already been studied but there are no comparative studies between them. Despite the wide variety of silane precursors available for surface modification in pure titanium, the majority of studies have used aminosilanes, in particular 3-minopropyltriethoxysilane (APTES). Nevertheless, the 3-chloropropyltriethoxysilane (CPTES) is, recently, proposed by other authors. Unlike APTES, CPTES does not require an activation step and offers the potential to directly bind the nucleophilic groups present on the biomolecule (e.g., amines or thiols). Since the chemical surface composition of this new alloy could be different to that pure titanium, both organosilanes have been compared and characterized by means of a complete surface characterization using contact angle goniometry and X-ray photoelectron spectroscopy. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B:495-502, 2015.Peer ReviewedPostprint (author's final draft

Assessment and comparison of surface chemical composition and oxide layer modification upon two different activation methods on a CoCrMo alloy

This study investigated the effect of two different activation methods on the surface chemical composition of a CoCrMo-alloy. The activation was performed with oxygen plasma (OP) or nitric acid (NA). The surface physical– chemical properties were thoroughly characterized by means of several analytical techniques: X-ray photoelectron spec- troscopy (XPS), time-of-flight secondary ion mass spec- trometry (ToF-SIMS), zinc-complex substitution technique, contact angle, and interferometry. The surface modification was evaluated by assessing contamination removal, the ‘‘active’’ hydroxyl groups (OH-act) present at the surface, the metal oxide ratio (Co y O x - /Cr y O x - ) and changes in the chem- ical composition and topography of the oxide layer. XPS experimental data showed for both methods (OP and NA) a significant decrease of the carbon contents (C 1 s ) associated with contaminants and at the same time changes in the atomic composition of the oxide layer (O 1 s ). In addition, the O 1 s XPS spectra showed differences between the percentage of OH - before and after OP or NA treatment, leading to the conclusion that both methods are effective for surface ‘‘cleaning’’ and activation. These results were further inves- tigated and corroborated by ToF-SIMS analysis and zinc complex substitution technique. The general conclusion was that NA is more efficient in terms of contaminants removal and generation of accessible OH-act present at the surface and without altering the native metal oxide ratio (Co y O x - /Cr y O x - ) considered to be essential for biocompatibility.Peer Reviewe

Dynamic point location in general subdivisions

The dynamic planar point location problem is the task of maintaining a dynamic set S of n non-intersecting, except possibly at endpoints, line segments in the plane under the following operations: Locate (q: point): Report the segment immediately above q, i.e., the first segment intersected by an upward vertical ray starting at q; Insert (s: segment): Add segment s to the collection of S of segments; Delete (s: segment): Remove segment s from the collectection S of segments. We present a solution which requires space O(n), has query and insertion time O(log n log log n) and deletion time O(log"2n). A query below O(log"2n) was previously only known for monotone subdivisions and horizontal segments and required non-linear space. (orig.)SIGLEAvailable from TIB Hannover: RR 2036(16) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Collagen-functionalised titanium surfaces for biological sealing of dental implants: Effect of immobilisation process on fibroblasts response

The clinical success of a dental implant requires not only an optimum osseointegration, but also the development of a biological sealing; i.e., a soft tissue seal around the transmucosal part of the implant. A promising approach to improve the biological seal of dental implants is the biomimetic modification of titanium surfaces with proteins or peptides that have specific cell-binding moieties. In this work we investigated the process of immobilising collagen on smooth and rough titanium surfaces and its effect on human dermal fibroblast (HDF) cell response. Titanium samples were activated by either oxygen plasma or acid etching to generate a smooth or nanorough surface, respectively. Subsequently, collagen grafting was achieved by either physisorption or covalent bonding through organosilane chemistry. The biofunctionalised titanium samples were then tested for stability and characterised by fluorescent labelling, wettability, OWLS and XPS studies. Biological characterisation was also performed through HDF adhesion, proliferation and gene expression. Covalent-bonded collagen showed higher stability than physisorbed collagen. A significant overexpression of the genes involved in fibroblast activation and extracellular matrix remodelling was observed in the collagen-coated surfaces. This effect was more pronounced on smooth than on rough surfaces. Immobilised collagen on the smooth plasma-treated surfaces favoured both fibroblast adhesion and activation. This study provides essential information for the design of implants with optimal biological sealing, a key aspect to avoid peri-implantitis and ensure long-lasting implant fixation. (C) 2014 Elsevier B.V. All rights reserved.Peer ReviewedPostprint (published version

Study on the use of 3-aminopropyltriethoxysilane and 3-chloropropyltriethoxysilane to surface biochemical modification of a novel low elastic modulus Ti-Nb-Hf alloy

A biocompatible new titanium alloy Ti-16Hf-25Nb with low elastic modulus (45 GPa) and the use of short bioadhesive peptides derived from the extracellular matrix have been studied. In terms of cell adhesion, a comparative study with mixtures of short peptides as RGD (Arg-Gly-Asp)/PHSRN (Pro-His-Ser-Arg-Asn) and RGD (Arg-Gly-Asp)/FHRRIKA (Phe-His-Arg-Arg-Ile-Lys-Ala) have been carried out with rat mesenchymal cells. The effect of these mixtures of short peptides have already been studied but there are no comparative studies between them. Despite the wide variety of silane precursors available for surface modification in pure titanium, the majority of studies have used aminosilanes, in particular 3-minopropyltriethoxysilane (APTES). Nevertheless, the 3-chloropropyltriethoxysilane (CPTES) is, recently, proposed by other authors. Unlike APTES, CPTES does not require an activation step and offers the potential to directly bind the nucleophilic groups present on the biomolecule (e.g., amines or thiols). Since the chemical surface composition of this new alloy could be different to that pure titanium, both organosilanes have been compared and characterized by means of a complete surface characterization using contact angle goniometry and X-ray photoelectron spectroscopy. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B:495-502, 2015.Peer Reviewe