A multistate model for early decision making in oncology

The development of oncology drugs progresses through multiple phases, where after each phase a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single arm studies based on RECIST tumor response as endpoint. This decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS). The surrogacy is most often assessed as weak, but sufficient to allow a rapid decision making as early phase studies lack the survival follow up and number of patients to properly assess PFS or OS. With the emergence of therapies with new mechanisms of action, for which the link between RECIST tumor response and long-term endpoints is either not accessible yet because not enough data is available to perform a meta-regression, or the link is weaker than with classical chemotherapies, tumor response based rules may not be optimal. In this paper, we explore the use of a multistate model for decision making based on single-arm early phase trials. The multistate model allows to account for more information than the simple RECIST response status, namely, the time to get to response, the duration of response, the PFS time and time to death. We propose to base the decision on efficacy on the OS hazard ratio (HR), predicted from a multistate model based on early phase data with limited survival follow-up, combined with historical control data. Using three case studies and simulations, we illustrate the feasibility of the estimation of the OS HR using a multistate model based on limited data from early phase studies. We argue that, in the presence of limited follow up and small sample size, and on assumptions within the multistate model, the OS prediction is acceptable and may lead to better decisions for continuing the development of a drug

Biological effects of cigarette smoke in cultured human retinal pigment epithelial cells.

The goal of the present study was to determine whether treatment with cigarette smoke extract (CSE) induces cell loss, cellular senescence, and extracellular matrix (ECM) synthesis in primary human retinal pigment epithelial (RPE) cells. Primary cultured human RPE cells were exposed to 2, 4, 8, and 12% of CSE concentration for 24 hours. Cell loss was detected by cell viability assay. Lipid peroxidation was assessed by loss of cis-parinaric acid (PNA) fluorescence. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was detected by histochemical staining. Expression of apolipoprotein J (Apo J), connective tissue growth factor (CTGF), fibronectin, and laminin were examined by real-time PCR, western blot, or ELISA experiments. The results showed that exposure of cells to 12% of CSE concentration induced cell death, while treatment of cells with 2, 4, and 8% CSE increased lipid peroxidation. Exposure to 8% of CSE markedly increased the number of SA-ß-Gal positive cells to up to 82%, and the mRNA expression of Apo J, CTGF, and fibronectin by approximately 3-4 fold. Treatment with 8% of CSE also increased the protein expression of Apo J and CTGF and the secretion of fibronectin and laminin. Thus, treatment with CSE can induce cell loss, senescent changes, and ECM synthesis in primary human RPE cells. It may be speculated that cigarette smoke could be involved in cellular events in RPE cells as seen in age-related macular degeneration

Kinematic analysis of handwriting movements in patients with Alzheimer's disease, mild cognitive impairment, depression and healthy subjects

A variety of studies have demonstrated that motor disorders, parkinsonism and extrapyramidal motor symptoms (EPMS) are common in patients with Alzheimer's disease (AD). Several studies have reported an association of EPMS with severity, progression and poor prognosis of AD. The majority of these studies used clinical assessments for the rating of EPMS. In this study, kinematic handwriting analysis was used to quantify differences in fine hand motor function in patients with probable AD and mild cognitive impairment (MCl, as an assumed initial stage of AD) compared to depressed patients and healthy controls. Both patients with MCl and patients with probable AD exhibited loss of fine motor performance. Movements of AD patients were significantly less regular than those of healthy controls. Copyright (C) 2003 S. Karger AG, Basel

Die Isomerisierung der Homoadamantan-3-carbonsäure zur Homoadamantan-1-carbonsäure

Durch D-, 13C- und Doppelmarkierungsexperimente wird gezeigt, daß die Isomerisierung der Homoadamantan-3-carbonsäure (2) zur Homoadamantan-1-carbonsäure (3) unter den Bedingungen der Koch-Haaf-Synthese durch reversible Decarbonylierung zustande kommt, die von intermolekularem Hydridtransfer zwischen den Brückenkopfpositionen der Homoadamantan-1-und Homoadamantan-3-carbenium-Ionen und Homoadamantanderivaten begleitet ist. Die Umlagerung ist mit Äquilibrierung der Isotopenmarkierung aller Methylengruppen verbunden. Hierfür wird die gleichzeitig stattfindende bekannte Adamantylmethyl-3-Homoadamantylcarbenium-Umlagerung verantwortlich gemacht. Im Gegensatz zu Hydridübertragungen im Adamantyl-system beteiligen sich die Methylenwasserstoffe des Homoadamantylsystems nicht an der Hydridübertragung zwischen den Brückenköpfen

Process Development of a Generative Method for Partial and Controlled Integration of Active Substances into Open-Porous Matrix Structures

A special generative manufacturing (AM) process was developed for the partial integration of active ingredients into open-porous matrix structures. A mixture of a silver-containing solution as an antibacterial material with an alginate hydrogel as a carrier system was produced as the active ingredient. The AM process developed was used to introduce the active ingredient solution into an open-porous niobium containing a β-titanium matrix structure, thus creating a reproducible active ingredient delivery system. The matrix structure had already been produced in a separate AM process by means of selective laser melting (SLM). The main advantage of this process is the ability to control porosity with high precision. To determine optimal surface conditions for the integration of active ingredients into the matrix structure, different surface conditions of the titanium substrate were tested for their impact on wetting behaviour of a silver-containing hydrogel solution. The solution-substrate contact angle was measured and evaluated to determine the most favourable surface condition. To develop the generative manufacturing process, an FDM printer underwent modifications that permitted partial application of the drug solution to the structure in accordance with the bioprinting principle. The modified process enabled flexible control and programming of both the position and volume of the applied drug. Furthermore, the process was able to fill up to 95% of the titanium matrix body pore volume used. The customised application of drug carriers onto implants as a drug delivery system can be achieved via the developed process, providing an alternative to established methods like dip coating that lack this capability

The use of external controls: To what extent can it currently be recommended?

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials. Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace randomized clinical trials as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research. However, it remains unclear in which situations conclusions about efficacy and a positive benefit/risk can reliably be based on the use of an external control. This paper will provide an overview on types of external control, their applications and the different sources of bias their use may incur, and discuss potential mitigation steps. It will also give recommendations on how the use of external controls can be justified

Online analysis of oxygen inside silicon-glass microreactors with integrated optical sensors

AbstractA powerful online analysis set-up for oxygen measurements within microfluidic devices is presented. It features integration of optical oxygen sensors into microreactors, which enables contactless, accurate and inexpensive readout using commercially available oxygen meters via luminescent lifetime measurements in the frequency domain (phase shifts). The fabrication and patterning of sensor layers down to a size of 100μm in diameter is performed via automated airbrush spraying and was used for the integration into silicon-glass microreactors. A novel and easily processable sensor material is also presented and consists of a polystyrene- silicone rubber composite matrix with embedded palladium(II) or platinum(II) meso-tetra(4-fluorophenyl) tetrabenzoporphyrin (PdTPTBPF and PtTPTBPF) as oxygen sensitive dye. The resulting sensor layers have several advantages such as being excitable with red light, emitting in the near-infrared spectral region, being photostable and covering a wide oxygen concentration range. The trace oxygen sensor (PdTPTBPF) in particular shows a resolution of 0.06–0.22hPa at oxygen concentrations lower than 20hPa (<2% oxygen) and the normal range oxygen sensor (PtTPTBPF) shows a resolution of 0.2–0.6hPa at low oxygen concentrations (<50hPa) and 1–2hPa at ambient air oxygen concentrations. The sensors were integrated into different silicon-glass microreactors which were manufactured using mass production compatible processes. The obtained microreactors were applied for online monitoring of enzyme transformations, including d-alanine or d-phenylalanine oxidation by d-amino acid oxidase, and glucose oxidation by glucose oxidase

Geothermal Potential of the Brenner Base Tunnel—Initial Evaluations

Increasing demands on mobility and transport, but limited space above ground, lead to new traffic routes being built, even more underground in the form of tunnels. In addition to improving the traffic situation, tunnels offer the possibility of contributing to climate-friendly heating by indirectly serving as geothermal power plants. In this study, the geothermal potential of the future longest railway tunnel in the world, the Brenner Base Tunnel, was evaluated. At the Brenner Base Tunnel, warm water naturally flows from the apex of the tunnel towards the city of Innsbruck, Austria. In order to estimate its geothermal potential, hydrological data of discharge rates and temperatures were investigated and analyzed. The investigations indicated the highest geothermal potential in the summertime, while the lowest occurs during winter. It could be shown that these variations were a result of cooling during discharge through areas of low overburden (mid mountain range), where the tunnel atmosphere is increasingly influenced by the air temperatures outside the tunnel. Nevertheless, the calculations showed that there will be a usable potential after completion of the tunnel

Statistical and data reporting guidelines for the European Journal of Cardio-Thoracic Surgery and the Interactive CardioVascular and Thoracic Surgery

As part of the peer review process for the European Journal of Cardio-Thoracic Surgery (EJCTS) and the Interactive CardioVascular and Thoracic Surgery (ICVTS), a statistician reviews any manuscript that includes a statistical analysis. To facilitate authors considering submitting a manuscript and to make it clearer about the expectations of the statistical reviewers, we present up-to-date guidelines for authors on statistical and data reporting specifically in these journals. The number of statistical methods used in the cardiothoracic literature is vast, as are the ways in which data are presented. Therefore, we narrow the scope of these guidelines to cover the most common applications submitted to the EJCTS and ICVTS, focusing in particular on those that the statistical reviewers most frequently comment o