Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

A two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m−2 over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35–82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1–21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8–31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2′-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile

The total margin of exposure of ethanol and acetaldehyde for heavy drinkers consuming cider or vodka

Heavy drinkers in Scotland may consume 1600 g ethanol per week. Due to its low price, cider may bepreferred over other beverages. Anecdotal evidence has linked cider to specific health hazards beyondother alcoholic beverages. To examine this hypothesis, nine apple and pear cider samples were chemicallyanalysed for constituents and contaminants. None of the products exceeded regulatory or toxicologicalthresholds, but the regular occurrence of acetaldehyde in cider was detected. To provide aquantitative risk assessment, two collectives of exclusive drinkers of cider and vodka were compared andthe intake of acetaldehyde was estimated using probabilistic MonteeCarlo type analysis. The ciderconsumers were found to ingest more than 200-times the amount of acetaldehyde consumed by vodkaconsumers. The margins of exposure (MOE) of acetaldehyde were 224 for the cider and over 220,000 forvodka consumers. However, if the effects of ethanol were considered in a cumulative assessment of thecombined MOE, the effect of acetaldehyde was minor and the combined MOE for both groups was 0.3.We suggest that alcohol policy priority should be given on reducing ethanol intake by measures such asminimum pricing, rather than to focus on acetaldehyde

Proceedings of the 2003 Winter Simulation Conference

In this paper we have applied an interval representation of time to represent and reason about activities, events, actions and situations relevant to the construction domain. The first part of the paper formally defines the situational simulation environment and develops a set of temporal axioms which can be used to 1) Express precedence constraints between time intervals and 2) Capture the causal relationships between actions and events. The second part of the paper looks at an agent reasoning mechanism used to perceive and predict actions and foresee future consequences of present actions within the simulation environment. Agent reasoning is based on awareness derived from a knowledge base of facts which captures the causal nature of events in the construction management domain

Advanced materials and electrochemical processes in high-temperature solid electrolytes

Fuel cells for the direct conversion of fossil fuels to electric energy necessitates the use of high-temperature solid electrodes. This study has included: (1) determination of electrical transport, thermal and electrical properties to illucidate the effects of microstructure, phase equilibria, oxygen partial pressure, additives, synthesis and fabrication on these properties; (2) investigation of synthesis and fabrication of advanced oxide materials, such as La{sub 0.9}Sn{sub 0.1}MnO{sub 3}; and (3) application of new analytical techniques using complex impedance coupled with conventional electrochemical methods to study the electrochemical processes and behavior of materials for solid oxide fuel cells and other high-temperature electrolyte electrochemical process. 15 refs., 10 figs., 2 tabs. (BM

The Real (Social) Experience of Monetary Policy

This paper takes a socio-economic approach to considering money in relation to real experience, focusing on the real effects of monetary policy. While most of the economics literature focuses on interest-rate setting as the core tool of monetary policy, we focus here instead on signalling by the central bank as a mechanism for influencing expectations and behaviour in conditions of uncertainty. This involves addressing the social-conventional expectations among different groups (a mechanism for dealing with uncertainty) applied to their particular ways of framing the real and financial sectors. Actual credit conditions faced by borrowers in turn are the outcome of the conventional view among banks as a result of their framing and the influence of central bank signalling. These relations between central banks, banks and the non-bank public in turn normally rest on long-established relations of trust. We consider the real effects of monetary policy in circumstances where trust has broken down