Molecular biomarkers in non-small-cell lung cancer : a retrospective analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. Methods: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. Findings: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). Interpretation: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Funding: Merck KGaA. © 2011 Elsevier Ltd.

Studies in terpenoids. Part 42. Synthesis of 3-(2-hydroxyisopropyl)5,8-dimethyl-1,2-naphthoquinone (emmotin-H)

Emmotin-H, a naturally occurring sesquiterpenoid 1,2-naphthoquinone pigment (1) has been synthesised in a four step sequence starting from the known 5,8-dimethyl-4-oxotetralin-2-carboxylic acid (3a). Selenium dioxide oxidation of its methyl ester (3b) gives 3-methoxycarbonyl-5,8-dimethyl-1,2-naphthoquinone (4) which on reductive acetylation affords the corresponding diacetoxynaphthalene ester (5). Its reaction with excess of methylmagnesium iodide is accompanied by aerial oxidation during work-up and furnishes emmotin-H (1).

Efficient Implementation of Spatially-Varying 3-D Ultrasound Deconvolution

Abstract—There are sometimes occasions when ultrasound beamforming is performed with only a subset of the total data that will eventually be available. The most obvious example is a mechanically-swept (wobbler) probe in which the three-dimensional data block is formed from a set of individual B-scans. In these circumstances, non-blind deconvolution can be used to improve the resolution of the data. Unfortunately, most of these situations involve large blocks of three-dimensional data. Furthermore, the ultrasound blur function varies spatially with distance from the transducer. These two facts make the deconvolution process time-consuming to implement. This paper is about ways to address this problem and produce spatially-varying deconvolution of large blocks of three-dimensional data in a matter of seconds. We present two approaches, one based on hardware and the other based on software. We compare the time they each take to achieve similar results and discuss the computational resources and form of blur model that each requires.

用1-苯基-3-甲基-4-苯甲酰基-5-吡唑啉酮从硝酸中萃取痕量钍

用1-苯基-3-甲基-4-苯甲酰基-5-吡唑啉酮(PMBP)为萃取剂,~(234)Th作示踪剂,完成了在硝酸介质中痕量钍溶剂萃取行为的研究。在~(234)Th萃取效率与酸度、萃取剂浓度、平衡时间等依赖关系的条件实验的基础上,获得了萃取钍的最佳条件。使用改进的PMBP萃取钍的流程,从~(18)O离子辐照过的铀靶中分离钍,钍样品的γ射线单谱显示绝大部分反应产物和大量铀的去除是满意的。