Genomic markers for decision making:What is preventing us from using markers?

The advent of novel genomic technologies that enable the evaluation of genomic alterations on a genome-wide scale has significantly altered the field of genomic marker research in solid tumors. Researchers have moved away from the traditional model of identifying a particular genomic alteration and evaluating the association between this finding and a clinical outcome measure to a new approach involving the identification and measurement of multiple genomic markers simultaneously within clinical studies. This in turn has presented additional challenges in considering the use of genomic markers in oncology, such as clinical study design, reproducibility and interpretation and reporting of results. This Review will explore these challenges, focusing on microarray-based gene-expression profiling, and highlights some common failings in study design that have impacted on the use of putative genomic markers in the clinic. Despite these rapid technological advances there is still a paucity of genomic markers in routine clinical use at present. A rational and focused approach to the evaluation and validation of genomic markers is needed, whereby analytically validated markers are investigated in clinical studies that are adequately powered and have pre-defined patient populations and study endpoints. Furthermore, novel adaptive clinical trial designs, incorporating putative genomic markers into prospective clinical trials, will enable the evaluation of these markers in a rigorous and timely fashion. Such approaches have the potential to facilitate the implementation of such markers into routine clinical practice and consequently enable the rational and tailored use of cancer therapies for individual patients. © 2010 Macmillan Publishers Limited. All rights reserved.

Genomic meningococcal load in the nasopharynx of children with meningococcal disease

This study demonstrates the feasibility of using quantitative real time PCR to measure genomic bacterial load in the nasopharynx of children with invasive meningococcal disease and shows that these loads are exceptionally high (median 6.6 x 105 (Range 1.2 x 105 to 1.1 x 108) genome copies of Neisseria meningitidis per swab).

The impact of hydrogeology on the instability of a road cutting through a drumlin in the North of Ireland

This paper describes the hydrogeological processes which caused unexpected instability and quick conditions during the excavation of a 25m deep cutting through a drumlin in County Down, Northern Ireland. A conceptual hydrogeological model of the cutting, based on pore pressures monitored during and after the excavation demonstrates how quick conditions at the toe of the cutting caused liquefaction of the till. Stability of the cutting was re-established by draining the highly permeable, weathered Greywacke which underlies the drumlin, through the use of a deep toe drain. In spite of this drainage, the cutting was only marginally stable due to the presence of a low permeability zone in the till above the bedrock which limits the reduction of elevated pore pressures within the upper to mid-depths of the drumlin. The factor of safety has been further improved by the addition of vertical relief drains at the crest and berm of the cutting to relieve the pore-pressures within the upper till by intercepting the weathered bedrock. The paper also highlights the importance of carrying out an adequate site investigation compliant with Eurocode 7 and additional monitoring in excavations in stiff, low permeability till.

Molecular Subtypes and Personalized Therapy in Metastatic Colorectal Cancer

Development of colorectal cancer occurs via a number of key pathways, with the clinicopathological features of specific subgroups being driven by underlying molecular changes. Mutations in key genes within the network of signalling pathways have been identified; however, therapeutic strategies to target these aberrations remain limited. As understanding of the biology of colorectal cancer has improved, this has led to a move toward broader genomic testing, collaborative research and innovative, adaptive clinical trial design. Recent developments in therapy include the routine adoption of wider mutational spectrum testing prior to use of targeted therapies and the first promise of effective immunotherapy for colorectal cancer patients. This review details current biomarkers in colorectal cancer for molecular stratification and for treatment allocation purposes, including open and planned precision medicine trials. Advances in our understanding, therapeutic strategy and technology will also be outlined.