The impact of personalised therapies on respiratory medicine

Stratified approaches to treating disease are very attractive, as efficacy is maximised by identifying responders using a companion diagnostic or by careful phenotyping. This approach will spare non-responders form potential side-effects. This has been pioneered in oncology where single genes or gene signatures indicate tumours that will respond to specific chemotherapies. Stratified approaches to the treatment of asthma with biological therapies are currently being extensively studied. In cystic fibrosis (CF), therapies have been developed that are targeted at specific functional classes of mutations. Ivacaftor, the first of such therapies, potentiates dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein Class III mutations and is now available in the USA and some European countries. Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Symptom scores are also greatly improved to a level that indicates that this is a transformational treatment for many patients. This stratified approach to the development of therapies based on the functional class of the mutations in CF is likely to lead to new drugs or combinations that will correct the basic defect in many patients with CF. © ERS 2013.

Forensic analysis of architectural finishes using fourier transform infrared and raman spectroscopy, part II:White paint

White household paints are commonly encountered as evidence in the forensic laboratory but they often cannot be readily distinguished by color alone so Fourier transform infrared (FT-IR) microscopy is used since it can sometimes discriminate between paints prepared with different organic resins. Here we report the first comparative study of FT-IR and Raman spectroscopy for forensic analysis of white paint. Both techniques allowed the 51 white paint samples in the study to be classified by inspection as either belonging to distinct groups or as unique samples. FT-IR gave five groups and four unique samples; Raman gave seven groups and six unique samples. The basis for this discrimination was the type of resin and/ or inorganic pigments/extenders present. Although this allowed approximately half of the white paints to be distinguished by inspection, the other half were all based on a similar resin and did not contain the distinctive modifiers/pigments and extenders that allowed the other samples to be identified. The experimental uncertainty in the relative band intensities measured using FT-IR was similar to the variation within this large group, so no further discrimination was possible. However, the variation in the Raman spectra was larger than the uncertainty, which allowed the large group to be divided into three subgroups and four distinct spectra, based on relative band intensities. The combination of increased discrimination and higher sample throughput means that the Raman method is superior to FT-IR for samples of this type. © 2005 Society for Applied Spectroscopy.

Personalized medicine: Has it started yet? A reconstruction of the early history

Within the last few years the field personalized medicine entered the stage. Accompanied with great hopes and expectations it is believed that this field may have the potential to revolutionize medical and clinical care by utilizing genomics information about the individual patients themselves. In this paper, we reconstruct the early footprints of personalized medicine as reflected by information retrieved from PubMed and Google Scholar. That means we are providing a data-driven perspective of this field to estimate its current status and potential problems.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.<br/><br/>Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.<br/><br/>Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.<br/><br/>Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Forensic Geomorphology

Geomorphology plays a critical role in two areas of geoforensics: searching the land for surface or buried objects and sampling or imaging rural scenes of crime and control locations as evidence. Most of the associated geoscience disciplines have substantial bodies of work dedicated to their relevance in forensic investigations, yet geomorphology (specifically landforms, their mapping and evolution, soils and relationship to geology and biogeography) have had no such exposure. This is strange considering how fundamental to legal enquiries the location of a crime and its evolution are, as this article will demonstrate. This work aims to redress the balance by showing how geomorphology is featured in one of the earliest works on forensic science methods, and has continued to play a role in the sociology, archaeology, criminalistics and geoforensics of crime. The application geomorphology has in military/humanitarian geography and environmental/engineering forensics is briefly discussed as these are also regularly reviewed in courts of law

Search protocols for hidden forensic objects beneath floors and within walls

The burial of objects (human remains, explosives, weapons) below or behind concrete, brick, plaster or tiling may be associated with serious crime and are difficult locations to search. These are quite common forensic search scenarios but little has been published on them to-date. Most documented discoveries are accidental or from suspect/witness testimony. The problem in locating such hidden objects means a random or chance-based approach is not advisable. A preliminary strategy is presented here, based on previous studies, augmented by primary research where new technology or applications are required. This blend allows a rudimentary search workflow, from remote desktop study, to non-destructive investigation through to recommendations as to how the above may inform excavation, demonstrated here with a case study from a homicide investigation. Published case studies on the search for human remains demonstrate the problems encountered when trying to find and recover sealed-in and sealed over locations. Established methods include desktop study, photography, geophysics and search dogs:these are integrated with new technology (LiDAR and laser scanning; photographic rectification; close quarter aerial imagery; ground-penetrating radar on walls and gamma-ray/neutron activation radiography) to propose this possible search strategy.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.