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. 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. 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. 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.

Corrosive attacks in the UK - Psychosocial perspectives and decontamination strategies.

Acid attacks, or vitriolage, are defined as violent assaults involving the deliberate throwing of an acid or similarly corrosive substance with the intention to "maim, disfigure, torture or kill" [1]. The Acid Survivors Trust International suggest a prevalence of 1500 attacks reported worldwide per annum, although this is likely to be an underestimate by 40% [2]. The UK is thought to have one of the highest of rates of recorded corrosive attacks, with an increase from 228 attacks in 2012 to 601 in 2016. Most were reported by the London Metropolitan police force followed by Northumbria, Cambridgeshire, Hertfordshire, Greater Manchester and Humberside [[2]]. The chemical agents involved include acids, alkalis, oxidising and reducing agents, alkylating and chelating agents and solvents. They cause injury by producing a chemical interaction which can lead to extensive tissue destruction and extreme pain. Herein, we present a review on the changing epidemiology of corrosive attacks in the UK and currently employed management strategies.

Development and pilot of a burns-specific patient-reported experience measure.

Patient -reported experience measures (PREMs) are a valuable tool in assessing patient's subjective experiences within healthcare settings. They assist the evaluation and development of clinical services, and could be considered most useful when they assess elements of care pertinent to the specific health condition or clinical service. Currently there is no existing PREM to assess this in an NHS burns service. In the current project, a burns-specific PREM was created by identifying pre-existing condition specific PREMs in the literature and selecting key items pertinent to burn care for use in a brief questionnaire tool adapted in multiple versions to patient age and care setting. The measure was reviewed by the burns multidisciplinary team and piloted with patients attending the service. Twenty-seven participants completed the measure alongside an evaluation tool briefly assessing clarity, relevance and acceptability. While small, this pilot suggested that patients found the measure acceptable to complete and relevant to their care. It also yielded information not currently assessed by the service in any other format, appearing to promise utility for service development activities. Further work is needed to validate the tool and determine how its use could be implemented at a local and national level.

Magnesium depletion in patients receiving cisplatin-based chemotherapy.

AIMS: To assess the incidence of hypomagnesaemia, the influence of different cisplatin dosages on the degree of hypomagnesaemia and the effect of routine magnesium supplementation on magnesium levels. MATERIALS AND METHODS: Magnesium levels for 214 consecutive patients receiving cisplatin-based chemotherapy were studied. Twenty different chemotherapy regimens were prescribed. Doses ranged from 7 to 51 mg/m(2)/week. The interval between cycles ranged from 1 to 4 weeks. The number of evaluable cycles ranged from one to eight. Patients receiving bleomycin, etoposide and cisplatin (BEP) chemotherapy routinely received 60 mmol magnesium per cycle; patients receiving cisplatin, vincristine, methotrexate, bleomycin - dactinomycin, cyclophosphamide, etoposide (POMB-ACE) chemotherapy routinely received 20 mmol magnesium per cycle. For all other chemotherapy regimens, magnesium was not routinely prescribed. RESULTS: Baseline magnesium levels were available for 195 patients, 92% were within the normal range. The average level was 0.82 mmol/l. There was a statistically significant decrease in magnesium levels from baseline to the lowest magnesium level (mean = 0.68 mmol/l, standard deviation = 0.13) (P < 0.0005). The incidence of hypomagnesaemia (serum magnesium < 0.7 mmol/l) at any point during chemotherapy was 43%. Multiple regression analysis showed a significant association between dose, frequency, and number of cycles given, and the degree of hypomagnesaemia (P = 0.001, P = 0.03 and P < 0.0005, respectively). Routine magnesium supplementation significantly reduced the degree of hypomagnesaemia if sufficient amounts of magnesium are given: 60 mmol magnesium per cycle for a regimen containing 33 mg/m(2)/week cisplatin is sufficient; 20 mmol magnesium per cycle for a regimen containing 40 mg/m(2)/week cisplatin is insufficient. CONCLUSIONS: It is recommended that magnesium levels should be measured routinely in all patients receiving cisplatin and that all cisplatin-based chemotherapy regimens should be supplemented routinely with sufficient doses of magnesium (40-80 mmol magnesium per cycle depending on the regimen).

A study of New Zealand wood workers: exposure to wood dust, respiratory symptoms, and suspected cases of occupational asthma.

A randomly selected group of 50 New Zealand wood workers was studied. The level of airborne wood dust to which they were exposed ranged from 1.0-24.5 mg/m3. The wood workers reported experiencing higher rates of both lower and upper respiratory tract symptoms than a control group of office workers. Inhaled wood dust, in particular from rimu (Dacrydium cupressinum), was frequently cited by workers as being associated with respiratory tract symptoms. The wood workers' responses to the respiratory symptom questionnaire, and serial recordings of peak expiratory flow rate were used to screen the group for suspected cases of occupational asthma. Five cases fulfilled the study's criteria for suspected occupational asthma. In four of these, further evidence was found to support this diagnosis. We conclude that exposure to wood dust may cause occupational asthma in the woodworking industry in New Zealand.

Microscopic and chemical studies of metal particulates in tree bark and attic dust: evidence for historical atmospheric smelter emissions, Humberside, UK.

Tree barks and attic dusts were examined as historical archives of smelter emissions, with the aim of elucidating the pathways of pollution associated with a plume of Sn and Pb contamination in top soils, found close to the former Capper Pass smelter, Humberside, UK. Samples were collected from three villages within the area of the contamination plume. Scanning electron microscopy (SEM) and bulk chemical analyses were used to assess particle type, number and deposition patterns. SEM analysis of dusts and bark revealed that Sn and Pb particles were present in samples from all three villages along with copper, zinc and iron particles. These were almost entirely <10 microm in diameter and occurred mostly as oxides, frequently forming clusters of sub-micron crystals. Samples further from the smelter contained considerably fewer particles. We present images of smelter derived Sn particles. Chemical assays of the barks and attic dusts demonstrated that concentrations of Sn, Pb, Cu, As, Sb and Cd diminished with increasing distance from the source. Strong positive correlations were found between Sn and Pb, As, Sb and Cd in the attic dusts. Enrichment factors (EF) were calculated for these trace elements based on topsoil element concentrations obtained from the soil survey of the study area. Decreases in these trace element concentrations and EF values with distance away from the smelter are consistent with trends found in the soil survey for Sn and Pb and are typical of deposition patterns around smelter stacks. The study demonstrates that tree bark and attic dusts can be effective archives of metal particulates deposited from large static emission sources.