Breath markers for therapeutic radiation

Dahlia Salman,Jens Langejuergen,Dorota Ruszkiewicz,Kareen Darnley,Andria Hadjithelki,Duncan B Mclaren,Iain Phillips,William H Nailon,Michael Eddleston,C L Paul Thomas,Yaser Alkhalifa

doi:10.1088/1752-7163/aba816

Abstract

Radiation dose is important in radiotherapy. Too little, and the treatment is not effective, too much causes radiation toxicity. A biochemical measurement of the effect of radiotherapy would be useful in personalisation of this treatment. This study evaluated changes in exhaled breath volatile organic compounds (VOC) associated with radiotherapy with thermal desorption gas chromatography mass-spectrometry followed by data processing and multivariate statistical analysis. Further the feasibility of adopting gas chromatography ion mobility spectrometry for radiotherapy point-of-care breath was assessed. A total of 62 participants provided 240 end-tidal 1 dm3 breath samples before radiotherapy and at 1, 3, and 6 h post-exposure, that were analysed by thermal-desorption/gas-chromatography/quadrupole mass-spectrometry. Data were registered by retention-index and mass-spectra before multivariate statistical analyses identified candidate markers.A panel of sulfur containing compounds (thio-VOC) were observed to increase in concentration over the 6 h following irradiation. 3-methylthiophene (80 ng.m−3 to 790 ng.m−3) had the lowest abundance while 2-thiophenecarbaldehyde(380 ng.m−3 to 3.85 μg.m−3) the highest; note, exhaled 2-thiophenecarbaldehyde has not been observed previously. The putative tumour metabolite 2,4-dimethyl-1-heptene concentration reduced by an average of 73% over the same time. Statistical scoring based on the signal intensities thio-VOC and 3-methylthiophene appears to reflect individuals’ responses to radiation exposure from radiotherapy. The thio-VOC are hypothesised to derive from glutathione and Maillard-based reactions and these are of interest as they are associated with radio-sensitivity. Further studies with continuous monitoring are needed to define the development of the breath biochemistry response to irradiation and to determine the optimum time to monitor breath for radiotherapy markers. Consequently, a single 0.5 cm3 breath-sample gas chromatography-ion mobility approach was evaluated. The calibrated limit of detection for 3-methylthiophene was 10 μg.m−3 with a lower limit of the detector’s response estimated to be 210 fg.s−1; the potential for a point-of-care radiation exposure study exists.

Highlights

Breath analysis as a supporting methodology for personalising treatment across a range of conditions is attractive to clinician and patient alike [1,2,3]
This study evaluated changes in exhaled breath volatile organic compounds (VOC) associated with radiotherapy with thermal desorption gas chromatography mass-spectrometry followed by data processing and multivariate statistical analysis
Identification of discriminatory features Unsupervised principle components analysis (PCA) was applied to the remaining 88 features in the breath matrix to indicate candidate VOC that discriminated between pre- and post-exposure, at 6 h

Summary

Introduction

Breath analysis as a supporting methodology for personalising treatment across a range of conditions is attractive to clinician and patient alike [1,2,3]. This work describes the association of exhaled sulphur containing volatile organic compounds (thio-VOC) with radiation exposure. The levels of thio-VOC in exhaled breath in combination with the reduction of the exhaled abundance of 2,4-dimethyl-1-heptene(a previously proposed tumour marker), were studied to establish if there may be a basis for a radio-therapeutic biomarker. Breath samples taken in a radiotherapy clinic, to verify and characterise previously reported volatile hydrocarbon markers of radiation exposure [5, 6], were unexpectedly found to contain elevated concentrations of five thio-VOC. Radio-therapy is an important cancer treatment [7] that is accompanied by risk, as a therapeutic radiation dose damages cancer-cells and healthy tissues alike. The severity of damage to healthy tissues and associated acute and late-onset radio-toxicity effects varies between individuals and is difficult to predict [8]. Radio-toxicity is managed by limiting the radiation dose to avoid unsafe and intolerable side-effects; this affects the treatment outcome; the survival rate; and the patient’s quality of life [9,10,11]

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