Breath markers for therapeutic radiation.

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.

VOCCluster: Untargeted Metabolomics Feature Clustering Approach for Clinical Breath Gas Chromatography/Mass Spectrometry Data.

Metabolic profiling of breath analysis involves processing, alignment, scaling, and clustering of thousands of features extracted from gas chromatography/mass spectrometry (GC/MS) data from hundreds of participants. The multistep data processing is complicated, operator error-prone, and time-consuming. Automated algorithmic clustering methods that are able to cluster features in a fast and reliable way are necessary. These accelerate metabolic profiling and discovery platforms for next-generation medical diagnostic tools. Our unsupervised clustering technique, VOCCluster, prototyped in Python, handles features of deconvolved GC/MS breath data. VOCCluster was created from a heuristic ontology based on the observation of experts undertaking data processing with a suite of software packages. VOCCluster identifies and clusters groups of volatile organic compounds (VOCs) from deconvolved GC/MS breath with similar mass spectra and retention index profiles. VOCCluster was used to cluster more than 15 000 features extracted from 74 GC/MS clinical breath samples obtained from participants with cancer before and after a radiation therapy. Results were evaluated against a panel of ground truth compounds and compared to other clustering methods (DBSCAN and OPTICS) that were used in previous metabolomics studies. VOCCluster was able to cluster those features into 1081 groups (including endogenous and exogenous compounds and instrumental artifacts) with an accuracy rate of 96% (±0.04 at 95% confidence interval).

Delivering chemotherapy at home: how much do we know?

Ambulatory chemotherapy offers many advantages from supporting a closer to home treatment approach to lowering the cost of care. Ambulatory devices such as elastomeric pumps can deliver prolonged infusions of a variety of chemotherapy agents. Elastomeric pumps are preferred by the patients, as they get them connected at the hospital or cancer centres, then go back home where they can have visits from the district nursing team. This minimises disruption to carers and families. Despite all the advantages, experiments carried out by the authors and others in the literature showed that the performance of these pumps varied depending on the temperature and/or viscosity of the diluent. Interestingly, a two-phase study that was carried out to observe and evaluate patients receiving ambulatory chemotherapy concluded that in 50% of the observed cases the infusion pump did not finish on time. This disrupted the patients' treatment schedule and, in some cases, resulted in sub-therapeutic dosing.

Breath analysis by two-dimensional gas chromatography with dual flame ionisation and mass spectrometric detection - Method optimisation and integration within a large-scale clinical study.

Precision medicine has spurred new innovations in molecular pathology leading to recent advances in the analysis of exhaled breath as a non-invasive diagnostic tool. Volatile organic compounds (VOCs) detected in exhaled breath have the potential to reveal a wealth of chemical and metabolomic information. This study describes the development of a method for the analysis of breath, based on automated thermal desorption (TD) combined with flow modulated comprehensive two-dimensional gas chromatography (GC×GC) with dual flame ionisation and quadrupole mass spectrometric detection (FID and qMS). The constrained optimisation and analytical protocol was designed to meet the practical demands of a large-scale multi-site clinical study, while maintaining analytical rigour to produce high fidelity data. The results demonstrate a comprehensive method optimisation for the collection and analysis of breath VOCs by GC×GC, integral to the standardisation and integration of breath analysis within large clinical studies.

Evaluation of the performance of elastomeric pumps in practice: are we under-delivering on chemotherapy treatments?

BACKGROUND AND AIMS: Elastomeric pumps are widely used to facilitate ambulatory chemotherapy, and studies have shown that they are safe and well received by patients. Despite these advantages, their end of infusion time can fluctuate significantly. The aim of this research was to observe the performance of these pumps in real practice and to evaluate patients' satisfaction. METHODS: This was a two-phase study conducted at three cancer units over 6 months. Phase-1 was an observational study recording the status of pumps at the scheduled disconnection time and noting remaining volume of infusion. Phase-2 was a survey of patients and their perception/satisfaction. Ethical approval was granted. RESULTS: A total of 92 cases were observed covering 50 cases disconnected at hospital and 42 disconnected at home. The infusion in 40% of hospital disconnection cases was slow, with patients arriving at hospital with unfinished pumps; 58% of these had an estimated remaining volume which exceeded 10 mL with 35% exceeded 20 mL. In 73% of these cases, and regardless of the remaining volume, the patient was disconnected and the pump was discarded. CONCLUSIONS: The performance of pumps varied, which affected nurse workload and patients' waiting-times. A smart system is an option to monitor the performance of pumps and to predict their accuracy.

Evaluation of the stability profile of anticancer drugs: A review of Ifosfamide and Mesna regimen for the treatment of metastatic soft tissue sarcoma.

PURPOSE: This paper aims to summarise and critically review the existing published literature with regard to clinical considerations as well as stability testing studies of Ifosfamide and Mesna. It also aims to highlight the factors that should be considered when designing and conducting stability testing experiments. SUMMARY: Ifosfamide and Mesna are currently given to patients for 14 days continuous home-based infusion for the treatment of soft tissue sarcoma. No previous work has evaluated their stability for more than 7 days under real-life conditions so the current regimen involves patients visiting hospital twice during the 14-day treatment. This may create extra disruption to patients' life style as well as increasing the workload for cancer services. CONCLUSION: There is a need to conduct stability testing experiments for Ifosfamide and Mesna taking into consideration all of the highlighted factors to mimic standard clinical practice.

New investigations into the stability of Mesna using LC-MS/MS and NMR.

INTRODUCTION: It is important for sarcoma patients to receive the correct dose of Mesna as an adjuvant with ifosfamide to reduce the risk of hemorrhagic cystitis. This paper describes a study conducted to evaluate the physicochemical stability of Mesna for injection formulation over 14 days. METHODS: Mesna samples (n = 4, 20 mg/ml) were incubated in glass vials at 37 + 0.5ºC. Mesna concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS), and nuclear magnetic resonance spectroscopy (NMR) was used to detect degradation products. Evaporative losses and pH were also monitored. RESULTS: Our results differed from those published in existing literature. Both LC-MS/MS and NMR indicated that Mesna was unstable. The mean percentage decrease in Mesna concentration was 40% by day 14 of the analysis. The presence of Mesna's dimer Dimesna was detected on day 0 and its concentration increased over time. Dimesna was the only by-product identified. CONCLUSION: Both LC-MS/MS and NMR analyses confirmed the instability of Mesna and its conversion into Dimesna.