Machine-learning with region-level radiomic and dosimetric features for predicting radiotherapy-induced rectal toxicities in prostate cancer patients.

BACKGROUND AND PURPOSE: This study aims to build machine learning models to predict radiation-induced rectal toxicities for three clinical endpoints and explore whether the inclusion of radiomic features calculated on radiotherapy planning computerised tomography (CT) scans combined with dosimetric features can enhance the prediction performance. MATERIALS AND METHODS: 183 patients recruited to the VoxTox study (UK-CRN-ID-13716) were included. Toxicity scores were prospectively collected after 2 years with grade ≥ 1 proctitis, haemorrhage (CTCAEv4.03); and gastrointestinal (GI) toxicity (RTOG) recorded as the endpoints of interest. The rectal wall on each slice was divided into 4 regions according to the centroid, and all slices were divided into 4 sections to calculate region-level radiomic and dosimetric features. The patients were split into a training set (75%, N = 137) and a test set (25%, N = 46). Highly correlated features were removed using four feature selection methods. Individual radiomic or dosimetric or combined (radiomic + dosimetric) features were subsequently classified using three machine learning classifiers to explore their association with these radiation-induced rectal toxicities. RESULTS: The test set area under the curve (AUC) values were 0.549, 0.741 and 0.669 for proctitis, haemorrhage and GI toxicity prediction using radiomic combined with dosimetric features. The AUC value reached 0.747 for the ensembled radiomic-dosimetric model for haemorrhage. CONCLUSIONS: Our preliminary results show that region-level pre-treatment planning CT radiomic features have the potential to predict radiation-induced rectal toxicities for prostate cancer. Moreover, when combined with region-level dosimetric features and using ensemble learning, the model prediction performance slightly improved.

Sub-regional analysis of the parotid glands: model development for predicting late xerostomia with radiomics features in head and neck cancer patients.

BACKGROUND: The irradiation of sub-regions of the parotid has been linked to xerostomia development in patients with head and neck cancer (HNC). In this study, we compared the xerostomia classification performance of radiomics features calculated on clinically relevant and de novo sub-regions of the parotid glands of HNC patients. MATERIAL AND METHODS: All patients (N = 117) were treated with TomoTherapy in 30-35 fractions of 2-2.167 Gy per fraction with daily mega-voltage-CT (MVCT) acquisition for image-guidance purposes. Radiomics features (N = 123) were extracted from daily MVCTs for the whole parotid gland and nine sub-regions. The changes in feature values after each complete week of treatment were considered as predictors of xerostomia (CTCAEv4.03, grade ≥ 2) at 6 and 12 months. Combinations of predictors were generated following the removal of statistically redundant information and stepwise selection. The classification performance of the logistic regression models was evaluated on train and test sets of patients using the Area Under the Curve (AUC) associated with the different sub-regions at each week of treatment and benchmarked with the performance of models solely using dose and toxicity at baseline. RESULTS: In this study, radiomics-based models predicted xerostomia better than standard clinical predictors. Models combining dose to the parotid and xerostomia scores at baseline yielded an AUCtest of 0.63 and 0.61 for xerostomia prediction at 6 and 12 months after radiotherapy while models based on radiomics features extracted from the whole parotid yielded a maximum AUCtest of 0.67 and 0.75, respectively. Overall, across sub-regions, maximum AUCtest was 0.76 and 0.80 for xerostomia prediction at 6 and 12 months. Within the first two weeks of treatment, the cranial part of the parotid systematically yielded the highest AUCtest. CONCLUSION: Our results indicate that variations of radiomics features calculated on sub-regions of the parotid glands can lead to earlier and improved prediction of xerostomia in HNC patients.

Assessing the generalisability of radiomics features previously identified as predictive of radiation-induced sticky saliva and xerostomia.

Background and purpose: While core to the scientific approach, reproducibility of experimental results is challenging in radiomics studies. A recent publication identified radiomics features that are predictive of late irradiation-induced toxicity in head and neck cancer (HNC) patients. In this study, we assessed the generalisability of these findings. Materials and Methods: The procedure described in the publication in question was applied to a cohort of 109 HNC patients treated with 50-70 Gy in 20-35 fractions using helical radiotherapy although there were inherent differences between the two patient populations and methodologies. On each slice of the planning CT with delineated parotid and submandibular glands, the imaging features that were previously identified as predictive of moderate-to-severe xerostomia and sticky saliva 12 months post radiotherapy (Xer12m and SS12m) were calculated. Specifically, Short Run Emphasis (SRE) and maximum CT intensity (maxHU) were evaluated for improvement in prediction of Xer12m and SS12m respectively, compared to models solely using baseline toxicity and mean dose to the salivary glands. Results: None of the associations previously identified as statistically significant and involving radiomics features in univariate or multivariate models could be reproduced on our cohort. Conclusion: The discrepancies observed between the results of the two studies delineate limits to the generalisability of the previously reported findings. This may be explained by the differences in the approaches, in particular the imaging characteristics and subsequent methodological implementation. This highlights the importance of external validation, high quality reporting guidelines and standardisation protocols to ensure generalisability, replication and ultimately clinical implementation.

Gender-related and geographic trends in interactions between radiotherapy professionals on Twitter.

Background and purpose: Twitter presence in academia has been linked to greater research impact which influences career progression. The purpose of this study was to analyse Twitter activity of the radiotherapy community around ESTRO congresses with a focus on gender-related and geographic trends. Materials and methods: Tweets, re-tweets and replies, here designated as interactions, around the ESTRO congresses held in 2012-2021 were collected. Twitter activity was analysed temporally and, for the period 2016-2021, the geographical span of the ESTRO Twitter network was studied. Tweets and Twitter users collated during the 10 years analysed were ranked based on number of 'likes', 're-tweets' and followers, considered as indicators of leadership/influence. Gender representation was assessed for the top-end percentiles. Results: Twitter activity around ESTRO congresses was multiplied by 60 in 6 years growing from 150 interactions in 2012 to a peak of 9097 in 2018. In 2020, during the SARS-CoV-2 pandemic, activity dropped by 60 % to reach 2945 interactions and recovered to half the pre-pandemic level in 2021. Europe, North America and Oceania were strongly connected and remained the main contributors. While overall, 58 % of accounts were owned by men, this proportion increased towards top liked/re-tweeted tweets and most-followed profiles to reach up to 84 % in the top-percentiles. Conclusion: During the SARS-CoV-2 pandemic, Twitter activity around ESTRO congresses substantially decreased. Men were over-represented on the platform and in most popular tweets and influential accounts. Given the increasing importance of social media presence in academia the gender-based biases observed may help in understanding the gender gap in career progression.

Predicting radiotherapy-induced xerostomia in head and neck cancer patients using day-to-day kinetics of radiomics features.

Background and purpose: The images acquired during radiotherapy for image-guidance purposes could be used to monitor patient-specific response to irradiation and improve treatment personalisation. We investigated whether the kinetics of radiomics features from daily mega-voltage CT image-guidance scans (MVCT) improve prediction of moderate-to-severe xerostomia compared to dose/volume parameters in radiotherapy of head-and-neck cancer (HNC). Materials and Methods: All included HNC patients (N = 117) received 30 or more fractions of radiotherapy with daily MVCTs. Radiomics features were calculated on the contra-lateral parotid glands of daily MVCTs. Their variations over time after each complete week of treatment were used to predict moderate-to-severe xerostomia (CTCAEv4.03 grade ≥ 2) at 6, 12 and 24 months post-radiotherapy. After dimensionality reduction, backward/forward selection was used to generate combinations of predictors.Three types of logistic regression model were generated for each follow-up time: 1) a pre-treatment reference model using dose/volume parameters, 2) a combination of dose/volume and radiomics-based predictors, and 3) radiomics-based predictors. The models were internally validated by cross-validation and bootstrapping and their performance evaluated using Area Under the Curve (AUC) on separate training and testing sets. Results: Moderate-to-severe xerostomia was reported by 46 %, 33 % and 26 % of the patients at 6, 12 and 24 months respectively. The selected models using radiomics-based features extracted at or before mid-treatment outperformed the dose-based models with an AUCtrain/AUCtest of 0.70/0.69, 0.76/0.74, 0.86/0.86 at 6, 12 and 24 months, respectively. Conclusion: Our results suggest that radiomics features calculated on MVCTs from the first half of the radiotherapy course improve prediction of moderate-to-severe xerostomia in HNC patients compared to a dose-based pre-treatment model.

Peppermint protocol: first results for gas chromatography-ion mobility spectrometry.

ThePeppermint Initiativeseeks to inform the standardisation of breath analysis methods. FivePeppermint Experimentswith gas chromatography-ion mobility spectrometry (GC-IMS), operating in the positive mode with a tritium3H 5.68 keV, 370 MBq ionisation source, were undertaken to provide benchmarkPeppermint Washoutdata for this technique, to support its use in breath-testing, analysis, and research. Headspace analysis of a peppermint-oil capsule by GC-IMS with on-column injection (0.5 cm3) identified 12 IMS responsive compounds, of which the four most abundant were: eucalyptol;ß-pinene;α-pinene; and limonene. Elevated concentrations of these four compounds were identified in exhaled-breath following ingestion of a peppermint-oil capsule. An unidentified compound attributed as a volatile catabolite of peppermint-oil was also observed. The most intense exhaled peppermint-oil component was eucalyptol, which was selected as a peppermint marker for benchmarking GC-IMS. Twenty-five washout experiments monitored levels of exhaled eucalyptol, by GC-IMS with on-column injection (0.5 cm3), att= 0 min, and then att+ 60,t+ 90,t+ 165,t+ 285 andt+ 360 min from ingestion of a peppermint capsule resulting in 148 peppermint breath analyses. Additionally, thePeppermint Washoutdata was used to evaluate clinical deployments with a further five washout tests run in clinical settings generating an additional 35 breath samples. Regression analysis yielded an average extrapolated time taken for exhaled eucalyptol levels to return to baseline values to be 429 ± 62 min (±95% confidence-interval). The benchmark value was assigned to the lower 95% confidence-interval, 367 min. Further evaluation of the data indicated that the maximum number of volatile organic compounds discernible from a 0.5 cm3breath sample was 69, while the use of an in-line biofilter appeared to reduce this to 34.

Fast and automated biomarker detection in breath samples with machine learning.

Volatile organic compounds (VOCs) in human breath can reveal a large spectrum of health conditions and can be used for fast, accurate and non-invasive diagnostics. Gas chromatography-mass spectrometry (GC-MS) is used to measure VOCs, but its application is limited by expert-driven data analysis that is time-consuming, subjective and may introduce errors. We propose a machine learning-based system to perform GC-MS data analysis that exploits deep learning pattern recognition ability to learn and automatically detect VOCs directly from raw data, thus bypassing expert-led processing. We evaluate this new approach on clinical samples and with four types of convolutional neural networks (CNNs): VGG16, VGG-like, densely connected and residual CNNs. The proposed machine learning methods showed to outperform the expert-led analysis by detecting a significantly higher number of VOCs in just a fraction of time while maintaining high specificity. These results suggest that the proposed novel approach can help the large-scale deployment of breath-based diagnosis by reducing time and cost, and increasing accuracy and consistency.

Dual Convolutional Neural Networks for Breast Mass Segmentation and Diagnosis in Mammography.

Deep convolutional neural networks (CNNs) have emerged as a new paradigm for Mammogram diagnosis. Contemporary CNN-based computer-aided-diagnosis systems (CADs) for breast cancer directly extract latent features from input mammogram image and ignore the importance of morphological features. In this paper, we introduce a novel end-to-end deep learning framework for mammogram image processing, which computes mass segmentation and simultaneously predicts diagnosis results. Specifically, our method is constructed in a dual-path architecture that solves the mapping in a dual-problem manner, with an additional consideration of important shape and boundary knowledge. One path, called the Locality Preserving Learner (LPL), is devoted to hierarchically extracting and exploiting intrinsic features of the input. Whereas the other path, called the Conditional Graph Learner (CGL), focuses on generating geometrical features via modeling pixel-wise image to mask correlations. By integrating the two learners, both the cancer semantics and cancer representations are well learned, and the component learning paths in return complement each other, contributing an improvement to the mass segmentation and cancer classification problem at the same time. In addition, by integrating an automatic detection set-up, the DualCoreNet achieves fully automatic breast cancer diagnosis practically. Experimental results show that in benchmark DDSM dataset, DualCoreNet has outperformed other related works in both segmentation and classification tasks, achieving 92.27% DI coefficient and 0.85 AUC score. In another benchmark INbreast dataset, DualCoreNet achieves the best mammography segmentation (93.69% DI coefficient) and competitive classification performance (0.93 AUC score).

50 years of radiotherapy research: Evolution, trends and lessons for the future.

Rapid and relentless technological advances in an ever-more globalized world have shaped the field of radiation oncology in which we practise today. These developments have drastically modified the habitus1 of health professionals and researchers at an individual and organisational level. In this article we present an analysis of trends in radiation oncology research over the last half a century. To do so, the data from >350,000 scientific publications pertaining to a yearly search of the PubMed database with the keywords cancer radiotherapy was analysed. This analysis revealed that, over the years, radiotherapy research output has declined relative to alternative cancer therapies, representing 64% in 1970 it decreased to 31% in 2019. Also, the pace of research has significantly accelerated with, in the last 15 years, a doubling in the number of articles published by the 10% most productive researchers. Researchers are also facing stronger competition today with a proportion of first authors that will never get to publish as a last author increasing steadily from 58% in 1970 to 84% in 2000. Additionally, radiotherapy research output is extremely unequally distributed in the world, with Africa and South America contributing to ∼3% of radiotherapy articles in 2019 while representing 23% of the world's population. This disparity, reflecting economic situations and radiotherapy capabilities, has a knock-on effect for the provision of routine clinical treatment. Since research activity is inherent to delivery of high quality clinical care, this contributes to the global inequity of radiotherapy services. Learning from these trends is crucial for the future not only of radiation oncology research but also for effective and equitable cancer care.

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.

From multisource data to clinical decision aids in radiation oncology: The need for a clinical data science community.

Big data are no longer an obstacle; now, by using artificial intelligence (AI), previously undiscovered knowledge can be found in massive data collections. The radiation oncology clinic daily produces a large amount of multisource data and metadata during its routine clinical and research activities. These data involve multiple stakeholders and users. Because of a lack of interoperability, most of these data remain unused, and powerful insights that could improve patient care are lost. Changing the paradigm by introducing powerful AI analytics and a common vision for empowering big data in radiation oncology is imperative. However, this can only be achieved by creating a clinical data science community in radiation oncology. In this work, we present why such a community is needed to translate multisource data into clinical decision aids.

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).

EPID-based in vivo dosimetry using Dosimetry Check™: Overview and clinical experience in a 5-yr study including breast, lung, prostate, and head and neck cancer patients.

BACKGROUND: Independent verification of the dose delivered by complex radiotherapy can be performed by electronic portal imaging device (EPID) dosimetry. This paper presents 5-yr EPID in vivo dosimetry (IVD) data obtained using the Dosimetry Check (DC) software on a large cohort including breast, lung, prostate, and head and neck (H&N) cancer patients. MATERIAL AND METHODS: The difference between in vivo dose measurements obtained by DC and point doses calculated by the Eclipse treatment planning system was obtained on 3795 radiotherapy patients treated with volumetric modulated arc therapy (VMAT) (n = 842) and three-dimensional conformal radiotherapy (3DCRT) (n = 2953) at 6, 10, and 15 MV. In cases where the dose difference exceeded ±10% further inspection and additional phantom measurements were performed. RESULTS: The mean and standard deviation ( µ ± σ ) of the percentage difference in dose obtained by DC and calculated by Eclipse in VMAT was: 0.19 ± 3.89 % in brain, 1.54 ± 4.87 % in H&N, and 1.23 ± 4.61 % in prostate cancer. In 3DCRT, this was 1.79 ± 3.51 % in brain, - 2.95 ± 5.67 % in breast, - 1.43 ± 4.38 % in bladder, 1.66 ± 4.77 % in H&N, 2.60 ± 5.35% in lung and - 3.62 ± 4.00 % in prostate cancer. A total of 153 plans exceeded the ±10% alert criteria, which included: 88 breast plans accounting for 7.9% of all breast treatments; 28 H&N plans accounting for 4.4% of all H&N treatments; and 12 prostate plans accounting for 3.5% of all prostate treatments. All deviations were found to be as a result of patient-related anatomical deviations and not from procedural errors. CONCLUSIONS: This preliminary data shows that EPID-based IVD with DC may not only be useful in detecting errors but has the potential to be used to establish site-specific dose action levels. The approach is straightforward and has been implemented as a radiographer-led service with no disruption to the patient and no impact on treatment time.

Quantitative cone-beam CT reconstruction with polyenergetic scatter model fusion.

Scatter can account for large errors in cone-beam CT (CBCT) due to its wide field of view, and its complicated nature makes its compensation difficult. Iterative polyenergetic reconstruction algorithms offer the potential to provide quantitative imaging in CT, but they are usually incompatible with scatter contaminated measurements. In this work, we introduce a polyenergetic convolutional scatter model that is directly fused into the reconstruction process, and exploits information readily available at each iteration for a fraction of additional computational cost. We evaluate this method with numerical and real CBCT measurements, and show significantly enhanced electron density estimation and artifact mitigation over pre-calculated fast adaptive scatter kernel superposition (fASKS). We demonstrate our approach has two levels of benefit: reducing the bias introduced by estimating scatter prior to reconstruction; and adapting to the spectral and spatial properties of the specimen.

Polyquant CT: direct electron and mass density reconstruction from a single polyenergetic source.

Quantifying material mass and electron density from computed tomography (CT) reconstructions can be highly valuable in certain medical practices, such as radiation therapy planning. However, uniquely parameterising the x-ray attenuation in terms of mass or electron density is an ill-posed problem when a single polyenergetic source is used with a spectrally indiscriminate detector. Existing approaches to single source polyenergetic modelling often impose consistency with a physical model, such as water-bone or photoelectric-Compton decompositions, which will either require detailed prior segmentation or restrictive energy dependencies, and may require further calibration to the quantity of interest. In this work, we introduce a data centric approach to fitting the attenuation with piecewise-linear functions directly to mass or electron density, and present a segmentation-free statistical reconstruction algorithm for exploiting it, with the same order of complexity as other iterative methods. We show how this allows both higher accuracy in attenuation modelling, and demonstrate its superior quantitative imaging, with numerical chest and metal implant data, and validate it with real cone-beam CT measurements.

Application of Texture Analysis to Study Small Vessel Disease and Blood-Brain Barrier Integrity.

OBJECTIVES: We evaluate the alternative use of texture analysis for evaluating the role of blood-brain barrier (BBB) in small vessel disease (SVD). METHODS: We used brain magnetic resonance imaging from 204 stroke patients, acquired before and 20 min after intravenous gadolinium administration. We segmented tissues, white matter hyperintensities (WMH) and applied validated visual scores. We measured textural features in all tissues pre- and post-contrast and used ANCOVA to evaluate the effect of SVD indicators on the pre-/post-contrast change, Kruskal-Wallis for significance between patient groups and linear mixed models for pre-/post-contrast variations in cerebrospinal fluid (CSF) with Fazekas scores. RESULTS: Textural "homogeneity" increase in normal tissues with higher presence of SVD indicators was consistently more overt than in abnormal tissues. Textural "homogeneity" increased with age, basal ganglia perivascular spaces scores (p < 0.01) and SVD scores (p < 0.05) and was significantly higher in hypertensive patients (p < 0.002) and lacunar stroke (p = 0.04). Hypertension (74% patients), WMH load (median = 1.5 ± 1.6% of intracranial volume), and age (mean = 65.6 years, SD = 11.3) predicted the pre/post-contrast change in normal white matter, WMH, and index stroke lesion. CSF signal increased with increasing SVD post-contrast. CONCLUSION: A consistent general pattern of increasing textural "homogeneity" with increasing SVD and post-contrast change in CSF with increasing WMH suggest that texture analysis may be useful for the study of BBB integrity.

Field correction factors for a PTW-31016 Pinpoint ionization chamber for both flattened and unflattened beams. Study of the main sources of uncertainties.

PURPOSE: The primary aim of this study was to determine correction factors, kQclin,Qmsrfclin,fmsr for a PTW-31016 ionization chamber on field sizes from 0.5 cm × 0.5 cm to 2 cm × 2 cm for both flattened (FF) and flattened filter-free (FFF) beams produced in a TrueBeam clinical accelerator. The secondary objective was the determination of field output factors, ΩQclin,Qmsrfclin,fmsr over this range of field sizes using both Monte Carlo (MC) simulation and measurements. METHODS: kQclin,Qmsrfclin,fmsr for the PTW-31016 chamber were calculated by MC simulation for field sizes of 0.5 cm × 0.5 cm, 1 cm × 1 cm, and 2 cm × 2 cm. MC simulations were performed with the PENELOPE code system for the 10 MV FFF Particle Space File from a TrueBeam linear accelerator (LINAC) provided by the manufacturer (Varian Medical Systems, Inc. Palo Alto, CA, USA). Simulations were repeated taking into account chamber manufacturing tolerances and accelerator jaw positioning in order to assess the uncertainty of the calculated correction factors. Output ratios were measured on square fields ranging from 0.5 cm × 0.5 cm to 10 cm × 10 cm for 6 MV and 10 MV FF and FFF beams produced by a TrueBeam using a PTW-31016 ionization chamber; a Sun Nuclear Edge detector (SunNuclear Corp., Melbourne, FL, USA) and TLD-700R (Harshaw, Thermo Scientific, Waltham, MA, USA). The validity of the proposed correction factors was verified using the calculated correction factors for the determination of ΩQclin,Qmsrfclin,fmsr using a PTW-31016 at the four TrueBeam energies and comparing the results with both TLD-700R measurements and MC simulations. Finally, the proposed correction factors were used to assess the correction factors of the SunNuclear Edge detector. RESULTS: The present work provides a set of MC calculated correction factors for a PTW-31016 chamber used on a TrueBeam FF and FFF mode. For the 0.5 cm × 0.5 cm square field size, kQclin,Qmsrfclin,fmsr is equal to 1.17 with a combined uncertainty of 2% (k = 1). A detailed analysis of the most influential parameters is presented in this work. PTW-31016 corrected measurements were used for the determination of ΩQclin,Qmsrfclin,fmsr for 6 MV and 10 MV FF and FFF and the results were in agreement with values obtained using a TLD-700R detector (differences < 3% for a 0.5 cm square field) for the four energies studied. Uncertainty in field collimation was found to be the main source of influence of ΩQclin,Qmsrfclin,fmsr and caused differences of up to 15% between calculations and measurements for the 0.5 cm × 0.5 cm field. This was also confirmed by repeating the same measurements at two different institutions. CONCLUSIONS: This study confirms the need to introduce correction factors when using a PTW-31016 chamber and the hypothesis of their low energy dependence. MC simulation has been shown to be a useful methodology to determine detector correction factors for small fields and to analyze the main sources of uncertainty. However, due to the influence of the LINAC jaw setup for field sizes below or equal to 1 cm, MC methods are not recommended in this range for field output factor calculations.

Correction: Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Correction for 'Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors' by Victoria L. Camus, et al., Analyst, 2016, 141, 5056-5061.

Targeted SERS nanosensors measure physicochemical gradients and free energy changes in live 3D tumor spheroids.

Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.