Bayesian methods provide a practical real-world evidence framework for evaluating the impact of changes in radiotherapy.

PURPOSE: Retrospective studies have identified a link between the average set-up error of lung cancer patients treated with image-guided radiotherapy (IGRT) and survival. The IGRT protocol was subsequently changed to reduce the action threshold. In this study, we use a Bayesian approach to evaluate the clinical impact of this change to practice using routine 'real-world' patient data. METHODS AND MATERIALS: Two cohorts of NSCLC patients treated with IGRT were compared: pre-protocol change (N = 780, 5 mm action threshold) and post-protocol change (N = 411, 2 mm action threshold). Survival models were fitted to each cohort and changes in the hazard ratios (HR) associated with residual set-up errors was assessed. The influence of using an uninformative and a skeptical prior in the model was investigated. RESULTS: Following the reduction of the action threshold, the HR for residual set-up error towards the heart was reduced by up to 10%. Median patient survival increased for patients with set-up errors towards the heart, and remained similar for patients with set-up errors away from the heart. Depending on the prior used, a residual hazard ratio may remain. CONCLUSIONS: Our analysis found a reduced hazard of death and increased survival for patients with residual set-up errors towards versus away from the heart post-protocol change. This study demonstrates the value of a Bayesian approach in the assessment of technical changes in radiotherapy practice and supports the consideration of adopting this approach in further prospective evaluations of changes to clinical practice.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy.

INTRODUCTION: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. METHOD: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. RESULTS: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. CONCLUSION: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

A preclinical radiotherapy dosimetry audit using a realistic 3D printed murine phantom.

Preclinical radiation research lacks standardized dosimetry procedures that provide traceability to a primary standard. Consequently, ensuring accuracy and reproducibility between studies is challenging. Using 3D printed murine phantoms we undertook a dosimetry audit of Xstrahl Small Animal Radiation Research Platforms (SARRPs) installed at 7 UK centres. The geometrically realistic phantom accommodated alanine pellets and Gafchromic EBT3 film for simultaneous measurement of the dose delivered and the dose distribution within a 2D plane, respectively. Two irradiation scenarios were developed: (1) a 10 × 10 mm2 static field targeting the pelvis, and (2) a 5 × 5 mm2 90° arc targeting the brain. For static fields, the absolute difference between the planned dose and alanine measurement across all centres was 4.1 ± 4.3% (mean ± standard deviation), with an overall range of - 2.3 to 10.5%. For arc fields, the difference was - 1.2% ± 6.1%, with a range of - 13.1 to 7.7%. EBT3 dose measurements were greater than alanine by 2.0 ± 2.5% and 3.5 ± 6.0% (mean ± standard deviation) for the static and arc fields, respectively. 2D dose distributions showed discrepancies to the planned dose at the field edges. The audit demonstrates that further work on preclinical radiotherapy quality assurance processes is merited.

Reliability and prognostic value of radiomic features are highly dependent on choice of feature extraction platform.

OBJECTIVE: To investigate the effects of Image Biomarker Standardisation Initiative (IBSI) compliance, harmonisation of calculation settings and platform version on the statistical reliability of radiomic features and their corresponding ability to predict clinical outcome. METHODS: The statistical reliability of radiomic features was assessed retrospectively in three clinical datasets (patient numbers: 108 head and neck cancer, 37 small-cell lung cancer, 47 non-small-cell lung cancer). Features were calculated using four platforms (PyRadiomics, LIFEx, CERR and IBEX). PyRadiomics, LIFEx and CERR are IBSI-compliant, whereas IBEX is not. The effects of IBSI compliance, user-defined calculation settings and platform version were assessed by calculating intraclass correlation coefficients and confidence intervals. The influence of platform choice on the relationship between radiomic biomarkers and survival was evaluated using univariable cox regression in the largest dataset. RESULTS: The reliability of radiomic features calculated by the different software platforms was only excellent (ICC > 0.9) for 4/17 radiomic features when comparing all four platforms. Reliability improved to ICC > 0.9 for 15/17 radiomic features when analysis was restricted to the three IBSI-compliant platforms. Failure to harmonise calculation settings resulted in poor reliability, even across the IBSI-compliant platforms. Software platform version also had a marked effect on feature reliability in CERR and LIFEx. Features identified as having significant relationship to survival varied between platforms, as did the direction of hazard ratios. CONCLUSION: IBSI compliance, user-defined calculation settings and choice of platform version all influence the statistical reliability and corresponding performance of prognostic models in radiomics. KEY POINTS: • Reliability of radiomic features varies between feature calculation platforms and with choice of software version. • Image Biomarker Standardisation Initiative (IBSI) compliance improves reliability of radiomic features across platforms, but only when calculation settings are harmonised. • IBSI compliance, user-defined calculation settings and choice of platform version collectively affect the prognostic value of features.

Radiomics as a personalized medicine tool in lung cancer: Separating the hope from the hype.

Radiomics has become a popular image analysis method in the last few years. Its key hypothesis is that medical images harbor biological, prognostic and predictive information that is not revealed upon visual inspection. In contrast to previous work with a priori defined imaging biomarkers, radiomics instead calculates image features at scale and uses statistical methods to identify those most strongly associated to outcome. This builds on years of research into computer aided diagnosis and pattern recognition. While the potential of radiomics to aid personalized medicine is widely recognized, several technical limitations exist which hinder biomarker translation. Aspects of the radiomic workflow lack repeatability or reproducibility under particular circumstances, which is a key requirement for the translation of imaging biomarkers into clinical practice. One of the most commonly studied uses of radiomics is for personalized medicine applications in Non-Small Cell Lung Cancer (NSCLC). In this review, we summarize reported methodological limitations in CT based radiomic analyses together with suggested solutions. We then evaluate the current NSCLC radiomics literature to assess the risk associated with accepting the published conclusions with respect to these limitations. We review different complementary scoring systems and initiatives that can be used to critically appraise data from radiomics studies. Wider awareness should improve the quality of ongoing and future radiomics studies and advance their potential as clinically relevant biomarkers for personalized medicine in patients with NSCLC.

Preclinical dosimetry: exploring the use of small animal phantoms.

Preclinical radiotherapy studies using small animals are an indispensable step in the pathway from in vitro experiments to clinical implementation. As radiotherapy techniques advance in the clinic, it is important that preclinical models evolve to keep in line with these developments. The use of orthotopic tumour sites, the development of tissue-equivalent mice phantoms and the recent introduction of image-guided small animal radiation research platforms has enabled similar precision treatments to be delivered in the laboratory.These technological developments, however, are hindered by a lack of corresponding dosimetry standards and poor reporting of methodologies. Without robust and well documented preclinical radiotherapy quality assurance processes, it is not possible to ensure the accuracy and repeatability of dose measurements between laboratories. As a consequence current RT-based preclinical models are at risk of becoming irrelevant.In this review we explore current standardization initiatives, focusing in particular on recent developments in small animal irradiation equipment, 3D printing technology to create customisable tissue-equivalent dosimetry phantoms and combining these phantoms with commonly used detectors.

Synthesis, Radiolabelling and In Vitro Imaging of Multifunctional Nanoceramics.

Molecular imaging has become a powerful technique in preclinical and clinical research aiming towards the diagnosis of many diseases. In this work, we address the synthetic challenges in achieving lab-scale, batch-to-batch reproducible copper-64- and gallium-68-radiolabelled metal nanoparticles (MNPs) for cellular imaging purposes. Composite NPs incorporating magnetic iron oxide cores with luminescent quantum dots were simultaneously encapsulated within a thin silica shell, yielding water-dispersible, biocompatible and luminescent NPs. Scalable surface modification protocols to attach the radioisotopes 64Cu (t1/2=12.7 h) and 68Ga (t1/2=68 min) in high yields are reported, and are compatible with the time frame of radiolabelling. Confocal and fluorescence lifetime imaging studies confirm the uptake of the encapsulated imaging agents and their cytoplasmic localisation in prostate cancer (PC-3) cells. Cellular viability assays show that the biocompatibility of the system is improved when the fluorophores are encapsulated within a silica shell. The functional and biocompatible SiO2 matrix represents an ideal platform for the incorporation of 64Cu and 68Ga radioisotopes with high radiolabelling incorporation.

Residual Setup Errors Towards the Heart After Image Guidance Linked With Poorer Survival in Lung Cancer Patients: Do We Need Stricter IGRT Protocols?

PURPOSE: Image guided radiation therapy (IGRT) is widely used, but data directly relating set-up errors to patient outcome are scarce. This study investigates the relationship between residual IGRT shifts and overall patient survival and uses the observed relations to identify structures sensitive to radiation dose. METHODS AND MATERIALS: Residual shift data for 780 patients with non-small cell lung cancer were summarized for each patient over the course of treatment by determining the mean shifts, standard deviations, and the vector shift in the direction of the heart. These variables were related to overall survival, and significant variables were used to produce Kaplan-Meier plots of survival. The effect of shift directionality was studied by splitting the cohort into left, right, anterior, posterior, superior, and inferior groups and by analyzing the vector shift in the direction of the heart. The observed relationship was independently validated in an esophageal cancer cohort (n = 177). RESULTS: The shift data showed strong associations with survival. Left and right cohorts showed opposite directional shift effects, suggesting shifts toward the mediastinum have a negative effect on survival. Projection of the vector shift in the direction of the heart showed that patients with a residual shift toward the heart have significantly worse overall survival (P = .007, hazard ratio 1.091). The same effect was observed in the esophageal cancer cohort (P = .041, hazard ratio 1.164). CONCLUSIONS: Residual shift metrics derived from IGRT data can categorize patients with non-small cell lung cancer and those with esophageal cancer into populations with significantly different survival times on the basis of the size of the residual shift in the direction of the heart, thus providing evidence of the importance of using strict IGRT protocols to spare organs at risk and highlighting the heart as a dose-sensitive organ.

Results from a clinical trial evaluating the efficacy of real-time body surface visual feedback in reducing patient motion during lung cancer radiotherapy.

INTRODUCTION: Optical surface measurement devices are a maturing technology in radiotherapy. The challenge for such devices is to demonstrate how they can improve clinical care. We present results from a phase 1 clinical trial designed to test the hypothesis that if presented with live data from a novel optical measurement device, showing their deviation from an ideal radiotherapy treatment position, patients will be able to better control their motion and increase their geometrical conformance. METHOD AND MATERIALS: Fourteen lung cancer patients were enrolled in a prospective clinical study and asked to use a variety of visual feedback schema from a novel in-house developed optical surface measurement device. The magnitude and regularity of their body surface motion using the different schema was compared to that when free-breathing at three time-points throughout their radiotherapy treatment schedule. Additionally, 4D Cone Beam CT data, acquired simultaneously with the optical measurements, was used to test if improvements in external motion are reflected in changes in internal tumor motion. RESULTS: The primary endpoint of the trial, device tolerability assessed by the fraction of participants completing all study sessions, was 86%. Secondary endpoints showed that use of the visual feedback device was found to statistically significantly decrease body surface motion magnitude by an average of 17% over the study cohort, although not universally. Similarly body surface motion variability was decreased by 18% on average. Internal tumor motion magnitude was also found to be statistically significantly decreased by an average of 14% when using the feedback device. Reduction in external motion was predictive of reduced internal motion but no evidence of a simple correlation between changes in internal and external motion magnitude was found. CONCLUSIONS: Visual feedback of live motion is well tolerated by lung cancer patients and can reduce both body surface and tumor motion.

Sonochemical production of nanoparticle metal oxides for potential use in dentistry.

Two types of ultrasonic instruments used in dentistry have been compared with a sonochemical horn for the production of copper oxide and zinc oxide nanoparticles. The nanoparticles can be produced from benign reagents using dental instruments as the source of sonochemical enhancement. The process has been operated in resin models of teeth in a preliminary exploration of the potential of the method for enhancing procedures such as root canal surgery. The technique is potentially useful but further work is needed for a full assessment of using in-situ generated nanoparticles as an aid to disinfection during some types of dental surgery.

Evaluation of drug delivery to intact and porated skin by coherent Raman scattering and fluorescence microscopies.

Stimulated Raman scattering microscopy was used to assess the permeation of topically applied drugs and formulation excipients into porcine skin. This chemically selective technique generates high-resolution 3D images, from which semi-quantitative information may be elucidated. Ibuprofen, applied as a close-to-saturated solution in propylene glycol, was directly observed to crystallise in/on the skin, as the co-solvent permeated more rapidly, resulting in precipitation of the drug. Coherent Raman scattering microscopy is also an excellent tool, in conjunction with more conventional confocal fluorescence microscopy, with which to image micro/nanoparticle-based formulations. Specifically, the uptake of particles into thermal ablation transport pathways in the skin has been examined.

Self-management of patient body position, pose, and motion using wide-field, real-time optical measurement feedback: results of a volunteer study.

PURPOSE: We present the results of a clinical feasibility study, performed in 10 healthy volunteers undergoing a simulated treatment over 3 sessions, to investigate the use of a wide-field visual feedback technique intended to help patients control their pose while reducing motion during radiation therapy treatment. METHODS AND MATERIALS: An optical surface sensor is used to capture wide-area measurements of a subject's body surface with visualizations of these data displayed back to them in real time. In this study we hypothesize that this active feedback mechanism will enable patients to control their motion and help them maintain their setup pose and position. A capability hierarchy of 3 different level-of-detail abstractions of the measured surface data is systematically compared. RESULTS: Use of the device enabled volunteers to increase their conformance to a reference surface, as measured by decreased variability across their body surfaces. The use of visual feedback also enabled volunteers to reduce their respiratory motion amplitude to 1.7 ± 0.6 mm compared with 2.7 ± 1.4 mm without visual feedback. CONCLUSIONS: The use of live feedback of their optically measured body surfaces enabled a set of volunteers to better manage their pose and motion when compared with free breathing. The method is suitable to be taken forward to patient studies.

Alcohol hand gel--a potential fire hazard.

Alcohol hand gel and wipes are the common method of disinfecting the hands of healthcare workers and working surfaces in clinical settings. We present a case of a 40-year-old health care support worker who was referred acutely to our burns unit following flame burns in association with alcohol gel use. Fortunately she was able to extinguish the flames without sustaining a significant thermal injury however this case highlights the potential danger associated with alcohol gel use, especially with smokers. With the ever increasing use of alcohol hand gel, not only in healthcare settings but also in the general population there needs to be clearer warnings regarding the potential for ignition after use. Alcohol hand gel and wipes are the common method of disinfecting the hands of healthcare workers and working surfaces in clinical settings. Most trusts have strict policies regarding mandatory sanitisation of hands before and after patient contact. This is most easily achieved by the use of alcohol gel due to its ease of use and quick drying properties. As a result alcohol hand disinfectant is available is a variety of formats including foam, gel and wipes. It is also now widely available for use to the general public.

Next generation optical surface sensing for real-time measurement in radiotherapy.

With the introduction of intensive new treatments such as hypo-fractionation and proton beam therapy, localization of the tumor target volume and tracking of points across the skin entrance surface have become critically important. Optical metrology has been used to monitor the patient's bulk position and motion throughout treatment. However systems have not been capable of high temporal and spatial resolution whole-surface topology measurement. We describe the implementation of such a system based on Fourier profilometry. Its algorithm is split into four separate processing stages, including spatial phase determination: descriptions of each stage are given along with the modifications made to increase performance. The optimized system is capable of processing 23 frames per second (fps), with each frame providing 512 × 512 measured points. The data density, accuracy and performance of the system are an order of magnitude improvement on commercially available clinical systems. We show that this performance permits genuinely real-time measurement of a patient, live during both setup and radiation treatment delivery. It is also fast enough to provide smooth dynamic visualizations of motion at all points on the wrap-around body surface for radiotherapy staff and intuitive, direct feed-back to patients.

Applications of inverse gas chromatography in the study of liquid crystalline stationary phases.

We describe measurements on a number of low-molar-mass and polymeric liquid crystals that contain the same mesogenic groups. Transition temperatures for the mesophases have been measured and the supercooled region of hexyloxycyanobiphenyl studied, revealing some differences from the stable mesophase. Activity coefficients and interaction parameters for a range of probes have been measured and allow us to determine the nature and origin of the thermodynamic interactions in the systems. A discussion of how this fundamental information can be used in designing more efficient stationary phases for analytical gas chromatography is also presented.

Inverse gas chromatographic measurement of solubility parameters in liquid crystalline systems.

Inverse gas chromatography, (IGC), has been used to measure interaction parameters in two low-molar-mass liquid crystals and a polymer substituted with the same mesogenic group. Solubility parameters have been calculated. The IGC method is shown to be applicable to this class of compounds and to give meaningful values over a range of temperatures.