Evaluating very high energy electron RBE from nanodosimetric pBR322 plasmid DNA damage.

This paper presents the first plasmid DNA irradiations carried out with Very High Energy Electrons (VHEE) over 100-200 MeV at the CLEAR user facility at CERN to determine the Relative Biological Effectiveness (RBE) of VHEE. DNA damage yields were measured in dry and aqueous environments to determine that ~ 99% of total DNA breaks were caused by indirect effects, consistent with other published measurements for protons and photons. Double-Strand Break (DSB) yield was used as the biological endpoint for RBE calculation, with values found to be consistent with established radiotherapy modalities. Similarities in physical damage between VHEE and conventional modalities gives confidence that biological effects of VHEE will also be similar-key for clinical implementation. Damage yields were used as a baseline for track structure simulations of VHEE plasmid irradiation using GEANT4-DNA. Current models for DSB yield have shown reasonable agreement with experimental values. The growing interest in FLASH radiotherapy motivated a study into DSB yield variation with dose rate following VHEE irradiation. No significant variations were observed between conventional and FLASH dose rate irradiations, indicating that no FLASH effect is seen under these conditions.

Technical Note: GATE-RTion: a GATE/Geant4 release for clinical applications in scanned ion beam therapy.

PURPOSE: GATE-RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE-RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments. METHODS: GATE-RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users. RESULTS: Three applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria). CONCLUSIONS: GATE-RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron- and synchrotron-based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project.

Experimental verification the electron return effect around spherical air cavities for the MR-Linac using Monte Carlo calculation.

PURPOSE: Dose deposition around unplanned air cavities during magnetic resonance-guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly-methyl methacrylate (PMMA) -air phantoms. METHOD: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7-MV photon beam under the influence of a 1.5-T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. RESULTS: The gamma analysis showed that >95% of the points agreed between the TPS-calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). CONCLUSIONS: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use.

In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

Validating a Monte Carlo approach to absolute dose quality assurance for proton pencil beam scanning.

For radiotherapy, it is crucial to guarantee that the delivered dose matches the planned dose. Therefore, patient specific quality assurance (QA) of absolute dose distributions is necessary. Here, we investigate the potential of replacing patient specific QA for pencil beam scanned proton therapy with Monte Carlo simulations. First, the set-up of the automated Monte Carlo model is presented with an emphasis on the absolute dose validation. Second, the absolute dose results obtained from the Monte Carlo simulation for a comprehensive set of patient fields are compared to patient specific QA measurements. Absolute doses measured with the Farmer chamber are shown to be 1.4% higher than the doses measured with the Semiflex chamber. For single energy layers, Monte Carlo simulated doses are 2.1% ± 0.4% lower than the ones measured with the ionization chamber and 1.1% ± 1.0% lower than measurements compared to patient field verification measurements. After rescaling to account for this 1.1% discrepancy, 98 fields (94.2%) agree within 2% to measurements, the maximum difference being 2.3%. In conclusion, an automated, easy-to-use Monte Carlo calculation system has been set up. This system reproduced patient specific QA results over a wide range of cases, showing that the time consuming measurements could be reduced or even replaced using Monte Carlo simulations without jeopardizing treatment quality.

Marvin: an anatomical phantom for dosimetric evaluation of complex radiotherapy of the head and neck.

We report on the design of Marvin, a Model Anatomy for Radiotherapy Verification and audit In the head and Neck and present results demonstrating its use in the development of the Elekta volumetric modulated arc therapy (VMAT) technique at the Christie, and in the audit of TomoTherapy and Varian RapidArc at other institutions. The geometry of Marvin was generated from CT datasets of eight male and female patients lying in the treatment position, with removable inhomogeneities modelling the sinuses and mandible. A modular system allows the phantom to be used with a range of detectors, with the locations of the modules being based on an analysis of a range of typical treatment plans (27 in total) which were mapped onto the phantom geometry. Results demonstrate the use of Gafchromic EBT2/EBT3 film for measurement of relative dose in a plane through the target and organs-at-risk, and the use of a small-volume ionization chamber for measurement of absolute dose in the target and spinal cord. Measurements made during the development of the head and neck VMAT protocol at the Christie quantified the improvement in plan delivery resulting from the installation of the Elekta Integrity upgrade (which permits an effectively continuously variable dose rate), with plans delivered before and after the upgrade having 88.5 ± 9.4% and 98.0 ± 2.2% respectively of points passing a gamma analysis (at 4%, 4 mm, global). Audits of TomoTherapy and Varian RapidArc neck techniques at other institutions showed a similar quality of plan delivery as for post-Integrity Elekta VMAT: film measurements for both techniques had >99% of points passing a gamma analysis at the clinical criteria of 4%, 4 mm, global, and >95% of points passing at tighter criteria of 3%, 3 mm, global; and absolute dose measurements in the PTV and spinal cord were within 1.5% and 3.5% of the planned doses respectively for both techniques. The results demonstrate that Marvin is an efficient and effective means of assessing the quality of delivery of complex radiotherapy in the head and neck, and is a useful tool to assist development and audit of these techniques.

Modelling the throughput capacity of a single-accelerator multitreatment room proton therapy centre.

OBJECTIVE: We describe a model for evaluating the throughput capacity of a single-accelerator multitreatment room proton therapy centre with the aims of (1) providing quantitative estimates of the throughput and waiting times and (2) providing insight into the sensitivity of the system to various physical parameters. METHODS: A Monte Carlo approach was used to compute various statistics about the modelled centre, including the throughput capacity, fraction times for different groups of patients and beam waiting times. A method of quantifying the saturation level is also demonstrated. RESULTS: Benchmarking against the MD Anderson Cancer Center showed good agreement between the modelled (140 ± 4 fractions per day) and reported (133 ± 35 fractions per day) throughputs. A sensitivity analysis of that system studied the impact of beam switch time, the number of treatment rooms, patient set-up times and the potential benefit of having a second accelerator. Finally, scenarios relevant to a potential UK facility were studied, finding that a centre with the same four-room, single-accelerator configuration as the MD Anderson Cancer Center but handling a more complex UK-type caseload would have a throughput reduced by approximately 19%, but still be capable of treating in excess of 100 fractions per 16-h treatment day. CONCLUSIONS: The model provides a useful tool to aid in understanding the operating dynamics of a proton therapy facility, and for investigating potential scenarios for prospective centres. ADVANCES IN KNOWLEDGE: The model helps to identify which technical specifications should be targeted for future improvements.

Survey of intrathecal opioid usage in the UK.

BACKGROUND AND OBJECTIVE: Intrathecal opioids are now used routinely in the UK for intra- and postoperative analgesia. The opioids of choice have altered over recent years and the dosage regimens used can vary between institutions. Concerns over safety have been reduced probably because much lower doses of opioids are now being used. This survey explored the practice of intrathecal opioid usage in the UK. METHODS: We sent a questionnaire survey to 270 anaesthetic departments and received 199 replies, a response rate of 73.7%. RESULTS: Intrathecal opioids were used in 175 (88.4%) departments. Of these departments, 107 (61.1%) had local guidelines or protocols in place. Opioids such as diamorphine (used in 136 (78.2%) of departments) and fentanyl (129 (74.1%)) with a shorter duration of action are now more commonly used than morphine (37 (21.3%)) for intrathecal analgesia. In 96 (54.5%) departments, patients were nursed on regular surgical wards following administration of spinal opioids. CONCLUSIONS: The use of low-dose lipophilic intrathecal opioids for postoperative analgesia is widespread in the UK. Patients are commonly nursed in low-dependency post-anaesthetic care areas. The low incidence of adverse events reported by the respondents along with the popularity of the technique suggests that low-dose spinal opioid administration is safe.

Description of a technique for anaesthetizing pregnant ewes for fetal surgery.

General anaesthesia in 12 pregnant ewes undergoing surgery for fetal physiological research was supplemented with an intravenous infusion of remifentanil. This allowed us to employ a lighter plane of surgical anaesthesia and to use intermittent positive pressure ventilation. Our aim was to improve fetomaternal outcome. We monitored maternal pulse, blood pressure, transcutaneous oxygen saturation and end-tidal carbon dioxide levels. Remifentanil doses of 0.75-2.0 microg/kg/min were needed and typically this allowed halothane concentrations of 1-1.5% to be used for maintenance of anaesthesia. Surgery lasted up to 2.5 h. All 12 ewes and their singleton fetuses survived the peri- and postoperative period in good condition.

Anaesthesiologists' views on the need for point-of-care information system in the operating room: a survey of the European Society of Anaesthesiologists.

BACKGROUND AND OBJECTIVE: In this preliminary study we wanted to explore the attitudes of anaesthesiologists to a point-of-care information system in the operating room. The study was conducted as a preliminary step in the process of developing such a system by the European Society of Anaesthesiologists (ESA). METHODS: A questionnaire was distributed to all 2240 attendees of the ESA's annual meeting in Gothenburg, Sweden, which took place in April 2001. RESULTS: Of the 329 responders (response rate of 14.6%), 79% were qualified specialists with more than 10 yr of experience (68%), mostly from Western Europe. Most responders admitted to regularly experiencing lack of medical knowledge relating to real-time patient care at least once a month (74%) or at least once a week (46%), and 39% admitted to having made errors during anaesthesia due to lack of medical information that can be otherwise found in a handbook. The choice ofa less optimal but more familiar approach to patient management due to lack of knowledge was reported by 37%. Eighty-eight percent of responders believe that having a point-of-care information system for the anaesthesiologists in the operating room is either important or very important. CONCLUSIONS: This preliminary survey demonstrates that lack of knowledge of anaesthesiologists may be a significant source of medical errors in the operating room, and suggests that a point-of-care information system for the anaesthesiologist may be of value.

Remifentanil sedation compared with propofol during regional anaesthesia.

BACKGROUND: The short onset and offset of remifentanil may allow for accurate dosing of sedative effect with few side-effects and rapid recovery. In this study remifentanil is compared with propofol for sedation during successful regional anaesthetic blocks. METHODS: After informed consent was given, 125 patients undergoing surgery under spinal or brachial plexus anaesthesia were randomized to receive, either propofol: bolus 500 microg/kg plus initial infusion 50 microgkg/min or remifentanil: bolus 0.5 microg/kg plus initial infusion 0.1 microgkg/min. Study drug infusion rate was titrated throughout the procedure according to level of sedation and side-effects. Pain, discomfort, sedation level and side-effects were recorded at regular intervals until discharge from the post operative care unit (PACU). RESULTS: Two patients in the remifentanil group versus ten in the propofol group were treated for discomfort or pain during surgery (P<0.02). Due to a significantly higher rate of respiratory depression (46% vs. 19% with propofol, P<0.01) the mean remifentanil infusion rate was decreased to 0.078 +/- 0.028 microgkg/min, whereas it was kept stable with propofol. Propofol patients had significantly higher (P<0.05) sedation levels and experienced more frequent amnesia of the procedure. Eleven propofol patients experienced pain at injection site, versus two remifentanil patients (P<0.02). Nausea and vomiting were more frequent in the remifentanil patients during infusion (27% vs. 2% in the propofol group, P<0.001) but similar postoperatively. Time to discharge from PACU was similar in the two groups. CONCLUSION: Propofol results in less respiratory depression and nausea when sedation is needed during a case with a successful regional block. Remifentanil may be considered as an alternative if pain during the procedure is a major concern or if amnesia is contraindicated.

Effect of videotape feedback on anaesthetists' performance while managing simulated anaesthetic crises: a multicentre study.

The aim of this study was to examine the performance of anaesthetists while managing simulated anaesthetic crises and to see whether their performance was improved by reviewing their own performances recorded on videotape. Thirty-two subjects from four hospitals were allocated randomly to one of two groups, with each subject completing five simulations in a single session. Individuals in the first group completed five simulations with only a short discussion between each simulation. Those in the second group were allowed to review their own performance on videotape between each of the simulations. Performance was measured by both 'time to solve the problem' and mental workload, using anaesthetic chart error as a secondary task. Those trainees exposed to videotape feedback had a shorter median 'time to solve' and a smaller decrease in chart error when compared to those not exposed to video feedback. However, the differences were not statistically significant, confirming the difficulties encountered by other groups in designing valid tests of the performance of anaesthetists.

Investigating hypoxemia during apnea: validation of a set of physiological models.

UNLABELLED: The aim of our study was to validate the Nottingham Physiology Simulator (NPS) for examining pulmonary denitrogenation and apnea by reproducing the methodology and results of previous clinical studies. Only four studies provided sufficient detail in their description of their methodology to allow accurate reproduction by using the NPS or provided a sufficiently detailed description of their subjects to allow accurate modelling. The results of the NPS recreation of the studies were within 13% of the values found clinically in all cases and were within 2% in the majority of cases. The four studies included healthy and morbidly obese patients, conscious and anesthetized patients, and included examination of the effect of denitrogenation and apnea on plasma pH and on lung and arterial oxygen and carbon dioxide tensions at various lung volumes. IMPLICATIONS: We used mathematical, physiological models to recreate the methods and subjects of four clinical studies investigating oxygenation and low oxygen levels during cessation of breathing. Our aim was to validate the models, allowing theoretical investigations into this area. The blindly recreated results closely matched the clinical studies, validating the models.

Factors determining the onset and course of hypoxemia during apnea: an investigation using physiological modelling.

UNLABELLED: We used the Nottingham Physiology Simulator to examine the onset and course of hypoxemia during apnea after pulmonary denitrogenation. The following factors, as possible determinants of the hypoxemia profile, were varied to examine their effect: functional residual capacity, oxygen consumption, respiratory quotient, hemoglobin concentration, ventilatory minute volume, duration of denitrogenation, pulmonary venous admixture, and state of the airway (closed versus open). Airway obstruction significantly reduced the time to 50% oxyhemoglobin saturation (8 vs 11 min). Provision of 100% oxygen rather than air to the open, apneic patient model greatly prolonged time to 50% oxyhemoglobin saturation (66 vs 11 min). Hemoglobin concentration, venous admixture, and respiratory quotient had small, insignificant effects on the time to desaturation. Reduced functional residual capacity, short duration of denitrogenation, hypoventilation, and increased oxygen consumption significantly shortened the time to 50% oxyhemoglobin saturation during apnea. IMPLICATIONS: Reduction in oxygen levels during cessation of breathing is dangerous and common in anesthetic practice. We used validated, mathematical, physiological models to reveal the impact of physiological factors on the deterioration of oxygen levels. This study could not be performed on patients and reveals important information.

Estimation of alveolar deadspace fraction using arterial and end-tidal CO2: a factor analysis using a physiological simulation.

The alveolar deadspace as a fraction of alveolar ventilation (VDalv/VTalv), while technically difficult to measure, is an objective monitor of pulmonary disease progression and a predictor of successful weaning from mechanical ventilation. The aim of the study was to examine the relationship between the arterial to end-tidal PCO2 gradient (Pa-E'CO2) and VDalv/VTalv and between (Pa-E'CO2)/PaCO2 and VDalv/VTalv using the Nottingham Physiology Simulator, an original, validated physiology simulation. The relationships were observed while pulmonary shunt, anatomical deadspace, ventilatory minute volume and metabolic rate were varied. The relationship between Pa-E'CO2 and VDalv/VTalv was non-linear and was affected significantly by all the factors except anatomical deadspace. The relationship between (Pa-E'CO2)/PaCO2 and VDalv/VTalv (best fit: VDalv VTalv = 1.135 x (Pa-E'CO2)/PaCO2-0.005) during normal physiological conditions was approximately linear and less influenced by physiological variation. Shunt and anatomical deadspace caused some inaccuracy, although they are unlikely to prevent the clinical usefulness of this formula.