Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters.

BACKGROUND: The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra-high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large-scale in vivo studies using murine models of human cancer are needed for these investigations. PURPOSE: To commission a high-throughput, variable dose rate platform providing uniform electron fields (≥15 cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. METHODS: A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3 cm thick Cerrobend collimator forming a 15 × 1.6 cm2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT-XD film at 1 cm depth in solid water and lung-density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2 cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision-machined copper alternative. RESULTS: This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse-square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120 Gy·s-1 . At depths of 0.5 to 1.5 cm, the depth range relevant to murine lung irradiation, measured PDDs varied within ±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3 mm at 0 cm depth to 5.1 mm at 2.0 cm. The presence of lung-density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator. CONCLUSIONS: A high-throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR-enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120 Gy·s-1 , owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high-throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies.

Practitioner characteristics, diagnostic accuracy metrics and discovering-individual with respect to 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Knowledge of accuracy for melanoma diagnosis and melanoma discovering-individual in primary care is limited. We describe general practitioner (GP) characteristics and analyse defined diagnostic accuracy metrics for GPs in the current study comparing this with a previous study for GPs common to both, and we analyse the individual first discovering each melanoma as a lesion of concern. METHODS: The characteristics and diagnostic accuracy of 27 Australasian GPs documenting 637 melanomas on the Skin Cancer Audit Research Database (SCARD) in 2013 were described and analysed. The number needed to treat (NNT) and percentage of melanomas that were in situ (percentage in situ) were analysed as surrogates for specificity and sensitivity, respectively. The discovering-individual was analysed according to patient age and sex and lesion Breslow thickness. RESULTS: The average NNT and percentage in situ were 5.73% and 65.07%, respectively. For 21 GPs in both a 2008-2010 study and the current study, the NNT was 10.78 and 5.56, respectively (p = 0.0037). A consistent trend of decreasing NNT and increasing percentage in situ through increasingly subspecialised GP categories did not reach statistical significance. NNT trended high at ages and sites for which melanoma was rare. While the patient or family member was more likely to discover thick melanomas and melanomas in patients under 40 years, GPs discovered 73.9% of the melanomas as lesions of concern. CONCLUSIONS: GPs were the discovering-individuals for the majority of melanomas in the current study and their accuracy metrics compared favourably with published figures for dermatologists and GPs.

Analysis of CyberKnife intracranial treatment plans using ICRU 91 dose reporting: A retrospective study.

ICRU 91, published in 2017, is an international standard for prescribing, recording, and reporting stereotactic treatments. Since its release, there has been limited research published on the implementation and impact of ICRU 91 on clinical practice. This work provides an assessment of the recommended ICRU 91 dose reporting metrics for their use in clinical treatment planning. A set of 180 intracranial stereotactic treatment plans for patients treated by the CyberKnife (CK) system were analyzed retrospectively using the ICRU 91 reporting metrics. The 180 plans comprised 60 trigeminal neuralgia (TGN), 60 meningioma (MEN), and 60 acoustic neuroma (AN) cases. The reporting metrics included the planning target volume (PTV) near-minimum dose ( D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ ), near-maximum dose ( D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ ), and median dose ( D 50 % ${D}_{50{\rm{\% }}}$ ), as well as the gradient index (GI) and conformity index (CI). The metrics were assessed for statistical correlation with several treatment plan parameters. In the TGN plan group, owing to the small targets, D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ was greater than D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ in 42 plans, whereas both metrics were not applicable in 17 plans. The D 50 % ${D}_{50{\rm{\% }}}$ metric was predominantly influenced by the prescription isodose line (PIDL). The GI was significantly dependent on target volume in all analyses performed, where the variables were inversely related. The CI was only dependent on target volume in treatment plans for small targets. The ICRU 91 D near - min ${D}_{{\rm{near}} - {\rm{min}}}$ and D near - max ${D}_{{\rm{near}} - {\rm{max}}}$ metrics breakdown in plans for small target volumes below 1 cm3 ; the Min and Max pixel should be reported in such cases. The D 50 % ${D}_{50{\rm{\% }}}$ metric is of limited use for treatment planning. Given their volume dependence, the GI and CI metrics could potentially serve as plan evaluation tools in the planning of the sites analyzed in this study, which would ultimately improve treatment plan quality.

Compensation for radiotherapy treatment interruptions due to a cyberattack: An isoeffective DVH-based dose compensation decision tool.

Unscheduled interruptions to radiotherapy treatments lead to decreased tumor control probability (TCP). Rapid cell repopulation in the tumor increases due to the absence of radiation dose, resulting in the loss of TCP. Compensation for this loss is required to prevent or reduce an extension of the patient's overall treatment time and regain the original TCP. The cyberattack on the Irish public health service in May 2021 prevented radiotherapy treatment delivery resulting in treatment interruptions of up to 12 days. Current standards for treatment gap calculations are performed using the Royal College of Radiologists (RCR) methodology, using a point-dose for planning target volume (PTV) and the organs at risk (OAR). An in-house tool, named EQD2 VH, was created in Python to perform treatment gap calculations using the dose-volume histogram (DVH) information in DICOM data extracted from commercial treatment planning system plans. The physical dose in each dose bin was converted into equivalent dose in 2-Gy fractions (EQD2 ), accounting for tumor cell repopulation. This EQD2 -based DVH provides a 2D representation of the impact of treatment gap compensation strategies on both PTV and OAR dose distributions compared to the intended prescribed treatment plan. This additional information can aid clinicians' choice of compensation options. EQD2 VH was evaluated using five high-priority patients experiencing a treatment interruption when the cyberattack occurred. Compensation plans were created using the RCR methodology to evaluate EQD2 VH as a decision-making tool. The EQD2 VH method demonstrated that the comparison of compensated treatment plans alongside the original intended treatment plans using isoeffective DVH analysis can be achieved. It enabled a visual and quantitative comparison between treatment plan options and provided an individual analysis of each structure in a patient's plan. It demonstrated potential to be a useful decision-making tool for finding a balance between optimizing dose to PTV while protecting OARs.

Characteristics, treatment and outcomes of 589 melanoma patients documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: General practitioners manage more melanomas than dermatologists or surgeons in Australia. Previously undescribed, the management and outcomes of melanoma patients treated by multiple Australasian general practitioners are examined. METHODS: The characteristics, management and outcomes of 589 melanoma patients, managed by 27 Australasian general practitioners and documented on the Skin Cancer Audit Research Database (SCARD), were analysed. RESULTS: Most patients (58.9%) were males with mean age at diagnosis of 62.7 years (range 18-96), and most melanomas were in situ or thin-invasive. Patients aged under 40 years had fewer melanomas, but a higher proportion (the majority) were invasive, compared with older patients (P < 0.0001). Most (55.9%) melanomas were diagnosed following elliptical excision biopsy, the rate of unintended involved margins being eightfold higher for shave biopsies. Wide re-excision was performed by the treating general practitioner for most (74.9%) melanomas, with thick melanomas preferentially referred to surgeons. The average Breslow thickness of invasive melanomas re-excised by general practitioners was 0.67 mm compared with 1.99 mm for those referred to other specialists (P < 0.0001). Of 205 patients with invasive melanoma, 14 progressed to metastatic disease, 50% of these being associated with nodular melanoma. Nine patients progressed to melanoma-specific death. The 5-year survival rate for patients with invasive melanoma was 95.2% (95% CI: 91.2-98.5%). CONCLUSIONS: Diagnostic and therapeutic management of a series of melanoma patients by Australasian general practitioners were closely aligned with current guidelines and 5-year survival with respect to invasive melanoma was at least as favourable as national population-based metrics.

Characteristics of 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Most melanomas (including melanomas in situ), in Australasia, are treated by general practitioners (GPs). Previously undescribed, the characteristics of a series of melanomas treated by multiple GPs are examined. PATIENTS AND METHODS: Six hundred and thirty-seven melanomas treated by 27 Australasian GPs during 2013 and documented on the Skin Cancer Audit Research Database (SCARD) were analysed by anatomical site, subtype, Breslow thickness, diameter, associated naevi and linked adverse outcomes. RESULTS: Most melanomas (59.7%) were on males, mean age at diagnosis being 62.7 years (range 18-96). Most (65.0%) were in situ, with a high incidence of lentiginous melanoma (LM) (38.8%) and 32% were naevus associated. Most LM (86.4%) were in situ, compared to 55% of superficial spreading melanoma (SSM) (P < 0.0001). There was male predominance on the head, neck and trunk and female predominance on extremities. There was no significant association between Breslow thickness and diameter, with small melanomas as likely to be thick as large melanomas, and melanomas ≤3 mm diameter, on average, more likely to be invasive than larger melanomas. There was a positive correlation between age and both melanoma diameter and Breslow thickness. Seven cases progressed to melanoma-specific death: Five nodular melanoma (NM) and two SSM, one of which was thin (Breslow thickness 0.5 mm). CONCLUSIONS: A large series of melanomas treated by Australasian GPs were predominantly in situ, with a high proportion of LM subtype. With implications for GP training, NM linked to death was over-represented and there was a novel finding that older patients had larger diameter melanomas.

A comparison of treatment planning techniques for low-dose-rate (LDR) prostate brachytherapy.

PURPOSE: The purpose of this study was to compare low-dose-rate prostate brachytherapy treatment plans created using three retrospectively applied planning techniques with plans delivered to patients. METHODS AND MATERIALS: Treatment plans were created retrospectively on transrectal ultrasound (TRUS) scans for 26 patients. The technique dubbed 4D Brachytherapy was applied, using TRUS and MRI to obtain prostatic measurements required for the associated webBXT online nomogram. Using a patient's MRI scan to create a treatment plan involving loose seeds was also explored. Plans delivered to patients were made using an intraoperative loose seed TRUS-based planning technique. Prostate V100 (%), prostate V150 (%), prostate D90 (Gy), rectum D0.1cc (Gy), rectum D2cc (Gy), urethra D10 (%), urethra D30 (%), and prostate volumes were measured for each patient. Statistical analysis was used to assess and compare plans. RESULTS: Prostate volumes measured by TRUS and MRI were significantly different. Prostate volumes calculated by the webBXT online nomogram using TRUS- and MRI-based measurements were not significantly different. Compared with delivered plans, TRUS-based 4D Brachytherapy plans showed significantly lower rectum D0.1cc (Gy) values, MRI-based 4D Brachytherapy plans showed significantly higher prostate V100 (%) values and significantly lower rectum D0.1cc (Gy), urethra D10 (%), and urethra D30 (%) values, and loose seed MRI-based plans showed significantly lower prostate V100 (%), prostate D90 (Gy), rectum D0.1cc (Gy), rectum D2cc (Gy), urethra D10 (%), and urethra D30 (%) values. CONCLUSIONS: TRUS-based 4D Brachytherapy plans showed similar dosimetry to delivered plans; rectal dosimetry was superior. MRI can be integrated into the 4D Brachytherapy workflow. The webBXT online nomogram overestimates the required number of seeds.

Review of recent radon research in Ireland, OPTI-SDS project and its impact on the National Radon Control Strategy.

Radon is a radioactive gas originating from uranium, present in all rocks and soils in the Earth's Crust; emanating from the ground, radon can be released into the atmosphere. It is the greatest source of natural radioactivity exposure for the population and, as declared by the World Health Organization (WHO), the leading cause of lung cancer only after smoking. Although radon is a natural gas, its accumulation provoking elevated indoor radon levels is a result from building practices and thus, not natural. In Ireland, exposure to radon is estimated to be responsible for approximately 14% of all lung cancers, which is equivalent to around 300 lung cancers annually. In 2011, an interagency group was established in Ireland to develop a strategy to address indoor radon exposure, considered a significant public health concern. In 2014 a National Radon Control Strategy (NRCS) for Ireland was first published, giving a list of recommendations to be accomplished in a 4-year period Phase 1. A series of research actions to achieve the effective implementation of the strategy were conducted, including the development of a research project (OPTI-SDS) on the optimum specifications for radon mitigation by soil depressurisation systems. An overview of Phase 1 of the NRCS is presented, including outcomes from the research work carried out.

Pituitary Adenoma on 18F-Fluciclovine PET/CT.

A 69-year-old man presented with lower urinary tract symptoms and prostate biopsy showed prostate cancer. F-Fluciclovine PET/CT revealed abnormal increased radiotracer uptake within the prostate gland, and multiple osseous structures, suspicious for tumoral involvement. Incidentally, an expansile soft tissue density mass arising from sella turcica demonstrated increased radiotracer activity. MRI showed a lobulated enhancing mass centered in the sella and eroding into the sphenoid sinus. The differential diagnosis includes pituitary macroadenoma versus prostate cancer metastasis. The tumor was resected and the pathological diagnosis was pituitary adenoma.

Benchmarking a novel inorganic scintillation detector for applications in radiation therapy.

PURPOSE: The aim of this study was to investigate the contribution of Cerenkov radiation to the overall signal measured with a novel inorganic scintillating detector (ISD). METHODS: An ISD based on terbium doped gadolinium oxysulphide (Gd2O2S:Tb) was used. A hyperspectral technique separated the Cerenkov signal from the radioluminescence (RL) signal of the ISD. The relative contribution of Cerenkov radiation was evaluated under different conditions. The efficiency of using simple spectral correction to reduce the Cerenkov contribution was quantified. Other experiments investigated were the dose-per-pulse dependence observed in our previous study and the absorbed-dose energy dependence when acquiring percentage depth dose curves using Monte Carlo (MC) simulations. RESULTS: The maximum relative contribution of Cerenkov radiation was 2.10% for a 10 × 10 cm2 field at 10 cm depth. However, this percentage increased to 24% when the ISD was 7 cm out of field and exposed to a 10 × 10 cm2 field. Using 15 nm and 5 nm band-pass filters reduced the Cerenkov contribution across all experimental conditions by a maximum of 75% and 82%, respectively. The MC simulation results show discrepancies between the measured and simulated PDD profiles using the Gd2O2S:Tb scintillator at depth. CONCLUSION: This study showed that while Gd2O2S:Tb ISD provides high-signal intensity, the contribution of Cerenkov radiation under specific conditions can be significant. However, narrow band-pass filters can reduce the Cerenkov signal to a negligible level. The MC simulations suggest mechanisms other than the stem effect and the absorbed-dose energy dependence influence the response of the Gd2O2S:Tb scintillator measurements at depth.

Off-axis dose distribution with stand-in and stand-off configurations for superficial radiotherapy treatments.

Current practice when delivering dose for superficial skin radiotherapy is to adjust the monitor units so that the prescribed dose is delivered to the central axis of the superficial unit applicator. Variations of source-to-surface distance due to patient's anatomy protruding into the applicator or extending away from the applicator require adjustments to the monitor units using the inverse square law. Off-axis dose distribution varies significantly from the central axis dose and is not currently being quantified. The dose falloff at the periphery of the field is not symmetrical in the anode-cathode axis due to the heel effect. This study was conducted to quantify the variation of dose across the surface being treated and model a simple geometric shape to estimate a patient's surface with stand-in and stand-off. Isodose plots and color-coded dose distribution maps were produced from scans of GAFChromic EBT-3 film irradiated by a Gulmay D3300 orthovoltage x-ray therapy system. It was clear that larger applicators show a greater dose falloff toward the periphery than smaller applicators. Larger applicators were found to have a lower percentage of points above 90% of central axis dose (SA90). Current clinical practice does not take this field variation into account. Stand-in can result in significant dose falloff off-axis depending on the depth and width of the protrusion, while stand-off can result in a flatter field due to the high-dose region near the central axis being further from the source than the peripheral regions. The central axis also received a 7% increased or decreased dose for stand-in or stand-off, respectively.

Optimal tumour control for early-stage non-small-cell lung cancer: A radiobiological modelling perspective.

A fully heterogeneous population tumour control probability (TCP) model, based on the linear-quadratic (LQ) cell survival concept combined with the Poisson statistic, was established to predict local tumour control after one, two and three years. This TCP model was created using data from 16 publications that reported on early-stage non-small-cell lung cancer (NSCLC) treated using either three-dimensional conformal radiation therapy (3D-CRT), continuous hyperfractionated accelerated radiotherapy (CHART) or stereotactic ablative body radiotherapy (SABR). The TCP model was fitted to the clinical outcome data using optimised radiosensitivity values produced by the Nelder-Mead simplex algorithm. The statistical analysis resulted in R2 values of 0.96, 0.96 and 0.97 and wRMSE values of 3.9%, 5.2% and 5.9% for one-, two- and three-year local tumour control rates, respectively. The TCP models for one, two and three years were internally validated using a bootstrap resampling approach. The mean R2 and 95% CI for the bootstrap samples were 0.98 (0.93-0.99), 0.98 (0.95-0.99) and 0.98 (0.96-0.99) for the one-, two- and three-year local tumour control rates, respectively. Variations in the TCP with clonogenic density were then further investigated by introducing a new mathematical model to vary the clonogenic cell and radiation dose distribution across the treated volume. Based on the above model, it was estimated that 60% of the dose was sufficient to maintain the TCP after two years for the areas with lower clonogenic cell density. If externally validated, this lower-dose treatment plan could have beneficial effects on the surrounding healthy tissue without negatively affecting tumour control.

Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.

BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma. METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual. FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths. INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials. FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.

Investigation of gas flow through soils and granular fill materials for the optimisation of radon soil depressurisation systems.

The purpose of this study is to investigate gas flow through different types of granular fill materials and soil by means of a series of experimental laboratory tests, in relation to soil depressurisation systems for radon reduction under buildings and the soil surrounding the foundation. Gas permeability characterisation of materials used as granular fill material beneath the slab in buildings is a key parameter for the optimum performance of soil depressurisation systems to mitigate radon. A test apparatus was developed, adapted from previous studies, to measure the gas permeability of the samples and Finite Element Method numerical simulations were validated to simulate the flow behaviour through them. Theoretical expressions for permeability were discussed based on the analysis of experimental results and numerical simulations, finding that Darcy-Forchheimer equation provides the best match to the experimental results. Darcy's law also proved to be suitable for low gas velocities, whereas Ergun's equation resulted in a poor fit of the experimental data. Benchmark analysis of the granular fill materials under study and other European standards (Spanish, Irish and British) is also presented.

A Monte Carlo study of the effect of an ultrasound transducer on surface dose during intrafraction motion imaging for external beam radiation therapy.

PURPOSE: The aim of this study was to estimate changes in surface dose due to the presence of the Clarity Autoscan™ ultrasound (US) probe during prostate radiotherapy using Monte Carlo (MC) methods. METHODS: MC models of the Autoscan US probe were developed using the BEAMnrc/DOSXYZnrc code based on kV and MV CT images. CT datasets were converted to voxelized mass density phantoms using a CT number-to-mass density calibration. The dosimetric effect of the probe, in the contact region (an 8 mm × 12 mm single layer of voxels), was investigated using a phantom set-up mimicking two scenarios (a) a transperineal imaging configuration (radiation beam perpendicular to the central US axial direction), and (b) a transabdominal imaging configuration (radiation beam parallel to the central US axial direction). For scenario (a), the dosimetric effect was evaluated as a function of the probe to inferior radiation field edge distance. Clinically applicable distances from 5 mm separation to 2 mm overlap were determined from the radiotherapy plans of 27 patients receiving Clarity imaging. Overlaps of 3 to 14 (1 to 3 SD) mm were also considered to include the effect of interfraction motion correction. The influence of voxel size on surface dose estimation was investigated. Approved clinical plans from two prostate patients were used to simulate worst-case dosimetric impact of the probe when large couch translations were applied to correct for interfraction prostate motion. RESULTS: The dosimetric impact of both the MV and kV probe models agreed within ±2% for both beam configurations. For scenario (a) and 1 mm voxel model, the probe gave mean dose increases of 1.2% to 4.6% (of the dose at isocenter) for 5 mm separation to 0 mm overlap in the probe-phantom contact region, respectively. This increased to 27.5% for the largest interfraction motion correction considered (14 mm overlap). For separations of ≥ 2 mm dose differences were < 2%. Simulated dose perturbations were found to be superficial; for the 14 mm overlap the dose increase reduced to < 3% at 5.0 mm within the phantom. For scenario (b), dose increases due to the probe were < 5% in all cases. The dose increase was underestimated by up to ~13% when the voxel size was increased from 1 mm to 3 mm. MC simulated dose to the PTV and OARs for the two clinical plans considered showed good agreement with commercial treatment planning system results (within 2%). Mean dose increases due to the presence of the probe, after the maximum interfraction motion correction, were ~16.3% and ~8.0%, in the contact region, for plan 1 and plan 2, respectively. CONCLUSIONS: The presence of the probe results in superficial dose perturbations for patients with an overlap between the probe and the radiation field present in either the original treatment plan or due to translation of the radiation field to simulate correction of interfraction internal prostate motion.

Functional imaging for regenerative medicine.

In vivo imaging is a platform technology with the power to put function in its natural structural context. With the drive to translate stem cell therapies into pre-clinical and clinical trials, early selection of the right imaging techniques is paramount to success. There are many instances in regenerative medicine where the biological, biochemical, and biomechanical mechanisms behind the proposed function of stem cell therapies can be elucidated by appropriate imaging. Imaging techniques can be divided according to whether labels are used and as to whether the imaging can be done in vivo. In vivo human imaging places additional restrictions on the imaging tools that can be used. Microscopies and nanoscopies, especially those requiring fluorescent markers, have made an extraordinary impact on discovery at the molecular and cellular level, but due to their very limited ability to focus in the scattering tissues encountered for in vivo applications they are largely confined to superficial imaging applications in research laboratories. Nanoscopy, which has tremendous benefits in resolution, is limited to the near-field (e.g. near-field scanning optical microscope (NSNOM)) or to very high light intensity (e.g. stimulated emission depletion (STED)) or to slow stochastic events (photo-activated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM)). In all cases, nanoscopy is limited to very superficial applications. Imaging depth may be increased using multiphoton or coherence gating tricks. Scattering dominates the limitation on imaging depth in most tissues and this can be mitigated by the application of optical clearing techniques that can impose mild (e.g. topical application of glycerol) or severe (e.g. CLARITY) changes to the tissue to be imaged. Progression of therapies through to clinical trials requires some thought as to the imaging and sensing modalities that should be used. Smoother progression is facilitated by the use of comparable imaging modalities throughout the discovery and trial phases, giving label-free techniques an advantage wherever they can be used, although this is seldom considered in the early stages. In this paper, we will explore the techniques that have found success in aiding discovery in stem cell therapies and try to predict the likely technologies best suited to translation and future directions.

Monte Carlo investigation of collapsed versus rotated IMRT plan verification.

IMRT QA requires, among other tests, a time-consuming process of measuring the absorbed dose, at least to a point, in a high-dose, low-dose-gradient region. Some clinics use a technique of measuring this dose with all beams delivered at a single gantry angle (collapsed delivery), as opposed to the beams delivered at the planned gantry angle (rotated delivery). We examined, established, and optimized Monte Carlo simulations of the dosimetry for IMRT verification of treatment plans for these two different delivery modes (collapsed versus rotated). The results of the simulations were compared to the treatment planning system dose calculations for the two delivery modes, as well as to measurements taken. This was done in order to investigate the validity of the use of a collapsed delivery technique for IMRT QA. The BEAMnrc, DOSXYZnrc, and egs_chamber codes were utilized for the Monte Carlo simulations along with the MMCTP system. A number of different plan complexity metrics were also used in the analysis of the dose distributions in a bid to qualify why verification in a collapsed delivery may or may not be optimal for IMRT QA. Following the Alfonso et al. formalism, the kfclin,frefQclin,Q correction factor was calculated to correct the deviation of small fields from the reference conditions used for beam calibration. We report on the results obtained for a cohort of 20 patients. The plan complexity was investigated for each plan using the complexity metrics of homogeneity index, conformity index, modulation complexity score, and the fraction of beams from a particular plan that intersect the chamber when performing the QA. Rotated QA gives more consistent results than the collapsed QA technique. The kfclin,frefQclin,Qfactor deviates less from 1 for rotated QA than for collapsed QA. If the homogeneity index is less than 0.05 then the kfclin,frefQclin,Q factor does not deviate from unity by more than 1%. A value this low for the homogeneity index can only be obtained with the rotated QA technique.

An investigation into the use of MMCTP to tune accelerator source parameters and testing its clinical application.

This paper presents an alternative method to tune Monte Carlo electron beam parameters to match measured data using a minimal set of variables in order to reduce the model setup time prior to clinical implementation of the model. Monte Carlo calculations provide the possibility of a powerful treatment planning verification technique. The nonstandardized and nonautomated process of tuning the required accelerator model is one of the reasons for delays in the clinical implementation of Monte Carlo techniques. This work aims to establish and verify an alternative tuning method that can be carried out in a minimal amount of time, allowing it to be easily implemented in a clinical setting by personnel with minimal experience with Monte Carlo methods. This tuned model can then be incorporated into the MMCTP system to allow the system to be used as a second dose calculation check for IMRT plans. The technique proposed was used to establish the primary electron beam parameters for accelerator models for the Varian Clinac 2100 6 MV photon beam using the BEAMnrc Monte Carlo system. The method is intended to provide a clear, direct, and efficient process for tuning an accelerator model using readily available clinical quality assurance data. The tuning provides a refined model, which agrees with measured dose profile curves within 1.5% outside the penumbra or 3 mm in the penumbra, for square fields with sides of 3 cm up to 30 cm. These models can then be employed as the basis for Monte Carlo recalculations of dose distributions, using the MMCTP system, for clinical treatment plans, providing an invaluable assessment tool. This was tested on six IMRT plans and compared to the measurements performed for the pretreatment QA process. These Monte Carlo values for the average dose to the chamber volume agreed with measurements to within 0.6%.

Characterization of an extendable multi-leaf collimator for clinical electron beams.

An extendable x-ray multi-leaf collimator (eMLC) is investigated for collimation of electron beams on a linear accelerator. The conventional method of collimation using an electron applicator is impractical for conformal, modulated and mixed beam therapy techniques. An eMLC would allow faster, more complex treatments with potential for reduction in dose to organs-at-risk and critical structures. The add-on eMLC was modelled using the EGSnrc Monte Carlo code and validated against dose measurements at 6-21 MeV with the eMLC mounted on a Siemens Oncor linear accelerator at 71.6 and 81.6 cm source-to-collimator distances. Measurements and simulations at 8.4-18.4 cm airgaps showed agreement of 2%/2 mm. The eMLC dose profiles and percentage depth dose curves were compared with standard electron applicator parameters. The primary differences were a wider penumbra and up to 4.2% reduction in the build-up dose at 0.5 cm depth, with dose normalized on the central axis. At 90 cm source-to-surface distance (SSD)--relevant to isocentric delivery--the applicator and eMLC penumbrae agreed to 0.3 cm. The eMLC leaves, which were 7 cm thick, contributed up to 6.3% scattered electron dose at the depth of maximum dose for a 10 × 10 cm2 field, with the thick leaves effectively eliminating bremsstrahlung leakage. A Monte Carlo calculated wedge shaped dose distribution generated with all six beam energies matched across the maximum available eMLC field width demonstrated a therapeutic (80% of maximum dose) depth range of 2.1-6.8 cm. Field matching was particularly challenging at lower beam energies (6-12 MeV) due to the wider penumbrae and angular distribution of electron scattering. An eMLC isocentric electron breast boost was planned and compared with the conventional applicator fixed SSD plan, showing similar target coverage and dose to critical structures. The mean dose to the target differed by less than 2%. The low bremsstrahlung dose from the 7 cm thick MLC leaves had the added advantage of reducing the mean dose to the whole heart. Isocentric delivery using an extendable eMLC means that treatment room re-entry and repositioning the patient for SSD set-up is unnecessary. Monte Carlo simulation can accurately calculate the fluence below the eMLC and subsequent patient dose distributions. The eMLC generates similar dose distributions to the standard electron applicator but provides a practical method for more complex electron beam delivery.

Accounting for the fringe magnetic field from the bending magnet in a Monte Carlo accelerator treatment head simulation.

PURPOSE: Monte Carlo (MC) simulation can be used for accurate electron beam treatment planning and modeling. Measurement of large electron fields, with the applicator removed and secondary collimator wide open, has been shown to provide accurate simulation parameters, including asymmetry in the measured dose, for the full range of clinical field sizes and patient positions. Recently, disassembly of the treatment head of a linear accelerator has been used to refine the simulation of the electron beam, setting tightly measured constraints on source and geometry parameters used in simulation. The simulation did not explicitly include the known deflection of the electron beam by a fringe magnetic field from the bending magnet, which extended into the treatment head. Instead, the secondary scattering foil and monitor chamber were unrealistically laterally offset to account for the beam deflection. This work is focused on accounting for this fringe magnetic field in treatment head simulation. METHODS: The magnetic field below the exit window of a Siemens Oncor linear accelerator was measured with a Tesla-meter from 0 to 12 cm from the exit window and 1-3 cm off-axis. Treatment head simulation was performed with the EGSnrc/BEAMnrc code, modified to incorporate the effect of the magnetic field on charged particle transport. Simulations were used to analyze the sensitivity of dose profiles to various sources of asymmetry in the treatment head. This included the lateral spot offset and beam angle at the exit window, the fringe magnetic field and independent lateral offsets of the secondary scattering foil and electron monitor chamber. Simulation parameters were selected within the limits imposed by measurement uncertainties. Calculated dose distributions were then compared with those measured in water. RESULTS: The magnetic field was a maximum at the exit window, increasing from 0.006 T at 6 MeV to 0.020 T at 21 MeV and dropping to approximately 5% of the maximum at the secondary scattering foil. It was up to three times higher in the bending plane, away from the electron gun, and symmetric within measurement uncertainty in the transverse plane. Simulations showed the magnetic field resulted in an offset of the electron beam of 0.80 cm (mean) at the machine isocenter for the exit window only configuration. The fringe field resulted in a 3.5%-7.6% symmetry and 0.25-0.35 cm offset of the clinical beam R(max) profiles. With the magnetic field included in simulations, a single (realistic) position of the secondary scattering foil and monitor chamber was selected. Measured and simulated dose profiles showed agreement to an average of 2.5%/0.16 cm (maximum: 3%/0.2 cm), which is a better match than previously achieved without incorporating the magnetic field in the simulation. The undulations from the 3 stepped layers of the secondary scattering foil, evident in the measured profiles of the higher energy beams, are now aligned with those in the simulated beam. The simulated fringe magnetic field had negligible effect on the central axis depth dose curves and cross-plane dose profiles. CONCLUSIONS: The fringe magnetic field is a significant contributor to the electron beam in-plane asymmetry. With the magnetic field included explicitly in the simulation, realistic monitor chamber and secondary scattering foil positions have been achieved, and the calculated fluence and dose distributions are more accurate.