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.

RESEARCH ON PASSIVE SOIL DEPRESSURIZATION SYSTEMS: STATE OF THE ART AND LAB TEST ON-GOING.

There is strong evidence both internationally and in Ireland that the correct installation of passive prevention systems in new buildings is the most cost-effective way of protecting the population against radon. Previous work considering membranes, granular fill material in the aggregate layer beneath the slab and sump system has been conducted in Ireland to improve the protection of buildings from radon. The implications of research on passive sumps potential to reduce radon concentrations are significant, as if it can be shown that the installation of passive sumps in Irish building is effective; this could constitute a low-cost, passive, sustainable method for minimizing radon levels in buildings. On-going experimental tests investigating the performance of different common cowls used for passive soil depressurization systems are presented, in addition to the impact of different vertical heights and horizontal lengths of pipe with a number of bends investigated.

An investigation of a passive opened top-end pipe as an alternative solution for passive soil depressurisation systems for indoor radon mitigation.

This study carried out a series of large-scale experimental tests and numerical simulations to investigate the performance of a passive opened top-end pipe as an alternative solution for passive soil depressurisation systems for indoor radon mitigation. Measurements were conducted in terms of wind velocity, extracted air velocity and negative pressure at the sump-end inside the pipe. Investigations were performed with controlled and natural wind conditions. Test results confirmed that the passive opened top-end pipe can be used as an alternative solution for indoor radon concentration mitigation at low additional construction cost. However, the extracted air velocity and negative pressure were found to fluctuate when tested under natural wind conditions. This fluctuation would reduce the effectiveness of the performance of the passive pipe. To reduce this fluctuation, a novel static ventilator has been developed and can be added on the top-end of the pipe.

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.

Radon mitigation by soil depressurisation case study: Radon concentration and pressure field extension monitoring in a pilot house in Spain.

A one-year monitoring study was conducted in a pilot house with extremely high radon levels to investigate the ability and efficiency of radon mitigation by soil depressurisation (SD) both active and passive. The study included monitoring of radon concentration, pressure field extension (PFE) under the slab and some atmospheric parameters for different testing phases. Periods in which the house remained closed to foster radon accumulation were alternated with phases of active and passive soil depressurisation under different conditions. The behaviour of the radon concentration in the pilot house was analysed along with the influence of atmospheric variables, significant correlations were found for the radon concentration with atmospheric pressure, outdoor temperature and wind. From the PFE analysis it was proven that the pressure drop with distance from the suction point of the SD system is proportional to the depressurisation generated. A behaviour law was found for the permeability characterisation of the house based on the active SD performance and also, the relationship between wind velocity and extraction airflow during passive SD operation by means of a rotating cowl was obtained. Radon reductions in excess of 85% were achieved for the different testing phases in all cases. Finally, from the results it was postulated that a fan power of 20 W is sufficient to ensure radon reductions over 85% for dwellings with similar aggregate layer and soil permeability.

Large-scale experimental investigations of specified granular fill materials for radon mitigation by active and passive soil depressurisations.

A series of large-scale experimental tests were performed to examine the flow behaviour of the T1 Struc and T2 Perm specified granular fill materials with active and passive depressurisations. Granular materials were compacted and tested at various compacted thicknesses. Compaction works were performed using a field compactor and compaction degrees of the materials were found to be higher than those induced by a standardised small-scale compactor. The air permeability (kah) values of the materials were obtained with active depressurisation. It was found that the overall trend of kah tended to decrease with the increase in the compacted thickness of the materials and were found to be compatible with those determined by the small-scale test apparatus. Results from passive depressurisation tests indicated that the rotating cowls performed the best, followed by a static open pipe and a pipe with a cap.

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.

Performance of radon monitors in a purpose-built radon chamber.

The purpose of this paper is to benchmark several different radon monitors, by quantifying their accuracy and response time. Radon monitors with different characteristics were tested in a purpose-built radon chamber under reference conditions. The radon concentration in the chamber was controlled and maintained at a stable radon concentration of (2648 ± 85) Bq m-3 to evaluate the accuracy and precision of these monitors. The response time of the monitors was analysed for two time intervals. To assess the response time of the monitors, radon concentration was varied from a theoretical value of 0-6441 Bq m-3 and then from 6441 to 2648 Bq m-3. The results from this study show that general purpose radon monitors are less accurate than those used by radon testing service providers and the research community. All monitors tested reported a mean radon concentration within the ±10% of the reference detector value at the radon equilibrium concentration. Different response time analysis methods were proposed and discussed, and for the particular time intervals analysed, response time was found to be slower for those radon monitors intended for general purpose applications.

Investigation of sub-slab pressure field extension in specified granular fill materials incorporating a sump-based soil depressurisation system for radon mitigation.

Design of bearing layers (granular fill material layers) is important for a house with a soil depressurisation (SD) system for indoor radon mitigation. These layers should not only satisfy the bearing capacity and serviceability criteria but should also provide a sufficient degree of the air permeability for the system. Previous studies have shown that a critical parameter for a SD system is the sub-slab pressure field extension in the bearing layers, but this issue has not been systematically investigated. A series of two-dimensional computational fluid dynamic simulations that investigate the behaviour of the sub-slab pressure field extension developed in a SD system is presented in this paper. The SD system considered in this paper consists of a granular fill material layer and a radon sump. The granular fill materials are 'T1 Struc' and 'T2 Perm', which are standard materials for building in the Republic of Ireland. Different conditions, which might be encountered in a practical situation, were examined. The results show that the air permeability and thickness of the granular fill materials are the two key factors which affect the sub slab pressure field extension (SPFE) significantly. Furthermore, the air permeability of native soil is found to be a fundamental factor for the SPFE so that it should be well understood when designing a SD system. Therefore, these factors should be considered sufficiently in each practical situation. Finally, a significant improvement of the pressure field extension can be achieved by ensuring air tightness of the SD system.