Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK.

Sealing faults and fluid-induced seismicity.

Sealing faults are nearly impermeable barriers that can form boundaries between subsurface pore-pressure domains. In hydrocarbon systems, sealing faults commonly form part of a structural trap; they are thus important elements for future storage of CO2 and other gases in depleted reservoirs. The Triassic Montney Formation in western Canada hosts low-permeability gas reservoirs containing sealing faults that have previously been assumed to compartmentalize pressure domains. In this study, we show that the distribution of induced seismicity associated with hydraulic fracturing (HF) exhibits a statistically significant spatial correlation with zones of high lateral gradient in pore pressure. These high-gradient zones are interpreted as sealing fault systems. The largest induced seismicity sequence, including a 4.5 ML mainshock on 30 November 2018, occurred during HF treatments in two horizontal wells, between which there is an exceptionally large contrast (~10 MPa) in measured pore pressure. Numerical simulation of a simplified model of a hydraulic fracture intersecting a nearby vertical fault, followed by fault rupture using rate-and-state friction rheology, generates results that are in good agreement with observed strike-slip faulting near one of the HF wells. Our study demonstrates that sealing faults exhibit previously unrecognized behaviour that may be important for understanding induced seismicity risk. This article is part of the theme issue 'Induced seismicity in coupled subsurface systems'.

Species differences in specific ligand-binding affinity and activation of AHR: The biological basis for calculation of relative effective potencies and toxic equivalence factors.

In 2022 the World Health Organization (WHO) published updated 'Toxic Equivalence Factors' (TEFs) for a wide variety of chlorinated dioxins, dibenzofurans and PCBs [collectively referred to as 'dioxin-like chemicals'; DLCs) that interact with the aryl hydrocarbon receptor (AHR)]. Their update used sophisticated statistical analysis of hundreds of published studies that reported estimation of 'Relative Effective Potency' (REP) values for individual DLC congeners. The weighting scheme used in their assessment of each study favored in vivo over in vitro studies and was based largely on rodent studies. In this Commentary, we highlight the large body of published studies that demonstrate large species differences in AHR-ligand activation and provide supporting evidence for our position that the WHO 2022 TEF values intended for use in human risk assessment of DLC mixtures will provide highly misleading overestimates of 'Toxic Equivalent Quotients' (TEQs), because of well-recognized striking differences in AHR ligand affinities between rodent (rat, mouse) and human. The data reviewed in our Commentary support the position that human tissue-derived estimates of REP/TEF values for individual DLC congeners, although uncertain, will provide much better, more realistic estimates of potential activation of the human AHR, when exposure to complex DLC mixtures occurs.

Application of failure mode and effects analysis to validate a novel hybrid Linac QC program that integrates automated and conventional QC testing.

A hybrid quality control (QC) program was developed that integrates automated and conventional Linac QC, realizing the benefits of both automated and conventional QC, increasing efficiency and maintaining independent measurement methods. Failure mode and effects analysis (FMEA) was then applied in order to validate the program prior to clinical implementation. The hybrid QC program consists of automated QC with machine performance check and DailyQA3 array on the TrueBeam Linac, and Delta4 volumetric modulated arc therapy (VMAT) standard plan measurements, alongside conventional monthly QC at a reduced frequency. The FMEA followed the method outlined in TG-100. Process maps were created for each treatment type at our center: VMAT, stereotactic body radiotherapy (SBRT), conformal, and palliative. Possible failure modes were established by evaluating each stage in the process map. The FMEA followed semiquantitative methods, using data from our QC records from eight Linacs over 3 years for the occurrence estimates, and simulation of failure modes in the treatment planning system, with scoring surveys for severity and detectability. The risk priority number (RPN) was calculated from the product of the occurrence, severity, and detectability scores and then normalized to the maximum and ranked to determine the most critical failure modes. The highest normalized RPN values (100, 90) were found to be for MLC position dynamic for both VMAT and SBRT treatments. The next highest score was 35 for beam position for SBRT, and the majority of scores were less than 20. Overall, these RPN scores for the hybrid Linac QC program indicated that it would be acceptable, but the high RPN score associated with the dynamic MLC failure mode indicates that it would be valuable to perform more rigorous testing of the MLC. The FMEA proved to be a useful tool in validating hybrid QC.

Long-term experience of MPC across multiple TrueBeam linacs: MPC concordance with conventional QC and sensitivity to real-world faults.

Machine Performance Check (MPC) is an automated Quality Control (QC) tool that is integrated into the TrueBeam and Halcyon linear accelerators (Linacs), utilizing the imaging systems to verify the Linac beam and geometry. This work compares the concordance of daily MPC results with conventional QC tests over a 3-year period for eight Linacs in order to assess the sensitivity of MPC in detecting faults. The MPC output measurements were compared with the monthly ionization chamber measurements for 6 and 10 MV photon beams and 6, 9, 12, 16, and 18 MeV electron beams. All 6 MV Beam and Geometry (6MVBG) MPC test failures were analyzed to determine the failure rate and the number of true and false negative results, using the conventional QC record as the reference. The concordance between conventional QC test failures and MPC test failures was investigated. The mean agreement across 1933 MPC output and monthly comparison chamber measurements for all beam energies was 0.2%, with 97.8% within 1.5%, and a maximum difference of 2.9%. Of the 5000-6000 MPC individual test parameter results for the 6MVBG test, the highest failure rate was BeamOutputChange (0.5%), then BeamCenterShift (0.3%), and was ≤ 0.1% for the remaining parameters. There were 50 true negative and 27 false negative out of tolerance MPC results, with false negatives resolved by repeating MPC or by independent measurement. The analysis of conventional QC failures demonstrated that MPC detected all failures, except occasions when MPC reported output within tolerance, a result of the MPC-chamber response variation. The variation in MPC output versus chamber measurement indicates MPC is appropriate for daily output constancy but not for the measurement of absolute output. The comparison of the 6MVBG results and conventional records provides evidence that MPC is a sensitive method of performing beam and mechanical checks in a clinical setting.

Cruciferous vegetables have variable effects on biomarkers of systemic inflammation in a randomized controlled trial in healthy young adults.

BACKGROUND: Isothiocyanates in cruciferous vegetables modulate signaling pathways critical to carcinogenesis, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a central regulator of inflammation. Glutathione S-transferase (GST) M1 and GSTT1 metabolize isothiocyanates; genetic variants may result in differences in biologic response. OBJECTIVE: The objective of this study was to test whether consumption of cruciferous or cruciferous plus apiaceous vegetables altered serum concentrations of interleukin (IL)-6, IL-8, C-reactive protein (CRP), tumor necrosis factor (TNF) α, and soluble TNF receptor (sTNFR) I and II, and whether this response was GSTM1/GSTT1 genotype dependent. METHODS: In a randomized crossover trial, healthy men (n = 32) and women (n = 31) aged 20-40 y consumed 4 14-d controlled diets: basal (vegetable-free), single-dose cruciferous (1xC) [7 g vegetables/kg body weight (BW)], double-dose cruciferous (2xC) (14 g/kg BW), and cruciferous plus apiaceous (carrot family) (1xC+A) vegetables (7 and 4 g/kg BW, respectively), with a 21-d washout period between each intervention. Urinary isothiocyanate excretion was also evaluated as a marker of systemic isothiocyanate exposure. Fasting morning blood and urine samples were collected on days 0 and 14 and analyzed. RESULTS: IL-6 concentrations were significantly lower on day 14 of the 2xC and 1xC+A diets than with the basal diet [-19% (95% CI: -30%, -0.1%) and -20% (95% CI: -31%, -0.7%), respectively]. IL-8 concentrations were higher after the 1xC+A diet (+16%; 95% CI: 4.2%, 35.2%) than after the basal diet. There were no effects of diet on CRP, TNF-α, or sTNFRI or II. There were significant differences between GSTM1-null/GSTT1+ individuals for several biomarkers in response to 1xC+A compared with basal diets (CRP: -37.8%; 95% CI: -58.0%, -7.4%; IL-6: -48.6%; 95% CI: -49.6%, -12.0%; IL-8: 16.3%; 95% CI: 6.7%, 57.7%) and with the 2xC diet compared with the basal diet (IL-8: -33.2%; 95% CI: -43.0%, -1.4%; sTNFRI: -7.5%; 95% CI: -12.7%, -2.3%). There were no significant reductions in biomarker concentrations in response to diet among GSTM1+/GSTT1+ or GSTM1-null/GSTT1-null individuals. Twenty-four-hour urinary isothiocyanate excretion was not associated with any of the inflammation markers overall; however, IL-6 was inversely associated with total isothiocyanate excretion in GSTM1-null/GSTT1-null individuals (ß = -0.12; 95% CI: -0.19, -0.05). CONCLUSIONS: In this young, healthy population, consumption of cruciferous and apiaceous vegetables reduced circulating IL-6; however, results for other biomarkers of inflammation were not consistent.

In vivo dosimetry for total body irradiation: five-year results and technique comparison.

The aim of this work is to establish if the new CT-based total body irradiation (TBI) planning techniques used at University College London Hospital (UCLH) and Royal Free Hospital (RFH) are comparable to the previous technique at the Middlesex Hospital (MXH) by analyzing predicted and measured diode results. TBI aims to deliver a homogeneous dose to the entire body, typically using extended SSD fields with beam modulation to limit doses to organs at risk. In vivo dosimetry is used to verify the accuracy of delivered doses. In 2005, when the Middlesex Hospital was decommissioned and merged with UCLH, both UCLH and the RFH introduced updated CT-planned TBI techniques, based on the old MXH technique. More CT slices and in vivo measurement points were used by both; UCLH introduced a beam modulation technique using MLC segments, while RFH updated to a combination of lead compensators and bolus. Semiconductor diodes were used to measure entrance and exit doses in several anatomical locations along the entire body. Diode results from both centers for over five years of treatments were analyzed and compared to the previous MXH technique for accuracy and precision of delivered doses. The most stable location was the field center with standard deviations of 4.1% (MXH), 3.7% (UCLH), and 1.7% (RFH). The least stable position was the ankles. Mean variation with fraction number was within 1.5% for all three techniques. In vivo dosimetry can be used to verify complex modulated CT-planned TBI, and demonstrate improvements and limitations in techniques. The results show that the new UCLH technique is no worse than the previous MXH one and comparable to the current RFH technique.

Recommendation on the technical and dosimetric data to be included in stereotactic body radiation therapy clinical trial publications based on a systematic review.

The results of phase II and III trials on Stereotactic Body Radiation Therapy (SBRT) increased adoption of SBRT worldwide. The ability to replicate clinical trial outcomes in routine practice depends on the capability to reproduce technical and dosimetric procedures used in the clinical trial. In this systematic review, we evaluated if peer-reviewed publications of clinical trials in SBRT reported sufficient technical data to ensure safe and robust implementation in real world clinics. Twenty papers were selected for inclusion, and data was extracted by a working group of medical physicists created following the ESTRO 2021 physics workshop. A large variability in technical and dosimetric data were observed, with frequent lack of required information for reproducing trial procedures. None of the evaluated studies were judged completely reproducible from a technical perspective. A list of recommendations has been provided by the group, based on the analysis and consensus process, to ensure an adequate reproducibility of technical parameters in primary SBRT clinical trials. Future publications should consider these recommendations to assist transferability of the clinical trial in real world practice.

Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.

The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo.

Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand - rifampicin (300mg/d) was given alone for 7days in arm 1, or in daily combination with 450µmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology.

Seismic evidence for convection-driven motion of the North American plate.

Since the discovery of plate tectonics, the relative importance of driving forces of plate motion has been debated. Resolution of this issue has been hindered by uncertainties in estimates of basal traction, which controls the coupling between lithospheric plates and underlying mantle convection. Hotspot tracks preserve records of past plate motion and provide markers with which the relative motion between a plate's surface and underlying mantle regions may be examined. Here we show that the 115-140-Myr surface expression of the Great Meteor hotspot track in eastern North America is misaligned with respect to its location at 200 km depth, as inferred from plate-reconstruction models and seismic tomographic studies. The misalignment increases with age and is consistent with westward displacement of the base of the plate relative to its surface, at an average rate of 3.8 +/- 1.8 mm yr(-1). Here age-constrained 'piercing points' have enabled direct estimation of relative motion between the surface and underside of a plate. The relative displacement of the base is approximately parallel to seismic fast axes and calculated mantle flow, suggesting that asthenospheric flow may be deforming the lithospheric keel and exerting a driving force on this part of the North American plate.

Review of backscatter measurement in kilovoltage radiotherapy using novel detectors and reduction from lack of underlying scattering material.

Lack of underlying material can lead to dose reduction in kilovoltage radiotherapy treatments because of backscatter reduction. Conversely, the use of lead shielding can lead to large dose enhancement close to the lead interface. GAFCHROMIC film has been shown to be of use in verification of local backscatter factors compared to reference data in codes of practice, but careful handling and multiple readings are required to reduce systematic uncertainties to between 3% and 4%. Monte Carlo modeling of the specific treatment unit should be performed in cases which are found to differ from reference values before alternative values are adopted clinically, but these cases are expected to be few. GAFCHROMIC film may also be used to estimate backscatter reduction more readily than customized ionization chambers, for a range of beam qualities, applicator sizes and depth, with and without lead shielding. Differences were found between different studies, and it is not clear to what extent these are due to variation in equipment and/or technique. However, a layer of wax around lead shielding of 1 mm thickness should be sufficient to eliminate lead enhancement effects for all kilovoltage energies from 40 kV to 300 kV.

Physics-informed deep learning to forecast [Formula: see text] during hydraulic fracturing.

Short-term forecasting of estimated maximum magnitude ([Formula: see text]) is crucial to mitigate risks of induced seismicity during fluid stimulation. Most previous methods require real-time injection data, which are not always available. This study proposes two deep learning (DL) approaches, along with two data-partitioning methods, that rely solely on preceding patterns of seismicity. The first approach forecasts [Formula: see text] directly using DL; the second incorporates physical constraints by using DL to forecast seismicity rate, which is then used to estimate [Formula: see text]. These approaches are tested using a hydraulic-fracture monitoring dataset from western Canada. We find that direct DL learns from previous seismicity patterns to provide an accurate forecast, albeit with a time lag that limits its practical utility. The physics-informed approach accurately forecasts changes in seismicity rate, but sometimes under- (or over-) estimates [Formula: see text]. We propose that significant exceedance of [Formula: see text] may herald the onset of runaway fault rupture.

Corrigendum to "Surface-guided radiotherapy for lung cancer can reduce the number of close patient contacts without compromising initial setup accuracy" [Tech. Innov. Patient Support Radiat. Oncol. 20 (2021) 61-63].

[This corrects the article DOI: 10.1016/j.tipsro.2021.11.005.].

Benchmarking Tests of Contemporary SRS Platforms: Have Technological Developments Resulted in Improved Treatment Plan Quality?

PURPOSE: Stereotactic radiosurgery treatment delivery can be performed with a range of devices, each of which have evolved over recent years. We sought to evaluate the differences in performance of contemporary stereotactic radiosurgery platforms and also to compare them with earlier platform iterations from a previous benchmarking study. METHODS AND MATERIALS: The following platforms were selected as "state of the art" in 2022: Gamma Knife Icon (GK), CyberKnife S7 (CK), Brainlab Elements (Elekta VersaHD and Varian TrueBeam), Varian Edge with HyperArc (HA), and Zap-X. Six benchmarking cases were used from a 2016 study. To reflect the evolution of increasing numbers of metastases treated per patient, a 14-target case was added. The 28 targets among the 7 patients ranged from 0.02 to 7.2 cc in volume. Participating centers were sent images and contours for each patient and asked to plan them to the best of their ability. Although some variation in local practice was allowed (eg, margins), groups were asked to prescribe a specified dose to each target and tolerance doses to organs at risk were agreed upon. Parameters compared included coverage, selectivity, Paddick conformity index, gradient index (GI), R50%, efficiency index, doses to organs at risk, and planning and treatment times. RESULTS: Mean coverage for all targets ranged from 98.2% (Brainlab/Elekta) to 99.7% (HA-6X). Paddick conformity index values ranged from 0.722 (Zap-X) to 0.894 (CK). GI ranged from a mean of 3.52 (GK), representing the steepest dose gradient, to 5.08 (HA-10X). The GI appeared to follow a trend with beam energy, with the lowest values from the lower energy platforms (GK, 1.25 MeV; Zap-X, 3 MV) and the highest value from the highest energy (HA-10X). Mean R50% values ranged from 4.48 (GK) to 5.98 (HA-10X). Treatment times were lowest for C-arm linear accelerators. CONCLUSIONS: Compared with earlier studies, newer equipment appears to deliver higher quality treatments. CyberKnife and linear accelerator platforms appear to give higher conformity whereas lower energy platforms yield a steeper dose gradient.

Short-term forecasting of Mmax during hydraulic fracturing.

Previous studies of injection-induced earthquake sequences have shown that the maximum magnitude (Mmax) of injection-induced seismicity increases with the net injected volume (V); however, different proposed seismic-hazard paradigms predict significantly different values of Mmax. Using injection and seismicity data from two project areas in northeastern British Columbia, Canada, where hydraulic fracturing induced seismicity was observed, we test the predictive power and robustness of three existing and one novel method to estimate Mmax. Due to their vastly different values of seismogenic index (Σ), these two project areas represent end-member cases of seismogenic response. Our novel method progressively adjusts the Mmax forecast under the assumption that each recorded event embodies an incremental release of fluid-induced stress. The results indicate that our method typically provides the lowest upper bound of the tested methods and it is less sensitive to site-specific calibration parameters such as Σ. This makes the novel method appealing for operational earthquake forecasting schemes as a real-time mitigation strategy to manage the risks of induced seismicity.

Basin-scale multi-decadal analysis of hydraulic fracturing and seismicity in western Canada shows non-recurrence of induced runaway fault rupture.

Hydraulic fracturing (HF) is a reservoir stimulation technique that has been widely deployed in recent years to increase the productivity of light oil and/or natural gas from organic-rich, low-permeability formations. Although the process of fracturing a rock typically results in microseismic events of magnitude < 0, many cases of felt seismic events (typically magnitude 3.0 or larger) have also been reported. In the Western Canada Sedimentary Basin (WCSB), where more than 40,000 wells have been drilled and hydraulically fractured in the past two decades, the occurrence of HF-induced events has surged in some areas. Yet, many other areas of the WCSB have not experienced a significant increase in induced seismicity, despite a sharp increase in both the number of HF wells and the volumes of injected fluid. The relationship between injected volume and induced magnitudes can be quantified using the seismic efficiency ratio (SEFF), which describes the ratio between the net seismic moment release and the injected fluid volume. Runaway rupture, in which the fault rupture is dominated by the release of accumulated tectonic stresses, is inferred to be marked by an abrupt increase in SEFF to a value > 0.5. Most previous studies of induced earthquakes have been limited to a single operation and/or seismicity sequence. To better understand the observed variability of the seismic response to HF stimulations at a basin scale, we compiled HF data for all unconventional wells hydraulic fractured in the WCSB between 2000 and 2020, together with the seismicity reported during the same period. We grouped these observations into bins measuring 0.2° in longitude and 0.1° in latitude, or approximately 13 by 11 km. We identified 14 areas where large magnitude events resulted in high SEFF values, implying runaway rupture had taken place. However, we find that in these areas, sustained fluid injection did not lead to persistent high SEFF values. Instead, as injection continued, SEFF values returned to values less than 0.5. This suggests that there is a limited budget of tectonic strain energy available to generate runaway rupture events: once this is released, event magnitudes decrease even if high volume injection persists.

InSAR data reveal that the largest hydraulic fracturing-induced earthquake in Canada, to date, is a slow-slip event.

For tectonic earthquakes, slip rate spans a continuum from creep to supershear earthquakes, where slow slip events (SSEs) are important in releasing stress without radiating damaging seismic energy. Industrial-scale subsurface fluid injection has caused induced earthquakes, but the role of SSEs in fault activation is currently unclear. Ground-deformation observations, measured by satellite radar, show that SSEs up to magnitude 5.0 occurred during hydraulic fracturing (HF) operations in northwestern Canada, corroborated by reported deformation of the steel well casing. Although the magnitude 5.0 SSE exceeded the magnitude of the largest induced earthquake in this region (magnitude 4.55), it was undetected by seismograph networks. The observed SSEs occurred within a buried thrust belt and their magnitude and duration are consistent with scaling behavior of SSEs in unbounded natural systems, e.g. slab interfaces in subduction zones.

Implementation of a comprehensive set of optimised CBCT protocols and validation through imaging quality and dose audit.

OBJECTIVES: Cone-beam computed tomography (CBCT) for radiotherapy treatment verification has increased in frequency; therefore, it is crucial to optimise image quality and radiation dose to patients. The aim of this study was to implement optimised CBCT protocols for the Varian TrueBeams for most tumour sites in adult patients. METHODS: A combination of patient size-specific CBCT protocols from the literature and developed in-house was used. Scans taken before and after optimisation were compared by senior radiographers and physicists to evaluate how changes affected image quality and clinical usability for online image registration. The change in dose for each new CBCT protocol was compared to the Varian default. A clinical audit was performed following implementation to evaluate the changes in imaging dose for all patients receiving a CBCT during that period. RESULTS: Ten CBCT protocols were introduced including head and neck and patient-size-specific thorax and pelvis/abdomen protocols. Scans from 102 patients with images before and after optimisation were assessed, none of the scans showed image quality changes compromising clinical usability and for some image quality was improved. Between November 2020 and June 2021, 1185 patients had CBCTs using the new protocols. The imaging dose was reduced for 52% of patients, remained the same for 37% and increased for 12%. CONCLUSIONS: This study showed that substantial dose reductions and image quality improvements can be achieved with simple changes in the default settings of the Varian TrueBeam CBCT without affecting the radiographers' confidence in online image registration. ADVANCES IN KNOWLEDGE: This study represents a comprehensive assessment and optimisation of CBCT protocols for most sites, validated on a large cohort of patients.