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BackgroundMetformin is an antihyperglycemic agent frequently used in the treatment of Type 2 Diabetes Mellitus (T2DM). Patients with T2DM are at increased risk of cardiovascular diseases, including coronary artery disease (CAD), silent myocardial infarction (MI) and coronary microvascular dysfunction (CMD), all of which can be detected and quantified using Cardiovascular Magnetic Resonance (CMR). We explored the association between metformin use, stress Myocardial Blood Flow (MBF), Myocardial Perfusion Reserve (MPR), survival and major adverse cardiovascular and cerbrovasular events (MACCE; a composite of all-cause death, MI, stroke, heart failure hospitalisation and coronary revascularisation) in patients with T2DM.MethodsA multi-centre study of patients with T2DM, and a cohort of healthy controls underwent quantitative myocardial perfusion CMR. Global MBF and MPR were derived using an automatic artificial intelligence-supported process. Multivariable regression analysis and cox proportional hazard models quantified associations between metformin use, MBF, MPR, all-cause death and MACCE.ResultsAnalysis included 572 patients with T2DM (68% prescribed metformin) with median follow-up 851 days (interquartile range 935-765). Metformin use was associated with an increase in MPR of 0.12 [0.08-0.40], P=0.004. There was a total of 82 (14.3%) first MACCE in all T2DM patients including a total of 25 (4.4%) deaths. Although the number of first MACCE events was similar for patients prescribed metformin (53 (14%)) compared to those who were not (29 (15.8%) (P=0.73)), there was a total of 9 deaths (2.3%) in patients prescribed metformin compred to 16 (8.7%) in patients who were not, adjusted hazard ratio 0.29 [95% CI 0.12-0.73] P=0.009).ConclusionIn patients with T2DM, metformin use is associated with higher MPR and improved survival.Clinical PerspectivePatients with Type 2 Diabetes Mellitus (T2DM) are at increased risk of cardiovascular disease. Cardiovascular Magnetic Resonane (CMR) can be used to detect and quantify absolute stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR), both of which are objective measures of coronary microvascular function. Metformin is frequently used in the treatment of T2DM. We investigated the association between metformin use, CMR-derived stress MBF, MPR and clinical outcomes in patients with T2DM.In a longitudinal cohort study of patients with T2DM, metformin use was associated with higher MPR as a marker of microvascular function, and improved survival after adjusting for certain confounding parameters.Further prospective studies are needed to confirm the association between metformin use and improved MPR and reduced mortality, as well as to clarify the mechanisms responsible and quantify the dose these associated outcomes are observed.Central illustration

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system.MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T 1) was measured alongside the change in 1/T 1 (termed ΔR 1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T 1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR 1 significantly increased (pCONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

Introduction: Limited evidence exists showing the benefit of magnetic resonance (MR)-only radiotherapy treatment planning for anal and rectal cancers. This study aims to assess the impact of MR-only planning on target volumes (TVs) and treatment plan doses to organs at risks (OARs) for anal and rectal cancers versus a computed tomography (CT)-only pathway. Materials and methods: Forty-six patients (29 rectum and 17 anus) undergoing preoperative or radical external beam radiotherapy received CT and T2 MR simulation. TV and OARs were delineated on CT and MR, and volumetric arc therapy treatment plans were optimized independently (53.2 Gy/28 fractions for anus, 45 Gy/25 fractions for rectum). Further treatment plans assessed gross tumor volume (GTV) dose escalation. Differences in TV volumes and OAR doses, in terms of Vx Gy (organ volume (%) receiving x dose (Gy)), were assessed. Results: MR GTV and primary planning TV (PTV) volumes systematically reduced by 13 cc and 98 cc (anus) and 44 cc and 109 cc (rectum) respectively compared to CT volumes. Statistically significant OAR dose reductions versus CT were found for bladder and uterus (rectum) and bladder, penile bulb, and genitalia (anus). With GTV boosting, statistically significant dose reductions were found for sigmoid, small bowel, vagina, and penile bulb (rectum) and vagina (anus). Conclusion: Our findings provide evidence that the introduction of MR (whether through MR-only or CT-MR pathways) to radiotherapy treatment planning for anal and rectal cancers has the potential to improve treatments. MR-related OAR dose reductions may translate into less treatment-related toxicity for patients or greater ability to dose escalate.

Introduction Model-driven registration (MDR) is a general approach to remove patient motion in quantitative imaging. In this study, we investigate whether MDR can effectively correct the motion in free-breathing MR renography (MRR). Materials and methods MDR was generalised to linear tracer-kinetic models and implemented using 2D or 3D free-form deformations (FFD) with multi-resolution and gradient descent optimization. MDR was evaluated using a kidney-mimicking digital reference object (DRO) and free-breathing patient data acquired at high temporal resolution in multi-slice 2D (5 patients) and 3D acquisitions (8 patients). Registration accuracy was assessed using comparison to ground truth DRO, calculating the Hausdorff distance (HD) between ground truth masks with segmentations and visual evaluation of dynamic images, signal-time courses and parametric maps (all data). Results DRO data showed that the bias and precision of parameter maps after MDR are indistinguishable from motion-free data. MDR led to reduction in HD (HDunregistered = 9.98 ± 9.76, HDregistered = 1.63 ± 0.49). Visual inspection showed that MDR effectively removed motion effects in the dynamic data, leading to a clear improvement in anatomical delineation on parametric maps and a reduction in motion-induced oscillations on signal-time courses. Discussion MDR provides effective motion correction of MRR in synthetic and patient data. Future work is needed to compare the performance against other more established methods.

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The use of magnetic resonance (MR) imaging scans alone for radiation therapy treatment planning (MR-only planning) has been highlighted as one method of improving patient outcomes. Recent technologic advances have meant that introducing MR-only planning to the clinic is becoming a reality, with several specialist radiation therapy clinics using this technique for treatment. As such, substantial efforts are being made to introduce this technique into wide-spread clinical implementation. A systematic review of publications investigating the clinical implementation of pelvic MR-only radiation therapy treatment planning was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Medline, Embase, Scopus, Science Direct, Cumulative Index to Nursing and Allied Health Literature, and Web of Science databases were searched (timespan: all years to January 2, 2019). Twenty-six articles met the inclusion criteria. The studies were grouped into the following categories: (1) MR acquisition and synthetic computed tomography generation verification, (2) MR distortion quantification and phantom development, (3) clinical validation of patient treatment positioning in an MR-only workflow, and (4) MR-only commissioning processes. Key conclusions from this review are (1) MR-only planning has been implemented clinically for prostate cancer treatments; (2) a substantial amount of work remains to translate MR-only planning into widespread clinical implementation for all pelvic sites; (3) MR scanner distortions are no longer a barrier to MR-only planning, but they must be managed appropriately; (4) MR-only-based patient positioning verification shows promise, but limited evidence is reported in the literature and further investigation is required; and (5) a number of MR-only commissioning processes have been reported, which can aid centers as they undertake local commissioning; however, this needs to be formalized in guidance from national bodies.

Accurate prediction of early treatment response in patients receiving neoadjuvant chemotherapy for breast cancer is essential to provide patients with the best care. Diffusion-weighted magnetic resonance imaging (DWI) provides a novel approach to distinguishing responders from non-responders. This article aims to review the literature regarding the accuracy of DWI in predicting patients who will respond to neoadjuvant chemotherapy at an early stage within their treatment pathway. The initial search yielded 11,171 articles. After careful review, 19 of these articles were found to adhere to the inclusion criteria. Despite the varied research methods and data analysis across the studies, 16 out of 19 of these studies (84%) demonstrated DWI to be an accurate predictor of neoadjuvant chemotherapy response. These results are promising; however, further multi-centre studies with larger sample sizes, homogenous imaging and treatment parameters and formal assessment of pathological response are required to accurately evaluate the use of DWI as an early predictor of neoadjuvant chemotherapy response in patients with breast cancer.

Objectives: Better markers of early response to neoadjuvant chemotherapy (NACT) in patients with breast cancer are required to enable the timely identification of non-responders and reduce unnecessary treatment side-effects. Early functional imaging may better predict response to treatment than conventional measures of tumour size. The purpose of this study was to test the hypothesis that the change in tumour blood flow after one cycle of NACT would predict pathological response. Methods: In this prospective cohort study, dynamic contrast-enhanced MRI was performed in 35 females with breast cancer before and after one cycle of epirubicin and cyclophosphamide-based NACT (EC90). Estimates of tumour blood flow and tumour volume were compared with pathological response obtained at surgery following completion of NACT. Results: Tumour blood flow at baseline (mean ± SD; 0.32 ± 0.17 ml/min/ml) reduced slightly after one cycle of NACT (0.28 ± 0.18 ml/min/ml). Following treatment 15 patients were identified as pathological responders and 20 as non-responders. There were no relationships found between tumour blood flow and pathological response. Conversely, tumour volume was found to be a good predictor of pathological response (smaller tumours did better) at both baseline (area under the receiver operating characteristic curve 0.80) and after one cycle of NACT (area under the receiver operating characteristic curve 0.81). Conclusion & advances in knowledge: The change in breast tumour blood flow following one cycle of EC90 did not predict pathological response. Tumour volume may be a better early marker of response with such agents.

Highlights • MR-only patient positioning for anal and rectal cancers using CBCT. • MR-only results in systematic positioning differences to of, Background and Purpose Magnetic resonance (MR)-only treatment pathways require either the MR-simulation or synthetic-computed tomography (sCT) as an alternative reference image for cone beam computed tomography (CBCT) patient position verification. This study assessed whether using T2 MR or sCT as CBCT reference images introduces systematic registration errors as compared to CT for anal and rectal cancers. Materials and Methods A total of 32 patients (18 rectum,14 anus) received pre-treatment CT- and T2 MR- simulation. Routine treatment CBCTs were acquired. sCTs were generated using a validated research model. The local clinical registration protocol, using a grey-scale registration algorithm, was performed for 216 CBCTs using CT, MR and sCT as the reference image. Linear mixed effects modelling identified systematic differences between modalities. Results Systematic translation and rotation differences to CT for MR were −0.3 to + 0.3 mm and −0.1 to 0.4° for anal cancers and −0.4 to 0.0 mm and 0.0 to 0.1° for rectal cancers, and for sCT were −0.4 to + 0.8 mm, −0.1 to 0.2° for anal cancers and −0.6 to + 0.2 mm, −0.1 to + 0.1° for rectal cancers. Conclusions T2 MR or sCT can successfully be used as reference images for anal and rectal cancer CBCT position verification with systematic differences to CT

Background Renal blood flow (RBF) can be measured with dynamic contrast enhanced-MRI (DCE-MRI) and arterial spin labeling (ASL). Unfortunately, individual estimates from both methods vary and reference-standard methods are not available. A potential solution is to include a third, arbitrating MRI method in the comparison. Purpose To compare RBF estimates between ASL, DCE, and phase contrast (PC)-MRI. Study Type Prospective. Population Twenty-five patients with type-2 diabetes (36% female) and five healthy volunteers (HV, 80% female). Field Strength/Sequences A 3 T; gradient-echo 2D-DCE, pseudo-continuous ASL (pCASL) and cine 2D-PC. Assessment ASL, DCE, and PC were acquired once in all patients. ASL and PC were acquired four times in each HV. RBF was estimated and split-RBF was derived as (right kidney RBF)/total RBF. Repeatability error (RE) was calculated for each HV, RE = 1.96 × SD, where SD is the standard deviation of repeat scans. Statistical Tests Paired t-tests and one-way analysis of variance (ANOVA) were used for statistical analysis. The 95% confidence interval (CI) for difference between ASL/PC and DCE/PC was assessed using two-sample F-test for variances. Statistical significance level was P 1) and results with outliers removed were presented. Results In patients, the mean RBF (mL/min/1.73m2) was 618 ± 62 (PC), 526 ± 91 (ASL), and 569 ± 110 (DCE). Differences between measurements were not significant (P = 0.28). Intrasubject agreement was poor for RBF with limits-of-agreement (mL/min/1.73m2) [−687, 772] DCE-ASL, [−482, 580] PC-DCE, and [−277, 460] PC-ASL. The difference PC-ASL was significantly smaller than PC-DCE, but this was driven by a single-DCE outlier (P = 0.31, after removing outlier). The difference in split-RBF was comparatively small. In HVs, mean RE (±95% CI; mL/min/1.73 m2) was significantly smaller for PC (79 ± 41) than for ASL (241 ± 85). Conclusions ASL, DCE, and PC RBF show poor agreement in individual subjects but agree well on average. Triangulation with PC suggests that the accuracy of ASL and DCE is comparable. Evidence Level 2 Technical Efficacy Stage 2

HEASA 2019 was the seventh conference in the annual series “High Energy Astrophysics in Southern Africa”. Its goal was to bring together scientists from the southern African region, the African continent, and around the world with an interest in high-energy astrophysical phenomena. Topics discussed include theoretical, multi-wavelength, and multi-messenger observational aspects of astrophysical sources (e.g. active galactic nuclei (AGNs), galaxy systems, gamma-ray bursts (GRBs), X-ray/gamma-ray binaries, supernovae and supernova remnants, neutron stars, pulsars and pulsar wind nebulae, cataclysmic variables (CVs)) as well as modern aspects of astro-particle physics.

Highlights • Accurate Synthetic-CT (sCT) generation for anorectal cancers. • Deep learning sCT generation with varied input data. • T2-SPACE MRI sequence use for generalisable pelvic synthetic-CT., Background and purpose Comprehensive dosimetric analysis is required prior to the clinical implementation of pelvic MR-only sites, other than prostate, due to the limited number of site specific synthetic-CT (sCT) dosimetric assessments in the literature. This study aims to provide a comprehensive assessment of a deep learning-based, conditional generative adversarial network (cGAN) model for a large ano-rectal cancer cohort. The following challenges were investigated; T2-SPACE MR sequences, patient data from multiple centres and the impact of sex and cancer site on sCT quality. Method RT treatment position CT and T2-SPACE MR scans, from two centres, were collected for 90 ano-rectal patients. A cGAN model trained using a focal loss function, was trained and tested on 46 and 44 CT-MR ano-rectal datasets, paired using deformable registration, respectively. VMAT plans were created on CT and recalculated on sCT. Dose differences and gamma indices assessed sCT dosimetric accuracy. A linear mixed effect (LME) model assessed the impact of centre, sex and cancer site. Results A mean PTV D95% dose difference of 0.1% (range: −0.5% to 0.7%) was found between CT and sCT. All gamma index (1%/1 mm threshold) measurements were >99.0%. The LME model found the impact of modality, cancer site, sex and centre was clinically insignificant (effect ranges: −0.4% and 0.3%). The mean dose difference for all OAR constraints was 0.1%. Conclusion Focal loss cGAN models using T2-SPACE MR sequences from multiple centres can produce generalisable, dosimetrically accurate sCTs for ano-rectal cancers.

Objective: This study aimed to assess the feasibility of extracellular volume-fraction (ECV) measurement, and time to achieve contrast equilibrium (CE), in healthy muscles, and to determine whether in-flow and partial-volume errors in the femoral artery affect measurements, and if there are differences in the partition coefficient (λ) between muscles. Methods: T1 was measured in the biceps femoris, vastus intermedius, femoral artery and aorta of 10 healthy participants. This was repeated alternately between the thigh and aorta for ≥25 min following a bolus of gadoterate meglumine. λ was calculated for each muscle/blood measurement. Time to CE was assessed semi-quantitatively. Results: 8/10 participants achieved CE. Time to CE = 19±2 min (mean ± 95% confidence interval). Measured λ: biceps femoris/aorta = 0.210±0.034, vastus intermedius/aorta = 0.165±0.015, biceps femoris/femoral artery = 0.265±0.054, vastus intermedius/femoral artery = 0.211±0.026. There were significant differences in λ between the muscles when using the same vessel (p < 0.05), and between λ calculated in the same muscle when using different vessels (p < 0.05). Conclusion: ECV measurements in the thigh are clinically feasible. The use of the femoral artery for the blood measurement is associated with small but significant differences in λ. ECV measurements are sensitive to differences between muscles within the healthy thigh. Advances in knowledge: This paper determines the time to contrast equilibrium in the healthy thigh and describes a method for measuring accurately ECV in skeletal muscle. This can aid in the diagnosis and understanding of inflammatory auto-immune diseases.

Purpose: To measure the arterial input function (AIF), an essential component of tracer kinetic analysis, in a population of patients using an optimized dynamic contrast-enhanced imaging sequence and to estimate inter- and intra-patient variability. From these data to extract a representative AIF that may be used for realistic simulation studies. Methods: Thirty-nine female patients were imaged on multiple visits before and during a course of neoadjuvant chemotherapy for breast cancer. A total of 97 T1-weighted dynamic contrast-enhanced studies were analyzed including bookend estimates of T1 and model-fitting to each individual AIF. Area under the curve and cardiac output were estimated from each first pass peak and these data were used to assess inter- and intra-patient variability of the AIF. Results: Inter-patient variability exceeded intra-patient variability of the AIF. There was no change in cardiac output as a function of MR visit (mean value 5.6 ± 1.1 L/min) but baseline blood T1 increased significantly following the start of chemotherapy (which was accompanied by a decrease in hematocrit). Conclusion: The AIF in an individual patient can be measured reproducibly but the variability of AIFs between patients suggests that use of a population AIF will decrease the precision of tracer kinetic analysis performed in cross-patient comparison studies. A representative AIF is presented that is typical of the population but retains the characteristics of an individually measured AIF.

Purpose To evaluate an interleaved MRI sampling strategy that acquires both high temporal resolution (HTR) dynamic contrast-enhanced (DCE) data for quantifying breast tumor blood flow (TBF) and high spatial resolution (HSR) DCE data for clinical reporting, following a single standard injection of contrast agent. Methods A simulation study was used to evaluate the performance of the interleaved technique under different conditions. In a prospective clinical study, 18 patients with primary breast cancer, who were due to undergo neoadjuvant chemotherapy (NACT), were examined using interleaved HTR and HSR DCE-MRI at 1.5 Tesla. Tumor regions of interest were analyzed with a two-compartment tracer kinetic model. Paired parameters (n = 10) from the data acquired before and post-cycle 2 of NACT were compared using the nonparametric Wilcoxon signed-rank test. Results Simulations demonstrated that TBF was reliably estimated using the proposed strategy. The region of interest analysis revealed significant changes in TBF (0.81-0.43 mL/min/mL; P = 0.002) following two cycles of NACT. The HSR data were reported in the normal way and enabled the assessment of tumor volume, which decreased by 53% following NACT (P = 0.065). Conclusions TBF can be measured reliably using the proposed strategy without compromising a standard clinical protocol. Furthermore, in our feasibility study, TBF decreased significantly following NACT, whereas capillary permeability surface-area product did not. Magn Reson Med 79:317-326, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

BACKGROUND Glioblastoma has a poor prognosis despite treatment with surgery and chemo-radiotherapy (CRT). Monitoring early response to CRT is challenging and conventional imaging is sub-optimal for stratifying poorly responding patients for novel agents. Also, imaging is not routinely performed during CRT and consequently, personalised treatment through individualised radiation dose adaption is not possible. AIMS: To evalutate the feasibility of Fluorine-18 Fluciclovine PET-CT for early response assessment during and post-treatment in patients with glioblastoma undergoing standard-of-care CRT. METHODS Patients with confirmed glioblastoma and macroscopic residual tumour post-surgery were consented for PET-CT and MRI prior to CRT (scan 1), after completing 2 weeks (10 fractions) of CRT (scan 2) and 6 weeks after completing treatment (scan 3). For each scan, patients were immobilised in a radiotherapy treatment mask. PET-CT and MRI scans were performed at each timepoint within a few days of each other. Patients were treated and followed up according to local guidelines. RESULTS 6 patients were recruited to the study between June 2018 and May 2019. All patients tolerated the additional imaging without problems. 2 patients were unable to attend their post-treatment PET-CT scan due to clinical deterioration. Fluciclovine PET-CT highlighted potentially active disease beyond the surgical cavity pre-radiotherapy (scan 1) in 3 patients. In 4/6, PET signal persisted after 2 weeks of radiotherapy with stable MRI appearances (scan 2). Frank disease progression was seen in 1 patient on both MRI and PET-CT mid-treatment. 3/4 patients with persistent activity at scan 2, showed disease progression post-treatment on both PET-CT and MRI (scan 3). Another had progressive changes on MRI but stable PET-CT appearances possibly representing pseudoprogression. CONCLUSION These preliminary results suggest that Fluciclovine PET-CT could help in monitoring treatment and further work to assess the ability to guide individualised treatment planning in glioblastoma is warranted.

The properties of the aperiodic brightness variability for the dwarf nova HL CMa are considered. The variability of the system HL CMa is shown to be suppressed at frequencies above $7\times10^{-3}$Hz. Different variability suppression mechanisms related to the radiation reprocessing time, partial disk evaporation, and characteristic variability formation time are proposed. It has been found that the variability suppression frequency does not change when the system passes from the quiescent state to the outburst one, suggesting that the accretion flow geometry is invariable. It is concluded from the optical and X-ray luminosities of the system that the boundary layer on the white dwarf surface is optically thick in both quiescent and outburst states. The latter implies that the optically thick part of the accretion flow (disk) reaches the white dwarf surface. The accretion rate in the system, the flow geometry and temperature have been estimated from the variability power spectra and spectral characteristics in a wide energy range, from the optical to X-ray., Comment: 14 pages, 6 figures

Software for Tomographic Image Reconstruction (STIR: http://stir.sf.net) is an open source C++ library available for reconstruction of emission tomography data. This work aims at the incorporation of the GE SIGNA PET/MR scanner in STIR and enables PET image reconstruction with data corrections. The data extracted from the scanner after an acquisition includes a list of raw data files (emission, normalisation, geometric and well counter calibration (wcc) factors), magnetic resonance attenuation correction (MRAC) images and the scanner-based reconstructions. The listmode (LM) file stores a list of ’prompt’ events and the singles per crystal per second. MRAC images from the scanner are used for attenuation correction. The modifications to STIR that allow accurate histogramming of this LM data in the same sinogram organisation as the scanner are also described. This allows reconstruction of acquisition data with all data corrections using STIR, and independent of any software supplied by the manufacturer. The implementations were validated by comparing the histogrammed data, data corrections and final reconstruction using the ordered subset expectation maximisation (OSEM) algorithm with the equivalents from the GE-toolbox, supplied by the manufacturer for the scanner. There is no difference in the histogrammed counts whereas an overall relative difference of 6.7 × 10−8% and from 0.01% to 0.86% is seen in the normalisation and randoms correction sinograms respectively. The STIR reconstructed images have similar resolution and quantification but have some residual differences due to wcc factors, decay and deadtime corrections, as well as the offset between PET and MR gantries that will be addressed in future work. This work will enable the use of all current and future STIR algorithms, including penalized image reconstruction, motion correction and direct parametric image estimation, on data from GE SIGNA PET/MR scanners.

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers.METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion.RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia.CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.

Purpose: To test the ability of shutter-speed dynamic contrast-enhanced (DCE) MRI to estimate water exchange (WX) using simulations and assess its performance in clinical case studies of malignant and benign breast tumors. Methods: Data were simulated using a one-compartment tracer kinetic (TK) model combined with a two-pool WX model (2PX) and with a two-compartment TK model. Typical DCE-MRI acquisition parameters were used with both WX-sensitive (8°) and insensitive (25°) flip angles. Clinical data were obtained from patients with malignant and benign breast tumors. Data were fitted using a two-compartment TK model and a one-compartment TK model combined with four WX models: fast exchange limit (FXL), no exchange, 2PX and shutter-speed. Results: Fits to the one-compartment simulated data were excellent but estimates of WX obtained using the 2PX and shutter-speed models were poor. One-compartment TK model fits to the clinical malignant tumor data were bad except for the shutter-speed model. However, that overestimated TK parameters compared to the best-fit two-compartment TK model which predicted a significant blood volume and leaky capillaries (one tracer compartment is insufficient, two are necessary). All models produced excellent fits to the clinical benign tumor data with little variation between parameter estimates (one tracer compartment is sufficient). Conclusion: The 2PX and shutter-speed models were unable to estimate WX from the DCE-MRI data. A good fit to malignant tumor data using the shutter-speed model was not explained by WX but the choice of an inappropriate TK model leading to distorted parameter estimates.

Purpose To compare methods designed to minimize or correct signal nonlinearity in quantitative myocardial dynamic contrast-enhanced (DCE) MRI. Methods DCE-MRI studies were simulated and data acquired in eight volunteers. Signal nonlinearity was corrected using either a dual-bolus approach or model-based correction using proton-density weighted imaging (conventional or dual-sequence acquisition) or T1 data (native or bookend). Scanning of healthy and infarcted myocardium at 3 T was simulated, including noise, saturation imperfection and T1 measurement error. Data were analyzed using model-based deconvolution with a one-compartment (mono-exponential) model. Results Substantial variation between methods was demonstrated in volunteers. In simulations the dual-bolus method proved stable for realistic levels of saturation efficiency but demonstrated bias due to residual nonlinearity. Model-based methods performed ideally in the absence of confounding error sources and were generally robust to noise or saturation imperfection, except for native T1 based correction which was highly sensitive to the latter. All methods demonstrated large variation in accuracy above an over-saturation level where baseline signal was nulled. For the dual-sequence approach this caused substantial bias at the saturation efficiencies observed in volunteers. Conclusion The choice of nonlinearity correction method in myocardial DCE-MRI impacts on accuracy and precision of estimated parameters, particularly in the presence of nonideal saturation

This work evaluates the precision and characteristics of the trigger level of the vacuum surveillance system of eXtend™ on Gamma Knife Perfexion and the effect of the potential displacement on the dose distribution.A total of 20 individually moulded mouthpieces based on human dental models were used to measure translational shift and rotation until the vacuum surveillance of eXtend interrupted the irradiation. The positional accuracy of the movement was 0.01 mm using a computerized numerically controlled positioning system. Rotation was introduced by peripheral pressure in superior or inferior direction on the mould and was measured with a digital inclinometer. In 10 patients with a large brain metastasis the effect of a potential displacement of the centre of the target was recalculated. Two out of the 10 targets were located near the optic nerve and chiasm. In addition, the potential displacement of the chiasm and the optic nerve due to rotation based on their distance to the centre of rotation (COR, the mouthpiece) was evaluated. For the recalculation of the delivered dose after a displacement, GammaPlan Software® was used. Dose distribution with displacement between ±0.1 mm and ±2.0 mm was simulated for ten targets with volumes between 7.7 cmThe vacuum between mouthpiece and dental model was broken by a mean translation of the mouthpiece of 0.15 mm (SD ±0.05 mm, range 0.05-0.29 mm) or a mean rotation of 0.33º (SD ±0.15º, range 0.05-1.0º). Rotation caused by pressure in the inferior direction was higher with 0.42º (SD ±0.16º) compared to rotation due to pressure in the superior direction with 0.21º (SD ±0.09º). The mean rotation would produce a mean displacement of 0.64 mm for the target, 0.39 mm for the chiasm and 0.33 mm for the optic nerve, for the group of patients studied. The biggest effect of positional deviation was seen in the minimum dose to the target, with 2.5% reduction for a 0.5 mm and 5% for a 1.0 mm shift in the Z-direction respectively.The trigger level is sensitive and reproducible. A sudden movement by the patient, such as an attempt to get out or correct an uncomfortable position would interrupt irradiation immediately. The dominant effect for a displacement is due to rotation. The resulting displacement depends on the distance between target and COR (magnitude) and the location (direction). Therefore, lesions near chiasm or brainstem, which are closer to the COR, are less affected from a rotation than peripheral targets.

Purpose This study investigates the feasibility of delivering focal boost dose to tumor regions, identified with multi-parametric MRI, in high-dose-rate prostate brachytherapy. Methods and Materials T2-weighted, diffusion-weighted, and dynamic-contrast-enhanced MRI were acquired the day before treatment and analyzed retrospectively for 15 patients. Twelve patients had hormone therapy before the MRI scan. The tumor was delineated on MRI by a radiologist and registered to treatment planning transrectal ultrasound images. A margin based on analysis of delineation and registration uncertainties was applied to create a focal boost planning target volume (F-PTV). Delivered treatment plans were compared with focal boost plans optimized to increase F-PTV dose as much as allowed by urethral and rectal dose constraints. Results Tumors were delineated in all patients with volumes 0.4–23.0 cc. The margin for tumor delineation and image registration uncertainties was estimated to be 4.5 mm. For F-PTV, the focal boost treatment plans increased median D90 from 17.6 to 20.9 Gy and median V150 from 27.3% to 75.9%. Conclusions MRI-guided high-dose-rate prostate brachytherapy focal tumor boost is feasible—tumor regions can be identified even after hormone therapy, and focal boost dose can be delivered without violating urethral and rectal dose constraints.

Purpose There is currently no adequate method of mapping physiologic and pathophysiologic tissue albumin concentrations in human subjects. The objective of this study was to devise and evaluate a biomarker of regional albumin concentration using gadofosveset-enhanced MRI. Theory and Methods A binding and relaxation model was devised and evaluated in vitro in solutions of albumin at 3.0 Tesla (T) and 4.7T. The method was evaluated in the heart in seven volunteers at 3.0T. Results MRI-derived estimates of albumin concentration were in good agreement with true values over the range 0.1–1.0 mM (Pearson correlation coefficients of 0.85 and 0.88 for 3.0T and 4.7T, respectively). The mean calculated albumin concentration in the myocardium for the volunteers was 0.02 mM (range, 0.01–0.03 mM). Conclusion Accurate estimates of albumin concentration in vitro suggest this may be a viable noninvasive alternative to existing techniques. In the myocardium the MRI-derived estimates of albumin concentration indicate the practical feasibility of the technique but were below expected values. Gadofosveset-enhanced MR relaxometry has potential in providing biomarkers of regional albumin concentration; further evaluation is required before it can be used reliably in vivo. Magn Reson Med 73:244–253, 2015. © 2014 Wiley Periodicals, Inc.

Dynamic contrast-enhanced MRI (DCE-MRI) is a functional MRI method where T1 -weighted MR images are acquired dynamically after bolus injection of a contrast agent. The data can be interpreted in terms of physiological tissue characteristics by applying the principles of tracer-kinetic modelling. In the brain, DCE-MRI enables measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), blood–brain barrier (BBB) permeability–surface area product (PS) and the volume of the interstitium (ve). These parameters can be combined to form others such as the volume-transfer constant Ktrans, the extraction fraction E and the contrast-agent mean transit times through the intra- and extravascular spaces. A first generation of tracer-kinetic models for DCE-MRI was developed in the early 1990s and has become a standard in many applications. Subsequent improvements in DCE-MRI data quality have driven the development of a second generation of more complex models. They are increasingly used, but it is not always clear how they relate to the models of the first generation or to the model-free deconvolution methods for tissues with intact BBB. This lack of understanding is leading to increasing confusion on when to use which model and how to interpret the parameters. The purpose of this review is to clarify the relation between models of the first and second generations and between model-based and model-free methods. All quantities are defined using a generic terminology to ensure the widest possible scope and to reveal the link between applications in the brain and in other organs. Copyright © 2013 John Wiley & Sons, Ltd.

The flat spectrum radio quasar 4C +01.02 became one of the brightest active galactic nuclei detected at high redshift (z = 2.1) in gamma rays when it underwent a series of outbursts during several months in 2016. We monitored this source in gamma rays using the Large Area Telescope onboard of the Fermi spacecraft (Fermi-LAT), and in optical using the Las Cumbres Observatory (LCO). The highest peak flux detected was F(E > 100 MeV) = (2.8 +/- 0.3) 10^-6 ph cm^-2 s^-1 on 10 July 2016 (MJD 57579, daily average). We also obtained optical spectropolarimetry with the Robert Stobie Spectrograph on the Southern African Large Telescope (SALT-RSS) and observed a degree of linear polarisation of up to 10% during flaring states, and ~1% during a quiescent period. We report recent updates we obtained in our time-domain and spectral studies of this source in July-August 2016, November-December 2016, and July 2017.

To evaluate an interleaved MRI sampling strategy that acquires both high temporal resolution (HTR) dynamic contrast-enhanced (DCE) data for quantifying breast tumor blood flow (TBF) and high spatial resolution (HSR) DCE data for clinical reporting, following a single standard injection of contrast agent.A simulation study was used to evaluate the performance of the interleaved technique under different conditions. In a prospective clinical study, 18 patients with primary breast cancer, who were due to undergo neoadjuvant chemotherapy (NACT), were examined using interleaved HTR and HSR DCE-MRI at 1.5 Tesla. Tumor regions of interest were analyzed with a two-compartment tracer kinetic model. Paired parameters (n = 10) from the data acquired before and post-cycle 2 of NACT were compared using the nonparametric Wilcoxon signed-rank test.Simulations demonstrated that TBF was reliably estimated using the proposed strategy. The region of interest analysis revealed significant changes in TBF (0.81-0.43 mL/min/mL; P = 0.002) following two cycles of NACT. The HSR data were reported in the normal way and enabled the assessment of tumor volume, which decreased by 53% following NACT (P = 0.065).TBF can be measured reliably using the proposed strategy without compromising a standard clinical protocol. Furthermore, in our feasibility study, TBF decreased significantly following NACT, whereas capillary permeability surface-area product did not. Magn Reson Med 79:317-326, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Purpose To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. Methods and Materials Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. Results Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining ( r = −0.79, p = 0.03) and VEGF expression ( r = −0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia ( r = −0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF ( r = 0.82, p = 0.02). Conclusions Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.

We present a brief description of the Berkeley Visible Imaging Tube (BVIT) detector system, which is a user instrument on the 10-m Southern African Large Telescope (SALT), and include some preliminary observational results gained in mid-2011. The data show that BVIT is capable of revealing emission features occurring on time-scales of < 0.1 sec, thus opening up for the general user a window of high time-resolution astronomy at visible wavelengths.

Dynamic contrast-enhanced MRI (DCE-MRI) is frequently used to provide response biomarkers in clinical trials of novel cancer therapeutics but assessment of their physiological accuracy is difficult. DCE-CT provides an independent probe of similar pharmacokinetic processes and may be modeled in the same way as DCE-MRI to provide purportedly equivalent physiological parameters. In this study, DCE-MRI and DCE-CT were directly compared in subjects with primary bladder cancer to assess the degree to which the model parameters report modeled physiology rather than artefacts of the measurement technique and to determine the interchangeability of the techniques in a clinical trial setting. The biomarker K(trans) obtained by fitting an extended version of the Kety model voxelwise to both DCE-MRI and DCE-CT data was in excellent agreement (mean across subjects was 0.085 � 0.030 min(-1) for DCE-MRI and 0.087 � 0.033 min(-1) for DCE-CT, intermodality coefficient of variation 9%). The parameter v(p) derived from DCE-CT was significantly greater than that derived from DCE-MRI (0.018 � 0.006 compared to 0.009 � 0.008, P = 0.0007) and v(e) was in reasonable agreement only for low values. The study provides evidence that the biomarker K(trans) is a robust parameter indicative of the underlying physiology and relatively independent of the method of measurement. Magn Reson Med, 2011. � 2011 Wiley-Liss, Inc.