Accuracy of four models and update strategies to estimate liver tumor motion from external respiratory motion.

Background: This study investigates different strategies for estimating internal liver tumor motion during radiotherapy based on continuous monitoring of external respiratory motion combined with sparse internal imaging. Methods: Fifteen patients underwent three-fraction stereotactic liver radiotherapy. The 3D internal tumor motion (INT) was monitored by electromagnetic transponders while a camera monitored the external marker block motion (EXT). The ability of four external-internal correlation models (ECM) to estimate INT as function of EXT was investigated: a simple linear model (ECM1), an augmented linear model (ECM2), an augmented quadratic model (ECM3), and an extended quadratic model (ECM4). Each ECM was constructed by fitting INT and EXT during the first 60s of each fraction. The fit accuracy was calculated as the root-mean-square error (RMSE) between ECM-estimated and actual tumor motion. Next, the RMSE of the ECM-estimated tumor motion throughout the fractions was calculated for four simulated ECM update strategies: (A) no update, 0.33Hz internal sampling with continuous update of either (B) all ECM parameters based on the last 2 minutes samples or (C) only the baseline term based on the last 5 samples, (D) full ECM update every minute using 20s continuous internal sampling. Results: The augmented quadratic ECM3 had best fit accuracy with mean (± SD)) RMSEs of 0.32 ± 0.11mm (left-right, LR), 0.79 ± 0.30mm (cranio-caudal, CC) and 0.56 ± 0.31mm (anterior-posterior, AP). However, the simpler augmented linear ECM2 combined with frequent baseline updates (update strategy C) gave best motion estimations with mean RMSEs of 0.41 ± 0.14mm (LR), 1.02 ± 0.33mm (CC) and 0.78 ± 0.48mm (AP). This was significantly better than all other ECM-update strategy combinations for CC motion (Wilcoxon signed rank p<0.05). Conclusion: The augmented linear ECM2 combined with frequent baseline updates provided the best compromise between fit accuracy and robustness towards irregular motion. It allows accurate internal motion monitoring by combining external motioning with sparse 0.33Hz kV imaging, which is available at conventional linacs.

Quantifying dose perturbations in high-risk prostate radiotherapy due to translational and rotational motion of prostate and pelvic lymph nodes.

BACKGROUND: Radiotherapy of the prostate and the pelvic lymph nodes (LN) is a part of the standard of care treatment for high-risk prostate cancer. The independent translational and rotational (i.e., six-degrees-of-freedom, [6DoF]) motion of the prostate and LN target during and between fractions can perturb the dose distribution. However, no standard dose reconstruction method accounting for differential 6DoF target motion is available. PURPOSE: We present a framework for monitoring motion-induced dose perturbations for two independently moving target volumes in 6DoF. The framework was used to determine the dose perturbation for the prostate and the LN target caused by differential 6DoF motion for a cohort of high-risk prostate cancer patients. As a potential first step toward real-time dose-guided high-risk prostate radiotherapy, we furthermore investigated if the dose reconstruction was fast enough for real-time application for both targets. METHODS: Twenty high-risk prostate cancer patients were treated with 3-arc volumetric modulated arc therapy (VMAT). Kilovoltage intrafraction monitoring (KIM) with triggered kilovoltage (kV) images acquired every 3 throughout 7-10 fractions per patient was used for retrospective 6DoF intrafraction prostate motion estimation. The 6DoF interfraction LN motion was determined from a pelvic bone match between the planning CT and a post-treatment cone beam CT (CBCT). Using the retrospectively extracted motion, real-time 6DoF motion-including dose reconstruction was simulated using the in-house developed software DoseTracker. A data stream with the 6DoF target positions and linac parameters was broadcasted at a 3-Hz frequency to DoseTracker. In a continuous loop, DoseTracker calculated the target dose increments including the specified motion and, for comparison, without motion. The motion-induced change in D99.5% for the prostate CTV (ΔD99.5%) and in D98% for the LN CTV (ΔD98%) was calculated using the final cumulative dose of each fraction and averaged over all imaged fractions. The real-time reconstructed dose distribution of DoseTracker was benchmarked against a clinical treatment planning system (TPS) and it was investigated whether the calculation speed was fast enough to keep up with the incoming data stream. RESULTS: Translational motion was largest in cranio-caudal (CC) direction (prostate: [-5.9, +8.4] mm; LN: [-9.9; +11.0] mm) and anterior-posterior (AP) direction (prostate:[-5.6; +6.9] mm; LN: [-9.6; +11.0] mm). The pitch was the largest rotation (prostate: [-22.5; +25.2] deg; LN: [-3.9; +5.5] deg). The prostate CTV ΔD99.5% was [-16.2; +2.5]% for single fractions and [-3.0; +1.7]% when averaged over all imaged fractions. The LN CTV ΔD98% was [-19.8; +1.2]% for single fractions and [-3.1; +0.9]% after averaging. Mean (Standard deviation) absolute dose errors in DoseTracker of 107.8% (Std: 1.9%) for the prostate and 105.5% (Std:1.4%) for the LN were corrected during dose reconstruction by automatically calculated normalization factors. It resulted in accurate calculation of the motion-induced dose errors with relative differences between DoseTracker and TPS dose calculations of -0.1% (Std: 0.5%) (prostate CTV ΔD99.5%) and -0.2% (Std: 0.5%) (LN CTV ΔD98%). The DoseTracker calculation was fast enough to keep up with the incoming inputs for all but two out of 107 184 dose calculations. CONCLUSION: Using the developed framework for dose perturbation monitoring, we found that the differential 6DoF target motion caused substantial dose perturbation for individual fractions, which largely averaged out after several fractions. The framework was shown to provide reliable dose calculations and a sufficiently high-dose reconstruction speed to be applicable in real-time.

Correlation between local instantaneous dose rate and oxygen pressure reduction during proton pencil beam scanning irradiation.

Background and purpose: Oxygen dynamics may be important for the tissue-sparing effect observed at ultra-high dose rates (FLASH sparing effect). This study investigated the correlation between local instantaneous dose rate and radiation-induced oxygen pressure reduction during proton pencil beam scanning (PBS) irradiations of a sample and quantified the oxygen consumption g-value. Materials and methods: A 0.2 ml phosphorescent sample (1 µM PtG4 Oxyphor probe in saline) was irradiated with a 244 MeV proton PBS beam. Four irradiations were performed with variations of a PBS spot pattern with 5 × 7 spots. During irradiation, the partial oxygen pressure (pO2) was measured with 4.5 Hz temporal resolution with a phosphorometer (Oxyled) that optically excited the probe and recorded the subsequently emitted light. A calibration was performed to calculate the pO2 level from the measured phosphorescence lifetime. A fiber-coupled scintillator simultaneously measured the instantaneous dose rate in the sample with 50 kHz sampling rate. The oxygen consumption g-value was determined on a spot-by-spot level and using the total pO2 change for full spot pattern irradiation. Results: A high correlation was found between the local instantaneous dose rate and pO2 reduction rate, with a correlation coefficient of 0.96-0.99. The g-vales were 0.18 ± 0.01 mmHg/Gy on a spot-by-spot level and 0.17 ± 0.01 mmHg/Gy for full spot pattern irradiation. Conclusions: The pO2 reduction rate was directly related to the local instantaneous dose rate per delivered spot in PBS deliveries. The methodology presented here can be applied to irradiation at ultra-high dose rates with modifications in the experimental setup.

Motion-induced dose perturbations in photon radiotherapy and proton therapy measured by deformable liver-shaped 3D dosimeters in an anthropomorphic phantom.

Background and purpose: The impact of intrafractional motion and deformations on clinical radiotherapy delivery has so far only been investigated by simulations as well as point and planar dose measurements. The aim of this study was to combine anthropomorphic 3D dosimetry with a deformable abdominal phantom to measure the influence of intra-fractional motion and gating in photon radiotherapy and evaluate the applicability in proton therapy. Material and methods: An abdominal phantom was modified to hold a deformable anthropomorphic 3D dosimeter shaped as a human liver. A liver-specific photon radiotherapy and a proton pencil beam scanning therapy plan were delivered to the phantom without motion as well as with 12 mm sinusoidal motion while using either no respiratory gating or respiratory gating. Results: Using the stationary irradiation as reference the local 3 %/2 mm 3D gamma index pass rate of the motion experiments in the planning target volume (PTV) was above 97 % (photon) and 78 % (proton) with gating whereas it was below 74 % (photon) and 45 % (proton) without gating. Conclusions: For the first time a high-resolution deformable anthropomorphic 3D dosimeter embedded in a deformable abdominal phantom was applied for experimental validation of both photon and proton treatments of targets exhibiting respiratory motion. It was experimentally shown that gating improves dose coverage and the geometrical accuracy for both photon radiotherapy and proton therapy.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

AIMS/HYPOTHESIS: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. CONCLUSIONS/INTERPRETATION: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

Proton FLASH: Impact of Dose Rate and Split Dose on Acute Skin Toxicity in a Murine Model.

PURPOSE: Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery. METHODS AND MATERIALS: The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. RESULTS: The dose rate50, which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity. CONCLUSIONS: The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session.

Two-dimensional time-resolved scintillating sheet monitoring of proton pencil beam scanning FLASH mouse irradiations.

BACKGROUND: Dosimetry in pre-clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra-high dose rates (UHDR) requires a detector with high spatial and temporal resolution. PURPOSE: To implement a novel camera-based system for time-resolved two-dimensional (2D) monitoring and apply it in vivo during pre-clinical proton PBS mouse irradiations. METHODS: Time-resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber-coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non-anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread-out Bragg peak formed from the mono-energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured. RESULTS: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber-coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations. CONCLUSIONS: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Oxygen Enhancement Ratio-Weighted Dose Quantitatively Describes Acute Skin Toxicity Variations in Mice After Pencil Beam Scanning Proton FLASH Irradiation With Changing Doses and Time Structures.

PURPOSE: The aim of this work was to investigate the ability of a biological oxygen enhancement ratio-weighted dose, DOER, to describe acute skin toxicity variations observed in mice after proton pencil beam scanning irradiations with changing doses and beam time structures. METHODS AND MATERIALS: In five independent experiments, the right hind leg of a total of 621 CDF1 mice was irradiated previously in the entrance plateau of a pencil beam scanning proton beam. The incidence of acute skin toxicity (of level 1.5-2.0-2.5-3.0-3.5) was scored for 47 different mouse groups that mapped toxicity as function of dose for conventional and FLASH dose rate, toxicity as function of field dose rate with and without repainting, and toxicity when splitting the treatment into 1 to 6 identical deliveries separated by 2 minutes. DOER was calculated for all mouse groups using a simple oxygen kinetics model to describe oxygen depletion. The three independent model parameters (oxygen-depletion rate, oxygen-recovery rate, oxygen level without irradiation) were fitted to the experimental data. The ability of DOER to describe the toxicity variations across all experiments was investigated by comparing DOER-response curves across the five independent experiments. RESULTS: After conversion from the independent variable tested in each experiment to DOER, all five experiments had similar MDDOER50 (DOER giving 50% toxicity incidence) with standard deviations of 0.45 - 1.6 Gy for the five toxicity levels. DOER could thus describe the observed toxicity variations across all experiments. CONCLUSIONS: DOER described the varying FLASH-sparing effect observed for a wide range of conditions. Calculation of DOER for other irradiation conditions can quantitatively estimate the FLASH-sparing effect for arbitrary irradiations for the investigated murine model. With appropriate fitting parameters DOER also may be able to describe FLASH effect variations with dose and dose rate for other assays and endpoints.

Evaluation of in vitro irradiation setup: Designed for the horizontal beamline at the Danish Centre for Particle Therapy.

BACKGROUND: Radiobiological experimental setups are challenged by precise sample positioning along depth dose profile, scattering conditions, and practical difficulties that must be addressed in individual designs. The aim of this study was to produce cell survival curves with several irradiation modalities, by using a setup designed at the Danish Centre for Particle Therapy (DCPT) for in vitro proton irradiations using a horizontal beam line and thereby evaluating the setups use for in vitro irradiations experiments. MATERIALS AND METHODS: The setup is a water phantom suitable for in vitro research with multiple irradiation modalities, in particular the pencil scanning proton beam available from a horizontal experimental beamline. The phantom included a water tank of 39.0 × 17.0 × 20.5 cm. Cell survival-curves were produced using the cell line V79 Chinese hamster lung fibroblast cells (V79s) in biological triplicates of clonogenic assays. Cell survival curves were produced with both a 18 MeV electron beam, 6 MV photon beam, and a Spread-Out Bragg Peak (SOBP) proton beam formed by pristine energies of 85-111 MeV where three positions were examined. RESULTS: Survival curves with uncertainty areas were made for all modalities. Dosimetric uncertainty amounted to, respectively, 4%, 3% and 3% for proton, electron, and high energy photon irradiations. Cell survival fraction uncertainty was depicted as the standard deviation between replications of the experiment. CONCLUSION: Cell survival curves could be produced with acceptable uncertainties using this novel water phantom and cellular laboratory workflow. The setup is useful for future in vitro irradiation experiments.

Separate and combined effects of empagliflozin and semaglutide on vascular function: A 32-week randomized trial.

AIM: Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. MATERIALS AND METHODS: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. RESULTS: The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo. CONCLUSIONS: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial.

AIMS: To evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. METHODS: Using the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. RESULTS: Compared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (-9 %, 95%CI (-18, -0.06)%, p = 0.035 and -0.05 %, 95%CI(-0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(-35 %, 95 % CI(-52, -14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(-21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. CONCLUSION: 23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. TRIAL NUMBER AND REGISTRY: EUDRACT 2019-000781-38, clinicaltrialsregister.eu.

The first clinical implementation of real-time 6 degree-of-freedom image-guided radiotherapy for liver SABR patients.

PURPOSE: Multiple survey results have identified a demand for improved motion management for liver cancer IGRT. Until now, real-time IGRT for liver has been the domain of dedicated and expensive cancer radiotherapy systems. The purpose of this study was to clinically implement and characterise the performance of a novel real-time 6 degree-of-freedom (DoF) IGRT system, Kilovoltage Intrafraction Monitoring (KIM) for liver SABR patients. METHODS/MATERIALS: The KIM technology segmented gold fiducial markers in intra-fraction x-ray images as a surrogate for the liver tumour and converted the 2D segmented marker positions into a real-time 6DoF tumour position. Fifteen liver SABR patients were recruited and treated with KIM combined with external surrogate guidance at three radiotherapy centres in the TROG 17.03 LARK multi-institutional prospective clinical trial. Patients were either treated in breath-hold or in free breathing using the gating method. The KIM localisation accuracy and dosimetric accuracy achieved with KIM + external surrogate were measured and the results were compared to those with the estimated external surrogate alone. RESULTS: The KIM localisation accuracy was 0.2±0.9 mm (left-right), 0.3±0.6 mm (superior-inferior) and 1.2±0.8 mm (anterior-posterior) for translations and -0.1◦±0.8◦ (left-right), 0.6◦±1.2◦ (superior-inferior) and 0.1◦±0.9◦ (anterior-posterior) for rotations. The cumulative dose to the GTV with KIM + external surrogate was always within 5% of the plan. In 2 out of 15 patients, >5% dose error would have occurred to the GTV and an organ-at-risk with external surrogate alone. CONCLUSIONS: This work demonstrates that real-time 6DoF IGRT for liver can be implemented on standard radiotherapy systems to improve treatment accuracy and safety. The observations made during the treatments highlight the potential false assurance of using traditional external surrogates to assess tumour motion in patients and the need for ongoing improvement of IGRT technologies.

Multi-institutional consensus on machine QA for isochronous cyclotron-based systems delivering ultra-high dose rate (FLASH) pencil beam scanning proton therapy in transmission mode.

BACKGROUND: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect. PURPOSE: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied. METHODS: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed. RESULTS: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus. CONCLUSIONS: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures.

[18F]FDOPA PET/CT is superior to [68Ga]DOTATOC PET/CT in diagnostic imaging of pheochromocytoma.

BACKGROUND: Both [18F]FDOPA (FDOPA) and [68Ga]DOTATOC PET/CT (DOTATOC) are widely used for detection of pheochromocytomas/paraganglioma (PPGL). However, direct comparisons of the performance of the two tracers are only available in small series. We conducted a retrospective comparative analysis of FDOPA and DOTATOC to assess their sensitivity and accuracy in detecting PPGL when administered based on suspicion of PPGL. We consecutively included patients referred on suspicion of PPGL or PPGL recurrence who were scanned with both FDOPA and DOTATOC. Both scans were reviewed retrospectively by two experienced observers, who were blinded to the final diagnosis. The assessment was made both visually and quantitatively. The final diagnosis was primarily based on pathology. RESULTS: In total, 113 patients were included (97 suspected of primary PPGL and 16 suspected of recurrence). Of the 97 patients, 51 had pheochromocytomas (PCC) (in total 55 lesions) and 6 had paragangliomas (PGL) (in total 7 lesions). FDOPA detected and correctly localized all 55 PCC, while DOTATOC only detected 25 (sensitivity 100% vs. 49%, p < 0.0001; specificity 95% vs. 98%, p = 1.00). The negative predictive value (100% vs. 63%, p < 0.001) and diagnostic accuracy (98% vs. 70%, p < 0.01) were higher for FDOPA compared to DOTATOC. FDOPA identified 6 of 6 patients with hormone producing PGL, of which one was negative on DOTATOC. Diagnostic performances of FDOPA and DOTATOC were similar in the 16 patients with previous PPGL suspected of recurrence. CONCLUSIONS: FDOPA is superior to DOTATOC for localization of PCC. In contrast to DOTATOC, FDOPA also identified all PGL but with a limited number of patient cases.

An experimental setup for proton irradiation of a murine leg model for radiobiological studies.

BACKGROUND: The purpose of this study was to introduce an experimental radiobiological setup used for in vivo irradiation of a mouse leg target in multiple positions along a proton beam path to investigate normal tissue- and tumor models with varying linear energy transfer (LET). We describe the dosimetric characterizations and an acute- and late-effect assay for normal tissue damage. METHODS: The experimental setup consists of a water phantom that allows the right hind leg of three to five mice to be irradiated at the same time. Absolute dosimetry using a thimble (Semiflex) and a plane parallel (Advanced Markus) ionization chamber and Monte Carlo simulations using Geant4 and SHIELD-HIT12A were applied for dosimetric validation of positioning along the spread-out Bragg peak (SOBP) and at the distal edge and dose fall-off. The mice were irradiated in the center of the SOBP delivered by a pencil beam scanning system. The SOBP was 2.8 cm wide, centered at 6.9 cm depth, with planned physical single doses from 22 to 46 Gy. The biological endpoint was acute skin damage and radiation-induced late damage (RILD) assessed in the mouse leg. RESULTS: The dose-response curves illustrate the percentage of mice exhibiting acute skin damage, and at a later point, RILD as a function of physical doses (Gy). Each dose-response curve represents a specific severity score of each assay, demonstrating a higher ED50 (50% responders) as the score increases. Moreover, the results reveal the reversible nature of acute skin damage as a function of time and the irreversible nature of RILD as time progresses. CONCLUSIONS: We want to encourage researchers to report all experimental details of their radiobiological setups, including experimental protocols and model descriptions, to facilitate transparency and reproducibility. Based on this study, more experiments are being performed to explore all possibilities this radiobiological experimental setup permits.

Difference between planned and delivered radiotherapy dose to the internal mammary nodes in high-risk breast cancer patients.

Background and purpose: Chest wall movement during radiotherapy can impact the delivered dose to the internal mammary nodes (IMN) in high-risk breast cancer patients. Using portal imaging and dose reconstruction we aimed to examine the delivered IMN dose coverage. Material and methods: Cine MV images were recorded for 39 breast cancer patients treated with daily image-guided radiotherapy (IGRT) in deep-inspiration breath-hold (DIBH). On the final frame of each cine MV recording the chest wall was matched with the Digitally Reconstructed Radiograph (DRR) from the treatment plan. The geometrical chest wall error was determined in the imager-plane perpendicular to the cranio-caudal direction, rounded to integer millimeters, and binned. For each 1 mm bin, an isocenter-shifted treatment plan was recalculated assuming that the projected error observed in the cine MV image was caused by anterior-posterior chest wall movement in the IMN region. A weighted plan sum yielded the IMN clinical target volume receiving at least 90% dose (V90_CTVn_IMN). Results: The mean number of cine MV observations per patient was 36 (range 26-55). Most patients (67%) had on average a posterior chest wall position at treatment compared to planned. This translated into a change in the delivered median V90_CTVn_IMN of -0.7% (range, -11.9-2.9%; p < 0.001). The V90_CTVn_IMN reduction was greater than 9% in three patients. No clinically relevant differences were found for the mean lung dose or mean heart dose. Conclusion: Using cine MV images, we found that the delivered V90_CTVn_IMN was significantly lower than planned. In 8% of the patients, the V90_CTVn_IMN reduction exceeded 9%.

Obstructive sleep apnea, coronary calcification and arterial stiffness in patients with diabetic kidney disease.

BACKGROUND AND AIMS: Obstructive sleep apnea (OSA) may accelerate arterial calcification, but the relation remains unexplored in diabetic kidney disease (DKD). We examined the associations between OSA, coronary calcification and large artery stiffness in patients with DKD and reduced renal function. METHODS: Patients with type 2 diabetes, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 and urine albumin-creatinine ratio (UACR) > 30 mg/g were tested for OSA quantified by the apnea-hypopnea index (AHI, events/hour). Patients without OSA (AHI< 5) were compared to patients with moderate (AHI 15-29) or severe (AHI ≥30) OSA and underwent computed tomography angiography with coronary Agatston scoring (CAS) to quantify coronary calcification. Arterial stiffness was determined as carotid-femoral pulse wave velocity (PWV). RESULTS: Among 114 patients with acceptable AHI recordings had 43 no OSA, 33 mild OSA and 38 moderate-severe OSA. Mean age of the 74 patients completing the study was 71.5 ± 9.4 years (73% males), eGFR 32.2 ± 12.3 ml/min/1.73 m2 and UACR 533 (192-1707) mg/g. CAS (ln-transformed) was significantly higher in patients with OSA compared to patients without (6.6 ± 1.7 vs. 5.6 ± 2.4, p = 0.04), and the same was observed for PWV (11.9 ± 2.7 vs. 10.5 ± 2.2 m/s, p = 0.02). In multivariable linear regression analyses adjusted for sex, age, body mass index, UACR, and mean arterial pressure, moderate-severe OSA remained significantly associated with PWV but not with CAS. Dominance analysis revealed OSA as the third and second most important factor relative to CAS and PWV respectively. CONCLUSIONS: In DKD patients, moderate-severe OSA is a significant predictor of arterial stiffness but is not independently associated with coronary calcification.

Adrenal incidentalomas and effectiveness of patient pathway transformation.

INTRODUCTION: A total of 10% of older individuals harbour adrenal incidentalomas and need dedicated adrenal CT to exclude malignancy and biochemical evaluation. These investigations tax medical resources, and diagnostic delay may cause anxiety for the patient. We implemented a no-need-to-see pathway (NNTS) in which low-risk patients only attend the clinic if adrenal CT or hormonal evaluation is abnormal. METHODS: We investigated the impact of a NNTS pathway on the share of patients not requiring an attendance consultation, time to malignancy and hormonal clarification, and time to end of investigation. We prospectively registered adrenal incidentaloma cases (n = 347) and compared them with historical controls (n = 103). RESULTS: All controls attended the clinic. A total of 63% of cases entered and 84% completed the NNTS pathway without seeing an endocrinologist; 53% of consultations were avoided. Time-to-event analysis revealed a shorter time to clarification of malignancy (28 days; 95% confidence interval (CI): 24-30 days versus 64 days; 95% CI: 47-117 days) and hormonal status (43 days; 95% CI: 38-48 days versus 56 days; 95% CI: 47-68 days) and a shorter time to end of pathway (47 days; 95% CI: 42-55 days versus 112 days; 95% CI: 84-131 days) in cases than controls (p ≤ 0.01). CONCLUSION: We demonstrated that NNTS pathways may be an efficient way of handling the increased burden of incidental radiological findings, avoiding 53% of attendance consultations and achieving a shorter time to end of pathway. FUNDING: Supported by a grant from Regional Hospital Central Denmark, Denmark. The study was approved by the institutional review boards of all participating hospitals. TRIAL REGISTRATION: Not relevant.