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While the vibrational spectra of semi-rigid molecules can be computed on approaches relying on the Watson Hamiltonian, floppy molecules or molecular clusters are better described by Hamiltonians, which are capable of dealing with any curvilinear coordinates. It is the kinetic energy operator (KEO) of these Hamiltonians, which render the correlated calculations relying on them rather costly. Novel implementation of vibrational self-consistent field theory and vibrational configuration interaction theory on the basis of the Podolsky Hamiltonian are reported, in which the inverse of the metric tensor, i.e., the G matrix, is represented by an n-mode expansion expressed in terms of polynomials. An analysis of the importance of the individual terms of the KEO with respect to the truncation orders of the n-mode expansion is provided. Benchmark calculations have been performed for the cis-HOPO and methanimine, H2CNH, molecules and are compared to experimental data and to calculations based on the Watson Hamiltonian and the internal coordinate path Hamiltonian. [ABSTRACT FROM AUTHOR]

The positions of grid points for representing a multidimensional potential energy surface (PES) have a non-negligible impact on its accuracy and the associated computational effort for its generation. Six different positioning schemes were studied for PESs represented by n-mode expansions as needed for the accurate calculation of anharmonic vibrational frequencies by means of vibrational configuration interaction theory. A static approach, which has successfully been used in many applications, and five adaptive schemes based on Gaussian process regression have been investigated with respect to the number of necessary grid points and the accuracy of the fundamental modes for a small set of test molecules. A comparison with a related, more sophisticated, and consistent approach by Christiansen et al. is provided. The impact of the positions of the ab initio grid points is discussed for multilevel PESs, for which the computational effort of the individual electronic structure calculations decreases for increasing orders of the n-mode expansion. As a result of that, the ultimate goal is not the maximal reduction of grid points but rather the computational cost, which is not directly related. [ABSTRACT FROM AUTHOR]

Aminoborane, H2NBH2 and its isotopologues, H2N10BH2, D2NBD2, and D2N10BD2, have been studied by high‐level ab initio methods. All calculations rely on multidimensional potential energy surfaces and dipole moment surfaces including high‐order mode coupling terms, which have been obtained from electronic structure calculations at the level of explicitly correlated coupled‐cluster theory, CCSD(T)‐F12, or the distinguishable cluster approximation, DCSD. Subsequent vibrational structure calculations based on second‐order vibrational perturbation theory, VPT2, and vibrational configuration interaction theory, VCI, were used to determine rotational constants, centrifugal distortion constants, vibrationally averaged geometrical parameters and (an)harmonic vibrational frequencies. The impact of core‐correlation effects is discussed in detail. Rovibrational VCI calculations were used to simulate the gas phase spectra of these species and an in‐depth analysis of the ν7 band of aminoborane is provided. Color‐coding is used to reveal the identity of the individual progressions of the rovibrational transitions for this particular mode. [ABSTRACT FROM AUTHOR]

Objective: CT serves as gold standard for the evaluation of pulmonary nodules. However, CT exposes patients to ionizing radiation, a concern especially in screening scenarios with repeated examinations. Due to recent technological advances, MRI emerges as a potential alternative for lung imaging using 3D steady state free precession and ultra-short echo-time sequences. Therefore, in this study we assessed the performance of three state-of-the-art MRI sequences for the evaluation of pulmonary nodules. Methods: Lesions of variable sizes were simulated in porcine lungs placed in a dedicated chest phantom mimicking a human thorax, followed by CT and MRI examinations. Two blinded readers evaluated the acquired MR-images locating and measuring every suspect lesion. Using the CT-images as reference, logistic regression was performed to investigate the sensitivity of the tested MRI-sequences for the detection of pulmonary nodules. Results: For nodules with a diameter of 6 mm, all three sequences achieved high sensitivity values above 0.91. However, the sensitivity dropped for smaller nodules, yielding an average of 0.83 for lesions with 4 mm in diameter and less than 0.69 for lesions with 2 mm in diameter. The positive predictive values ranged between 0.91 and 0.96, indicating a low amount of false positive findings. Furthermore, the size measurements done on the MR-images were subject to a bias ranging from 0.83 mm to -1.77 mm with standard deviations ranging from 1.40 mm to 2.11 mm. There was no statistically significant difference between the three tested sequences. Conclusion: While showing promising sensitivity values for lesions larger than 4 mm, MRI appears to be not yet suited for lung cancer screening. Nonetheless, the three tested MRI sequences yielded high positive predictive values and accurate size measurements; therefore, MRI could potentially figure as imaging method of the chest in selected follow-up scenarios, e.g. of incidental findings subject to the Fleischner Criteria. [ABSTRACT FROM AUTHOR]

Rationale: Probe-based confocal endomicroscopy provides real time videos of autoflourescent elastin structures within the alveoli. With it, multiple changes in the elastin structure due to different diffuse parenchymal lung diseases have previously been described. However, these evaluations have mainly relied on qualitative evaluation by the examiner and manually selected parts post-examination. Objectives: To develop a fully automatic method for quantifying structural properties of the imaged alveoli elastin and to perform a preliminary assessment of their diagnostic potential. Methods: 46 patients underwent probe-based confocal endomicroscopy, of which 38 were divided into 4 groups categorizing different diffuse parenchymal lung diseases. 8 patients were imaged in representative healthy lung areas and used as control group. Alveolar elastin structures were automatically segmented with a trained machine learning algorithm and subsequently evaluated with two methods developed for quantifying the local thickness and structural connectivity. Measurements and main results: The automatic segmentation algorithm performed generally well and all 4 patient groups showed statistically significant differences with median elastin thickness, standard deviation of thickness and connectivity compared to the control group. Conclusion: Alveoli elastin structures can be quantified based on their structural connectivity and thickness statistics with a fully-automated algorithm and initial results highlight its potential for distinguishing parenchymal lung diseases from normal alveoli. [ABSTRACT FROM AUTHOR]

In this paper, we extend the implicit-explicit (IMEX) methods of Peer type recently developed by Lang and Hundsdorfer (2017) [16] to a broader class of two-step methods that allow the construction of super-convergent IMEX-Peer methods with A-stable implicit part. IMEX schemes combine the necessary stability of implicit and low computational costs of explicit methods to efficiently solve systems of ordinary differential equations with both stiff and non-stiff parts included in the source term. To construct super-convergent IMEX-Peer methods with favourable stability properties, we derive necessary and sufficient conditions on the coefficient matrices and apply an extrapolation approach based on already computed stage values. Optimised super-convergent IMEX-Peer methods of order s + 1 for s = 2 , 3 , 4 stages are given as result of a search algorithm carefully designed to balance the size of the stability regions and the extrapolation errors. Numerical experiments and a comparison to other IMEX-Peer methods are included. [ABSTRACT FROM AUTHOR]

Purpose Variability across devices, patients, and time still hinders widespread recognition of dynamic contrast-enhanced magnetic resonance imaging ( DCE- MRI) as quantitative biomarker. The purpose of this work was to introduce and characterize a dedicated microchannel phantom as a model for quantitative DCE- MRI measurements. Methods A perfusable, MR-compatible microchannel network was constructed on the basis of sacrificial melt-spun sugar fibers embedded in a block of epoxy resin. Structural analysis was performed on the basis of light microscopy images before DCE- MRI experiments. During dynamic acquisition the capillary network was perfused with a standard contrast agent injection system. Flow-dependency, as well as inter- and intrascanner reproducibility of the computed DCE parameters were evaluated using a 3.0 T whole-body MRI. Results Semi-quantitative and quantitative flow-related parameters exhibited the expected proportionality to the set flow rate (mean Pearson correlation coefficient: 0.991, P < 2.5e-5). The volume fraction was approximately independent from changes of the applied flow rate through the phantom. Repeatability and reproducibility experiments yielded maximum intrascanner coefficients of variation ( CV) of 4.6% for quantitative parameters. All evaluated parameters were well in the range of known in vivo results for the applied flow rates. Conclusion The constructed phantom enables reproducible, flow-dependent, contrast-enhanced MR measurements with the potential to facilitate standardization and comparability of DCE- MRI examinations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to propose and evaluate a new wavelet-based technique for classification of arterial and venous vessels using time-resolved cerebral CT perfusion data sets. Methods: Fourteen consecutive patients (mean age 73 yr, range 17-97) with suspected stroke but no pathology in follow-up MRI were included. A CT perfusion scan with 32 dynamic phases was performed during intravenous bolus contrast-agent application. After rigid-body motion correction, a Paul wavelet (order 1) was used to calculate voxelwise the wavelet power spectrum (WPS) of each attenuation-time course. The angiographic intensity A was defined as the maximum of the WPS, located at the coordinates T (time axis) and W (scale/width axis) within the WPS. Using these three parameters (A, T, W) separately as well as combined by (1) Fisher's linear discriminant analysis (FLDA), (2) logistic regression (LogR) analysis, or (3) support vector machine (SVM) analysis, their potential to classify 18 different arterial and venous vessel segments per subject was evaluated. Results: The best vessel classification was obtained using all three parameters A and T and W [area under the curve (AUC): 0.953 with FLDA and 0.957 with LogR or SVM]. In direct comparison, the wavelet-derived parameters provided performance at least equal to conventional attenuation-timecourse parameters. The maximum AUC obtained from the proposed wavelet parameters was slightly (although not statistically significantly) higher than the maximum AUC (0.945) obtained from the conventional parameters. Conclusions: A new method to classify arterial and venous cerebral vessels with high statistical accuracy was introduced based on the time-domain wavelet transform of dynamic CT perfusion data in combination with linear or nonlinear multidimensional classification techniques. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to develop and evaluate a new method that reliably differentiates between cerebral arteries and veins using voxel-wise CT-perfusion-derived parameters. Materials and Methods: Fourteen consecutive patients with suspected stroke but without pathological findings were examined on a multi-detector CT system: 32 dynamic phases (∆t = 1.5 s) during application of 35 mL iomeprol-350 were acquired at 80 kV/200mAs. Three hemodynamic parameters were calculated for 18 arterial and venous vessel segments: A (maximum of the time-density-curve), T (time-to-peak), and W (full-width-at-half-maximum). Using receiver operator characteristic (ROC) curve analysis and Fisher's linear discriminant analysis (FLDA), the performance of every classifier ( A, T, W) and of all linear combinations for the differentiation of arterial and venous vessels was determined. Results: A maximum area under the ROC-curve (AUC) of 0.945 (accuracy = 86.8 %) was obtained using the FLDA combination of A&T or the triplet FLDA of A&T&W for the classification of venous and arterial vessels. The best single parameter was T with an AUC of 0.871 (accuracy = 79.0 %), which performed significantly worse than the combination A&T ( p < 0.001). Conclusions: Arteries and veins can be accurately differentiated based on dynamic CT perfusion data using the maximum of the time-density curve, its time-to-peak, its width, and FLDA combinations of these parameters, which yield accuracies up to 87 %. Key points: • For classification of cerebral vasculature, time-to-peak has the best single-parameter accuracy. • Fisher's linear discriminant analysis improves the performance of the individual classifiers. • Combining signal maximum and time-to-peak parameters significantly increased the classifying potential. • Pre-processing of time-density-curves by Gaussian filtering or fitting can improve diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model. Materials and Methods: 23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10–800 s/mm2) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher's linear discriminant analysis (FLDA). Results: All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10−3 mm2/s to 0.90±0.12×10−3 mm2/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10−3 mm2/s vs. 0.03±0.09×10−3 mm2/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm3; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm3; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%. Conclusions: Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring. [ABSTRACT FROM AUTHOR]

Dynamical systems with sub-processes evolving on many different time scales are ubiquitous in applications. Their efficient solution is greatly enhanced by automatic time step variation. This paper is concerned with the theory, construction and application of IMEX-Peer methods that are super-convergent for variable step sizes and A-stable in the implicit part. IMEX schemes combine the necessary stability of implicit and low computational costs of explicit methods to efficiently solve systems of ordinary differential equations with both stiff and non-stiff parts included in the source term. To construct super-convergent IMEX-Peer methods which keep their higher order for variable step sizes and exhibit favourable linear stability properties, we derive necessary and sufficient conditions on the nodes and coefficient matrices and apply an extrapolation approach based on already computed stage values. New super-convergent IMEX-Peer methods of order s + 1 for s = 2 , 3 , 4 stages are given as result of additional order conditions which maintain the super-convergence property independent of step size changes. Numerical experiments and a comparison to other super-convergent IMEX-Peer methods show the potential of the new methods when applied with local error control. [ABSTRACT FROM AUTHOR]

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques. [ABSTRACT FROM AUTHOR]

Diffusion-weighted magnetic resonance imaging (DWI) is a non-invasive method sensitive to local water motion in the tissue. As a tool to probe the microstructure, including the presence and potentially the degree of renal fibrosis, DWI has the potential to become an effective imaging biomarker. The aim of this review is to discuss the current status of renal DWI in diffuse renal diseases. DWI biomarkers can be classified in the following three main categories: (i) the apparent diffusion coefficient—an overall measure of water diffusion and microcirculation in the tissue; (ii) true diffusion, pseudodiffusion and flowing fraction—providing separate information on diffusion and perfusion or tubular flow; and (iii) fractional anisotropy—measuring the microstructural orientation. An overview of human studies applying renal DWI in diffuse pathologies is given, demonstrating not only the feasibility and intra-study reproducibility of DWI but also highlighting the need for standardization of methods, additional validation and qualification. The current and future role of renal DWI in clinical practice is reviewed, emphasizing its potential as a surrogate and monitoring biomarker for interstitial fibrosis in chronic kidney disease, as well as a surrogate biomarker for the inflammation in acute kidney diseases that may impact patient selection for renal biopsy in acute graft rejection. As part of the international COST (European Cooperation in Science and Technology) action PARENCHIMA (Magnetic Resonance Imaging Biomarkers for Chronic Kidney Disease), aimed at eliminating the barriers to the clinical use of functional renal magnetic resonance imaging, this article provides practical recommendations for future design of clinical studies and the use of renal DWI in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Hybrid devices that combine radiation therapy and MR-imaging have been introduced in the clinical routine for the treatment of lung cancer. This opened up not only possibilities in terms of accurate tumor tracking, dose delivery and adapted treatment planning, but also functional lung imaging. The aim of this study was to show the feasibility of Non-uniform Fourier Decomposition (NuFD) MRI at a 0.35 T MR-Linac as a potential treatment response assessment tool, and propose two signal normalization strategies for enhancing the reproducibility of the results. Methods: Ten healthy volunteers (median age 28 ± 8 years, five female, five male) were repeatedly scanned at a 0.35 T MR-Linac using an optimized 2D+t balanced steady-state free precession (bSSFP) sequence for two coronal slice positions. Image series were acquired in normal free breathing with breaks inside and outside the scanner as well as deep and shallow breathing. Ventilation- and perfusion-weighted maps were generated for each image series using NuFD. For intra-volunteer ventilation map reproducibility, a normalization factor was defined based on the linear correlation of the ventilation signal and diaphragm position of each scan as well as the diaphragm motion amplitude of a reference scan. This allowed for the correction of signal dependency on the diaphragm motion amplitude, which varies with breathing patterns. The second strategy, which can be used for ventilation and perfusion, eliminates the dependency on the signal amplitude by normalizing the ventilation/perfusion maps with the average ventilation/perfusion signal within a selected region-of-interest (ROI). The position and size dependency of this ROI was analyzed. To evaluate the performance of both approaches, the normalized ventilation/perfusion-weighted maps were compared and the deviation of the mean ventilation/perfusion signal from the reference was calculated for each scan. Wilcoxon signed-rank tests were performed to test whether the normalization methods can significantly improve the reproducibility of the ventilation/perfusion maps. Results: The ventilation- and perfusion-weighted maps generated with the NuFD algorithm demonstrated a mostly homogenous distribution of signal intensity as expected for healthy volunteers regardless of the breathing maneuver and slice position. Evaluation of the ROI's size and position dependency showed small differences in the performance. Applying both normalization strategies improved the reproducibility of the ventilation by reducing the median deviation of all scans to 9.1%, 5.7% and 8.6% for the diaphragm-based, the best and worst performing ROI-based normalization, respectively, compared to 29.5% for the non-normalized scans. The significance of this improvement was confirmed by the Wilcoxon signed rank test with p < 0.01 at α = 0.05 . A comparison of the techniques against each other revealed a significant difference in the performance between best ROI-based normalization and worst ROI ( p = 0.01 ) and between best ROI-based normalization and scaling factor ( p = 0.02 ), but not between scaling factor and worst ROI ( p = 0.71 ). Using the ROI-based approach for the perfusion-maps, the uncorrected deviation of 10.2% was reduced to 5.3%, which was shown to be significant ( p < 0.01 ). Conclusions: Using NuFD for non-contrast enhanced functional lung MRI at a 0.35 T MR-Linac is feasible and produces plausible ventilation- and perfusion-weighted maps for volunteers without history of chronic pulmonary diseases utilizing different breathing patterns. The reproducibility of the results in repeated scans significantly benefits from the introduction of the two normalization strategies, making NuFD a potential candidate for fast and robust early treatment response assessment of lung cancer patients during MR-guided radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The implementation of volumetric in‐room imaging for online adaptive radiotherapy makes extensive testing of this image data for treatment planning necessary. Especially for proton beams the higher sensitivity to stopping power properties of the tissue results in more stringent requirements. Current approaches mainly focus on recalculation of the plans on the new image data, lacking experimental verification, and ignoring the impact on the plan re‐optimization process. The aim of this study was to use gel and film dosimetry coupled with a three‐dimensional (3D) printed head phantom (based on the planning CT of the patient) for 3D range verification of intensity‐corrected cone beam computed tomography (CBCT) image data for adaptive proton therapy. Methods: Single field uniform dose pencil beam scanning proton plans were optimized for three different patients on the patients' planning CT (planCT) and the patients' intensity‐corrected CBCT (scCBCT) for the same target volume using the same optimization constraints. The CBCTs were corrected on projection level using the planCT as a prior. The dose optimized on planCT and recalculated on scCBCT was compared in terms of proton range differences (80% distal fall‐off, recalculation). Moreover, the dose distribution resulting from recalculation of the scCBCT‐optimized plan on the planCT and the original planCT dose distribution were compared (simulation). Finally, the two plans of each patient were irradiated on the corresponding patient‐specific 3D printed head phantom using gel dosimetry inserts for one patient and film dosimetry for all three patients. Range differences were extracted from the measured dose distributions. The measured and the simulated range differences were corrected for range differences originating from the initial plans and evaluated. Results: The simulation approach showed high agreement with the standard recalculation approach. The median values of the range differences of these two methods agreed within 0.1 mm and the interquartile ranges (IQRs) within 0.3 mm for all three patients. The range differences of the film measurement were accurately matching with the simulation approach in the film plane. The median values of these range differences deviated less than 0.1 mm and the IQRs less than 0.4 mm. For the full 3D evaluation of the gel range differences, the median value and IQR matched those of the simulation approach within 0.7 and 0.5 mm, respectively. scCBCT‐ and planCT‐based dose distributions were found to have a range agreement better than 3 mm (median and IQR) for all considered scenarios (recalculation, simulation, and measurement). Conclusions: The results of this initial study indicate that an online adaptive proton workflow based on scatter‐corrected CBCT image data for head irradiations is feasible. The novel presented measurement‐ and simulation‐based method was shown to be equivalent to the standard literature recalculation approach. Additionally, it has the capability to catch effects of image differences on the treatment plan optimization. This makes the measurement‐based approach particularly interesting for quality assurance of CBCT‐based online adaptive proton therapy. The observed uncertainties could be kept within those of the registration and positioning. The proposed validation could also be applied for other alternative in‐room images, e.g. for MR‐based pseudoCTs. [ABSTRACT FROM AUTHOR]

Real-time motion monitoring of lung tumors with low-field magnetic resonance imaging-guided linear accelerators (MR-Linacs) is currently limited to sagittal 2D cine magnetic resonance imaging (MRI). To provide input data for improved intrafractional and interfractional adaptive radiotherapy, the 4D anatomy has to be inferred from data with lower dimensionality. The purpose of this study was to experimentally validate a previously proposed propagation method that provides continuous time-resolved estimated 4D-MRI based on orthogonal cine MRI for a low-field MR-Linac. Ex vivo porcine lungs were injected with artificial nodules and mounted in a dedicated phantom that allows for the simulation of periodic and reproducible breathing motion. The phantom was scanned with a research version of a commercial 0.35 T MR-Linac. Respiratory-correlated 4D-MRI were reconstructed and served as ground truth images. Series of interleaved orthogonal slices in sagittal and coronal orientation, intersecting the injected targets, were acquired at 7.3 Hz. Estimated 4D-MRI at 3.65 Hz were created in post-processing using the propagation method and compared to the ground truth 4D-MRI. Eight datasets at different breathing frequencies and motion amplitudes were acquired for three porcine lungs. The overall median (95 percentile) deviation between ground truth and estimated deformation vector fields was 2.3 mm (5.7 mm), corresponding to 0.7 (1.6) times the in-plane imaging resolution (3.5 × 3.5 mm2). Median (95 percentile) estimated nodule position errors were 1.5 mm (3.8 mm) for nodules intersected by orthogonal slices and 2.1 mm (7.1 mm) for nodules located more than 2 cm away from either of the orthogonal slices. The estimation error depended on the breathing phase, the motion amplitude and the location of the estimated position with respect to the orthogonal slices. By using the propagation method, the 4D motion within the porcine lung phantom could be accurately and robustly estimated. The method could provide valuable information for treatment planning, real-time motion monitoring, treatment adaptation, and post-treatment evaluation of MR-guided radiotherapy treatments. [ABSTRACT FROM AUTHOR]

Purpose: To investigate αvβ3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. Materials and methods: Human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvβ3-integrin-targeted fluorescent probe. The αvβ3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ß3 –integrin expression, CD31 –microvascular density, Ki-67 –proliferation). Results: The αvβ3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107±42 mm3; control +112±44mm3, p = 0.841). In vivo blocking studies with αvβ3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe. Conclusions: αvβ3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria. [ABSTRACT FROM AUTHOR]

• Unique open dataset with multi-modal imaging of proton irradiated mouse brains. • Provided data: Cone-beam computed tomography (CBCT) with dose and linear energy transfer (LET) simulations, brain atlas, longitudinal magnetic resonance imaging (MRI), brain atlas, and comprehensive tissue histology of whole mouse brains after proton irradiation of brain subvolumes. • All data are spatially registered to the CBCT. • Correlation of clinical, biological, and physical endpoints on single-cell level. • Dataset accessible under https://doi.org/10.14278/rodare.557. Comprehending cellular changes of radiation-induced brain injury is crucial to prevent and treat the pathology. We provide a unique open dataset of proton-irradiated mouse brains consisting of medical imaging, radiation dose simulations, and large-scale microscopy images, all registered into a common coordinate system. This allows dose-dependent analyses on single-cell level. [ABSTRACT FROM AUTHOR]

Purpose:Doxorubicin (DOX)-loaded phosphatidyldiglycerol-based thermosensitive liposomes (DPPG2-TSL-DOX) combined with local hyperthermia (HT) was evaluated in cats with locally advanced spontaneous fibrosarcomas (soft tissue sarcoma [STS]). The study was designed to evaluate the safety and pharmacokinetic profile of the drug. Results from four dose-levels are reported. Methods:Eleven client-owned cats with advanced STS were enrolled. Five cats received escalating doses of 0.1–0.4 mg/kg DOX (group I), three received 0.4 mg/kg constantly (group II) and three 0.6 mg/kg (group III) IV over 15 min. HT with a target temperature of 41.5 °C was started 15 min before drug application and continued for a total of 60 min. Six HT treatments were applied every other week using a radiofrequency applicator. Tumour growth was monitored by magnetic resonance imaging (MRI) and for dose level III also with18F-FDG PET. Results:Treatment was generally well tolerated and reasons for premature study termination in four cats were not associated with drug-induced toxicity. No DPPG2-TSL-DOX based hypersensitivity reaction was observed. One cat showed simultaneous partial response (PR) in MRI and positron emission tomography (PET) whereas one cat showed stable disease in MRI and PR in PET (both cats in dose level III). Pharmacokinetic measurements demonstrated DOX release triggered by HT. Conclusion:DPPG2-TSL-DOX + HT is a promising treatment option for advanced feline STS by means of targeted drug delivery. As MTD was not reached further investigation is warranted to determine if higher doses would result in even better tumour responses. [ABSTRACT FROM PUBLISHER]

Objectives: To investigate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring therapy effects of regorafenib on experimental colon carcinomas in rats with correlation to dynamic contrast-enhanced MRI (DCE-MRI) and immunohistochemistry. Materials and Methods: Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 21 (n = 11 therapy group; n = 10 control group) female athymic nude rats (Hsd: RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment with regorafenib or a placebo (10 mg/kg bodyweight), using CEUS with VEGFR2-targeted microbubbles and DCE-MRI. In CEUS tumor perfusion was assessed during an early vascular phase (wash-in area under the curve = WiAUC) and VEGFR2-specific binding during a late molecular phase (signal intensity after 8 (SI8min) and 10 minutes (SI10min)), using a conventional 15L8 linear transducer (transmit frequency 7 MHz, dynamic range 80 dB, depth 25 mm). In DCE-MRI functional parameters plasma flow (PF) and plasma volume (PV) were quantified. For validation purposes, CEUS parameters were correlated with DCE-MRI parameters and immunohistochemical VEGFR2, CD31, Ki-67 and TUNEL stainings. Results: CEUS perfusion parameter WiAUC decreased significantly (116,989 ± 77,048 a.u. to 30,076 ± 27,095a.u.; p = 0.005) under therapy with no significant changes (133,932 ± 65,960 a.u. to 84,316 ± 74,144 a.u.; p = 0.093) in the control group. In the therapy group, the amount of bound microbubbles in the late phase was significantly lower in the therapy than in the control group on day 7 (SI8min: 283 ± 191 vs. 802 ± 460 a.u.; p = 0.006); SI10min: 226 ± 149 vs. 645 ± 461 a.u.; p = 0.009). PF and PV decreased significantly (PF: 147 ± 58 mL/100 mL/min to 71 ± 15 mL/100 mL/min; p = 0.003; PV: 13 ± 3% to 9 ± 4%; p = 0.040) in the therapy group. Immunohistochemistry revealed significantly fewer VEGFR2 (7.2 ± 1.8 vs. 17.8 ± 4.6; p < 0.001), CD31 (8.1 ± 3.0 vs. 20.8 ± 5.7; p < 0.001) and Ki-67 (318.7 ± 94.0 vs. 468.0 ± 133.8; p = 0.004) and significantly more TUNEL (672.7 ± 194.0 vs. 357.6 ± 192.0; p = 0.003) positive cells in the therapy group. CEUS parameters showed significant (p < 0.05) correlations to DCE-MRI parameters and immunohistochemistry. Conclusions: CEUS with VEGFR2-targeted microbubbles allowed for monitoring regorafenib functional and molecular therapy effects on experimental colorectal adenocarcinomas with a significant decline of CEUS and DCE-MRI perfusion parameters as well as a significant reduction of specifically bound microbubbles under therapy, consistent with a reduced expression of VEGFR2. [ABSTRACT FROM AUTHOR]

Objectives: To validate the anatomical accuracy, homogeneity and sensitivity of two-compartment modeled inversion recovery (TCIR) magnetic resonance imaging (MRI) in a multimodal animal experiment as a non-invasive alternative to standard functional imaging techniques.Methods: Seven pigs were studied on a 1.5 T whole-body MR scanner and SPECT/CT. The specimens were intubated and maintained in general anesthesia throughout the experiment. TCIR maps of the fractional pulmonary blood volume were compared to dynamic contrast enhanced MRI and SPECT/CT via a region of interest (ROI) based reader study. A comprehensive statistical analysis was performed on the coefficient of variation to evaluate homogeneity properties. Sensitivity was assessed by detecting gravitation dependent perfusion variation and delineation of pathological areas.Results: The fPBV-maps of all examined specimens indicate a superior homogeneity in the computed values (p<1.3×10(-4)). The sensitivity of the TCIR maps to a gravitation effect on the blood distribution was verified and a similar anteroposterior signal and count dependency was observed in DCE MRI and SPECT. Bland-Altman analysis showed no significant intra- or inter-observer difference within the ROI reader study (p>0.06).Conclusion: Superior information content, significantly higher homogeneity and similar sensitivity of TCIR when compared to DCE and SPECT/CT demonstrated the feasibility of TCIR MRI as an alternative contrast agent-free, non-invasive functional lung imaging approach. [ABSTRACT FROM AUTHOR]

Objectives: To investigate a multimodal, multiparametric perfusion MRI / 18F-fluoro-deoxyglucose-(18F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation. Materials and Methods: Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group; n = 7 control group) female athymic nude rats (Hsd:RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/18F-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV, %) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In 18F-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67). Results: Regorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters ΔPF, ΔPV and ΔPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter ΔTTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05). Conclusions: A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and 18F-FDG-PET validated by immunohistochemistry. [ABSTRACT FROM AUTHOR]