The Quality Assurance of a 1.5 T MR-Linac.

The recent introduction of a commercial 1.5 T MR-linac system has considerably improved the image quality of the patient acquired in the treatment unit as well as enabling online adaptive radiation therapy (oART) treatment strategies. Quality Assurance (QA) of this new technology requires new methodology that allows for the high field MR in a linac environment. The presence of the magnetic field requires special attention to the phantoms, detectors, and tools to perform QA. Due to the design of the system, the integrated megavoltage imager (MVI) is essential for radiation beam calibrations and QA. Additionally, the alignment between the MR image system and the radiation isocenter must be checked. The MR-linac system has vendor-supplied phantoms for calibration and QA tests. However, users have developed their own routine QA systems to independently check that the machine is performing as required, as to ensure we are able to deliver the intended dose with sufficient certainty. The aim of this work is therefore to review the MR-linac specific QA procedures reported in the literature.

Enantioselective conjugate addition to nitroolefins catalysed by helical peptides with a single remote stereogenic centre.

Two short pentapeptides rich in α-aminoisobutyric acid (Aib) residues have been shown to act as enantioselective organocatalysts for the conjugate addition of nucleophiles to nitroolefins. An L-alanine terminated peptide, (Aib)4(L-Ala)NHtBu, which has neither functionalised sidechains nor a highly designed reactive site, used an exposed N-terminal primary amine and the amide bonds of the backbone to mediate catalysis. Folding of this peptide into a 310 helical structure was observed by crystallography. Folding into a helix relays the conformational preference of the chiral alanine residue at the C-terminus to the primary amine at the N-terminus, 0.9 nm distant. The chiral environment and defined shape produced by the 310 helix brings the amine site into proximity to two exposed amide NHs. Reaction scope studies implied that the amine acts as a Brønsted base and the solvent-exposed NH groups of the helix, shown to weakly bind ß-nitrostyrene, are needed to obtain an enantiomeric excess. Replacement of L-alanine with D-phenylalanine gave (Aib)4(D-Phe)NHtBu, a peptide that now catalysed the benchmark reaction with the opposite enantioselectivity. These studies show how achiral residues can play a key role in enantioselective catalysis by peptides through the promotion of folding.

Anion-Dependent Hydrogen-Bond Polarity Switching in Ethylene-bridged Urea Oligomers.

The reversible coordination of anions to an N,N'-disubstituted 3,5-bis(trifluoromethyl)phenylurea located at a terminus of a linear chain of ethylene-bridged hydrogen-bonded ureas triggers a cascade of conformational changes. A series of hydrogen-bond polarity reversals propagates along the oligomer, leading to a global switch of its hydrogen-bond directionality. The induced polarity switch, transmitted through four reversible urea groups, results in a change in emission and excitation wavelengths of a fluorophore located at the opposite terminus of the oligomer. The molecule thus behaves as a chemical sensor with a relayed remote spectroscopic response to variations in anion concentration. The polarity switch induced by anion concentration constitutes an artificial communication mechanism for conveying information through oligomeric structures.

Switching imidazole reactivity by dynamic control of tautomer state in an allosteric foldamer.

Molecular biology achieves control over complex reaction networks by means of molecular systems that translate a chemical input (such as ligand binding) into an orthogonal chemical output (such as acylation or phosphorylation). We present an artificial molecular translation device that converts a chemical input - the presence of chloride ions - into an unrelated chemical output: modulation of the reactivity of an imidazole moiety, both as a Brønsted base and as a nucleophile. The modulation of reactivity operates through the allosteric remote control of imidazole tautomer states. The reversible coordination of chloride to a urea binding site triggers a cascade of conformational changes in a chain of ethylene-bridged hydrogen-bonded ureas, switching the chain's global polarity, that in turn modulates the tautomeric equilibrium of a distal imidazole, and hence its reactivity. Switching reactivities of active sites by dynamically controlling their tautomer states is an untapped strategy for building functional molecular devices with allosteric enzyme-like properties.

Dosimetric validation of the couch and coil model for high-field MR-linac treatment planning.

PURPOSE: The precision of the dose delivery in radiation therapy with high-field MR-linacs is challenging due to the substantial variation in the beam attenuation of the patient positioning system (PPS) (the couch and coils) as a function of the gantry angle. This work aimed to compare the attenuation of two PPSs located at two different MR-linac sites through measurements and calculations in the treatment planning system (TPS). METHODS: Attenuation measurements were performed at every 1° gantry angle at the two sites with a cylindrical water phantom with a Farmer chamber inserted along the rotational axis of the phantom. The phantom was positioned with the chamber reference point (CRP) at the MR-linac isocentre. A compensation strategy was applied to minimise sinusoidal measurement errors due to, e.g. air cavity or setup. A series of tests were performed to assess the sensitivity to measurement uncertainties. The dose to a model of the cylindrical water phantom with the PPS added was calculated in the TPS (Monaco v5.4 as well as in a development version Dev of an upcoming release), for the same gantry angles as for the measurements. The TPS PPS model dependency of the dose calculation voxelisation resolution was also investigated. RESULTS: A comparison of the measured attenuation of the two PPSs yielded differences of less than 0.5% for most gantry angles. The maximum deviation between the attenuation measurements for the two different PPSs exceeded ±1% at two specific gantry angles 115° and 245°, where the beam traverses the most complex PPS structures. The attenuation increases from 0% to 25% in 15° intervals around these angles. The measured and calculated attenuation, as calculated in v5.4, was generally within 1-2% with a systematic overestimation of the attenuation for gantry angles around 180°, as well as a maximum error of 4-5% for a few discrete angles in 10° gantry angle intervals around the complex PPS structures. The PPS modelling was improved compared to v5.4 in Dev, especially around 180°, and the results of those calculations were within ±1%, but with a similar 4% maximum deviation for the most complex PPS structures. CONCLUSIONS: Generally, the two tested PPS structures exhibit very similar attenuation as a function of the gantry angle, including the angles with a steep change in attenuation. Both TPS versions, v5.4 and Dev delivered clinically acceptable accuracy of the calculated dose, as the differences in the measurements were overall better than ±2%. Additionally, Dev improved the accuracy of the dose calculation to ±1% for gantry angles around 180°.

Supramolecular interactions between ethylene-bridged oligoureas: nanorings and chains formed by cooperative positive allostery.

Ethylene-bridged oligoureas are dynamic foldamers in which the polarity of a coherent chain of intramolecular hydrogen bonds may be controlled by intra- or intermolecular interactions with hydrogen-bond donors or acceptors. In this paper, we describe the way that supramolecular interactions between ethylene-bridged oligoureas bearing a 3,5-bis(trifluoromethyl)phenylurea (BTMP) terminus leads to higher-order structures both in the crystalline state and in solution. The oligoureas self-assemble by head-to-tail hydrogen bonding interactions to form either supramolecular 'nanorings' with cyclic hydrogen bond chain directionality, or supramolecular helical chains of hydrogen bonds. The self-assembly process features a cascade of cooperative positive allostery, in which each intermolecular hydrogen bond formation at the BTMP terminus switches the native hydrogen bond chain directionality of monomers, favouring further assembly. Monomers with a benzyl urea terminus self-assemble into nanorings, whereas monomers with a N-ethyl urea terminus form helical chains. In the crystal state, parallel helices have identical handedness and polarity, whereas antiparallel helices have opposite handedness. The overall dipole moment of crystals is zero due to the antiparallel arrangements of local dipoles in the crystal packing. Supramolecular interactions in solution were also examined by VT and DOSY NMR spectroscopy, up to the point of crystal formation. The size of higher aggregates in dichloromethane was estimated by their hydrodynamic radius. The relative orientation of the monomers within the aggregates, determined by 2D ROESY NMR, was the same as in the crystals, where syn-orientations lead to the formation of rings and anti-orientations result in chains. Overall, the switch of hydrogen bond polarity propagates intermolecularly in crystal and solution states, constituting an example of intermolecular communication within supramolecular polymers.

Adaptive dose painting for prostate cancer.

Purpose: Dose painting (DP) is a radiation therapy (RT) strategy for patients with heterogeneous tumors delivering higher dose to radiation resistant regions and less to sensitive ones, thus aiming to maximize tumor control with limited side effects. The success of DP treatments is influenced by the spatial accuracy in dose delivery. Adaptive RT (ART) workflows can reduce the overall geometric dose delivery uncertainty. The purpose of this study is to dosimetrically compare ART and non-adaptive conventional RT workflows for delivery of DP prescriptions in the treatment of prostate cancer (PCa). Materials and methods: We performed a planning and treatment simulation study of four study arms. Adaptive and conventional workflows were tested in combination with DP and Homogeneous dose. We used image data from 5 PCa patients that had been treated on the Elekta Unity MR linac; the patients had been imaged in treatment position before each treatment fraction (7 in total). The local radiation sensitivity from apparent diffusion coefficient maps of 15 high-risk PCa patients was modelled in a previous study. these maps were used as input for optimization of DP plans aiming for maximization of tumor control probability (TCP) under rectum dose constraints. A range of prostate doses were planned for the homogeneous arms. Adaptive plans were replanned based on the anatomy-of-the-day, whereas conventional plans were planned using a pre-treatment image and subsequently recalculated on the anatomy-of-the-day. The dose from 7 fractions was accumulated using dose mapping. The endpoints studied were the TCP and dose-volume histogram metrics for organs at risk. Results: Accumulated DP doses (adaptive and conventional) resulted in high TCP, between 96-99%. The largest difference between adaptive and conventional DP was 2.6 percentage points (in favor of adaptive DP). An analysis of the dose per fraction revealed substantial target misses for one patient in the conventional workflow that-if systematic-could jeopardize the TCP. Compared to homogeneous prescriptions with equal mean prostate dose, DP resulted in slightly higher TCP. Conclusion: Compared to homogeneous dose, DP maintains or marginally increases the TCP. Adaptive DP workflows could avoid target misses compared to conventional workflows.

Patient specific deep learning based segmentation for magnetic resonance guided prostate radiotherapy.

Background and Purpose: Treatments on combined Magnetic Resonance (MR) scanners and Linear Accelerators (Linacs) for radiotherapy, called MR-Linacs, often require daily contouring. Currently, deformable image registration (DIR) algorithms propagate contours from reference scans, however large shape and size changes can be troublesome. Artificial neural network (ANN) based contouring may alleviate this issue, however generally requires large datasets for training. Mitigating the problem of scarcity of data, we propose patient specific networks trained on a single dataset for each patient, for contouring onto the following datasets in an adaptive MR-Linacworkflow. Materials and Methods: MR-scans from 17 prostate patients treated on an MR-Linac with contours of Clinical Target Volume (CTV), bladder and rectum were utilized. U-net shaped models were trained based on the image from the first fraction of each patient, and subsequently applied onto the following treatment images. Results were compared with manual contours in terms of the Dice coefficient and Added Path Length (APL). As benchmark, contours propagated through the clinical DIR algorithm were similarly evaluated. Results: In Dice coefficient the ANN output was 0.92 ± 0.03, 0.93 ± 0.07 and 0.84 ± 0.10 while for DIR 0.95 ± 0.03, 0.93 ± 0.08, 0.88 ± 0.06 for CTV, bladder and rectum respectively. Similarly, APL where 3109 ± 1642, 7250 ± 4234 and 5041 ± 2666 for ANN and 1835 ± 1621, 7236 ± 4287 and 4170 ± 2920 voxels for DIR. Conclusions: Patient specific ANN models trained on images from the first fraction of a prostate MR-Linac treatment showed similar accuracy when applied to the subsequent fraction images as a clinically implemented DIR method.

α-Amino-iso-Butyric Acid Foldamers Terminated with Rhodium(I) N-Heterocyclic Carbene Catalysts.

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α-amino-iso-butyric acid (Aib) peptide foldamers bearing rhodium(I) N-heterocyclic carbene (NHC) complexes have been synthesized and studied. X-ray crystallography of a foldamer with an N-terminal azide and a C-terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral L-α-methylvaline (L-αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N-terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.

Intrafractional motion models based on principal components in Magnetic Resonance guided prostate radiotherapy.

BACKGROUND AND PURPOSE: Devices that combine an MR-scanner with a Linac for radiotherapy, referred to as MR-Linac systems, introduce the possibility to acquire high resolution images prior and during treatment. Hence, there is a possibility to acquire individualised learning sets for motion models for each fraction and the construction of intrafractional motion models. We investigated the feasibility for a principal component analysis (PCA) based, intrafractional motion model of the male pelvic region. MATERIALS AND METHODS: 4D-scans of nine healthy male volunteers were utilized, FOV covering the entire pelvic region including prostate, bladder and rectum with manual segmentation of each organ at each time frame. Deformable image registration with an optical flow algorithm was performed for each subject with the first time frame as reference. PCA was performed on a subset of the resulting displacement vector fields to construct individualised motion models evaluated on the remaining fields. RESULTS: The registration algorithm produced accurate registration result, in general DICE overlap > 0.95 across all time frames. Cumulative variance of the eigen values from the PCA showed that 50% or more of the motion is explained in the first component for all subjects. However, the size and direction for the components differed between subjects. Adding more than two components did not improve the accuracy significantly and the model was able to explain motion down to about 1 mm. CONCLUSIONS: An individualised intrafractional male pelvic motion model is feasible. Geometric accuracy was about 1 mm based on 1-2 principal components.

A molecular communication channel consisting of a single reversible chain of hydrogen bonds in a conformationally flexible oligomer.

Communication of information through the global switching of conformation in synthetic molecules has hitherto entailed the inversion of chirality. Here, we report a class of oligomer through which information may be communicated through a global reversal of polarity. Ethylene-bridged oligoureas are constitutionally symmetrical, conformationally flexible molecules organized by a single chain of hydrogen bonds running the full length of the oligomer. NMR reveals that this hydrogen-bonded chain may undergo a coherent reversal of directionality. The directional uniformity of the hydrogen-bond chain allows it to act as a channel for the spatial communication of information on a molecular scale. A binding site at the terminus of an oligomer detects local information about changes in pH or anion concentration and transmits that information-in the form of a directionality switch in the hydrogen-bond chain-to a remote polarity-sensitive fluorophore. This propagation of polarity-encoded information provides a new mechanism for molecular communication.

End-to-end validation of the geometric dose delivery performance of MR linac adaptive radiotherapy.

The clinical introduction of hybrid magnetic resonance (MR) guided radiotherapy (RT) delivery systems has led to the need to validate the end-to-end dose delivery performance on such machines. In the current study, an MR visible phantom was developed and used to test the spatial deviation between planned and delivered dose at two 1.5 T MR linear accelerator (MR linac) systems, including pre-treatment imaging, dose planning, online imaging, image registration, plan adaptation, and dose delivery. The phantom consisted of 3D printed plastic and MR visible silicone rubber. It was designed to minimise air gaps close to the radiochromic film used as a dosimeter. Furthermore, the phantom was designed to allow submillimetre, reproducible positioning of the film in the phantom. At both MR linac systems, 54 complete adaptive, MR guided RT workflow sessions were performed. To test the dose delivery performance of the MR linac systems in various adaptive RT (ART) scenarios, the sessions comprised a range of systematic positional shifts of the phantom and imaging or plan adaptation conditions. In each workflow session, the positional translation between the film and the adaptive planned dose was determined. The results showed that the accuracy of the MR linac systems was between 0.1 and 0.9 mm depending on direction. The highest mean deviance observed was in the posterior-anterior direction, and the direction of the error was consistent between centres. The precision of the systems was related to whether the workflow utilized the internal image registration algorithm of the MR linac. Workflows using the internal registration algorithm led to a worse precision (0.2-0.7 mm) compared to workflows where the algorithm was decoupled (0.2 mm). In summary, the spatial deviation between planned and delivered dose of MR-guided ART at the two MR linac systems was well below 1 mm and thus acceptable for clinical use.

Probabilistic optimization of dose coverage in radiotherapy.

BACKGROUND AND PURPOSE: Probabilistic optimization is an alternative to margins for handling geometrical uncertainties in treatment planning of radiotherapy where uncertainties are explicitly incorporated in the optimization. We present a novel probabilistic method based on the same statistical measures as those behind conventional margin based planning. MATERIAL AND METHODS: Percentile Dosage (PD) was defined as the dose coverage that a treatment plan meet or exceed to a given probability. For optimization, we used the convex measure Expected Percentile Dosage (EPD) defined as the average dose coverage below a given PD. An iterative method gradually adjusted the constraint tolerance associated with the EPD until the desired target PD was met. It was applied to planning of cervical cancer patients focusing on systematic uncertainty caused by organ deformation. The resulting plans were compared to margin based plans using target and organ at risk PDs. RESULTS: The EPD tolerance converged in less than ten iterations to produce a PD within 0.1 Gy of the requested. The PD was on average within 0.5% of the requested PD when validated versus independent scenarios. The rectum volume, extracted from the PDs, receiving 90% of the intended target dose was decreased with 16% for the same target PD in comparison to margin based plans. CONCLUSIONS: The proposed probabilistic optimization method enabled prescription of a dose volume histogram metric to a chosen confidence. The probabilistic plans showed improved target dose homogeneity and decreased rectum dose for the same target dose coverage compared to margin based plans.

Dose coverage calculation using a statistical shape model-applied to cervical cancer radiotherapy.

A comprehensive methodology for treatment simulation and evaluation of dose coverage probabilities is presented where a population based statistical shape model (SSM) provide samples of fraction specific patient geometry deformations. The learning data consists of vector fields from deformable image registration of repeated imaging giving intra-patient deformations which are mapped to an average patient serving as a common frame of reference. The SSM is created by extracting the most dominating eigenmodes through principal component analysis of the deformations from all patients. The sampling of a deformation is thus reduced to sampling weights for enough of the most dominating eigenmodes that describe the deformations. For the cervical cancer patient datasets in this work, we found seven eigenmodes to be sufficient to capture 90% of the variance in the deformations of the, and only three eigenmodes for stability in the simulated dose coverage probabilities. The normality assumption of the eigenmode weights was tested and found relevant for the 20 most dominating eigenmodes except for the first. Individualization of the SSM is demonstrated to be improved using two deformation samples from a new patient. The probabilistic evaluation provided additional information about the trade-offs compared to the conventional single dataset treatment planning.

Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy.

A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.

Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy - applied to prostate proton treatments.

BACKGROUND: Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths. RESULTS: The planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk. CONCLUSIONS: The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.

Computed CH acidity of biaryl compounds and their deprotonative metalation by using a mixed lithium/zinc-TMP base.

With the aim of synthesizing biaryl compounds, several aromatic iodides were prepared by the deprotonative metalation of methoxybenzenes, 3-substituted naphthalenes, isoquinoline, and methoxypyridines by using a mixed lithium/zinc-TMP (TMP=2,2,6,6-tetramethylpiperidino) base and subsequent iodolysis. The halides thus obtained, as well as commercial compounds, were cross-coupled under palladium catalysis (e.g., Suzuki coupling with 2,4-dimethoxy-5-pyrimidylboronic acid) to afford various representative biaryl compounds. Deprotometalation of the latter compounds was performed by using the lithium/zinc-TMP base and evaluated by subsequent iodolysis. The outcome of these reactions has been discussed in light of the CH acidities of these substrates, as determined in THF solution by using the DFT B3LYP method. Except for in the presence of decidedly lower pKa values, the regioselectivities of the deprotometalation reactions tend to be governed by nearby coordinating atoms rather than by site acidities. In particular, azine and diazine nitrogen atoms have been shown to be efficient in inducing the reactions with the lithium/zinc-TMP base at adjacent sites (e.g., by using 1-(2-methoxyphenyl)isoquinoline, 4-(2,5-dimethoxyphenyl)-3-methoxypyridine, or 5-(2,5-dimethoxyphenyl)-2,4-dimethoxypyrimidine as the substrate), a behavior that has already been observed upon treatment with lithium amides under kinetic conditions. Finally, the iodinated biaryl derivatives were involved in palladium-catalyzed reactions.

Directed remote aromatic metalations: mechanisms and driving forces.

Directed remote aromatic metalations are useful synthetic transformations allowing for rapid regioselective access to elaborate highly substituted carbocyclic aromatic and heteroaromatic systems. This review unravels the tangle of data reported on directed remote aromatic metalations. Through a careful analysis of critically selected examples, advanced rationalizations of remote metalation regioselectivities are presented. These extend beyond the complex-induced proximity effect (CIPE). Mechanisms, driving forces, and parameters influencing remote metalations are discussed. An understanding of these metalation mechanisms enables more accurate predictability of justification of regiochemical outcomes of these useful synthetic transformations.