Asymmetric azidohydroxylation of styrene derivatives mediated by a biomimetic styrene monooxygenase enzymatic cascade.

Enantioenriched azido alcohols are precursors for valuable chiral aziridines and 1,2-amino alcohols, however their chiral substituted analogues are difficult to access. We established a cascade for the asymmetric azidohydroxylation of styrene derivatives leading to chiral substituted 1,2-azido alcohols via enzymatic asymmetric epoxidation, followed by regioselective azidolysis, affording the azido alcohols with up to two contiguous stereogenic centers. A newly isolated two-component flavoprotein styrene monooxygenase StyA proved to be highly selective for epoxidation with a nicotinamide coenzyme biomimetic as a practical reductant. Coupled with azide as a nucleophile for regioselective ring opening, this chemo-enzymatic cascade produced highly enantioenriched aromatic α-azido alcohols with up to >99% conversion. A bi-enzymatic counterpart with halohydrin dehalogenase-catalyzed azidolysis afforded the alternative ß-azido alcohol isomers with up to 94% diastereomeric excess. We anticipate our biocatalytic cascade to be a starting point for more practical production of these chiral compounds with two-component flavoprotein monooxygenases.

Singlet-Oxygen Generation by Peroxidases and Peroxygenases for Chemoenzymatic Synthesis.

Singlet oxygen is a reactive oxygen species undesired in living cells but a rare and valuable reagent in chemical synthesis. We present a fluorescence spectroscopic analysis of the singlet-oxygen formation activity of commercial peroxidases and novel peroxygenases. Singlet-oxygen sensor green (SOSG) is used as fluorogenic singlet oxygen trap. Establishing a kinetic model for the reaction cascade to the fluorescent SOSG endoperoxide permits a kinetic analysis of enzymatic singlet-oxygen formation. All peroxidases and peroxygenases show singlet-oxygen formation. No singlet oxygen activity could be found for any catalase under investigation. Substrate inhibition is observed for all reactive enzymes. The commercial dye-decolorizing peroxidase industrially used for dairy bleaching shows the highest singlet-oxygen activity and the lowest inhibition. This enzyme was immobilized on a textile carrier and successfully applied for a chemical synthesis. Here, ascaridole was synthesized via enzymatically produced singlet oxygen.

Chemoenzymatic Halocyclization of γ,δ-Unsaturated Carboxylic Acids and Alcohols.

Invited for this month's cover is the group of Prof. Dr. Frank Hollmann at Delft University of Technology in the Netherlands. The Front Cover shows the vanadium-dependent haloperoxidase from the marine organism Curcuvaria inaequalis, which efficiently activates halides as hypohalites that can then initiate spontaneous halo-lactonization and halo-etherification reactions. The Communication itself is available at 10.1002/cssc.201902240.

Chemoenzymatic Halocyclization of γ,δ-Unsaturated Carboxylic Acids and Alcohols.

A chemoenzymatic method for the halocyclization of unsaturated alcohols and acids by using the robust V-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) as catalyst has been developed for the in situ generation of hypohalites. A broad range of halolactones and cyclic haloethers are formed with excellent performance of the biocatalyst.

Dose-guided patient positioning in proton radiotherapy using multicriteria-optimization.

Proton radiotherapy (PT) requires accurate target alignment before each treatment fraction, ideally utilizing 3D in-room X-ray computed tomography (CT) imaging. Typically, the optimal patient position is determined based on anatomical landmarks or implanted markers. In the presence of non-rigid anatomical changes, however, the planning scenario cannot be exactly reproduced and positioning should rather aim at finding the optimal position in terms of the actually applied dose. In this work, dose-guided patient alignment, implemented as multicriterial optimization (MCO) problem, was investigated in the scope of intensity-modulated and double-scattered PT (IMPT and DSPT) for the first time. A method for automatically determining the optimal patient position with respect to pre-defined clinical goals was implemented. Linear dose interpolation was used to access a continuous space of potential patient shifts. Fourteen head and neck (H&N) and eight prostate cancer patients with up to five repeated CTs were included. Dose interpolation accuracy was evaluated and the potential dosimetric advantages of dose-guided over bony-anatomy-based patient alignment investigated by comparison of clinically relevant target and organ-at-risk (OAR) dose-volume histogram (DVH) parameters. Dose interpolation was found sufficiently accurate with average pass-rates of 90% and 99% for an exemplary H&N and prostate patient, respectively, using a 2% dose-difference criterion. Compared to bony-anatomy-based alignment, the main impact of automated MCO-based dose-guided positioning was a reduced dose to the serial OARs (spinal cord and brain stem) for the H&N cohort. For the prostate cohort, under-dosage of the target structures could be efficiently diminished. Limitations of dose-guided positioning were mainly found in reducing target over-dosage due to weight loss for H&N patients, which might require adaptation of the treatment plan. Since labor-intense online quality-assurance is not required for dose-guided patient positioning, it might, nevertheless, be considered an interesting alternative to full online re-planning for initially mitigating the effects of anatomical changes.

Multi-criterial patient positioning based on dose recalculation on scatter-corrected CBCT images.

BACKGROUND AND PURPOSE: Our aim was to evaluate the feasibility and potential advantages of dose guided patient positioning based on dose recalculation on scatter corrected cone beam computed tomography (CBCT) image data. MATERIAL AND METHODS: A scatter correction approach has been employed to enable dose calculations on CBCT images. A recently proposed tool for interactive multicriterial dose-guided patient positioning which uses interpolation between pre-calculated sample doses has been utilized. The workflow was retrospectively evaluated for two head and neck patients with a total of 39 CBCTs. Dose-volume histogram (DVH) parameters were compared to rigid image registration based isocenter corrections (clinical scenario). RESULTS: The accuracy of the dose interpolation was found sufficient, facilitating the implementation of dose guided patient positioning. Compared to the clinical scenario, the mean dose to the parotid glands could be improved for 2 out of 5 fractions for the first patient while other parameters were preserved. For the second patient, the mean coverage over all fractions of the high dose PTV could be improved by 4%. For this patient, coverage improvements had to be traded against organ at risk (OAR) doses within their clinical tolerance limits. CONCLUSIONS: Dose guided patient positioning using in-room CBCT data is feasible and offers increased control over target coverage and doses to OARs.

A novel method for interactive multi-objective dose-guided patient positioning.

In intensity-modulated radiation therapy (IMRT), 3D in-room imaging data is typically utilized for accurate patient alignment on the basis of anatomical landmarks. In the presence of non-rigid anatomical changes, it is often not obvious which patient position is most suitable. Thus, dose-guided patient alignment is an interesting approach to use available in-room imaging data for up-to-date dose calculation, aimed at finding the position that yields the optimal dose distribution. This contribution presents the first implementation of dose-guided patient alignment as multi-criteria optimization problem. User-defined clinical objectives are employed for setting up a multi-objective problem. Using pre-calculated dose distributions at a limited number of patient shifts and dose interpolation, a continuous space of Pareto-efficient patient shifts becomes accessible. Pareto sliders facilitate interactive browsing of the possible shifts with real-time dose display to the user. Dose interpolation accuracy is validated and the potential of multi-objective dose-guided positioning demonstrated for three head and neck (H&N) and three prostate cancer patients. Dose-guided positioning is compared to replanning for all cases. A delineated replanning CT served as surrogate for in-room imaging data. Dose interpolation accuracy was high. Using a [Formula: see text] dose difference criterion, a median pass-rate of 95.7% for H&N and 99.6% for prostate cases was determined in a comparison to exact dose calculations. For all patients, dose-guided positioning allowed to find a clinically preferable dose distribution compared to bony anatomy based alignment. For all H&N cases, mean dose to the spared parotid glands was below [Formula: see text] (up to [Formula: see text] with bony alignment) and clinical target volume (CTV) [Formula: see text] above 99.1% (compared to 95.1%). For all prostate patients, CTV [Formula: see text] was above 98.9% (compared to 88.5%) and [Formula: see text] to the rectum below [Formula: see text] (compared to 56.1%). Replanning yielded improved results for the H&N cases. For the prostate cases, differences to dose-guided positioning were minor.

Interactive multi-criteria planning for radiofrequency ablation.

PURPOSE: Image-guided radiofrequency ablation (RFA) is a broadly used minimally invasive method for the thermal destruction of focal liver malignancies using needle-shaped instruments. The established planning workflow is based on examination of 2D slices and manual definition of the access path. During that process, multiple criteria for all possible trajectories have to be taken into account. Hence, it demands considerable experience and constitutes a significant mental task. METHODS: An access path determination method based on image processing and numerical optimization is proposed. Fast GPU-based simulation approximation is utilized to incorporate the heat distribution including realistic cooling effects from nearby blood vessels. A user interface for intuitive exploration of the optimization results is introduced. RESULTS: The proposed methods are integrated into a clinical software assistant. To evaluate the suitability of the interactive optimization approach for the identification of meaningful therapy strategies, a retrospective study has been carried out. The system is able to propose clinically relevant trajectories to the target by incorporating multiple criteria. CONCLUSIONS: A novel method for planning of image-guided radiofrequency ablation by means of interactive access path determination based on optimization is presented. A first retrospective study indicates that the method is suited to improve the classical planning of RFA.

The critical spot eraser-a method to interactively control the correction of local hot and cold spots in IMRT planning.

Common problems in inverse radiotherapy planning are localized dose insufficiencies like hot spots in organs at risk or cold spots inside targets. These are hard to correct since the optimization is based on global evaluations like maximum/minimum doses, equivalent uniform doses or dose-volume constraints for whole structures. In this work, we present a new approach to locally correct the dose of any given treatment plan. Once a treatment plan has been found that is acceptable in general but requires local corrections, these areas are marked by the planner. Then the system generates new plans that fulfil the local dose goals. Consequently, it is possible to interactively explore all plans between the locally corrected plans and the original treatment plan, allowing one to exactly adjust the degree of local correction and how the plan changes overall. Both the amount (in Gy) and the size of the local dose change can be navigated. The method is introduced formally as a new mathematical optimization setting, and is evaluated using a clinical example of a meningioma at the base of the skull. It was possible to eliminate a hot spot outside the target volume while controlling the dose changes to all other parts of the treatment plan. The proposed method has the potential to become the final standard step of inverse treatment planning.

Balancing control and simplicity: A variable aggregation method in intensity modulated radiation therapy planning.

It is commonly believed that not all degrees of freedom are needed to produce good solutions for the treatment planning problem in intensity modulated radiation therapy (IMRT). However, typical methods to exploit this fact either increase the complexity of the optimization problem or are heuristic in nature. In this work we introduce a technique based on adaptively refining variable clusters to successively attain better treatment plans. The approach creates approximate solutions based on smaller models that may come arbitrarily close to the optimal solution. Although the method is illustrated using a specific treatment planning model, the components constituting the variable clustering and the adaptive refinement are independent of the particular optimization problem.

The tradeoff between treatment plan quality and required number of monitor units in intensity-modulated radiotherapy.

PURPOSE: To provide a mathematical approach for quantifying the tradeoff between intensity-modulated radiotherapy (IMRT) complexity and plan quality. METHODS AND MATERIALS: We solve a multi-objective program that includes IMRT complexity, measured as the number of monitor units (MU) needed to deliver the plan using a multileaf collimator, as an objective. Clinical feasibility of plans is ensured by the use of hard constraints in the formulation. Optimization output is a Pareto surface of treatment plans, which allows the tradeoffs between IMRT complexity, tumor coverage, and tissue sparing to be observed. Paraspinal and lung cases are presented. RESULTS: Although the amount of possible MU reduction is highly dependent on the difficulty of the underlying treatment plan (difficult plans requiring a high degree of intensity modulation are more sensitive to MU reduction), in some cases the number of MU can be reduced more than twofold with a <1% increase in the objective function. CONCLUSIONS: The largely increased number of MU and irradiation time in IMRT is sometimes unnecessary. Tools like the one presented should be considered for integration into daily clinical practice to avoid this problem.