Search

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.

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 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.

Graphical abstract, Highlights • A novel probabilistic planning method based on the same statistics as PTV margins. • Applied to treatment planning for deforming cervical cancer patients. • Probabilistic plans decreased dose to the rectum for the same target coverage., 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.

Because of its low-lying σ* orbitals, the C–S bond can interact with electron donors. In this short review, our goal is to focus on intramolecular interactions between bivalent sulfur and basic nitrogen atoms. In particular, we will consider the synthesis of selected heterobiaryls for which 1,4 N···S inter-ring interactions can be identified from X-ray diffraction data. Finally, we will briefly touch on the use of such conformational preferences in various applications. 1 Introduction 2 Cross-Coupling with C–C Bond Formation 3 Cross-Coupling with C–N Bond Formation 4 Nucleophilic Addition to Azine Followed by Oxidation 5 Multicomponent Reactions 6 Heterobiaryl Formation by Azine Building 7 Heterobiaryl Formation by Building of the Sulfur-Containing Heterocycle 8 Cycloaddition Reactions 9 Other Syntheses 10 Conclusion

This review provides a perspective on C–H bond functionalization mediated by cobalt complexes used in either stoichiometric or catalytic amounts, without the contribution of any other transition metal, for organic synthesis applications. The competitive cost, availability and lower toxicity of cobalt compared to precious transition metals constitute valuable advantages of the methods.

This article describes how a purposeful sample of 62 elementary schools from 17 states implemented a Response to Intervention (RtI) framework for reading. School informants answered surveys and were interviewed about differentiated instruction in Tier 1, screening/benchmarking, where Tier 2 interventions were located, typical group size and the minutes/day of intervention in Tiers 2 and 3 groups, and how students with individualized educational programs (IEPs) in reading were served in the school’s RtI model. Schools reported using differentiated instruction in Tier 1, favored curriculum-based measures for screening/benchmarking and progress monitoring, reported more intensive interventions and more progress monitoring in Tier 3, and used a wide variety of models for serving students with IEPs within the schools’ RtI models.

The deprotonating ability of mixed lithium–zinc or lithium–magnesium–zinc combinations containing amido and alkyl ligands in tetrahydrofuran were compared using anisole as substrate and iodine to quantitatively trap the formed arylmetal species. The results showed that the deprotonating ability is hampered if a Grignard reagent is employed to introduce the alkyl ligand, and is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic chiral amido or alkyls. Concerning the interception of the generated lithium–zinc aryl species by aldehydes, the presence of amido ligands leads to side reactions/lower yields, and no clear improvement was observed if lithium–magnesium–zinc aryl species are used. Racemic mixtures to very low enantioselectivities were noted when chiral amido ligands were incorporated in the composition of the bases. Still with enantioselective aryl transfer to aldehyde as purpose, the deprotonating ability of mixed lithium–cobalt combinations containing amido and alkyl ligands were compared using anisole as substrate and anisaldehyde to trap the formed arylmetal species. As before, the deprotonating ability is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic alkyls or chiral amido. The trapping step using aldehydes being in this case more efficient, even in the presence of amido ligands, the alcohols were obtained in higher yields. With recourse to a lower interception temperature, and using only bis[(R)-1-phenylethyl]amino as ligands, 32 and 22% yield, and 69 and 65% ee were obtained using, respectively, anisaldehyde and 3,4,5-trimethoxybenzaldehyde to intercept the metalated anisole.

A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of α-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis.MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorter-chain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo.We conclude that MitoVES, a mitochondrially targeted analog of α-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing.

Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC(50) of 80 μM, whereas the electron transfer from CII to CIII was inhibited with IC(50) of 1.5 μM. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1α fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser(68) within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.

A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).

The new sequential stereoselective synthesis of diversely substituted 9H-fluoren-9-ones by ortho-lithiation/Bu3SnCl quench of unprotected benzoic acids followed by Stille cross-coupling reaction and remote metalation is reported.

Because of its low-lying σ* orbitals, the C–S bond can interact with electron donors. In this short review, our goal is to focus on intramolecular interactions between bivalent sulfur and basic nitrogen atoms. In particular, we will consider the synthesis of selected heterobiaryls for which 1,4 N···S inter-ring interactions can be identified from X-ray diffraction data. Finally, we will briefly touch on the use of such conformational preferences in various applications. 1 Introduction 2 Cross-Coupling with C–C Bond Formation 3 Cross-Coupling with C–N Bond Formation 4 Nucleophilic Addition to Azine Followed by Oxidation 5 Multicomponent Reactions 6 Heterobiaryl Formation by Azine Building 7 Heterobiaryl Formation by Building of the Sulfur-Containing Heterocycle 8 Cycloaddition Reactions 9 Other Syntheses 10 Conclusion

Studies detailing synthetic approaches to a variety of biosynthetically related vibsanin-type diterpenes (i.e. vibsanin E, 15-O-methylcyclovibsanin B, 3-hydroxy-vibsanin E, furano-vibsanin A, and 3-O-methylfuranovibsanin A) are discussed. Biogenetically modelled approaches are coupled with an in-vestigation of classical and modern six- to seven-membered ring-expansion protocols, which gain access to the central core of these natural products. (c) Wiley-VCH Verlag GmbH & Co.

Heartland Area Education Agency in Iowa illustrates how it has sustained a problem-solving service delivery system for 15 years and adapted to changing state and federal requirements while remainin...

Unprotected biphenyl-2-carboxylic acid can be cleanly metalated with sec-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution. The remote C2′-position is attacked by the superbasic mixture of n-butyllithium and potassium tert-butoxide (LICKOR, 3.5 equiv.) in THF or benzene at 20–60 °C. The resulting dianion cyclizes to give the fluorenone skeleton. The metalation reactions of biphenyl-3- and -4-carboxylic acids are also described. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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.

ortho -Substituted-2-biphenyl carboxylic acids of the type 3a – j were prepared by the tandem metalation sequence from 2-biphenyl carboxylic acid 1 with sec -butyllithium in THF at −78°C followed by quenching with electrophiles. The carboxylic acids 3a – f were converted into 1-substituted fluorenones 4a – f upon treatment with methanesulfonic acid.

This review provides a perspective on C–H bond functionalization mediated by cobalt complexes used in either stoichiometric or catalytic amounts, without the contribution of any other transition metal, for organic synthesis applications. The competitive cost, availability and lower toxicity of cobalt compared to precious transition metals constitute valuable advantages of the methods.

The mechanism of the metalation of 2-(pyridin-3-yl)benzoic acid derivatives with strong bases is discussed.

International audience; no abstract

[reaction: see text] Construction of the 15-O-methylcyclovibsanin B core was achieved expediently in eight linear steps utilizing a biogenetically modeled approach.

Lan-Feng Dong , Victoria J.A. Jameson , David Tilly , Lubomir Prochazka , Jakub Rohlena , Karel Valis , Jaroslav Truksa , Renata Zobalova , Elahe Mahdavian , Katarina Kluckova , Marina Stantic , Jan Stursa , Ruth Freeman , Paul K. Witting , Erik Norberg , Jacob Goodwin , Brian A. Salvatore , Jana Novotna , Jaroslav Turanek , Miroslav Ledvina , Pavel Hozak , Boris Zhivotovsky , Mark J. Coster , Stephen J. Ralph , Robin A.J. Smith , Jiri Neuzil a,e,n

International audience; A no. of substituted biaryls, arylpyridines, arylpyrimidines and arylquinolines was prepd. by coupling reactions; deprotonation-iodination with a mixed lithium/zinc-TMP base gives the corresponding iodides. The obtained exptl. results on acidity are compared with calcd. values of Gibbs energies of deprotonation at different positions of the considered biaryl and arylheterocyclic systems. With the aim of synthesizing biaryl compds., several arom. iodides were prepd. 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 com. compds., were cross-coupled under palladium catalysis (e.g., Suzuki coupling with 2,4-dimethoxy-5-pyrimidylboronic acid) to afford various representative biaryl compds. Deprotometalation of the latter compds. 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 detd. in THF soln. 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 obsd. upon treatment with lithium amides under kinetic conditions. Finally, the iodinated biaryl derivs. were involved in palladium-catalyzed reactions. [on SciFinder(R)]

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.

International audience; Enantioselective deprotonative metalations of substituted ferrocenes using mixed lithium-metal bases are described. Using N,N-diisopropylferrocenecarboxamide as substrate, magnesium, iron, cobalt, zinc, and cadmium were tested as metals in bis[(S)-1-phenylethyl]amido-based combinations; after interception of the metalated species with iodine, very high enantiomeric excess (96 %) but low yield was obtained with cobalt, whereas zinc and cadmium only gave 27 and 30 % ee, respectively, but in excellent yields. The small alkyl groups methyl and ethyl were identified as particularly suitable in the reaction using the putative dialkyl bis[(S)-1-phenylethyl]amido-based lithium and dilithium zincates. The dimethyl dilithium zincate was selected for a study of dependency on the temperature, reaction time, and amount of base. Increased enantioselectivities with temperature, reaction time, and amount of base were noted (ee = 86 % at 0 °C after 2 h, 2 equiv. of base). The best result using methyl ferrocenecarboxylate as substrate was observed without alkyl ligand.

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.

Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested here a novel approach, whereby the mitochondrially targeted delivery of anti-cancer drugs is enhanced by the addition of a triphenylphosphonium group (TPP(+)). A mitochondrially targeted analog of vitamin E succinate (MitoVES), modified by tagging the parental compound with TPP(+), induced considerably more robust apoptosis in cancer cells with a 1-2 log gain in anti-cancer activity compared to the unmodified counterpart, while maintaining selectivity for malignant cells. This is because MitoVES associates with mitochondria and causes fast generation of reactive oxygen species that then trigger mitochondria-dependent apoptosis, involving transcriptional modulation of the Bcl-2 family proteins. MitoVES proved superior in suppression of experimental tumors compared to the untargeted analog. We propose that mitochondrially targeted delivery of anti-cancer agents offers a new paradigm for increasing the efficacy of compounds with anti-cancer activity.

Polycyclic indole structures, possessing fused seven-membered rings were efficiently synthesized via the Pd-catalyzed intramolecular carbopalladation-annulation of 3-(2-iodobenzyl)-indoles and alkynes. A remarkable base effect on the chemoselectivity of this transformation has been found: switching from Et3N to CsOAc completely reverses the reaction path to intramolecular cyclization forming fused five-membered rings.

Reading traditionally is characterized as having two major components, decoding and comprehension. Published reading tests are created using these two components. Reading fluency, a combination of ...

Polycyclic indole structures, possessing fused seven-membered rings were efficiently synthesized via the Pd-catalyzed intramolecular carbopalladation-annulation of 3-(2-iodobenzyl)-indoles and alkynes. A remarkable base effect on the chemoselectivity of this transformation has been found: switching from Et(3)N to CsOAc completely reverses the reaction path to intramolecular cyclization forming fused five-membered rings.

The new sequential stereoselective synthesis of diversely substituted 9H-fluoren-9-ones by ortho-lithiation/Bu3SnCl quench of unprotected benzoic acids followed by Stille cross-coupling reaction and remote metalation is reported.

Whereas treatment of unprotected naphthalene-1-carboxylic acid with alkyllithiums (RLi) affords 1,4-addition products, the reaction with LTMP/Me3SiCl under in situ quench conditions provides the ar...

The mechanism of the metalation of 2-biphenyl carboxylic acid (1) with the Lochmann-Schlosser superbase was determined by deuteriolysis. Both ortho (C(3)) and remote (C(2')) positions are metalated. The C(2')-metalated species 2 cyclizes instantaneously. Under suitable conditions, the doubly charged geminal dimetallo dialkoxide group C(OM)(2) 4 directs metalation in the adjacent position (C(1)), affording a stable 1-metallo-9H-fluorene-9,9-dimetallo dialkoxide 5 that can be trapped by diverse electrophiles to give 1-substituted 9H-fluoren-9-ones 7 and 9 after acidic workup. [structure: see text]

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.