What is the optimal isodose line for stereotactic radiotherapy for single brain metastases using HyperArc?

PURPOSE: The study aimed to investigate the optimal isodose line (IDL) in linear accelerator-based stereotactic radiotherapy for single brain metastasis, using HyperArc. We compared the dosimetric parameters for target and normal brain tissue among six plans with different IDLs. METHODS: This study included 30 patients with single brain metastasis. We retrospectively generated six plans for each tumor with different IDLs (80%, 70%, 60%, 50%, 40%, and 33%) using HyperArc. All treatment plans were normalized to the prescription dose of 35 Gy in five fractions which was covered by 95% of the planning target volume (PTV), defined by adding a 1.0 mm margin to the gross tumor volume (GTV). The dosimetric parameters were compared among the six plans. RESULTS: For GTV > 0.1 cm3, the ratio of brain-GTV volumes receiving 25 Gy to PTV (V25Gy/PTV) was significantly lower at IDL 40%-70% than at IDL 80% and 33% (p < 0.01, retrospectively). For GTV < 0.1 cm3, V25Gy/PTV decreased continuously as IDL decreased. The values of D99% and D80% for GTV increased with decreasing IDL. An IDL of 50% or less was required to achieve D99% of greater than 43 Gy and D80% of greater than 50 Gy. The mean values of D99% and D80% for IDL 50% were 44.3 and 51.9 Gy. CONCLUSION: The optimal IDL is 40%-50% for GTV > 0.1 cm3. These lower IDLs could increase D99% and D80% of GTV while lowering V25Gy of normal brain tissue, which may help reduce the risk of radiation necrosis and improve local control.

Exploring feasibility criteria for stereotactic radiosurgical treatment of multiple brain metastases using five linac machines.

PURPOSE: This study aimed to find descriptors that correlates with normal brain dose to determine the feasibility of performing fractionated stereotactic radiosurgery (SRS) for multiple brain metastases (BMs) using five linac machines. METHODS: Thirty-two patients with 1-30 BMs were enrolled. Treatment plans were created using TrueBeam, Novalis Tx, TrueBeam Edge, Halcyon, and Tomotherapy linacs. The sum of all planning target volumes (PTVs) was defined as PTVall, and the brain region excluding PTVall was defined as normal brain. The total surface area (TSA) of the PTV was calculated from the sum of the surface areas of the equivalent spheres for each PTV. Volumes receiving more than 5, 12, and 18 Gy (V5Gy, V12Gy, and V18Gy, respectively) were used for evaluation of normal brain dose. Correlations between normal brain dose and each tumor characteristic (number, PTVall, and TSA) were investigated using the Spearman rank correlation coefficient. RESULTS: Correlations between each characteristic and normal brain dose were statistically significant (p < 0.05) across all machines. The correlation coefficients between each characteristic and V18Gy for the five machines were as follows: tumor number, 0.39-0.60; PTVall, 0.79-0.93; TSA, 0.93-0.99. The fit equations between TSA and V18Gy exhibited high coefficients of determination, ranging from 0.92 to 0.99 across five machines. CONCLUSION: This study devised fractionated SRS plans using for 1-30 BMs across five linac machines to find descriptors for determining SRS feasibility based on normal brain dose. TSA proved to be a promising descriptor of SRS feasibility for treating multiple BMs.

The close environments of accreting massive black holes are shaped by radiative feedback.

The majority of the accreting supermassive black holes in the Universe are obscured by large columns of gas and dust. The location and evolution of this obscuring material have been the subject of intense research in the past decades, and are still debated. A decrease in the covering factor of the circumnuclear material with increasing accretion rates has been found by studies across the electromagnetic spectrum. The origin of this trend may be driven by the increase in the inner radius of the obscuring material with incident luminosity, which arises from the sublimation of dust; by the gravitational potential of the black hole; by radiative feedback; or by the interplay between outflows and inflows. However, the lack of a large, unbiased and complete sample of accreting black holes, with reliable information on gas column density, luminosity and mass, has left the main physical mechanism that regulates obscuration unclear. Here we report a systematic multi-wavelength survey of hard-X-ray-selected black holes that reveals that radiative feedback on dusty gas is the main physical mechanism that regulates the distribution of the circumnuclear material. Our results imply that the bulk of the obscuring dust and gas is located within a few to tens of parsecs of the accreting supermassive black hole (within the sphere of influence of the black hole), and that it can be swept away even at low radiative output rates. The main physical driver of the differences between obscured and unobscured accreting black holes is therefore their mass-normalized accretion rate.

Dosimetric potential of knowledge-based planning model trained with HyperArc plans for brain metastases.

OBJECTIVE: Dosimetric potential of knowledge-based RapidPlan planning model trained with HyperArc plans (Model-HA) for brain metastases has not been reported. We developed a Model-HA and compared its performance with that of clinical volumetric modulated arc therapy (VMAT) plans. METHODS: From 67 clinical stereotactic radiosurgery (SRS) HyperArc plans for brain metastases, 47 plans were used to build and train a Model-HA. The other 20 clinical HyperArc plans were recalculated in RapidPlan system with Model-HA. The model performance was validated with the 20 plans by comparing dosimetric parameters for normal brain tissue between clinical plans and model-generated plans. The 20 clinical conventional VMAT-based SRS or stereotactic radiotherapy plans (CL-VMAT) were reoptimized with Model-HA (RP) and HyperArc system (HA), respectively. The dosimetric parameters were compared among three plans (CL-VMAT vs. RP vs. HA) in terms of planning target volume (PTV), normal brain excluding PTVs (Brain - PTV), brainstem, chiasm, and both optic nerves. RESULTS: In model validation, the optimization performance of Model-HA was comparable to that of HyperArc system. In comparison to CL-VMAT, there were no significant differences among three plans with respect to PTV coverage (p > 0.17) and maximum dose for brainstem, chiasm, and optic nerves (p > 0.40). RP provided significantly lower V20 Gy , V12 Gy , and V4 Gy for Brain - PTV than CL-VMAT (p < 0.01). CONCLUSION: The Model-HA has the potential to significantly reduce the normal brain dose of the original VMAT plans for brain metastases.

Thymocyte Development of Humanized Mice Is Promoted by Interactions with Human-Derived Antigen Presenting Cells upon Immunization.

Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via the intra-bone marrow injection of CD133+ cord blood cells into irradiated adult immunodeficient mice (IBMI-huNSG mice), which could mount functional immune responses against HTLV-1, although the underlying mechanisms were still unknown. Here, we investigated thymocyte development in IBMI-huNSG mice, focusing on the roles of human and mouse MHC restriction. IBMI-huNSG mice had normal developmental profiles but aberrant thymic structures. Surprisingly, the thymic medulla-like regions expanded after immunization due to enhanced thymocyte expansion in association with the increase in HLA-DR+ cells, including CD205+ dendritic cells (DCs). The organ culture of thymus from immunized IBMI-huNSG mice with a neutralizing antibody to HLA-DR showed the HLA-DR-dependent expansion of CD4 single positive thymocytes. Mature peripheral T-cells exhibited alloreactive proliferation when co-cultured with human peripheral blood mononuclear cells. Live imaging of the thymus from immunized IBMI-huNSG mice revealed dynamic adhesive contacts of human-derived thymocytes and DCs accompanied by Rap1 activation. These findings demonstrate that an increase in HLA-DR+ cells by immunization promotes HLA-restricted thymocyte expansion in humanized mice, offering a unique opportunity to generate humanized mice with ease.

Rotaxane Synthesis by an End-Capping Strategy via Swelling Axle-Phenols.

A method for rotaxane synthesis by enlargement of the size of the terminal phenol group of the axle component by aromatic bromination has been developed. This method may be regarded as an end-capping strategy involving the swelling of the phenol group at the axle terminal. The advantages of the present strategy include: ready availability of axle components with a variety of swelling precursors, wide product scope (19 examples given including a [3]rotaxane), mild conditions for the swelling process, rich potential for the derivatization of the brominated rotaxanes, and possible release of the axle component by degradative dethreading of the thermally stable brominated rotaxanes under the basic conditions.

Practical Antibody Recruiting by Metabolic Labeling with Caged Glycans.

We propose a de novo glycan display approach that combines metabolic labeling and a glycan-caging strategy as a facile editing method for cell-surface glycans. This method enables the introduction of antigen glycans onto cancer cells to induce immune responses through antibody recruiting. The caging strategy prevents the capture of α-rhamnose (an antigen glycan) by endogenous antibodies during the introduction of the glycan to the targeted cell surface, and subsequent uncaging successfully induces immune responses. Therefore, this study proposes a practical method for editing the cell-surface glycocalyx under promiscuous conditions, such as those in vivo, which paves the way for the development of glycan function analysis and regulation.

Structural Determination and Chemical Synthesis of the N-Glycan from the Hyperthermophilic Archaeon Thermococcus kodakarensis.

Asparagine-linked protein glycosylations (N-glycosylations) are one of the most abundant post-translational modifications and are essential for various biological phenomena. Herein, we describe the isolation, structural determination, and chemical synthesis of the N-glycan from the hyperthermophilic archaeon Thermococcus kodakarensis. The N-glycan from the organism possesses a unique structure including myo-inositol, which has not been found in previously characterized N-glycans. In this structure, myo-inositol is highly glycosylated and linked with a disaccharide unit through a phosphodiester. The straightforward synthesis of this glycan was accomplished through diastereoselective phosphorylation and phosphodiester construction by SN 2 coupling. Considering the early divergence of hyperthermophilic organisms in evolution, this study can be expected to open the door to approaching the primitive function of glycan modification at the molecular level.

Self-assembly of tetravalent Goldberg polyhedra from 144 small components.

Rational control of the self-assembly of large structures is one of the key challenges in chemistry, and is believed to become increasingly difficult and ultimately impossible as the number of components involved increases. So far, it has not been possible to design a self-assembled discrete molecule made up of more than 100 components. Such molecules-for example, spherical virus capsids-are prevalent in nature, which suggests that the difficulty in designing these very large self-assembled molecules is due to a lack of understanding of the underlying design principles. For example, the targeted assembly of a series of large spherical structures containing up to 30 palladium ions coordinated by up to 60 bent organic ligands was achieved by considering their topologies. Here we report the self-assembly of a spherical structure that also contains 30 palladium ions and 60 bent ligands, but belongs to a shape family that has not previously been observed experimentally. The new structure consists of a combination of 8 triangles and 24 squares, and has the symmetry of a tetravalent Goldberg polyhedron. Platonic and Archimedean solids have previously been prepared through self-assembly, as have trivalent Goldberg polyhedra, which occur naturally in the form of virus capsids and fullerenes. But tetravalent Goldberg polyhedra have not previously been reported at the molecular level, although their topologies have been predicted using graph theory. We use graph theory to predict the self-assembly of even larger tetravalent Goldberg polyhedra, which should be more stable, enabling another member of this polyhedron family to be assembled from 144 components: 48 palladium ions and 96 bent ligands.

Repetitive patterns in rapid optical variations in the nearby black-hole binary V404 Cygni.

How black holes accrete surrounding matter is a fundamental yet unsolved question in astrophysics. It is generally believed that matter is absorbed into black holes via accretion disks, the state of which depends primarily on the mass-accretion rate. When this rate approaches the critical rate (the Eddington limit), thermal instability is supposed to occur in the inner disk, causing repetitive patterns of large-amplitude X-ray variability (oscillations) on timescales of minutes to hours. In fact, such oscillations have been observed only in sources with a high mass-accretion rate, such as GRS 1915+105 (refs 2, 3). These large-amplitude, relatively slow timescale, phenomena are thought to have physical origins distinct from those of X-ray or optical variations with small amplitudes and fast timescales (less than about 10 seconds) often observed in other black-hole binaries-for example, XTE J1118+480 (ref. 4) and GX 339-4 (ref. 5). Here we report an extensive multi-colour optical photometric data set of V404 Cygni, an X-ray transient source containing a black hole of nine solar masses (and a companion star) at a distance of 2.4 kiloparsecs (ref. 8). Our data show that optical oscillations on timescales of 100 seconds to 2.5 hours can occur at mass-accretion rates more than ten times lower than previously thought. This suggests that the accretion rate is not the critical parameter for inducing inner-disk instabilities. Instead, we propose that a long orbital period is a key condition for these large-amplitude oscillations, because the outer part of the large disk in binaries with long orbital periods will have surface densities too low to maintain sustained mass accretion to the inner part of the disk. The lack of sustained accretion--not the actual rate--would then be the critical factor causing large-amplitude oscillations in long-period systems.

Intra-fractional motion error during HyperArc stereotactic radiosurgery on patients with brain metastases: Comparison of open and full-face clamshell-style immobilization devices.

PURPOSE: To compare the intrafractional motion error (IME) during stereotactic irradiation (STI) in patients with brain metastases immobilized using open- (Encompass) and full-face (DSPS) clamshell-style immobilization devices. METHODS: Encompass (38 patients) and DSPS (38 patients) were used for patient immobilization, and HyperArc plans with three to four non-coplanar beams were generated to deliver 25 to 35 Gy in three to five fractions. Cone-beam computed tomography (CBCT) was performed on patients before and after the treatment. Moreover, the difference in patient position between the two CBCT images was considered as the IME. The margins to compensate for IME were calculated using the van Herk margin formula. RESULTS: For Encompass, the mean values of IME in the translational setup were 0.1, 0.2, and 0.0 mm in the anterior-posterior, superior-inferior, and left-right directions, respectively, and the mean values of IME about rotational axes were -0.1, 0.0, and 0.0° for the Pitch, Roll, and Yaw rotations, respectively. For DSPS, the mean values of IME in the translational setup were 0.2, 0.2, and 0.0 mm in the anterior-posterior, superior-inferior, and left-right directions, respectively, and the mean values of IME about rotational axes were -0.1, -0.1, and 0.0° for the Pitch, Roll, and Yaw rotations, respectively. No statistically significant difference was observed between the IME of the two immobilization systems except in the anterior-posterior direction (p = 0.02). Moreover, no statistically significant correlation was observed between three-dimensional IME and treatment time. The margin compensation for IME was less than 1 mm for both immobilization devices. CONCLUSIONS: The IME during STI using open- and full-face clamshell-style immobilization devices is approximately equal considering the adequate accuracy in patient positioning.

Improvement in bladder volume reproducibility using A-mode portable ultrasound bladder scanner in moderate-hypofractionated volumetric modulated arc therapy for prostate cancer patients.

PURPOSE: This study introduced an A-mode portable ultrasound bladder scanner, the Lilium® α-200 (here after Lilium; Lilium Otsuka, Kanagawa, Japan), for the treatment of prostate cancer patients with hypofractionated volumetric modulated arc therapy to improve the reproducibility of bladder volume (BV). MATERIALS AND METHODS: Thirty patients were advised to maintain full BV prior to computed tomography (CT) simulation and daily treatment. Among these, the BV of 15 patients was measured using Lilium until a BV of 80% in the simulation was achieved (with the Lilium group). Daily cone-beam CT (CBCT) was performed for treatment. The correlation between BV measured by CBCT and Lilium was assessed. The differences in the BV and dosimetric parameters of the bladder in the CBCT versus planning CT were compared between the groups with and without Lilium. RESULTS: There was a significantly strong relationship (r = 0.796, p < 0.05) between the BVs measured using CBCT and Lilium. The relative BV ratios to simulation CT < 0.5 and > 2 were observed in 10.3% and 12.7%, respectively, of treatment sessions without Lilium group, while these ratios were 1% and 2.8%, respectively, in the Lilium group. The mean absolute difference in the range of V30Gy to V40Gy without Lilium sessions was significantly larger (p < 0.05) than that in the Lilium group. CONCLUSION: The use of the A-mode portable ultrasound bladder scanner significantly improved the reproducibility of the BV, resulting in few variations in the dosimetric parameters for the bladder.

Assessment of using a gamma index analysis for patient-specific quality assurance in Japan.

PURPOSE: The Task Group 218 (TG-218) report was published by the American Association of Physicists in Medicine in 2018, recommending the appropriate use of gamma index analysis for patient-specific quality assurance (PSQA). The paper demonstrates that PSQA for radiotherapy in Japan appropriately applies the gamma index analysis considering TG-218. MATERIALS/METHODS: This survey estimated the acceptance state of radiotherapeutic institutes or facilities in Japan for the guideline using a web-based questionnaire. To investigate an appropriate PSQA of the facility-specific conditions, we researched an optimal tolerance or action level for various clinical situations, including different treatment machines, clinical policies, measurement devices, staff or their skills, and patient conditions. The responded data were analyzed using principal component analysis (PCA) and multidimensional scaling (MDS). The PCA focused on factor loading values of the first contribution over 0.5, whereas the MDS focused on mapped distances among data. RESULTS: Responses were obtained from 148 facilities that use intensity-modulated radiation therapy (IMRT), which accounted for 42.8% of the probable IMRT use in Japan. This survey revealed the appropriate application of the following universal criteria for gamma index analysis from the guideline recommendation despite the facility-specific variations (treatment machines/the number of IMRT cases/facility attributes/responded [representative] expertise or staff): (a) 95% pass rate, (b) 3% dose difference and 2-mm distance-to-agreement, and (c) 10% threshold dose. Conditions (a)-(c) were the principal components of the data by the PCA method and were mapped in a similar distance range, which was easily clustered from other gamma index analytic factors by the MDS method. Conditions (a)-(c) were the universally essential factors for the PSQA in Japan. CONCLUSION: We found that the majority of facilities using IMRT in each region of Japan complied with the guideline and conducted PSQA with deliberation under the individual facility-specific conditions.

Catalytic Substrate-Selective Silylation of Primary Alcohols via Remote Functional-Group Discrimination.

Silylation of alcohols has generally been known to take place at the sterically most accessible less-hindered hydroxy group. Herein, the catalyst-controlled substrate-selective silylation of primary alcohols, in which the selectivity was controlled independently of the innate reactivity of the hydroxy group, based on the steric environment, is reported. The chain-length-selective silylation of 1,n-amino alcohol derivatives was achieved and 1,5-amino alcohol derivatives showed outstandingly high reactivity in the presence of analogues with a shorter or longer chain length under catalyst-controlled conditions. A highly substrate-selective catalytic silylation of pentanol analogues was also developed, in which the remote functionality at C(5) from the reacting hydroxy groups was effectively discriminated on silylation.

Setup accuracy and dose attenuation of a wooden immobilization system for lung stereotactic body radiotherapy.

Background: We evaluated the setup error and dose absorption of an immobilization system with a shell and wooden baseplate (SW) for lung stereotactic body radiotherapy (SBRT). Materials and methods: Setup errors in 109 patients immobilized with an SW or BodyFix system (BF) were compared. Dose attenuation rates of materials for baseplates were measured with an ion-chamber. Ionization measurements were performed from 90° to 180° gantry angle in 10° increments, with the ball water equivalent phantom placed at the center of the wood and carbon baseplates whose effects on dose distribution were compared using an electron portal imaging device. Results: The ratio for the anterior-posterior, cranial-caudal, and right-left of the cases within 3-mm registered shifts in interfractional setup error were 90.9%, 89.2%, and 97.4% for the SW, and 93.2%, 91.6%, and 98.0% for the BF, respectively. For intrafractional setup error, 98.3%, 97.4%, and 99.1% for the SW and 96.6%, 95.8%, and 98.7% for the BF were within 3-mm registered shifts, respectively. In the center position, the average (minimum/maximum) dose attenuation rates from 90° to 180° for the wooden and carbon baseplates were 0.5 (0.1/2.8)% and 1.0 (-0.1/10.1)% with 6 MV, respectively. The gamma passing rates of 2%/2 mm for the wooden and carbon baseplates were 99.7% and 98.3% (p < 0.01). Conclusions: The immobilization system with an SW is effective for lung SBRT since it is comparable to the BF in setup accuracy. Moreover, the wooden baseplate had lower radiation attenuation rates and affected the dose distribution less than the carbon baseplate.

Seven-Step Stereodivergent Total Syntheses of Punicafolin and Macaranganin.

The first total syntheses of punicafolin (1) and macaranganin (2) were achieved in seven steps, respectively, from commercial α-d-glucose. The characteristic features of the synthesis are (1) sequential site-selective introduction of the adequate galloyl groups into unprotected d-glucose by a catalyst-controlled manner and (2) stereodivergent construction of the 3,6-HHDP bridge by oxidative phenol coupling of a common intermediate via a ring-flipping process of the glucose core. Because no protective groups were used for glucose throughout the process, extremely short-step total syntheses of natural glycosides 1 and 2 (MW 938) were performed.

A Third-Generation Adaptive Statistical Iterative Reconstruction for Contrast-Enhanced 4-Dimensional Dual-Energy Computed Tomography for Pancreatic Cancer.

OBJECTIVES: The objective of this study was to assess the objective and subjective qualities of the contrast-enhanced 4-dimensional dual-energy computed tomography using adaptive statistical iterative reconstruction (ASiR) and ASiR-V. METHODS: The virtual monochromatic images at 60 keV were reconstructed using filtered back projection, ASiR, and ASiR-V (10%-100%) for 14 patients with pancreatic cancer. The contrast-to-noise ratio (CNR) was calculated, and the subjective measurements were compared based on a 5-point score scale. RESULTS: The ASiR-V yielded a significantly higher CNR than ASiR (P < 0.05). The subjective image quality (peak) was significantly improved (P < 0.01) with ASiR (50%) (3.8, 3.5, and 4.0; overall image quality, tumor delineation, and noise, respectively) and with ASiR-V (50%) (3.9, 3.5, and 4.2, respectively) compared with the filtered back projection (3.2, 3.2, and 3.0, respectively). CONCLUSIONS: The ASiR-V yielded higher CNR than ASiR and provided the highest subjective scores regarding the overall image quality.

Site-Selective Molecular Transformation: Acylation of Hydroxy Groups and C-H Amination.

Control of site selectivity is an exciting direction for synthetic organic chemistry owing to the possibility of selective modification of multifunctionalized molecules, ultimately including biomacromolecules. In this review, our recent research related to site selectivity in two types of transformation, namely, the acylation of hydroxy groups and C-H amination, is summarized. Regarding the acylation of hydroxy groups, catalyst-controlled site selectivity enables unconventional retrosynthetic analysis, leading to efficient syntheses of sugar-related natural and unnatural products. Regarding C-H amination, the discovery of unprecedented reaction sites in intermolecular amination mediated by dirhodium nitrenes is described. The findings of this research demonstrate the power of site-selective transformation in the synthesis of a particular class of compounds.

Intra-fractional patient motion when using the Qfix Encompass immobilization system during HyperArc treatment of patients with brain metastases.

PURPOSE: This study investigated the intra-fractional motion (IM) of patients immobilized using the QFix Encompass Immobilization System during HyperArc (HA) treatment. METHOD: HA treatment was performed on 89 patients immobilized using the Encompass. The IM during treatment (including megavoltage (MV) registration) was analyzed for six degrees of freedom including three axes of translation (anterior-posterior, superior-inferior (SI) and left-right (LR)) and three axes of rotation (pitch, roll, and yaw). Then, the no corrected IM (IMNC ) was retrospectively simulated (excluding MV registration) in three directions (SI, LR, and yaw). Finally, the correlation between the treatment time and the IM of the 3D vector was assessed. RESULTS: The average IM in terms of the absolute displacement were 0.3 mm (SI), 0.3 mm (LR) and 0.2° (yaw) for Stereotactic radiosurgery (SRS), and 0.3 mm (SI), 0.2 mm (LR), and 0.2° (yaw) for stereotactic radiotherapy (SRT). The absolute maximum values of IM were <1 mm along the SI and LR axes and <1° along the yaw axis. The absolute maximum displacements for IMNC were >1 mm along the SI and LR axes and >1° along the yaw axis. In the correlation between the treatment time and the IM, the r-values were -0.025 and 0.027 for SRS and SRT respectively, along the axes of translation. For the axes of rotation, the r-values were 0.012 and 0.206 for SRS and SRT, respectively. CONCLUSION: Encompass provided patient immobilization with adequate accuracy during HA treatment. The absolute maximum displacement IM was less than IMNC along the translational/rotational axes, and no statistically significant relationship between the treatment time and the IM was observed.

An updating approach for knowledge-based planning models to improve plan quality and variability in volumetric-modulated arc therapy for prostate cancer.

PURPOSE: The purpose of this study was to compare the dose-volume parameters and regression scatter plots of the iteratively improved RapidPlan (RP) models, specific knowledge-based planning (KBP) models, in volumetric-modulated arc therapy (VMAT) for prostate cancer over three periods. METHODS: A RP1 model was created from 47 clinical intensity-modulated radiation therapy (IMRT)/VMAT plans. A RP2 model was created to exceed dosimetric goals which set as the mean values +1SD of the dose-volume parameters of RP1 (50 consecutive new clinical VMAT plans). A RP3 model was created with more strict dose constraints for organs at risks (OARs) than RP1 and RP2 models (50 consecutive anew clinical VMAT plans). Each RP model was validated against 30 validation plans (RP1, RP2, and RP3) that were not used for model configuration, and the dose-volume parameters were compared. The Cook's distances of regression scatterplots of each model were also evaluated. RESULTS: Significant differences (p < 0.05) between RP1 and RP2 were found in Dmean (101.5% vs. 101.9%), homogeneity index (3.90 vs. 4.44), 95% isodose conformity index (1.22 vs. 1.20) for the target, V40Gy (47.3% vs. 45.7%), V60Gy (27.9% vs. 27.1%), V70Gy (16.4% vs. 15.2%), and V78Gy (0.4% vs. 0.2%) for the rectal wall, and V40Gy (43.8% vs. 41.8%) and V70Gy (21.3% vs. 20.5%) for the bladder wall, whereas only V70Gy (15.2% vs. 15.8%) of the rectal wall differed significantly between RP2 and RP3. The proportions of cases with a Cook's distance of <1.0 (RP1, RP2, and RP3 models) were 55%, 78%, and 84% for the rectal wall, and 77%, 68%, and 76% for the bladder wall, respectively. CONCLUSIONS: The iteratively improved RP models, reflecting the clear dosimetric goals based on the RP feedback (dose-volume parameters) and more strict dose constraints for the OARs, generated superior dose-volume parameters and the regression scatterplots in the model converged. This approach could be used to standardize the inverse planning strategies.