Organ-contour-driven auto-matching algorithm in image-guided radiotherapy.

PURPOSE: This study aimed to demonstrate the potential clinical applicability of an organ-contour-driven auto-matching algorithm in image-guided radiotherapy. METHODS: This study included eleven consecutive patients with cervical cancer who underwent radiotherapy in 23 or 25 fractions. Daily and reference magnetic resonance images were converted into mesh models. A weight-based algorithm was implemented to optimize the distance between the mesh model vertices and surface of the reference model during the positioning process. Within the cost function, weight parameters were employed to prioritize specific organs for positioning. In this study, three scenarios with different weight parameters were prepared. The optimal translation and rotation values for the cervix and uterus were determined based on the calculated translations alone or in combination with rotations, with a rotation limit of ±3°. Subsequently, the coverage probabilities of the following two planning target volumes (PTV), an isotropic 5 mm and anisotropic margins derived from a previous study, were evaluated. RESULTS: The percentage of translations exceeding 10 mm varied from 9% to 18% depending on the scenario. For small PTV sizes, more than 80% of all fractions had a coverage of 80% or higher. In contrast, for large PTV sizes, more than 90% of all fractions had a coverage of 95% or higher. The difference between the median coverage with translational positioning alone and that with both translational and rotational positioning was 1% or less. CONCLUSION: This algorithm facilitates quantitative positioning by utilizing a cost function that prioritizes organs for positioning. Consequently, consistent displacement values were algorithmically generated. This study also revealed that the impact of rotational corrections, limited to ±3°, on PTV coverage was minimal.

Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes.

OBJECTIVE: The hepatic metabolism of six compounds newly synthesized as retinoid X receptor agonists was characterized in rat and human liver microsomes to examine the relationship between their hepatic metabolism profiles and side chain structures, considering the interspecies difference. MATERIALS AND METHODS: The compounds used have a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic or 6-[N-ethyl-N-(4-alkoxy-3-isopropylphenyl)amino]nicotinic acid skeleton, in which the isopropoxy, isobutoxy or cyclopropylmethoxy group is employed for the alkoxy group. These compounds were incubated with the microsomes, and their Michaelis--Menten parameters were determined. The incubation study was also performed with various cytochrome P450 (CYP) inhibitors to examine their susceptibilities to the inhibitors. In addition, a molecular docking simulation was conducted to assess the compound's spatial configuration with the CYP isoform when necessary. RESULTS: The Michaelis--Menten parameters determined are comparable between rats and humans for the compounds having 3-isobutoxy, 4-isobutoxy, 4-isopropoxy and 4-cyclopropylmethoxy groups. However, it was indicated that all compounds except that having the 3-isobutoxy group are metabolized in a different manner between rats and humans. That is, the extent of the contribution of each CYP isozyme is different between those two species. A molecular docking simulation showed that the spatial configuration of the compound to be associated with CYP2D6 markedly changes depending on whether the isobutoxy group is situated at the 3- or 4-position. CONCLUSION: A slight difference in the side chain structures markedly alters the compound's metabolic profile, which amplifies the interspecies difference regarding the profile, increasing the difficulty in characterizing the profile in humans with the structural-property relationship and interspecies extrapolation.

Small-field dosimetry with detector-specific output correction factor for single-isocenter stereotactic radiotherapy of single and multiple brain metastases.

Recently, the International Atomic Energy Agency and the American Association of Physicists in Medicine reported correction factors (CFs) for detector-response variation considering the uncertainty in detector readings in small-field dosimetry. In this study, the effect of CFs on small-field dosimetry measurements was evaluated for single-isocenter stereotactic radiotherapy for brain metastases. The output factors (OPFs) were measured with and without CFs in a water-equivalent sphere phantom using TrueBeam with a flattening-filter-free energy of 10 MV. Five detectors were used in a perpendicular orientation: CC01, 3D pinpoint ionization chambers, unshielded SFD detector, shielded EDGE detector, and microDiamond detector. First, the square-field sizes were set to 5-100 mm using a multi-leaf collimator (MLC) field. The OPFs were evaluated in the presence and absence of CFs. Second, single-isocenter stereotactic irradiation was performed on 22 brain metastases in 15 patients following dynamic conformal arc (DCA) treatment. The equivalent field size was calculated using the MLC aperture for each planning target volume. For the OPFs, the mean deviations from the median of the doses measured with detectors other than the CC01 for square-field sizes larger than 10 mm were within ± 4.3% of the median without CFs, and ± 3.3% with CFs. For DCA plans, the deviations without and with CFs were - 2.3 ± 1.9% and - 4.8 ± 2.4% for CC01, - 1.1 ± 3.0% and 1.0 ± 1.6% for 3D pinpoint, 8.8 ± 3.0% and 2.9 ± 2.8% for SFD, - 3.1 ± 3.0% and - 13.5 ± 4.0% for EDGE, and 8.9 ± 2.1% and 0.8 ± 1.9% for microDiamond. This feasibility study confirmed that the deviation of the detectors can be reduced using an appropriate detector with CFs.

Applicability evaluation of the TRS-483 protocol for the determination of small-field output factors using different multi-leaf collimator and field-shaping types.

PURPOSE: To evaluate the applicability of TRS-483 output correction factors (CFs) for small-field output factors (OFs) using different multi-leaf collimators (MLC) and field-shaping types. METHODS: All measurements were performed on TrueBeam, TrueBeam STx, and Halcyon using 6 MV flattening filter-free energy. Four detectors, including CC01, CC04, microDiamond, and EDGE, were used. Nominal field sizes ranging from 1 × 1 to 4 × 4, and 10 × 10 cm2 were used to measure small-field OFs at source-to-axis distance of 100 cm with a 0° gantry angle in a 3D water phantom. Further, the field-shaping types were defined using jaw collimator or MLC (five different configurations). A field size of 10 × 10 cm2 was used as the reference for calculation of OFs obtained as ratio of detector readings (OFdet). The percentage difference and coefficient of variation of OFdet and OFdet corrected by applying CF were compared for each field size and configuration. RESULTS: For OFdet corrected by applying CF, the ranges of percentage difference and coefficient of variation in all configurations for ≥ 2 × 2 cm2 fields were reduced from 1.2-2.2 to 0.8-1.3 percentage points (%pt) and from 0.5-1.0 to 0.4-0.7%, respectively. For 1 × 1 cm2 field, the ranges of percentage difference and coefficient of variation were reduced from 3.3-5.7 to 1.2-2.2 %pt and from 2.2-3.7 to 0.8-1.1%, respectively. CONCLUSIONS: The CFs described in TRS-483 dosimetry protocol have broad applicability in reducing OF variations between detectors under different MLC and field-shaping types.

Effect of angular dependence for small-field dosimetry using seven different detectors.

BACKGROUND: Small-field dosimetry is challenging for radiotherapy dosimetry because of the loss of lateral charged equilibrium, partial occlusion of the primary photon source by the collimating devices, perturbation effects caused by the detector materials and their design, and the detector size relative to the radiation field size, which leads to a volume averaging effect. Therefore, a suitable tool for small-field dosimetry requires high spatial resolution, tissue equivalence, angular independence, and energy and dose rate independence to achieve sufficient accuracy. Recently, with the increasing use of combinations of coplanar and non-coplanar beams for small-field dosimetry, there is a need to clarify angular dependence for dosimetry where the detector is oriented at various angles to the incident beam. However, the effect of angular dependence on small-field dosimetry with coplanar and non-coplanar beams has not been fully clarified. PURPOSE: This study clarified the effect of angular dependence on small-field dosimetry with coplanar and non-coplanar beams using various detectors. METHODS: Seven different detectors were used: CC01, RAZOR, RAZOR Nano, Pinpoint 3D, stereotactic field diode (SFD), microSilicon, and microDiamond. All measurements were taken using a TrueBeam STx with 6 MV and 10 MV flattening filter-free (FFF) energies using a water-equivalent spherical phantom with a source-to-axis distance of 100 cm. The detector was inserted in a perpendicular orientation, and the gantry was rotated at 15° increments from the incidence beam angle. A multi-leaf collimator (MLC) with four field sizes of 0.5 × 0.5, 1 × 1, 2 × 2, and 3 × 3 cm2 , and four couch angles from 0°, 30°, 60°, and 90° (coplanar and non-coplanar) were adopted. The angular dependence response (AR) was defined as the ratio of the detector response at a given irradiation gantry angle normalized to the detector response at 0°. The maximum AR differences were calculated between the maximum and minimum AR values for each detector, field size, energy, and couch angle. RESULTS: The maximum AR difference for the coplanar beam was within 3.3% for all conditions, excluding the maximum AR differences in 0.5 × 0.5 cm2 field for CC01 and RAZOR. The maximum AR difference for non-coplanar beams was within 2.5% for fields larger than 1 × 1 cm2 , excluding the maximum AR differences for RAZOR Nano, SFD, and microSilicon. The Pinpoint 3D demonstrated stable AR tendencies compared to other detectors. The maximum difference was within 2.0%, except for the 0.5 × 0.5 cm2 field and couch angle at 90°. The tendencies of AR values for each detector were similar when using different energies. CONCLUSION: This study clarified the inherent angular dependence of seven detectors that were suitable for small-field dosimetry. The Pinpoint 3D chamber had the smallest angular dependence of all detectors for the coplanar and non-coplanar beams. The findings of this study can contribute to the calculation of the AR correction factor, and it may be possible to adapt detectors with a large angular dependence on coplanar and non-coplanar beams. However, note that the gantry sag and detector-specific uncertainties increase as the field size decreases.

Evaluation of newly implemented dose calculation algorithms for multileaf collimator-based CyberKnife tumor-tracking radiotherapy.

PURPOSE: In the previous treatment planning system (TPS) for CyberKnife (CK), multileaf collimator (MLC)-based treatment plans could be created only by using the finite-size pencil beam (FSPB) algorithm. Recently, a new TPS, including the FSPB with lateral scaling option (FSPB+) and Monte Carlo (MC) algorithms, was developed. In this study, we performed basic and clinical end-to-end evaluations for MLC-based CK tumor-tracking radiotherapy using the MC, FSPB+, and FSPB. METHODS: Water- and lung-equivalent slab phantoms were combined to obtain the percentage depth dose (PDD) and off-center ratio (OCR). The CK M6 system and Precision TPS were employed, and PDDs and OCRs calculated by the MC, FSPB+, and FSPB were compared with the measured doses obtained for 30.8 × 30.8 mm2 and 60.0 × 61.6 mm2 fields. A lung motion phantom was used for clinical evaluation and MLC-based treatment plans were created using the MC. The doses were subsequently recalculated using the FSPB+ and FSPB, while maintaining the irradiation parameters. The calculated doses were compared with the doses measured using a microchamber (for target doses) or a radiochromic film (for dose profiles). The dose volume histogram (DVH) indices were compared for all plans. RESULTS: In homogeneous and inhomogeneous phantom geometries, the PDDs calculated by the MC and FSPB+ agreed with the measurements within ±2.0% for the region between the surface and a depth of 250 mm, whereas the doses calculated by the FSPB in the lung-equivalent phantom region were noticeably higher than the measurements, and the maximum dose differences were 6.1% and 4.4% for the 30.8 × 30.8 mm2 and 60.0 × 61.6 mm2 fields, respectively. The maximum distance to agreement values of the MC, FSPB+, and FSPB at the penumbra regions of OCRs were 1.0, 0.6, and 1.1 mm, respectively, but the best agreement was obtained between the MC-calculated curve and measurements at the boundary of the water- and lung-equivalent slabs, compared with those of the FSPB+ and FSPB. For clinical evaluations using the lung motion phantom, under the static motion condition, the dose errors measured by the microchamber were -1.0%, -1.9%, and 8.8% for MC, FSPB+, and FSPB, respectively; their gamma pass rates for the 3%/2 mm criterion comparing to film measurement were 98.4%, 87.6%, and 31.4% respectively. Under respiratory motion conditions, there was no noticeable decline in the gamma pass rates. In the DVH indices, for most of the gross tumor volume and planning target volume, significant differences were observed between the MC and FSPB, and between the FSPB+ and FSPB. Furthermore, significant differences were observed for lung Dmean , V15 Gy , and V20 Gy between the MC, FSPB+, and FSPB. CONCLUSIONS: The results indicate that the doses calculated using the MC and FSPB+ differed remarkably in inhomogeneous regions, compared with the FSPB. Because the MC was the most consistent with the measurements, it is recommended for final dose calculations in inhomogeneous regions such as the lung. Furthermore, the sufficient accuracy of dose delivery using MLC-based tumor-tracking radiotherapy by CK was demonstrated for clinical implementation.

RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.

Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid and structural development to increase potency.

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists.

Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.

We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).