Fully automated volumetric modulated arc therapy planning for locally advanced rectal cancer: feasibility and efficiency.

BACKGROUND: Volumetric modulated arc therapy (VMAT) for locally advanced rectal cancer (LARC) has emerged as a promising technique, but the planning process can be time-consuming and dependent on planner expertise. We aimed to develop a fully automated VMAT planning program for LARC and evaluate its feasibility and efficiency. METHODS: A total of 26 LARC patients who received VMAT treatment and the computed tomography (CT) scans were included in this study. Clinical target volumes and organs at risk were contoured by radiation oncologists. The automatic planning program, developed within the Raystation treatment planning system, used scripting capabilities and a Python environment to automate the entire planning process. The automated VMAT plan (auto-VMAT) was created by our automated planning program with the 26 CT scans used in the manual VMAT plan (manual-VMAT) and their regions of interests. Dosimetric parameters and time efficiency were compared between the auto-VMAT and the manual-VMAT created by experienced planners. All results were analyzed using the Wilcoxon signed-rank sum test. RESULTS: The auto-VMAT achieved comparable coverage of the target volume while demonstrating improved dose conformity and uniformity compared with the manual-VMAT. V30 and V40 in the small bowel were significantly lower in the auto-VMAT compared with those in the manual-VMAT (p < 0.001 and < 0.001, respectively); the mean dose of the bladder was also significantly reduced in the auto-VMAT (p < 0.001). Furthermore, auto-VMAT plans were consistently generated with less variability in quality. In terms of efficiency, the auto-VMAT markedly reduced the time required for planning and expedited plan approval, with 93% of cases approved within one day. CONCLUSION: We developed a fully automatic feasible VMAT plan creation program for LARC. The auto-VMAT maintained target coverage while providing organs at risk dose reduction. The developed program dramatically reduced the time to approval.

Isolation and identification of the new baicalin target protein to develop flavonoid structure-based therapeutic agents.

Proteins are vital constituents of all living organisms. As many therapeutic agents alter the activity of functional proteins, identifying functional target proteins of small bioactive molecules isessential for the rational design of stronger medicines. Flavonoids with antioxidant, anti-allergy, and anti-inflammatory effects are expected to have preventive effects for several diseases closely related to oxidation and inflammation, including heart disease, cancer, neurodegenerative disorders, and eye diseases. Therefore, identifying the proteins involved in the pharmacological actions of flavonoids, and designing a flavonoid structure-based medicine that strongly and specifically inhibits flavonoid target proteins, could aid the development of more effective medicines for treating heart disease, cancer, neurodegenerative disorders, and ocular diseases with few side effects. To isolate the flavonoid target protein, we conducted a novel affinity chromatography in a column wherein baicalin, a representative flavonoid, was attached to Affi-Gel 102. Through affinity chromatography and nano LC-MS/MS, we identified GAPDH as a flavonoid target protein. Then, we performed fluorescence quenching and an enzyme inhibition assay to experimentally confirmbaicalin's binding affinity for, and inhibition of, GAPDH. We also conducted in silico docking simulations to visualize the binding modes of baicalin and the newly identified flavonoid target protein, GAPDH. From the results of this study, it was considered that one of the reasons why baicalin exhibits the effects on cancer and neurodegenerative diseases is that it inhibits the activity of GAPDH. In summary, we showed that Affi-Gel102 could quickly and accurately isolate the target protein for bioactive small molecules, without the need for isotopic labeling or a fluorescent probe. By using the method presented here, it was possible to easily isolate the target protein of a medicine containing a carboxylic acid.

Synthesis and properties of PNA containing a dicationic nucleobase based on N4-benzoylated cytosine.

We report the synthesis of a peptide nucleic acid (PNA) monomer containing N4-bis(aminomethyl)benzoylated cytosine (BzC2+ base). The BzC2+ monomer was incorporated into PNA oligomers using Fmoc-based solid-phase synthesis. The BzC2+ base in PNA had two positive charges and exhibited greater affinity for DNA G base than the natural C base. The BzC2+ base stabilized PNA-DNA heteroduplexes through electrostatic attractions, even in high salt conditions. The two positive charges on the BzC2+ residue did not compromise the sequence specificity of PNA oligomers. These insights will aid the future design of cationic nucleobases.

Impact of Anatomical Position Errors on Dose Distribution in Head and Neck Radiotherapy and Robust Image Registration Against Anatomical Changes.

BACKGROUND/AIM: This study pursued two goals: Firstly, to search for anatomical structures strongly correlating with dose deterioration, and secondly to investigate the effectiveness of image registration focusing on critical anatomy by comparing it with a conventional method. The aim was to achieve robust image registration to correct for anatomical changes during treatment. PATIENTS AND METHODS: Twenty patients with head and neck cancer were enrolled, and 68 simulation computed tomography (CT) and rescan CT image sets were retrospectively analyzed. Forty volumetric-modulated arc therapy and intensity-modulated proton therapy plans were generated and recalculated according to the rescan CT to evaluate the dose effects of anatomical changes. Correlation coefficients were calculated for the relationships between the six-axis motion of the anatomy and the dose indices for the clinical target volume (CTV) and organs at risk. In the image registration, we compared a conventional method and target-based registration that limited the registration range to the CTV and vertebrae. RESULTS: The CTV coverage and spinal cord dose were correlated with the position error associated with the pitch and vertical position of the vertebrae, and the parotid gland and oral cavity dose were strongly correlated with the position error associated with the roll of the clivus and mandible. The target registration improved CTV coverage and suppressed the increase in dose to organs at risk compared with conventional methods. CONCLUSION: Monitoring vertebral alignment, the assessment and correction of positioning errors associated with the clivus and mandible position errors are important to ensure the quality of daily treatment. Target-based registration may allow for more robust image registration.

Evaluation of the four-dimensional motion of lung tumors during end-exhalation breath-hold conditions using volumetric cine computed tomography images.

BACKGROUND AND PURPOSE: This study was performed to evaluate the four-dimensional motion of lung tumors during end-exhalation (EE) breath-holding (BH) using cine computed tomography (CT) and investigate the correlation between tumor and surrogate marker motions. MATERIALS AND METHODS: This study included 28 patients who underwent stereotactic body radiation therapy at our institution and were capable of 15-20 s of EE BH within a ±1.5-mm gating window with external markers. During EE BH with cine CT, 21 s of continuous data were acquired using 320-row multislice CT. Displacements in the tumor position during EE BH were assessed in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions. Pearson's correlation coefficient (r) between tumor motions during EE BH and diaphragm/external marker motions was also determined. RESULTS: The mean absolute maximum displacements of the tumor position during EE BH were 1.3 (range: 0.2-4.0), 1.9 (range: 0.3-12.0), and 1.3 (range: 0.1-7.2) mm in the LR, AP, and SI directions, respectively. The displacement of the tumor position in the AP direction was weakly correlated (|r| < 0.4) with the external marker and diaphragm displacements in many cases (proportions of 50% and 46%, respectively). CONCLUSION: We found some cases showing substantial displacement in lung tumor positions during EE BH, especially in the AP direction. Because these tumor position displacements did not correlate with surrogate markers and were difficult to detect, we recommend pretreatment evaluation of the four-dimensional motions of tumors during BH using cine CT.

Explainability and controllability of patient-specific deep learning with attention-based augmentation for markerless image-guided radiotherapy.

BACKGROUND: We reported the concept of patient-specific deep learning (DL) for real-time markerless tumor segmentation in image-guided radiotherapy (IGRT). The method was aimed to control the attention of convolutional neural networks (CNNs) by artificial differences in co-occurrence probability (CoOCP) in training datasets, that is, focusing CNN attention on soft tissues while ignoring bones. However, the effectiveness of this attention-based data augmentation has not been confirmed by explainable techniques. Furthermore, compared to reasonable ground truths, the feasibility of tumor segmentation in clinical kilovolt (kV) X-ray fluoroscopic (XF) images has not been confirmed. PURPOSE: The first aim of this paper was to present evidence that the proposed method provides an explanation and control of DL behavior. The second purpose was to validate the real-time lung tumor segmentation in clinical kV XF images for IGRT. METHODS: This retrospective study included 10 patients with lung cancer. Patient-specific and XF angle-specific image pairs comprising digitally reconstructed radiographs (DRRs) and projected-clinical-target-volume (pCTV) images were calculated from four-dimensional computer tomographic data and treatment planning information. The training datasets were primarily augmented by random overlay (RO) and noise injection (NI): RO aims to differentiate positional CoOCP in soft tissues and bones, and NI aims to make a difference in the frequency of occurrence of local and global image features. The CNNs for each patient-and-angle were automatically optimized in the DL training stage to transform the training DRRs into pCTV images. In the inference stage, the trained CNNs transformed the test XF images into pCTV images, thus identifying target positions and shapes. RESULTS: The visual analysis of DL attention heatmaps for a test image demonstrated that our method focused CNN attention on soft tissue and global image features rather than bones and local features. The processing time for each patient-and-angle-specific dataset in the training stage was ∼30 min, whereas that in the inference stage was 8 ms/frame. The estimated three-dimensional 95 percentile tracking error, Jaccard index, and Hausdorff distance for 10 patients were 1.3-3.9 mm, 0.85-0.94, and 0.6-4.9 mm, respectively. CONCLUSIONS: The proposed attention-based data augmentation with both RO and NI made the CNN behavior more explainable and more controllable. The results obtained demonstrated the feasibility of real-time markerless lung tumor segmentation in kV XF images for IGRT.

Image preprocessing to improve the accuracy and robustness of mutual-information-based automatic image registration in proton therapy.

PURPOSE: We propose a method that potentially improves the outcome of mutual-information-based automatic image registration by using the contrast enhancement filter (CEF). METHODS: Seventy-six pairs of two-dimensional X-ray images and digitally reconstructed radiographs for 20 head and neck and nine lung cancer patients were analyzed retrospectively. Automatic image registration was performed using the mutual-information-based algorithm in VeriSuite®. Images were preprocessed using the CEF in VeriSuite®. The correction vector for translation and rotation error was calculated and manual image registration was compared with automatic image registration, with and without CEF. In addition, the normalized mutual information (NMI) distribution between two-dimensional images was compared, with and without CEF. RESULTS: In the correction vector comparison between manual and automatic image registration, the average differences in translation error were < 1 mm in most cases in the head and neck region. The average differences in rotation error were 0.71 and 0.16 degrees without and with CEF, respectively, in the head and neck region; they were 2.67 and 1.64 degrees, respectively, in the chest region. When used with oblique projection, the average rotation error was 0.39 degrees with CEF. CEF improved the NMI by 17.9 % in head and neck images and 18.2 % in chest images. CONCLUSIONS: CEF preprocessing improved the NMI and registration accuracy of mutual-information-based automatic image registration on the medical images. The proposed method achieved accuracy equivalent to that achieved by experienced therapists and it will significantly contribute to the standardization of image registration quality.

Detection of anatomical changes using two-dimensional x-ray images for head and neck adaptive radiotherapy.

PURPOSE: To develop a system for detecting anatomical changes using two-dimensional (2D) x-ray images. METHODS: Ten patients with head and neck cancer were retrospectively analyzed using 2D x-ray and cone-beam computed tomography (CBCT) images. The 2D x-ray images were acquired daily, whereas the CBCT images were acquired weekly during the treatment period. The developed system imported the 2D x-ray images obtained on the initial treatment day and on another day, and thereafter converted them into the water equivalent thickness (WET) using the conversion table. The difference between the WET images for the first and other treatment days (ΔWET) was calculated as the quantitative value for anatomical changes and visualized to recognize the anatomical change location. We compared ΔWET and the difference in the lateral neck distance (ΔLND) on the corresponding CBCT images. ΔLND was used as the ground truth for anatomical changes. ΔWET and ΔLND were measured at the first cervical vertebra (C1) and the tumor center (TC). C1 and TC were selected to observe the volume changes in the parotid gland and tumor, respectively. Sensitivity and specificity were calculated to evaluate the performance of the 2D-WET system. The cut-off values of WET and LND were set to 2-10 mm. Furthermore, intensity-modulated proton therapy (IMPT) plans for six patients with rescan CT images were generated. The IMPT plans on the rescan CT images were compared to the original plans on simulation CT using the dosimetric parameters for the target and the organs at risk. RESULTS: The mean differences between ΔWET and ΔLND for C1 and TC were -0.62 ± 1.66 mm and -0.93 ± 1.28 mm (mean ± 1 SD), respectively. ΔWET in the proposed system was in good agreement with ΔLND using the CBCT images. In the sensitivity and specificity results for C1 and TC with cut-off values from 2 to 10 mm, the sensitivity was >85% for all cut-off values, while the specificity was >90% at 5-10 mm and <90% at less than 5 mm. The average ΔWET at the time of replanning was 12.8 mm which resulted in maximum dose increase in the spinal cord D1cc by 8.4 Gy, the parotid gland D50 by 26.6 Gy, and the oral cavity D50 by 23.2 Gy. CONCLUSIONS: We developed a new system for detecting anatomical changes using 2D x-ray images. The developed system with ΔWET showed an agreement with ΔLND at C1 and TC with an average difference of less than 1 mm. ΔWET detected anatomical changes with high sensitivity and specificity with a cut-off value of 5-10 mm. This system can monitor daily anatomical changes without causing high exposure to patients and requiring any inefficient work, and it can be applied to daily online adaptive proton beam therapy and triggered adaptive radiotherapy.

Synthesis and characterization of PNA oligomers containing preQ1 as a positively charged guanine analogue.

We report the synthesis of a peptide nucleic acid (PNA) monomer containing preQ1, a positively charged guanine analogue. The new monomer was incorporated into PNA oligomers using standard Fmoc-chemistry-based solid-phase synthesis. The preQ1 unit-containing PNA oligomers exhibited improved affinity for their complementary DNA through electrostatic attraction, and their sequence specificity was not compromised. It could be beneficial to incorporate preQ1 into PNA oligomers instead of guanine when creating antisense/antigene agents or research tools.

Differentiation of Positional Isomers of Halogenated Benzoylindole Synthetic Cannabinoid Derivatives in Serum by Hybrid Quadrupole/Orbitrap Mass Spectrometry.

Legally regulated synthetic cannabinoids (SCs) are continuously being created by making minor positional modifications to pre-existing analogs; thus, compounds with minor structural differences must be isolated and identified accurately. For iodo-benzoylindole derivatives of SCs, only specific isomers are currently the target of legal control, and it is necessary to establish an analytical method for accurately identifying positional isomers. In this study, we synthesized a series of 57 designer drugs and developed a screening method for identifying halogen positional isomers on the phenyl ring of benzoylindole derivative SCs in serum. Analytical methods using the Discovery F5 pentafluorophenyl column gave the best selectivity and retention of the positional isomer analytes. Some of the meta and para iodo-substituted SCs were eluted at similar retention times and were difficult to separate by liquid chromatography (LC). However, they were identified via the relative abundance of the two product ions in the collision-induced dissociation reaction using LC-hybrid quadrupole/orbitrap high-resolution mass spectrometry. Our synthesized halogen-substituted positional isomer SC library and method for differentiating positional isomers of halogenated benzoylindole SC derivatives could provide an indispensable analysis tool for identifying illegal drugs in serum of drug users.

Feasibility of image quality improvement for high-speed CBCT imaging using deep convolutional neural network for image-guided radiotherapy in prostate cancer.

PURPOSE: High-speed cone-beam computed tomography (CBCT) scan for image-guided radiotherapy (IGRT) can reduce both the scan time and the exposure dose. However, it causes noise and artifacts in the reconstructed images due to the lower number of acquired projection data. The purpose of this study is to improve the image quality of high-speed CBCT using a deep convolutional neural network (DCNN). METHODS: CBCT images of 36 prostate cancer patients were selected. The CBCT images acquired at normal scan speed were defined as CBCT100%. Simulated high-speed CBCT images acquired at twofold and fourfold scan speed were created, which were defined as CBCT50% and CBCT25%, respectively. The image quality of the CBCT50% was treated as the requirement for IGRT in this study because previous studies reported that its image is sufficient with respect to IGRT. The DCNN model was trained to learn direct mapping from CBCT25% to the corresponding CBCT100%. The performance of the DCNN model was evaluated using the sixfold cross-validation method. CBCT images generated by DCNN (CBCT25%+DCNN) were evaluated for voxel value accuracy and image quality. RESULTS: The DCNN model can process CBCT25% of a new patient within 0.06 s/slice. The CBCT25%+DCNN was comparable to the CBCT50% in terms of both voxel value accuracy and image quality. CONCLUSIONS: We developed a DCNN model to remove noise and artifacts from high-speed CBCT. We emphasize that it is possible to reduce exposure to one quarter and to increase the CBCT scan speed by a factor of four.

ESI-Q-TOF-MS determination of polyamines and related enzyme activity for elucidating cellular polyamine metabolism.

We developed a new procedure for the comprehensive analysis of metabolites and enzymes involved in polyamine metabolism pathways. The procedure utilizes stable isotope-labeled polyamines and directly and precisely determines labeled products from enzymatic reactions by ESI-Q-TOF-MS. The activity of different enzymes could be determined in essentially the same manner by suitably adjusting the reaction conditions for each individual enzyme. We applied the procedure to extracts of regenerating rat liver and analyzed the changes in polyamine-metabolizing enzymes and polyamine contents during recovery from partial hepatectomy. A general outline of polyamine metabolism and information of polyamine dynamics were obtained. This kind of comprehensive information would be valuable in unifying detailed but fragmentary information obtained through conventional analyses focusing on one or a few enzymes and on a limited aspect of polyamine metabolic pathway.

Proteomic analysis revealed different responses to hypergravity of soleus and extensor digitorum longus muscles in mice.

Investigating protein abundance profiles is important to understand the differences in the slow and fast skeletal muscle characteristics. The profiles in soleus (Sol) and extensor digitorum longus (EDL) muscles in mice exposed to 1 g or 3 g for 28 d were compared. The biological implications of the profiles revealed that hypergravity exposure activated a larger number of pathways involved in protein synthesis in Sol. In contrast, the inactivation of signalling pathways involved in oxidative phosphorylation were conspicuous in EDL. These results suggested that the reactivity of molecular pathways in Sol and EDL differed. Additionally, the levels of spermidine synthase and spermidine, an important polyamine for cell growth, increased in both muscles following hypergravity exposure, whereas the level of spermine oxidase (SMOX) increased in EDL alone. The SMOX level was negatively correlated with spermine content, which is involved in muscle atrophy, and was higher in EDL than Sol, even in the 1 g group. These results indicated that the contribution of SMOX to the regulation of spermidine and spermine contents in Sol and EDL differed. However, contrary to expectations, the difference in the SMOX level did not have a significant impact on the growth of these muscles following hypergravity exposure. SIGNIFICANCE: The skeletal muscle-specific protein abundance profiles result in differences in the characteristics of slow and fast skeletal muscles. We investigated differences in the profiles in mouse slow-twitch Sol and fast-twitch EDL muscles following 28-d of 1 g and 3 g exposure by LC-MS/MS analysis and label-free quantitation. A two-step solubilisation of the skeletal muscle proteins increased the coverage of proteins identified by LC-MS/MS analysis. Additionally, this method reduced the complexity of samples more easily than protein or peptide fractionation by SDS-PAGE and offline HPLC while maintaining the high operability of samples and was reproducible. A larger number of hypergravity-responsive proteins as well as a prominent increase in the wet weights was observed in Sol than EDL muscles. The biological implications of the difference in the protein abundance profiles in 1 g and 3 g groups revealed that the reactivity of each molecular pathway in Sol and EDL muscles to hypergravity exposure differed significantly. In addition, we found that the biosynthetic and interconversion pathway of polyamines, essential factors for cell growth and survival in mammals, was responsive to hypergravity exposure; spermidine and spermine contents in Sol and EDL muscles were regulated by different mechanisms even in the 1 g group. However, our results indicated that the difference in the mechanism regulating polyamine contents is unlikely to have a significant effect on the differences in Sol and EDL muscle growth following hypergravity exposure.

Range optimization for target and organs at risk in dynamic adaptive passive scattering proton beam therapy - A proof of concept.

PURPOSE: The purpose of this study was to design and develop a new range optimization for target and organs at risk (OARs) in dynamic adaptive proton beam therapy (PBT). METHODS: The new range optimization for target and OARs (RO-TO) was optimized to maintain target dose coverage but not to increase the dose exposure of OARs, while the other procedure, range optimization for target (RO-T), only focused on target dose coverage. A retrospective analysis of a patient who received PBT for abdominal lymph node metastases was performed to show the effectiveness of our new approach. The original plan (OP), which had a total dose of 60 Gy (relative biological effectiveness; RBE), was generated using six treatment fields. Bone-based registration (BR) and tumor-based registration (TR) were performed on each pretreatment daily CT image dataset acquired once every four fractions, to align the isocenter. RESULTS: Both range adaptive approaches achieved better coverage (D95%) and homogeneity (D5%-D95%) than BR and TR only. However, RO-T showed the greatest increases in D2cc and Dmean values of the small intestine and stomach and exceeded the limitations of dose exposure for those OARs. RO-TO showed comparable or superior dose sparing compared with the OP for all OARs. CONCLUSIONS: Our results suggest that BR and TR alone may reduce target dose coverage, and that RO-T may increase the dose exposure to the OARs. RO-TO may achieve the planned dose delivery to the target and OARs more efficiently than the OP. The technique requires testing on a large clinical dataset.

Impact of shoulder deformation on volumetric modulated arc therapy doses for head and neck cancer.

PURPOSE: When using volumetric modulated arc therapy (VMAT) for head and neck cancer, setup errors regarding the shoulders can create loss of target coverage or increased organ-at-risk doses. This study created variations of realistic shoulder deformations to understand the associated VMAT dosimetric effects and investigated water-equivalent thickness (WET) differences using in-house software. METHODS: Ten patients with head and neck cancer with lower neck involvement were retrospectively and randomly enrolled. Their retrospective analysis comprised treatment planning using RayStation 5.0 (RaySearch Laboratories, Stockholm, Sweden), shoulder deformation of 5-15 mm in three-dimensional axes using the ImSimQA package (Oncology Systems Limited, Shrewsbury, Shropshire, UK), and evaluation of the clinical impact of the dose distribution after recalculating the dose distribution using computed tomography images of deformed shoulders and deforming the dose distribution. Additionally, our in-house software program was used to measure WET differences for shoulder deformation. RESULTS: WET differences were greater in the superoinferior (SI) direction than in the other directions (the WET difference was >20 mm for 15-mm SI deformation). D99%, D98%, and D95% for all clinical target volumes were within 3%. Local dose differences of more than ±10% were found for normal tissues at the level of the shoulder for 15-mm movement in the SI direction. CONCLUSIONS: Shoulder deformation of >6 mm could cause large dose variations delivered to the targeted tissue at the level of the shoulder. Thus, to ensure delivery of appropriate treatment coverage to the targeted tissue, shoulder deformation should be taken into consideration during the planning stage.

Evaluation of deformation parameters for deformable image registration-based ventilation imaging using an air-ventilating non-rigid phantom.

PURPOSE: This study aimed to evaluate different deformable image registration (DIR) parameters for the open-source NiftyReg package in its application to DIR-based ventilation imaging. METHODS: Two three-dimensional (3D)-computed tomography (CT) scans of a non-rigid air-ventilating phantom were acquired at peak exhalation and peak inhalation, with xenon (Xe) gas being used as an air-based contrast agent. We compared four different sets of DIR parameters, including one set with two-step deformation and three sets with four-step deformation. For spatial accuracy, the target registration error (TRE) was calculated for 16 landmarks. For ventilation imaging accuracy, DIR-based ventilation images were generated using Jacobian determinant (JD) metrics, and changes in Hounsfield unit (HU) values between the two exhalation and inhalation CT images were subsequently measured. The correlation coefficients between the JD metrics and changes in HU values were calculated. RESULTS: The mean TRE values were 4.5 ±â€¯4.7 mm (maximum, 12.3 mm), 1.47 ±â€¯0.71 mm (maximum, 2.6 mm), 1.56 ±â€¯0.70 mm (maximum, 2.8 mm), and 1.53 ±â€¯0.66 mm (maximum, 2.5 mm) for the two-step deformation and three four-step deformations, respectively. The four-step deformations (R =  - 0.71, -0.65, and -0.61) showed stronger correlation coefficients than the two-step deformation (R =  -0.40). CONCLUSIONS: The accuracy of DIR-based ventilation imaging may vary with different DIR parameter settings, even though spatial accuracy may be tolerable and within guidelines. We found adequate parameter settings for four-step NiftyReg DIR for visualization of simulated pulmonary ventilation function.

Design and development of a nonrigid phantom for the quantitative evaluation of DIR-based mapping of simulated pulmonary ventilation.

PURPOSE: The validation of deformable image registration (DIR)-based pulmonary ventilation mapping is time consuming and prone to inaccuracies and is also affected by deformation parameters. In this study, we developed a nonrigid phantom as a quality assurance (QA) tool that simulates ventilation to evaluate DIR-based images quantitatively. METHODS: The phantom consists of an acrylic cylinder filled with polyurethane foam designed to simulate pulmonic alveoli. A polyurethane membrane is attached to the inferior end of the phantom to simulate the diaphragm. In addition, tracheobronchial-tree-shaped polyurethane tubes are inserted through the foam and converge outside the phantom to simulate the trachea. Solid polyurethane is also used to model arteries, which closely follow the model airways. Two three-dimensional (3D) CT scans were performed during exhalation and inhalation phases using xenon (Xe) gas as the inhaled contrast agent. The exhalation 3D-CT image is deformed to an inhalation 3D-CT image using our in-house program based on the NiftyReg open-source package. The target registration error (TRE) between the two images was calculated for 16 landmarks located in the simulated lung volume. The DIR-based ventilation image was generated using Jacobian determinant (JD) metrics. Subsequently, differences in the Hounsfield unit (HU) values between the two images were measured. The correlation coefficient between the JD and HU differences was calculated. In addition, three 4D-CT scans are performed to evaluate the reproducibility of the phantom motion and Xe gas distribution. RESULTS: The phantom exhibited a variety of displacements for each landmark (range: 1-20 mm). The reproducibility analysis indicated that the location differences were <1 mm for all landmarks, and the HU variation in the Xe gas distribution was close to zero. The mean TRE in the evaluation of spatial accuracy according to the DIR software was 1.47 ± 0.71 mm (maximum: 2.6 mm). The relationship between the JD and HU differences had a large correlation (R = -0.71) for the DIR software. CONCLUSION: The phantom implemented new features, namely, deformation and simulated ventilation. To assess the accuracy of the DIR-based mapping of the simulated pulmonary ventilation, the phantom allows for simulation of Xe gas wash-in and wash-out. The phantom may be an effective QA tool, because the DIR algorithm can be quickly changed and its accuracy evaluated with a high degree of precision.

A multi-institutional study of independent calculation verification in inhomogeneous media using a simple and effective method of heterogeneity correction integrated with the Clarkson method.

In inhomogeneous media, there is often a large systematic difference in the dose between the conventional Clarkson algorithm (C-Clarkson) for independent calculation verification and the superposition-based algorithms of treatment planning systems (TPSs). These treatment site-dependent differences increase the complexity of the radiotherapy planning secondary check. We developed a simple and effective method of heterogeneity correction integrated with the Clarkson algorithm (L-Clarkson) to account for the effects of heterogeneity in the lateral dimension, and performed a multi-institutional study to evaluate the effectiveness of the method. In the method, a 2D image reconstructed from computed tomography (CT) images is divided according to lines extending from the reference point to the edge of the multileaf collimator (MLC) or jaw collimator for each pie sector, and the radiological path length (RPL) of each line is calculated on the 2D image to obtain a tissue maximum ratio and phantom scatter factor, allowing the dose to be calculated. A total of 261 plans (1237 beams) for conventional breast and lung treatments and lung stereotactic body radiotherapy were collected from four institutions. Disagreements in dose between the on-site TPSs and a verification program using the C-Clarkson and L-Clarkson algorithms were compared. Systematic differences with the L-Clarkson method were within 1% for all sites, while the C-Clarkson method resulted in systematic differences of 1-5%. The L-Clarkson method showed smaller variations. This heterogeneity correction integrated with the Clarkson algorithm would provide a simple evaluation within the range of -5% to +5% for a radiotherapy plan secondary check.

Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to perform a dosimetric comparison between proton beam therapy (PBT) and photon radiation therapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were treated with PBT in our institution. In addition, we evaluated the correlation between toxicities and dosimetric parameters, especially the doses to normal lung or heart tissue, to clarify the clinical advantage of PBT over photon radiation therapy. METHODS: A total of 37 consecutive patients with Stage III thoracic ESCC who had received PBT with or without concurrent chemotherapy between October 2012 and December 2015 were evaluated in this study. The dose distributions of PBT were compared with those of dummy 3-dimensional conformal radiation therapy (3DCRT) and Intensity Modulated Radiation Therapy (IMRT), focusing especially on the doses to organs at risk, such as normal lung and heart tissue. RESULTS: Of the 37 patients, the data from 27 patients were analyzed. Among these 27 patients, four patients (15%) developed grade 2 pericardial effusion as a late toxicity. None of the patients developed grade 3 or worse acute or late pulmonary and cardiac toxicities. When the dosimetric parameters between PBT and planned 3DCRT were compared, all the PBT domestic variables for the lung dose except for lung V10 GyE and V15 GyE were significantly lower than those for the dummy 3DCRT plans, and the PBT domestic variables for the heart dose were also significantly lower than those for the dummy 3DCRT plans. When the PBT and IMRT plans were compared, all the PBT domestic variables for the doses to the lung and heart were significantly lower than those for the dummy IMRT plans. Regarding the correlation between the grades of toxicities and the dosimetric parameters, no significant correlation was seen between the occurrence of grade 2 pericardial effusion and the dose to the heart. CONCLUSIONS: When the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT.

Usefulness of a new online patient-specific quality assurance system for respiratory-gated radiotherapy.

PURPOSE: The accuracy of gated irradiation may decrease when treatment is performed with short "beam-on" times. Also, the dose is subject to variation between treatment sessions if the respiratory rate is irregular. We therefore evaluated the impact of the differences between gated and non-gated treatment on doses using a new online quality assurance (QA) system for respiratory-gated radiotherapy. METHODS: We generated dose estimation models to associate dose and pulse information using a 0.6 cc Farmer chamber and our QA system. During gated irradiation with each of seven regular and irregular respiratory patterns, with the Farmer chamber readings as references, we evaluated our QA system's accuracy. We then used the QA system to assess the impact of respiratory patterns on dose distribution for three lung and three liver radiotherapy plans. Gated and non-gated plans were generated and compared. RESULTS: There was agreement within 1.7% between the ionization chamber and our system for several regular and irregular motion patterns. For dose distributions with measured errors, there were larger differences between gated and non-gated treatment for high-dose regions within the planned treatment volume (PTV). Compared with a non-gated plan, PTV D95% for a gated plan decreased by -1.5% to -2.6%. Doses to organs at risk were similar with both plans. CONCLUSIONS: Our simple system estimated the radiation dose to the patient using only pulse information from the linac, even during irregular respiration. The quality of gated irradiation for each patient can be verified fraction by fraction.