Objective:To evaluate the effects of the changes in respiratory status on gated stereotactic radiotherapy under free breathing guided by real-time position management (RPM).Methods:This study simulated the baseline shift, change in respiratory rate, end-expiratory delay, end-inspiratory delay, and irregular breathing using an in-house developed motion phantom. Moreover, this study analyzed the correlation between the changes in the above states of three plans, three-dimensional conformal radiotherapy(3D-CRT), intensity modulated radiotherapy(IMRT), and volumetric modulated arc therapy(VMAT) and the position of the ball at the center of the motion phantom (L) and the exposed dose of the phantom in the ionization chamber (the dose).Results:The in-house developed phantom presented high setup repeatability and measurement stability. There was a positive correlation between L and the baseline shift ( r = 0.99, P < 0.01). The change in the dose was less than 4% when the baseline shift was less than the setup error, while the dose declined rapidly and was negatively correlated with the baseline shift otherwise ( r= -0.95, P < 0.01). Moreover, there was statistically significant difference in dose when the baseline shift exceeded the setup error or not ( Z = -3.06, P < 0.01). There was no significant difference in the rate of the dose affected by baseline shift in the three plans ( P > 0.05). The changes in respiratory rate had little effect on L and the dose. Both end-inspiratory delay and end-expiratory delay reduced the planned dose of the three plans, with a maximum decrease of up to -1.74%. Furthermore, the end-inspiratory delay has greater effects on the planned dose than the end-expiratory delay( Z = -2.67, P< 0.01). However, there was no significant correlation between the dose and the delay duration ( P > 0.05), and no significant difference in the rate of the planned dose of the three plans affected by respiratory waveform change ( P > 0.05). Irregular breathing had greater effects on the dose. Specifically, the dose from six repeated measurements of 3D-CR, IMRT, VMAT was (709.68±180.00), (751.40±127.16), and (750.00±185.60) cGy, respectively, all less than the prescribed dose with a poor consistency. Conclusions:The changes in the patients′ respiratory status will reduce the dose, especially when the baseline shift exceeds the setup error threshold or large respiratory waveform variation corresponding to irregular breathing occurs. Moreover, there is no correlation between the decrease in the dose and the radiotherapy technology.

Objective:To compare the dosimetric parameters and plan complexity between newly-delicated HyperArc (HA) and conventional volumetric-modulated arc therapy (VMAT) in the treatment of brain metastases.Methods:For 26 patients with brain metastases, HA, conventional coplanar (Cop) and non-coplanar (Non-cop) VMAT plans with a prescription dose of 9 Gy 3fx or 6 Gy 5fx were generated. The dosimetric parameters for planning target volume (PTV), RTOG conformity index (RTOG CI), Paddick CI, homogeneity index (HI), gradient index (GI), maximum dose (D max) of brainstem and dose-volume parameters of brain-PTV(V 2Gy-V 26Gy) were statisticaly compared among these three approaches. In addition, the monitor unit (MU) and the plan complexity parameters (including MCSv and AlPO) were statistically compared. Results:To prevent missed targets during treatment, all plans were established with RTOG CI of greater than 1.1. For Paddick CI, HA provided significantly higher conformity (0.89±0.019) than Non-cop (0.87±0.036, P=0.001) and Cop (0.88±0.017, P=0.003) VMAT. For GI, the fastest dose fall-off was noted in HA (3.35±0.64), followed by conventional Non-cop VMAT of (3.70±0.80), and conventional Cop VMAT of (4.90±1.85)(all P<0.05). For the brainstem sparing, HA plan performed better than Non-cop plan[(604.14±531.61) cGy vs.(682.75±558.22) cGy, P<0.05)]. For normal brain tissue sparing, HA approach showed significant reduction than conventional Cop and Non-cop VMAT (both P<0.05). For MU, HA approach (2 872.60 ± 566.93) was significantly lower than those of Non-cop VMAT (3 771.28 ± 1 022.38, P<0.05) and Cop VMAT (4 494.08 ± 1 323.09, P<0.05). In terms of plan complexity, the MCSv of Cop plan was the lowest, indicating that the complexity was the highest ( P<0.05). The AlPO of HA was significantly higher than that of Non-cop VMAT ( P<0.05), suggesting that the complexity of HA plan was lower ( P<0.05). Conclusion:For the treatment of brain metastases, HA provides better conformity, more rapid dose fall-off, better sparing of brainstem and normal brain tissues and less plan complexity compared with conventional VMAT.

Objective:To help clinicians simplify the post-processing operations of structures by developing rapid processing software for target area and organs at risk structures based on ESAPI.Methods:SmartStructure script software was developed based on ESAPI, verified and evaluated in clinical work. 10 cases of rectal cancer receiving neoadjuvant radiotherapy, 10 breast cancer treated with postoperative radiotherapy, 10 cervical cancer receiving postoperative radiotherapy, 10 nasopharyngeal carcinoma receiving radical radiotherapy and 10 lung stereotactic body radiotherapy (SBRT) were selected, and different types of tumors had different post-processing operations of structures. In each case, three methods were used for post-processing of structures. In the control group (manual group), normal manual processing was employed. In the experimental group 1(SmaStru-N group), scripts without templates were utilized. In the experimental group 2(SmaStru-P group). scripts combined with templates were adopted. The processing time of the three methods was compared. Clinicians scored the scripting software from multiple aspects and compared the feeling scores of scripting software and manual operation.Results:All three methods can be normally applied in clinical settings. The error rate in the manual group was 7.0%, 3.0% in the SmaStru-N group 0% in the SmaStru-P group, respectively. Compared with the manual method, SmaStru-N shortened the processing time of target area and organs at risk by 60.9% and 93.3% for SmaStru-P. In addition, SmartStructure was superior to manual method in terms of using feeling scores. Clinicians gave lower score for the" applicability" and" simplicity" , and higher score on the" accuracy" and" efficiency" .Conclusions:Compared with conventional manual structure processing method, SmartStructure software can rapidly and accurately process all structures of the target area and organs at risk, and its advantages become more obvious with the increasing number of structures that need to be processed. SmartStructure software can meet clinical requirements, reduce the error rate, elevate processing speed, improve the working efficiency of clinicians, providing basis for the development of adaptive radiotherapy.

Objective:To evaluate the robustness of fully automated adaptive planning for Ethos online adaptive radiotherapy (ART) based on the intelligent optimization engine (IOE).Methods:Clinical data of 11 stage ⅠB cervical cancer patients admitted to Peking Union Medical College Hospital between June 2021 and June 2022 were retrospectively analyzed. Original planning images and iterative cone-beam computed tomography (iCBCT) images of each radiotherapy treatment were acquired, and all patient data were imported into the Ethos simulator. IOE-based 9-field automatic plan generation was performed for 11 patients using Ethos, and the generated plans were sent to online adaptive radiotherapy simulation to obtain each online adaptive radiotherapy plan (273 fractions in total) and complete the simulated treatment. For comparison, manual plan design was performed based on the images and contoured structures used for online adaptive radiotherapy planning, and the manually plans created with evenly divided 9 fields. Dosimetric parameters, plan complexity parameters, and Mobius quality assurance (QA) pass rates were collected to compare and evaluate the robustness of the online adaptive radiotherapy plan in terms of organs at risk (OAR), target volume dosimetric parameters, and plan complexity by using paired t-test or rank sum test. Results:The online adaptive plan of cervical cancer had comparable planning target volume (PTV) coverage compared to the manual plan. For the clinical target volume (CTV) D 99%, online adaptive plan was significantly higher than the manual plan [(45.93±0.36) vs. (45.32±0.31) Gy, P<0.001]. For hot dose area, the maximum point dose (PTV D max) of adaptive plan was significantly higher than the manual plan [(49.89±1.25) vs. (48.48±0.77) Gy, P<0.001], but the PTV D 1% of adaptive plan was significantly lower than the manual plan [(47.22±0.29) vs. (47.59±0.48) Gy, P<0.001]. There was no statistical difference in the conformal index ( P=0.967). And there was significant difference in the homogeneity index, with same medians and less dispersion in adaptive plan ( P<0.001). For OAR dose, bladder D mean, rectal V 40 Gy, small intestine D mean of adaptive plan was slightly higher than that of the manual plan; the rectal D mean, small intestine D 2 cm3 of the adaptive plan was slightly lower than that of manual plan; dosimetric parameters of right and left femoral heads, spinal cord and bone marrow of the adaptive plan were better than those of manual plan. The adaptive plan had more monitor units (MU) than the manual plan, but the complexity of the adaptive plan was significantly lower than that of the manual plan (0.135±0.012 vs. 0.151±0.015, P<0.001). For Mobius γ pass rate (5%/3 mm), both adaptive and manual plans met clinical requirements. Conclusion:Ethos cervical cancer online adaptive plan, which is based on the IOE engine, demonstrates good robustness and ensures the quality of online adaptive plans generated for each treatment fraction.

Objective:To evaluate the automatic optimization performance and clinical feasibility of the intelligent optimization engine (IOE) in the Ethos online adaptive radiotherapy platform.Methods:Clinical data of 11 patients with postoperative cervical cancer treated with Halcyon accelerator were retrospectively analyzed. Manual planning was performed for all patients using the 4 full arc volumetric modulated arc therapy (VMAT) (Manual-4Arc) in Eclipse, with a prescription dose of 45 Gy/25F. Patient images and structures were imported into the Ethos simulator, and appropriate clinical goals were added based on clinical requirements. The target coverage was normalized to 95%. Automatic plan generation was conducted using IOE, resulting in 7, 9, and 12 field intensity modulated radiotherapy (IMRT) plans (IMRT-7F、IMRT-9F、IMRT-12F), as well as 2 and 3 arc VMAT plans (VMAT-2Arc、VMAT-3Arc). Dosimetric index comparisons were made between the Manual-4Arc plans and the 5 groups of IOE-generated plans through one-way analysis of variance. Based on the analysis results, Turky post hoc multiple comparisons were performed to evaluate the automatic optimization performance of IOE.Results:In terms of the high dose area, the IMRT-12F plans showed the lowest D 1% for the planning target volume (PTV), and there were significant differences compared to the Manual-4Arc plans ( P=0.004). Regarding target coverage, all groups produced clinical target volume (CTV) plans that met the clinical requirements. Although the Ethos online adaptive plans were normalized during planning, the PTV coverage was slightly insufficient. For organs at risk (OAR) close to the target, such as the bladder, there were significant differences in V 30 Gy, V 40 Gy, and D mean among the 6 groups of plans. The dose ranking for the bladder was generally as follows: IMRT-12F

Objective:To propose an automatic planning approach for Eclipse15.6 planning system based on Eclipse scripting application programming interface (ESAPI) and evaluate its clinical application.Methods:20 patients with nasopharyngeal carcinoma and 20 cases of rectal cancer were selected in the clinical planning. The developed automatic planning script SmartPlan and RapidPlan were used for automatic planning and dosimetric parameters were compared with manual planning. The differences were compared between two groups by using Wilcoxon signed rank test. Results:The dosimetric results of automatic and manual plans could meet clinical requirements. There was no significant difference in target coverage in nasopharyngeal carcinoma planning between two groups ( P>0.05), and automatic plans were superior to manual plans in organs at risk sparing ( P<0.05). Except for the homogeneity index of PTV and the maximum dose of bowel in rectal cancer plans, the other dosimetric parameters of the automatic plans were better than those of the manual plans (all P<0.05). Conclusions:Compared with the manual plans, the automatic plans have the same or similar target coverage, similar or better protection of organs at risk, and more convenient implementation. The developed SmartPlan based on ESAPI has clinical feasibility and effectiveness.

A large number of β-adrenergic receptor (β-AR) agonists and antagonists are widely used in the treatment of cardiovascular diseases and other diseases. Nonetheless, it remains unclear whether these commonly used β-AR drugs can activate downstream β- arrestin-biased signaling pathways. The objective of this study was to investigate β-arrestin2 recruitment effects of β-AR agonists and antagonists that were commonly used in clinical practice. We used TANGO (transcriptional activation following arrestin translocation) assay to detect the β-arrestin2 recruitment by β-AR ligands in HEK293 cell line (HTLA cells) stably transfected with tetracycline transactivator protein (tTA) dependent luciferase reporter and β-arrestin2-TEV fusion gene. Upon activation of β-AR by a β-AR ligand, β-arrestin2 was recruited to the C terminus of the receptor, followed by cleavage of the G protein-coupled receptors (GPCRs) fusion protein at the TEV protease-cleavage site. The cleavage resulted in the release of tTA, which, after being transported to the nucleus, activated transcription of the luciferase reporter gene. The results showed that β-AR non-selective agonists epinephrine, noradrenaline and isoprenaline all promoted β-arrestin2 recruitment at β1-AR and β2-AR. β1-AR selective agonists dobutamine and denopamine both promoted β-arrestin2 recruitment at β1-AR. β2-AR selective agonists procaterol and salbutamol promoted β-arrestin2 recruitment at β2-AR. β-AR non-selective antagonists alprenolol and pindolol promoted β-arrestin2 recruitment at β1-AR. β1-AR selective antagonists celiprolol and bevantolol showed β-arrestin2 recruitment at β1-AR. β2-AR selective antagonists butoxamine showed β-arrestin2 recruitment at β1-AR. These results provide some clues for the potential action of β-AR drugs, and lay a foundation for the screening of β-arrestin-biased β-AR ligands.
Humans ; beta-Arrestin 2/metabolism* ; HEK293 Cells ; Adrenergic beta-Agonists/pharmacology* ; Isoproterenol/pharmacology* ; Receptors, Adrenergic, beta-2/metabolism* ; Norepinephrine/pharmacology*