Technical note: TIGRE-DE for the creation of virtual monoenergetic images from dual-energy cone-beam CT.

BACKGROUND: Dual-energy (DE)-CBCT represents a promising imaging modality that can produce virtual monoenergetic (VM) CBCT images. VM images, which provide enhanced contrast and reduced imaging artifacts, can be used to assist in soft-tissue visualization during image-guided radiotherapy. PURPOSE: This work reports the development of TIGRE-DE, a module in the open-source TIGRE toolkit for the performance of DE-CBCT and the production of VM CBCT images. This module is created to make DE-CBCT tools accessible in a wider range of clinical and research settings. METHODS: We developed an add-on (TIGRE-DE) to the TIGRE toolkit that performs DE material decomposition. To verify its performance, sequential CBCT scans at 80 and 140 kV of a Catphan 604 phantom were decomposed into equivalent thicknesses of aluminum (Al) and polymethyl-methylacrylate (PMMA) basis materials. These basis material projections were used to synthesize VM projections for a range of x-ray energies, which were then reconstructed using the Feldkamp-Davis-Kress (FDK) algorithm. Image quality was assessed by computing Hounsfield units (HU) and contrast-to-noise ratios (CNR) for the material inserts of the phantom and comparing with the constituent 80 and 140 kV images. RESULTS: All VM images generated using TIGRE-DE showed good general agreement with the theoretical HU values of the material inserts of the phantom. Apart from the highest-density inserts imaged at the extremes of the energy range, the measured HU values agree with theoretical HUs within the clinical tolerance of ±50 HU. CNR measurements for the various inserts showed that, of the energies selected, 60 keV provided the highest CNR values. Moreover, 60 keV VM images showed average CNR enhancements of 63% and 66% compared to the 80 and 140 kV full-fan protocols. CONCLUSIONS: TIGRE-DE successfully implements DE-CBCT material decomposition and VM image creation in an accessible, open-source platform.

Prostate segmentation accuracy using synthetic MRI for high-dose-rate prostate brachytherapy treatment planning.

Objective. Both computed tomography (CT) and magnetic resonance imaging (MRI) images are acquired for high-dose-rate (HDR) prostate brachytherapy patients at our institution. CT is used to identify catheters and MRI is used to segment the prostate. To address scenarios of limited MRI access, we developed a novel generative adversarial network (GAN) to generate synthetic MRI (sMRI) from CT with sufficient soft-tissue contrast to provide accurate prostate segmentation without MRI (rMRI).Approach. Our hybrid GAN, PxCGAN, was trained utilizing 58 paired CT-MRI datasets from our HDR prostate patients. Using 20 independent CT-MRI datasets, the image quality of sMRI was tested using mean absolute error (MAE), mean squared error (MSE), peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM). These metrics were compared with the metrics of sMRI generated using Pix2Pix and CycleGAN. The accuracy of prostate segmentation on sMRI was evaluated using the Dice similarity coefficient (DSC), Hausdorff distance (HD) and mean surface distance (MSD) on the prostate delineated by three radiation oncologists (ROs) on sMRI versus rMRI. To estimate inter-observer variability (IOV), these metrics between prostate contours delineated by each RO on rMRI and the prostate delineated by treating RO on rMRI (gold standard) were calculated.Main results. Qualitatively, sMRI images show enhanced soft-tissue contrast at the prostate boundary compared with CT scans. For MAE and MSE, PxCGAN and CycleGAN have similar results, while the MAE of PxCGAN is smaller than that of Pix2Pix. PSNR and SSIM of PxCGAN are significantly higher than Pix2Pix and CycleGAN (p < 0.01). The DSC for sMRI versus rMRI is within the range of the IOV, while the HD for sMRI versus rMRI is smaller than the HD for the IOV for all ROs (p ≤ 0.03).Significance. PxCGAN generates sMRI images from treatment-planning CT scans that depict enhanced soft-tissue contrast at the prostate boundary. The accuracy of prostate segmentation on sMRI compared to rMRI is within the segmentation variation on rMRI between different ROs.

Dosimetric and workflow impact of synthetic-MRI use in prostate high-dose-rate brachytherapy.

PURPOSE: Target and organ delineation during prostate high-dose-rate (HDR) brachytherapy treatment planning can be improved by acquiring both a postimplant CT and MRI. However, this leads to a longer treatment delivery workflow and may introduce uncertainties due to anatomical motion between scans. We investigated the dosimetric and workflow impact of MRI synthesized from CT for prostate HDR brachytherapy. METHODS AND MATERIALS: Seventy-eight CT and T2-weighted MRI datasets from patients treated with prostate HDR brachytherapy at our institution were retrospectively collected to train and validate our deep-learning-based image-synthesis method. Synthetic MRI was assessed against real MRI using the dice similarity coefficient (DSC) between prostate contours drawn using both image sets. The DSC between the same observer's synthetic and real MRI prostate contours was compared with the DSC between two different observers' real MRI prostate contours. New treatment plans were generated targeting the synthetic MRI-defined prostate and compared with the clinically delivered plans using target coverage and dose to critical organs. RESULTS: Variability between the same observer's prostate contours from synthetic and real MRI was not significantly different from the variability between different observer's prostate contours on real MRI. Synthetic MRI-planned target coverage was not significantly different from that of the clinically delivered plans. There were no increases above organ institutional dose constraints in the synthetic MRI plans. CONCLUSIONS: We developed and validated a method for synthesizing MRI from CT for prostate HDR brachytherapy treatment planning. Synthetic MRI use may lead to a workflow advantage and removal of CT-to-MRI registration uncertainty without loss of information needed for target delineation and treatment planning.

Effect of scattered megavoltage x-rays on markerless tumor tracking using dual energy kilovoltage imaging.

PURPOSE: To determine the effect of megavoltage (MV) scatter on the accuracy of markerless tumor tracking (MTT) for lung tumors using dual energy (DE) imaging and to consider a post-processing technique to mitigate the effects of MV scatter on DE-MTT. METHODS: A Varian TrueBeam linac was used to acquire a series of interleaved 60/120 kVp images of a motion phantom with simulated tumors (10 and 15 mm diameter). Two sets of consecutive high/low energy projections were acquired, with and without MV beam delivery. The MV field sizes (FS) ranged from 2 × 2 cm2 -6 × 6 cm2 in steps of 1 × 1 cm2 . Weighted logarithmic subtraction was performed on sequential images to produce soft-tissue images for kV only (DEkV ) and kV with MV beam on (DEkV+MV ). Wavelet and fast Fourier transformation filtering (wavelet-FFT) was used to remove stripe noise introduced by MV scatter in the DE images ( DE kV + MV Corr ${\rm{DE}}_{{\rm{kV}} + {\rm{MV}}}^{{\rm{Corr}}}$ ). A template-based matching algorithm was then used to track the target on DEkV, DEkV+MV , and DE kV + MV Corr ${\rm{DE}}_{{\rm{kV}} + {\rm{MV}}}^{{\rm{Corr}}}$ images. Tracking accuracy was evaluated using the tracking success rate (TSR) and mean absolute error (MAE). RESULTS: For the 10 and 15 mm targets, the TSR for DEkV images was 98.7% and 100%, and MAE was 0.53 and 0.42 mm, respectively. For the 10 mm target, the TSR, including the effects of MV scatter, ranged from 86.5% (2 × 2 cm2 ) to 69.4% (6 × 6 cm2 ), while the MAE ranged from 2.05 mm to 4.04 mm. The application of wavelet-FFT algorithm to remove stripe noise ( DE kV + MV Corr ${\rm{DE}}_{{\rm{kV}} + {\rm{MV}}}^{{\rm{Corr}}}$ ) resulted in TSR values of 96.9% (2 × 2 cm2 ) to 93.4% (6 × 6 cm2 ) and subsequent MAE values were 0.89 mm to 1.37 mm. Similar trends were observed for the 15 mm target. CONCLUSION: MV scatter significantly impacts the tracking accuracy of lung tumors using DE images. Wavelet-FFT filtering can improve the accuracy of DE-MTT during treatment.

Effect of different noise reduction techniques and template matching parameters on markerless tumor tracking using dual-energy imaging.

PURPOSE: To evaluate the impact of various noise reduction algorithms and template matching parameters on the accuracy of markerless tumor tracking (MTT) using dual-energy (DE) imaging. METHODS: A Varian TrueBeam linear accelerator was used to acquire a series of alternating 60 and 120 kVp images (over a 180° arc) using fast kV switching, on five early-stage lung cancer patients. Subsequently, DE logarithmic weighted subtraction was performed offline on sequential images to remove bone. Various noise reduction techniques-simple smoothing, anticorrelated noise reduction (ACNR), noise clipping (NC), and NC-ACNR-were applied to the resultant DE images. Separately, tumor templates were generated from the individual planning CT scans, and band-pass parameter settings for template matching were varied. Template tracking was performed for each combination of noise reduction techniques and templates (based on band-pass filter settings). The tracking success rate (TSR), root mean square error (RMSE), and missing frames (percent unable to track) were evaluated against the estimated ground truth, which was obtained using Bayesian inference. RESULTS: DE-ACNR, combined with template band-pass filter settings of σlow  = 0.4 mm and σhigh  = 1.6 mm resulted in the highest TSR (87.5%), RMSE (1.40 mm), and a reasonable amount of missing frames (3.1%). In comparison to unprocessed DE images, with optimized band-pass filter settings of σlow  = 0.6 mm and σhigh  = 1.2 mm, the TSR, RMSE, and missing frames were 85.3%, 1.62 mm, and 2.7%, respectively. Optimized band-pass filter settings resulted in improved TSR values and a lower missing frame rate for both unprocessed DE and DE-ACNR as compared to the use previously published band-pass parameters based on single energy kV images. CONCLUSION: Noise reduction strategies combined with the optimal selection of band-pass filter parameters can improve the accuracy and TSR of MTT for lung tumors when using DE imaging.

Fully automated planning and delivery of hippocampal-sparing whole brain irradiation.

The goal of this study is to fully automate the treatment planning and delivery process of hippocampal-sparing whole brain irradiation (HS-WBRT) by combining a RapidPlan (RP) knowledge-based planning model and HyperArc (HA) technology. Additionally, this study compares the dosimetric performance of RapidPlan-HyperArc (RP-HA) treatment plans with RP plans and volumetric modulated arc therapy (VMAT) plans. Ten patients previously treated with HS-WBRT using conventional VMAT were re-planned using RP-HA technique and RP model for HS-WBRT. Treatment plans were generated for 30Gy in 3Gy fractions using 6MV photon beam on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA) equipped with high definition multileaf collimator (HDMLC). Target coverage, homogeneity index (HI), Paddick Conformity index (CI), dose to organs-at-risk (OARs) provided by the 3 planning modalities were compared, and a paired t-test was performed. Total number of monitor units (MU), effective planning time and beam-on-time time were reported and evaluated for each plan. RP-HA plans achieved on average a 4% increase in D98% of PTV, a 26% improvement in HI, a 2.3% increase in CI, when compared to RP plans. Furthermore, RP-HA plans provided on average 11% decrease in D100% of hippocampi when compared to VMAT plans. All RP-HA plans were generated in less than 30 minutes while RP plans took 40 minutes and VMAT plans required on average 9 hours to complete. Regarding beam-on-time time, it was estimated that RP-HA plans take on average 5 minutes to deliver while RP and VMAT plans require 6.5 and 10 minutes, respectively. RP-HA method provides fully automated planning and delivery for HS-WBRT. The auto-generated plans together with automated treatment delivery allow standardization of plan quality, increased efficiency and ultimately improved patient care.

Dosimetric assessment of brass mesh bolus and transparent polymer-gel type bolus for commonly used breast treatment delivery techniques.

We investigated skin dose enhancements of brass mesh bolus (BMB) and a recently developed transparent polymer-gel bolus (PGB) for clinically relevant breast treatment delivery techniques. The dose enhancement of the breast surface with BMB and PGB were compared to that of tissue-equivalent bolus. Three breast treatment plans were generated on CT scans of an anthropomorphic chest phantom: tangential step-and-shoot 3D conformal (3DCRT) planned using Field-in-Field (FiF), tangential sliding-window 3DCRT using Electronic Compensator (EC), and volumetric modulated arc therapy (VMAT). All plans were created using 6 MV photons and a prescription dose (Rx) of 180 cGy per fraction. Skin doses of all 3 plans were measured with radiochromic films, separately delivered in triplicate. Each plan was delivered to the phantom without bolus, and then with BMB (1 or 2 layers; 3 or 10 mm tissue-equivalent), PGB, and Superflab (3, 5, and 10 mm tissue-equivalent). Doses were determined by reading the radiochromic films with a flatbed scanner, and analyzing the images using a calibration curve for each specific batch. For all bolus types and plans, surface doses averaged over the 3 measurements were between 88.4% and 107.4% of Rx. Without bolus, average measured skin doses were between 51.2% and 64.2% of Rx. Skin doses with BMB and PGB were comparable to that with tissue-equivalent bolus. Over all 3 treatment delivery techniques, using BMB resulted in average skin doses of 92.8% and 102.1% for 1- and 2 layers, respectively, and using PGB results in average skin doses of 94.8%, 98.2%, and 99.7% for 3, 5, and 10-mm tissue-equivalent, respectively. The average measured skin doses with BMB and PGB agreed within ± 3% compared to the tissue-equivalent thickness bolus. We concluded that BMB and PGB are clinically equivalent in skin dose enhancement for breast treatment as the 3, 5, and 10 mm tissue-equivalent bolus.

Computed tomography versus magnetic resonance imaging in high-dose-rate prostate brachytherapy planning: The impact on patient-reported health-related quality of life.

PURPOSE: High-dose-rate (HDR) prostate brachytherapy uses volumetric imaging for treatment planning. Our institution transitioned from computed tomography (CT)-based planning to MRI-based planning with the hypothesis that improved visualization could reduce treatment-related toxicity. This study aimed to compare the patient-reported health-related quality of life (hrQOL) and physician-graded toxicity outcomes of CT-based and MRI-based HDR prostate brachytherapy. METHODS: From 2016 to 2019, 122 patients with low- or intermediate-risk prostate cancer were treated with HDR brachytherapy as monotherapy. Patients underwent CT only or CT and MRI imaging for treatment planning and were grouped per treatment planning imaging modality. Patient-reported hrQOL in the genitourinary (GU), gastrointestinal (GI), and sexual domains was assessed using International Prostate Symptom Score and Expanded Prostate Cancer Index Composite Short Form-26 questionnaires. Baseline characteristics, changes in hrQOL scores, and physician-graded toxicities were compared between groups. RESULTS: The median follow-up was 18 months. Patient-reported GU, GI, and sexual scores worsened after treatment but returned toward baseline over time. The CT cohort had a lower baseline mean International Prostate Symptom Score (5.8 vs. 7.8, p = 0.03). The other patient-reported GU and GI scores did not differ between groups. Overall, sexual scores were similar between the CT and MRI cohorts (p = 0.08) but favored the MRI cohort at later follow-up with a smaller decrease in Expanded Prostate Cancer Index Composite Short Form-26 sexual score from baseline at 18 months (4.9 vs. 19.8, p = 0.05). Maximum physician-graded GU, GI, and sexual toxicity rates of grade ≥2 were 68%, 3%, and 53%, respectively, with no difference between the cohorts (p = 0.31). CONCLUSION: Our study shows that CT- and MRI-based HDR brachytherapy results in similar rates of GU and GI toxicity. MRI-based planning may result in improved erectile function recovery compared with CT-based planning.

The hypothalamic-pituitary-gonadal axis and thyroid hormone regulation interact to influence seasonal breeding in green anole lizards (Anolis carolinensis).

Reproductive physiology and behavior is mainly regulated by the hypothalamus-pituitary-gonad (HPG) axis, although abnormal thyroid hormone (TH) levels alter HPG axis activity. Seasonally breeding animals, such as green anole lizards (Anolis carolinensis), undergo drastic hormonal and behavioral changes between breeding and non-breeding seasons, with increased sex steroid hormones, larger gonads and increased reproductive behaviors during the breeding compared to non-breeding seasons. Relatively less is known regarding the regulation of gonadal TH in seasonal reproduction. We examined whether the gonadal expression of enzymes involved in TH activation are altered in concert with seasonal reproduction. Type 2 deiodinase (Dio2) mRNA, the TH activating enzyme, was upregulated in breeding compared to non-breeding testes, while type 3 deiodinase (Dio3) mRNA, the TH deactivating enzyme, was upregulated in breeding ovaries. To study the association between the HPG axis and local activation of TH, we manipulated the HPG axis during the non-breeding season by subcutaneously injecting luteinizing hormone (LH) and follicle stimulating hormone (FSH) in male lizards. We found that acute LH and FSH injections induced many aspects of breeding, with increased testes size and testosterone levels. Surprisingly, Dio3 was upregulated in the testes after LH and FSH injections, while Dio2 mRNA levels were unchanged. These results suggest that there might be different roles for local TH activation in developing and maintaining fully mature and functional gonads. Our findings continue to support the role for TH in regulating reproduction.

Efficient quality assurance method with automated data acquisition of a single phantom setup to determine radiation and imaging isocenter congruence.

We developed a quality assurance (QA) method to determine the isocenter congruence of Optical Surface Monitoring System (OSMS, Varian, CA, USA), kilovoltage (kV), and megavoltage (MV) imaging, and the radiation isocenter using a single setup of the OSMS phantom for frameless Stereotactic Radiosurgery (SRS) treatment. After aligning the phantom to the OSMS isocenter, a cone-beam computed tomography (CBCT) of the phantom was acquired and registered to a computed tomography (CT) scan of the phantom to determine the CBCT isocenter. Without moving the phantom, MV and kV images were simultaneously acquired at four gantry angles to localize MV and kV isocenters. Then, Winston-Lutz (W-L) test images of the central BB in the phantom were acquired to analyze the radiation isocenter. The gantry and couch were automatically controlled using the TrueBeam Developer Mode during MV, kV, and W-L image acquisition. All the images were acquired weekly for 17 weeks to track the congruence of all the imaging modalities' isocenter in six-dimensional (6D) translations and rotations, and the radiation isocenter in three-dimensional (3D) translations. The shifts of isocenters of all imaging modalities and the radiation isocenter from the OSMS isocenter were within 0.2 mm and 0.2° on average over 17 weeks. The maximum discrepancy between OSMS and other imaging modalities or radiation isocenters was 0.8 mm and 0.3°. However, systematic shifts of radiation isocenter anteriorly and laterally relative to the OSMS isocenter were observed. The measured discrepancies were consistent from week-to-week except for two weeks when the isocenter discrepancies of 0.8 mm were noted due to drifts of the OSMS isocenter. Once recalibration was performed on OSMS, the discrepancy was reduced to 0.3 mm and 0.2°.By performing the proposed QA on a weekly basis, the isocenter congruencies of multiple imaging systems and radiation isocenter were validated for a linear accelerator.

Transitioning From a Low-Dose-Rate to a High-Dose-Rate Prostate Brachytherapy Program: Comparing Initial Dosimetry and Improving Workflow Efficiency Through Targeted Interventions.

PURPOSE: We transitioned from a low-dose-rate (LDR) to a high-dose-rate (HDR) prostate brachytherapy program. The objective of this study was to describe our experience developing a prostate HDR program, compare the LDR and HDR dosimetry, and identify the impact of several targeted interventions in the HDR workflow to improve efficiency. METHODS AND MATERIALS: We performed a retrospective cohort study of patients treated with LDR or HDR prostate brachytherapy. We used iodine-125 seeds (145 Gy as monotherapy, and 110 Gy as a boost) and preoperative planning for LDR. For HDR, we used iridium-192 (13.5 Gy × 2 as monotherapy and 15 Gy × 1 as a boost) and computed tomography-based planning. Over the first 18 months, we implemented several targeted interventions into our HDR workflow to improve efficiency. To evaluate the progress of the HDR program, we used linear mixed-effects models to compare LDR and HDR dosimetry and identify changes in the implant procedure and treatment planning durations over time. RESULTS: The study cohort consisted of 122 patients (51 who received LDR and 71 HDR). The mean D90 was similar between patients who received LDR and HDR (P = .28). HDR mean V100 and V95 were higher (P < .0001), but mean V200 and V150 were lower (P < .0001). HDR rectum V100 and D1cc were lower (P < .0001). The HDR mean for the implant procedure duration was shorter (54 vs 60 minutes; P = .02). The HDR mean for the treatment planning duration dramatically improved with the implementation of targeted workflow interventions (3.7 hours for the first quartile to 2.0 hours for the final quartile; P < .0001). CONCLUSIONS: We successfully developed a prostate HDR brachytherapy program at our institution with comparable dosimetry to our historic LDR patients. We identified several targeted interventions that improved the efficiency of treatment planning. Our experience and workflow interventions may help other institutions develop similar HDR programs.

Single-institution report of setup margins of voluntary deep-inspiration breath-hold (DIBH) whole breast radiotherapy implemented with real-time surface imaging.

PURPOSE: We calculated setup margins for whole breast radiotherapy during voluntary deep-inspiration breath-hold (vDIBH) using real-time surface imaging (SI). METHODS AND MATERIALS: Patients (n = 58) with a 27-to-31 split between right- and left-sided cancers were analyzed. Treatment beams were gated using AlignRT by registering the whole breast region-of-interest to the surface generated from the simulation CT scan. AlignRT recorded (three-dimensional) 3D displacements and the beam-on-state every 0.3 s. Means and standard deviations of the displacements during vDIBH for each fraction were used to calculate setup margins. Intra-DIBH stability and the intrafraction reproducibility were estimated from the medians of the 5th to 95th percentile range of the translations in each breath-hold and fraction, respectively. RESULTS: A total of 7269 breath-holds were detected over 1305 fractions in which a median dose of 200 cGy was delivered. Each fraction was monitored for 5.95 ± 2.44 min. Calculated setup margins were 4.8 mm (A/P), 4.9 mm (S/I), and 6.4 mm (L/R). The intra-DIBH stability and the intrafraction reproducibility were ≤0.7 mm and ≤2.2 mm, respectively. The isotropic margin according to SI (9.2 mm) was comparable to other institutions' calculations that relied on x-ray imaging and/or spirometry for patients with left-sided cancer (9.8-11.0 mm). Likewise, intra-DIBH variability and intrafraction reproducibility of breast surface measured with SI agreed with spirometry-based positioning to within 1.2 and 0.36 mm, respectively. CONCLUSIONS: We demonstrated that intra-DIBH variability, intrafraction reproducibility, and setup margins are similar to those reported by peer studies who utilized spirometry-based positioning.

Automated calculation of point A coordinates for CT-based high-dose-rate brachytherapy of cervical cancer.

PURPOSE: The goal is to develop a stand-alone application, which automatically and consistently computes the coordinates of the dose calculation point recommended by the American Brachytherapy Society (i.e., point A) based solely on the implanted applicator geometry for cervical cancer brachytherapy. MATERIAL AND METHODS: The application calculates point A coordinates from the source dwell geometries in the computed tomography (CT) scans, and outputs the 3D coordinates in the left and right directions. The algorithm was tested on 34 CT scans of 7 patients treated with high-dose-rate (HDR) brachytherapy using tandem and ovoid applicators. A single experienced user retrospectively and manually inserted point A into each CT scan, whose coordinates were used as the "gold standard" for all comparisons. The gold standard was subtracted from the automatically calculated points, a second manual placement by the same experienced user, and the clinically used point coordinates inserted by multiple planners. Coordinate differences and corresponding variances were compared using nonparametric tests. RESULTS: Automatically calculated, manually placed, and clinically used points agree with the gold standard to < 1 mm, 1 mm, 2 mm, respectively. When compared to the gold standard, the average and standard deviation of the 3D coordinate differences were 0.35 ± 0.14 mm from automatically calculated points, 0.38 ± 0.21 mm from the second manual placement, and 0.71 ± 0.44 mm from the clinically used point coordinates. Both the mean and standard deviations of the 3D coordinate differences were statistically significantly different from the gold standard, when point A was placed by multiple users (p < 0.05) but not when placed repeatedly by a single user or when calculated automatically. There were no statistical differences in doses, which agree to within 1-2% on average for all three groups. CONCLUSIONS: The study demonstrates that the automated algorithm calculates point A coordinates consistently, while reducing inter-user variability. Point placement using the algorithm expedites the planning process and minimizes associated potential human errors.

An ethanol extract of Aster yomena (Kitam.) Honda inhibits lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 macrophages.

Aster yomena (Kitam.) Honda has been widely used as a traditional herbal medicine for centuries to treat cough, asthma, insect bites, etc. Recent reports indicate that A. yomena possesses a wide spectrum of pharmacological activities; however, few experiments have described its anti-inflammatory properties. The present study examined the anti-inflammatory effects of an ethanol extract of A. yomena leaves (EEAY) on lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Treatment with EEAY significantly reduced the secretion of pro-inflammatory molecules, such as nitric oxide and interleukin-1ß, in LPS-stimulated RAW 264.7 cells, without incurring any significant cytotoxicity. These protective effects were accompanied by a marked reduction in the expression of regulatory genes at the transcription level. Treatment with EEAY also inhibited the DNA-binding activity of nuclear factor-κB (NF-κB) by suppression of nuclear translocation of NF-κB and by degradation of the inhibitor of NF-κB; these effects were associated with suppression of the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways. The EEAY treatment also potently suppressed LPS-induced toll like receptor (TLR) 4 expression and attenuated the binding of LPS to the macrophage cell surface. In addition, EEAY treatment markedly inhibited LPS-induced accumulation of intracellular reactive oxygen species in RAW 264.7 macrophages. Therefore, the inhibitory effects of EEAY on LPS-stimulated inflammatory responses in RAW 264.7 macrophages were apparently associated with suppression of the TLR-mediated NF-κB signaling pathway. More work is needed to fully understand the critical role and clinical usefulness of EEAY treatment, but the findings of the present study provide some insights into the potential of EEAY as a therapeutic agent for treatment of inflammatory disorders.

Fructus sophorae attenuates secretion of proinflammatory mediators and cytokines through the modulation of NF-κB and MAPK signaling pathways in LPS-stimulated RAW 264.7 macrophages.

This study investigated the inhibitory effects and underlying mechanisms of fructus sophorae, the dried ripe fruit of Styphnolobium japonicum (L.) Schott, on the production of proinflammatory molecules in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The results indicated that pretreatment with noncytotoxic concentrations of fructus sophorae extract (FSE) significantly inhibited the release of the proinflammatory mediators nitric oxide (NO) and prostaglandin E(2), which were associated with the downregulation of both mRNA and protein for inducible NO synthase and cyclooxygenase-2, respectively, in LPS-challenged RAW 264.7 cells. FSE also blocked the LPS-induced expression of the proinflammatory cytokines interleukin (IL)-6 and IL-1ß. Furthermore, the results showed that FSE efficiently attenuated the LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) and phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 MAPK. These results suggest that FSE exhibits anti-inflammatory activity by inhibiting proinflammatory mediators and cytokines through the inactivation of NF-κB, ERK and JNK, and it may offer therapeutic potential for treating inflammatory diseases accompanied with macrophage activation.

Assessment of interfractional variation of the breast surface following conventional patient positioning for whole-breast radiotherapy.

The purpose of this study was to quantify the variability of the breast surface position when aligning whole-breast patients to bony landmarks based on MV portal films or skin marks alone. Surface imaging was used to assess the breast surface position of 11 whole-breast radiotherapy patients, but was not used for patient positioning. On filmed fractions, AlignRT v5.0 was used to capture the patient's surface after initial positioning based on skin marks (28 "preshifts" surfaces), and after treatment couch shifts based on MV films (41 "postshifts" surfaces). Translations and rotations based on surface captures were recorded, as well as couch shifts based on MV films. For nonfilmed treatments, "daily" surface images were captured following positioning to skin marks alone. Group mean and systematic and random errors were calculated for all datasets. Pearson correlation coefficients, setup margins, and 95% limits of agreement (LOA) were calculated for preshifts translations and MV film shifts. LOA between postshifts surfaces and the filmed treatment positions were also computed. All the surface captures collected were retrospectively compared to both a DICOM reference surface created from the planning CT and to an AlignRT reference surface. All statistical analyses were performed using the DICOM reference surface dataset. AlignRT reference surface data was only used to calculate the LOA with the DICOM reference data. This helped assess any outcome differences between both reference surfaces. Setup margins for preshifts surfaces and MV films range between 8.3-12.0 mm and 5.4-13.4 mm, respectively. The largest margin is along the left-right (LR) direction for preshift surfaces, and along craniocaudal (CC) for films. LOA ranges between the preshifts surfaces and MV film shifts are large (12.6-21.9 mm); these decrease for postshifts surfaces (9.8-18.4 mm), but still show significant disagreements between the two modalities due to their focus on different anatomical landmarks (patient's topography versus bony anatomy). Pearson's correlation coefficients further support this by showing low to moderate correlations in the anterior-posterior (AP) and LR directions (0.47-0.69) and no correlation along CC (< 0.15). The use of an AlignRT reference surface compared to the DICOM reference surface does not significantly affect the LOA. Alignment of breast patients based solely on bony alignment may lead to interfractional inconsistencies in the breast surface position. The use of surface imaging tools highlights these discrepancies, and allows the radiation oncology team to better assess the possible effects on treatment quality.

Spatial and temporal performance of 3D optical surface imaging for real-time head position tracking.

PURPOSE: The spatial and temporal tracking performance of a commercially available 3D optical surface imaging system is evaluated for its potential use in frameless stereotactic radiosurgery head tracking applications. METHODS: Both 3D surface and infrared (IR) marker tracking were performed simultaneously on a head phantom mounted on an xyz motion stage and on four human subjects. To allow spatial and temporal comparison on human subjects, three points were simultaneously monitored, including the upper facial region (3D surface), a dental plate (IR markers), and upper forehead (IR markers). RESULTS: For both static and dynamic phantom studies, the 3D surface tracker was found to have a root mean squared error (RMSE) of approximately 0.30 mm for region-of-interest (ROI) surface sizes greater than 1000 vertex points. Although, the processing period (1/fps) of the 3D surface system was found to linearly increase as a function of the number of ROI vertex points, the tracking accuracy was found to be independent of ROI size provided that the ROI was sufficiently large and contained features for registration. For human subjects, the RMSE between 3D surface tracking and IR marker tracking modalities was 0.22 mm left-right (x-axis), 0.44 mm superior-inferior (y-axis), 0.27 mm anterior-posterior (z-axis), 0.29° pitch (around x-axis), 0.18° roll (around y-axis), and 0.15° yaw (around z-axis). CONCLUSIONS: 3D surface imaging has the potential to provide submillimeter level head motion tracking. This is provided that a highly accurate camera-to-LINAC frame of reference calibration can be performed and that the reference ROI is of sufficient size and contains suitable surface features for registration.

An EPID based method for performing high accuracy calibration between an optical external marker tracking device and the LINAC reference frame.

PURPOSE: With the increasing use of external 3D optical tracking cameras to guide modern radiation therapy procedures, it has become vitally important to have an accurate camera to linear accelerator (LINAC) reference frame calibration. To eliminate errors present in current calibration procedures based on the manual hand alignment of a device using the light field crosshairs and in room guidance lasers, a semiautomated quantitative calibration approach requiring only use of an electronic portal imaging device (EPID) was developed. METHODS: A phantom comprised of seven highly IR reflective plastic BBs was placed on the LINAC treatment couch and imaged with both a 3D stereoscopic IR imager and the on board megavoltage (MV) EPID imager. Having knowledge of the optically determined 3D positions and projected EPID images of the BBs, simulated annealing was used to optimize the location of the BBs in the LINAC frame using four different optimization functions. Singular value decomposition was then used to calculate the transformation matrix between the camera and LINAC reference frames. Results were then compared to a traditional camera calibration method for overall accuracy. RESULTS: Using modeled data, the simulated annealing process was able to determine the actual locations of the BBs with a RMSE of 0.23 mm. Using projection images acquired with an MV imager, the process was able to determine locations of BBs within .26 mm. The results depend on the choice of optimization function. CONCLUSIONS: Results show that the method can be used to provide highly accurate spatial registration between an external 3D imaging reference frame and the LINAC frame. The experimental MV imager results, while not as precise as the simulated results, exceed 1 mm accuracy and the current accepted AAPM TG-142 standard of ≤2 mm positioning accuracy.

Motion monitoring for cranial frameless stereotactic radiosurgery using video-based three-dimensional optical surface imaging.

PURPOSE: To establish a new clinical procedure in frameless stereotactic radiosurgery (SRS) for patient setup verification at treatment couch angles as well as for head-motion monitoring during treatment using video-based optical surface imaging (OSI). METHODS: A video-based three-dimensional (3D) OSI system with three ceiling-mounted camera pods was employed to verify setup at treatment couch angles as well as to monitor head motion during treatment. A noninvasive head immobilization device was utilized, which includes an alpha head mold and a dental mouthpiece with vacuum suction; both were locked to the treatment couch. Cone beam computed tomography (CBCT) was used as the standard for image-guided setup. Orthogonal 2D-kV imaging was applied for setup verification before treatment, between couch rotations, and after treatment at zero couch angle. At various treatment couch angles, OSI setup verification was performed, relative to initial OSI setup verification at zero couch angle after CBCT setup through a coordinate transformation. For motion monitoring, the setup uncertainty was decoupled by taking an on-site surface image as new reference to detect motion-induced misalignment in near real-time (1-2 frames per second). Initial thermal instability baseline of the real-time monitoring was corrected. An anthropomorphous head phantom and a 1D positioning platform were used to assess the OSI accuracy in motion detection in longitudinal and lateral directions. Two hypofractionated (9 Gy x 3 and 6 Gy x 5) frameless stereotactic radiotherapy (SRT) patients as well as two single-fraction (21 and 18 Gy) frameless SRS patients were treated using this frameless procedure. For comparison, 11 conventional frame-based SRS patients were monitored using the OSI to serve as clinical standards. Multiple noncoplanar conformal beams were used for planning both frameless and frame-based SRS with a micromultileaf collimator. RESULTS: The accuracy of the OSI in 1D motion detection was found to be 0.1 mm with uncertainty of +/- 0.1 mm using the head phantom. The OSI registration against simulation computed tomography (CT) external contour was found to be dependent on the CT skin definition with -0.4 mm variation. For frame-based SRS patients, head-motion magnitude was detected to be <1.0 mm (0.3 +/- 0.2 mm) and <1.0 degree (0.2 degrees +/- 0.2 degrees) for 98% of treatment time, with exception of one patient with head rotation <1.5 degrees for 98% of the time. For frameless SRT/SRS patients, similar motion magnitudes were observed with an average of 0.3 +/- 0.2 mm and 0.2 degrees +/- 0.1 degree in ten treatments. For 98% of the time, the motion magnitude was <1.1 mm and 1.0 degree. Complex head-motion patterns within 1.0 mm were observed for frameless SRT/SRS patients. The OSI setup verification at treatment couch angles was found to be within 1.0 mm. CONCLUSIONS: The OSI system is capable of detecting 0.1 +/- 0.1 mm 1D spatial displacement of a phantom in near real time and useful in head-motion monitoring. This new frameless SRS procedure using the mask-less head-fixation system provides immobilization similar to that of conventional frame-based SRS. Head-motion monitoring using near-real-time surface imaging provides adequate accuracy and is necessary for frameless SRS in case of unexpected head motion that exceeds a set tolerance.

Evaluation of tumor motion effects on dose distribution for hypofractionated intensity-modulated radiotherapy of non-small-cell lung cancer.

Respiration-induced tumor motion during intensity-modulated radiotherapy (IMRT) of non-small-cell lung cancer (NSCLC) could cause substantial differences between planned and delivered doses. While it has been shown that, for conventionally fractionated IMRT, motion effects average out over the course of many treatments, this might not be true for hypofractionated IMRT (IMHFRT). Numerical simulations were performed for nine NSCLC patients (11 tumors) to evaluate this problem. Dose distributions to the Clinical Target Volume (CTV) and Internal Target Volume (ITV) were retrospectively calculated using the previously-calculated leaf motion files but with the addition of typical periodic motion (i.e. amplitude 0.36-1.26cm, 3-8sec period). A typical IMHFRT prescription of 20Gy x 3 fractions was assumed. For the largest amplitude (1.26 cm), the average +/- standard deviation of the ratio of simulated to planned mean dose, minimum dose, D95 and V95 were 0.98+/-0.01, 0.88 +/- 0.09, 0.94 +/- 0.05 and 0.94 +/- 0.07 for the CTV, and 0.99 +/-0.01, 0.99 +/- 0.03, 0.98 +/- 0.02 and 1.00 +/- 0.01 for the ITV, respectively. There was minimal dependence on period or initial phase. For typical tumor geometries and respiratory amplitudes, changes in target coverage are minimal but can be significant for larger amplitudes, faster beam delivery, more highly-modulated fields, and smaller field margins.