Towards clinical implementation of ultrafast combined kV-MV CBCT for IGRT of lung cancer : Evaluation of registration accuracy based on phantom study.

PURPOSE: Combined kV-MV cone-beam CT (CBCT) is a promising approach to accelerate imaging for patients with lung tumors treated with deep inspiration breath-hold. During a single breath-hold (15 s), a 3D kV-MV CBCT can be acquired, thus minimizing motion artifacts and increasing patient comfort. Prior to clinical implementation, positioning accuracy was evaluated and compared to clinically established imaging techniques. METHODS AND MATERIALS: An inhomogeneous thorax phantom with four tumor-mimicking inlays was imaged in 10 predefined positions and registered to a planning CT. Novel kV-MV CBCT imaging (90° arc) was compared to clinically established kV-chest CBCT (360°) as well as nonclinical kV-CBCT and low-dose MV-CBCT (each 180°). Manual registration, automatic registration provided by the manufacturer and an additional in-house developed manufacturer-independent framework based on the MATLAB registration toolkit were applied. RESULTS: Systematic setup error was reduced to 0.05 mm by high-precision phantom positioning with optical tracking. Stochastic mean displacement errors were 0.5 ± 0.3 mm in right-left, 0.4 ± 0.4 mm in anteroposterior and 0.0 ± 0.4 mm in craniocaudal directions for kV-MV CBCT with manual registration (maximum errors of no more than 1.4 mm). Clinical kV-chest CBCT resulted in mean errors of 0.2 mm (other modalities: 0.4-0.8 mm). Similar results were achieved with both automatic registration methods. CONCLUSION: The comparison study of repositioning accuracy between novel kV-MV CBCT and clinically established volume imaging demonstrated that registration accuracy is maintained below 1 mm. Since imaging time is reduced to one breath-hold, kV-MV CBCT is ideal for image guidance, e.g., in lung stereotactic ablative radiotherapy.

Transcutaneous measurement of renal function in conscious mice.

Determination of glomerular filtration rate (GFR) in conscious mice is cumbersome for the experimenter and stressful for the animals. Here we report on a simple new technique allowing the transcutaneous measurement of GFR in conscious mice. This approach extends our previously developed technique for rats to mice. The technique relies on a miniaturized device equipped with an internal memory that permits the transcutaneous measurement of the elimination kinetics of the fluorescent renal marker FITC-sinistrin. This device is described and validated compared with FITC-sinistrin plasma clearance in healthy, unilaterally nephrectomized and pcy mice. In summary, we describe a technique allowing the measurement of renal function in freely moving mice independent of blood or urine sampling as well as of laboratory assays.

Online feedback-controlled renal constant infusion clearances in rats.

Constant infusion clearance techniques using exogenous renal markers are considered the gold standard for assessing the glomerular filtration rate. Here we describe a constant infusion clearance method in rats allowing the real-time monitoring of steady-state conditions using an automated closed-loop approach based on the transcutaneous measurement of the renal marker FITC-sinistrin. In order to optimize parameters to reach steady-state conditions as fast as possible, a Matlab-based simulation tool was established. Based on this, a real-time feedback-regulated approach for constant infusion clearance monitoring was developed. This was validated by determining hourly FITC-sinistrin plasma concentrations and the glomerular filtration rate in healthy and unilaterally nephrectomized rats. The transcutaneously assessed FITC-sinistrin fluorescence signal was found to reflect the plasma concentration. Our method allows the precise determination of the onset of steady-state marker concentration. Moreover, the steady state can be monitored and controlled in real time for several hours. This procedure is simple to perform since no urine samples and only one blood sample are required. Thus, we developed a real-time feedback-based system for optimal regulation and monitoring of a constant infusion clearance technique.

Transcutaneous assessment of renal function in conscious rats with a device for measuring FITC-sinistrin disappearance curves.

Determination of the urinary or plasma clearance of exogenous renal markers, such as inulin or iohexol, is considered to be the gold standard for glomerular filtration rate (GFR) measurement. Here, we describe a technique allowing determination of renal function based on transcutaneously measured elimination kinetics of fluorescein isothiocyanate (FITC)-sinistrin, the FITC-labeled active pharmaceutical ingredient of a commercially available marker of GFR. A low cost device transcutaneously excites FITC-sinistrin at 480 nm and detects the emitted light through the skin at 520 nm. A radio-frequency transmission allows remote monitoring and real-time analysis of FITC-sinistrin excretion as a marker of renal function. Due to miniaturization, the whole device fits on the back of freely moving rats, and requires neither blood sampling nor laboratory assays. As proof of principle, comparative measurements of transcutaneous and plasma elimination kinetics of FITC-sinistrin were compared in freely moving healthy rats, rats showing reduced kidney function due to unilateral nephrectomy and PKD/Mhm rats with cystic kidney disease. Results show highly comparable elimination half-lives and GFR values in all animal groups. Bland-Altman analysis of enzymatically compared with transcutaneously measured GFR found a mean difference (bias) of 0.01 and a -0.30 to 0.33 ml/min per 100 g body weight with 95% limit of agreement. Thus, with this device, renal function can be reliably measured in freely moving rats eliminating the need for and influence of anesthesia on renal function.

Evaluation of clip localization for different kilovoltage imaging modalities as applied to partial breast irradiation setup.

Surgical clip localization and image quality were evaluated for different types of kilovoltage cone beam imaging modalities as applied to partial breast irradiation (PBI) setup. These modalities included (i) clinically available radiographs and cone beam CT (CB-CT) and (ii) various alternative modalities based on partial/sparse/truncated CB-CT. An anthropomorphic torso-breast phantom with surgical clips was used for the imaging studies. The torso phantom had artificial lungs, and the attached breast phantom was a mammographic phantom with realistic shape and tissue inhomogeneities. Three types of clips of variable size were used in two orthogonal orientations to assess their in-/cross-plane characteristics for image-guided setup of the torso-breast phantom in supine position. All studies were performed with the Varian on-board imaging (OBI, Varian) system. CT reconstructions were calculated with the standard Feldkamp-Davis-Kress algorithm. First, the radiographs were studied for a wide range of viewing angles to characterize image quality for various types of body anatomy in the foreground/background of the clips. Next, image reconstruction quality was evaluated for partial/sparse/truncated CB-CT. Since these modalities led to reconstructions with strong artifacts due to insufficient input data, a knowledge-based CT reconstruction method was also tested. In this method, the input data to the reconstruction algorithm were modified by combining complementary data sets selected from the treatment and reference projections. Different partial/sparse/truncated CB-CT scan types were studied depending on the total are angle, angular increment between the consequent views (CT projections), orientation of the arc center with respect to the imaged breast and chest wall, and imaging field size. The central angles of the viewing arcs were either tangential or orthogonal to the chest wall. Several offset positions of the phantom with respect to the reference position were studied. The acquired and reconstructed image data sets were analyzed using home-built software focusing on the ability to localize clips in 3D. Streaking and leakage reconstruction artifacts and spatial distortions of breast surface were analyzed as well. Advantages and disadvantages of each kilovoltage CB imaging modality as applied to partial breast setup evaluation based on clips are presented. Because clips were found to be difficult to recognize in radiographs, 3D reconstructions were preferred. Even though it was possible to localize clips with about +/-1 mm accuracy based on reconstructions for short arcs of 40 degrees and incremental angle up to about 5 degrees, identification of clips in such reconstructions is difficult. Reconstructions obtained for arcs of as low as 80 degrees and incremental angle of as high as 3 degrees were suggested for easier clip identification. For more severely undersampled data, iterative CB-CT reconstruction is recommended to decrease the artifacts.

Evaluation of a new image reconstruction method for digital breast tomosynthesis: effects on the visibility of breast lesions and breast density.

OBJECTIVE: To compare image quality and breast density of two reconstruction methods, the widely-used filtered-back projection (FBP) reconstruction and the iterative heuristic Bayesian inference reconstruction (Bayesian inference reconstruction plus the method of total variation applied, HBI). METHODS: Thirty-two clinical DBT data sets with malignant and benign findings, n = 27 and 17, respectively, were reconstructed using FBP and HBI. Three experienced radiologists evaluated the images independently using a 5-point visual grading scale and classified breast density according to the American College of Radiology Breast Imaging-Reporting And Data System Atlas, fifth edition. Image quality metrics included lesion conspicuity, clarity of lesion borders and spicules, noise level, artifacts surrounding the lesion, visibility of parenchyma and breast density. RESULTS: For masses, the image quality of HBI reconstructions was superior to that of FBP in terms of conspicuity,clarity of lesion borders and spicules (p < 0.01). HBI and FBP were not significantly different in calcification conspicuity. Overall, HBI reduced noise and supressed artifacts surrounding the lesions better (p < 0.01). The visibility of fibroglandular parenchyma increased using the HBI method (p < 0.01). On average, five cases per radiologist were downgraded from BI-RADS breast density category C/D to A/B. CONCLUSION: HBI significantly improves lesion visibility compared to FBP. HBI-visibility of breast parenchyma increased, leading to a lower breast density rating. Applying the HBIR algorithm should improve the diagnostic performance of DBT and decrease the need for additional imaging in patients with dense breasts. ADVANCES IN KNOWLEDGE: Iterative heuristic Bayesian inference (HBI) image reconstruction substantially improves the image quality of breast tomosynthesis leading to a better visibility of breast carcinomas and reduction of the perceived breast density compared to the widely-used filtered-back projection (FPB) reconstruction. Applying HBI should improve the accuracy of breast tomosynthesis and reduce the number of unnecessary breast biopsies. It may also reduce the radiation dose for the patients, which is especially important in the screening context.

Automated ultrafast kilovoltage-megavoltage cone-beam CT for image guided radiotherapy of lung cancer: System description and real-time results.

PURPOSE: To establish a fully automated kV-MV CBCT imaging method on a clinical linear accelerator that allows image acquisition of thoracic targets for patient positioning within one breath-hold (∼15s) under realistic clinical conditions. METHODS AND MATERIALS: Our previously developed FPGA-based hardware unit which allows synchronized kV-MV CBCT projection acquisition is connected to a clinical linear accelerator system via a multi-pin switch; i.e. either kV-MV imaging or conventional clinical mode can be selected. An application program was developed to control the relevant linac parameters automatically and to manage the MV detector readout as well as the gantry angle capture for each MV projection. The kV projections are acquired with the conventional CBCT system. GPU-accelerated filtered backprojection is performed separately for both data sets. After appropriate grayscale normalization both modalities are combined and the final kV-MV volume is re-imported in the CBCT system to enable image matching. To demonstrate adequate geometrical accuracy of the novel imaging system the Penta-Guide phantom QA procedure is performed. Furthermore, a human plastinate and different tumor shapes in a thorax phantom are scanned. Diameters of the known tumor shapes are measured in the kV-MV reconstruction. RESULTS: An automated kV-MV CBCT workflow was successfully established in a clinical environment. The overall procedure, from starting the data acquisition until the reconstructed volume is available for registration, requires ∼90s including 17s acquisition time for 100° rotation. It is very simple and allows target positioning in the same way as for conventional CBCT. Registration accuracy of the QA phantom is within ±1mm. The average deviation from the known tumor dimensions measured in the thorax phantom was 0.7mm which corresponds to an improvement of 36% compared to our previous kV-MV imaging system. CONCLUSIONS: Due to automation the kV-MV CBCT workflow is speeded up by a factor of >10 compared to the manual approach. Thus, the system allows a simple, fast and reliable imaging procedure and fulfills all requirements to be successfully introduced into the clinical workflow now, enabling single-breath-hold volume imaging.

Phantom-based evaluation of dose exposure of ultrafast combined kV-MV-CBCT towards clinical implementation for IGRT of lung cancer.

PURPOSE: Combined ultrafast 90°+90° kV-MV-CBCT within single breath-hold of 15s has high clinical potential for accelerating imaging for lung cancer patients treated with deep inspiration breath-hold (DIBH). For clinical feasibility of kV-MV-CBCT, dose exposure has to be small compared to prescribed dose. In this study, kV-MV dose output is evaluated and compared to clinically-established kV-CBCT. METHODS: Accurate dose calibration was performed for kV and MV energy; beam quality was determined. For direct comparison of MV and kV dose output, relative biological effectiveness (RBE) was considered. CT dose index (CTDI) was determined and measurements in various representative locations of an inhomogeneous thorax phantom were performed to simulate the patient situation. RESULTS: A measured dose of 20.5mGE (Gray-equivalent) in the target region was comparable to kV-CBCT (31.2mGy for widely-used, and 9.1mGy for latest available preset), whereas kV-MV spared healthy tissue and reduced dose to 6.6mGE (30%) due to asymmetric dose distribution. The measured weighted CTDI of 12mGE for kV-MV lay in between both clinical presets. CONCLUSIONS: Dosimetric properties were in agreement with established imaging techniques, whereas exposure to healthy tissue was reduced. By reducing the imaging time to a single breath-hold of 15s, ultrafast combined kV-MV CBCT shortens patient time at the treatment couch and thus improves patient comfort. It is therefore usable for imaging of hypofractionated lung DIBH patients.

A Novel Analysis Technique for Transcutaneous Measurement of Glomerular Filtration Rate With Ultralow Dose Marker Concentrations.

OBJECTIVE: A novel high-precision approach [lifetime-decomposition measurement (LTDM)] for the assessment of the glomerular filtration rate (GFR) based on clearance measurements of exogenous filtration marker. METHODS: The time-correlated single photon counting (TCSPC) acquisition in combination with a new decomposition method allows the separation of signal and background from transcutaneous measurements of GFR. RESULTS: The performance of LTDM is compared versus the commercially available NIC-kidney patch-based system for transcutaneous GFR measurement. Measurements are performed in awake Sprague Dawley (SD) rats. Using the standard concentration required for the NIC-kidney system [7-mg/100-g body weight (b.w.) FITC-Sinistrin] as reference, the mean difference (bias) of the elimination curves GFR between LTDM and NIC-kidney was 4.8%. On the same animal and same day, the capability of LTDM to measure GFR with a FITC-Sinistrin dose reduced by a factor of 200 (35-µg/100-g b.w.) was tested as well. The mean differences (half lives with low dose using LTDM compared with those using first, the NIC-Kidney system and its standard concentration, and second, LTDM with the same concentration as for the NIC-Kidney system) were 3.4% and 4.5%, respectively. CONCLUSION: We demonstrate that with the LTDM strategy substantial reductions in marker concentrations are possible at the same level of accuracy. SIGNIFICANCE: LTDM aims to resolve the issue of the currently necessary large doses of fluorescence tracer required for transcutaneous GFR measurement. Due to substantially less influences from autofluorescence and artifacts, the proposed method outperforms other existing techniques for accurate percutaneous organ function measurement.

Incorporation of local dependent reliability information into the Prior Image Constrained Compressed Sensing (PICCS) reconstruction algorithm.

PURPOSE: The reduction of dose in cone beam computer tomography (CBCT) arises from the decrease of the tube current for each projection as well as from the reduction of the number of projections. In order to maintain good image quality, sophisticated image reconstruction techniques are required. The Prior Image Constrained Compressed Sensing (PICCS) incorporates prior images into the reconstruction algorithm and outperforms the widespread used Feldkamp-Davis-Kress-algorithm (FDK) when the number of projections is reduced. However, prior images that contain major variations are not appropriately considered so far in PICCS. We therefore propose the partial-PICCS (pPICCS) algorithm. This framework is a problem-specific extension of PICCS and enables the incorporation of the reliability of the prior images additionally. MATERIAL AND METHODS: We assumed that the prior images are composed of areas with large and small deviations. Accordingly, a weighting matrix considered the assigned areas in the objective function. We applied our algorithm to the problem of image reconstruction from few views by simulations with a computer phantom as well as on clinical CBCT projections from a head-and-neck case. All prior images contained large local variations. The reconstructed images were compared to the reconstruction results by the FDK-algorithm, by Compressed Sensing (CS) and by PICCS. To show the gain of image quality we compared image details with the reference image and used quantitative metrics (root-mean-square error (RMSE), contrast-to-noise-ratio (CNR)). RESULTS: The pPICCS reconstruction framework yield images with substantially improved quality even when the number of projections was very small. The images contained less streaking, blurring and inaccurately reconstructed structures compared to the images reconstructed by FDK, CS and conventional PICCS. The increased image quality is also reflected in large RMSE differences. CONCLUSIONS: We proposed a modification of the original PICCS algorithm. The pPICCS algorithm incorporates prior images as well as information about location dependent uncertainties of the prior images into the algorithm. The computer phantom and experimental data studies indicate the potential to lowering the radiation dose to the patient due to imaging while maintaining good image quality.

Automation of clip localization in Digital Tomosynthesis for setup of breast cancer patients.

The objective of this study is to develop an automatic clip localization procedure for breast cancer patient setup based on Digital Tomosynthesis (DTS) and to characterize its performance with respect to the overall registration accuracy and robustness. The study was performed under an IRB-approved protocol for 12 breast cancer patients with surgical clips implanted around the tumor cavity. The registration of DTS images to planning CTs was performed using an automatic algorithm developed to overcome specific challenges of localization and registration of clips in the breast setup images. The automatic method consisted of auto-segmentation (intensity-based thresholding with a priori knowledge about clip size and location to distinguish clips from bony features) and auto-registration of the segmented clip clusters. To determine the inherent accuracy and robustness of the registration algorithm, additional simulated DTS data was analyzed. The developed algorithm is efficient in removing false positives and negatives and provides an accuracy of better than 2.3mm for 60° and 3.3mm for 40° DTS. When incorporated in clinical software, this algorithm helps to facilitate fast and accurate setup evaluation with minimal dose delivered to patients.

Reliability of transcutaneous measurement of renal function in various strains of conscious mice.

Measuring renal function in laboratory animals using blood and/or urine sampling is not only labor-intensive but puts also a strain on the animal. Several approaches for fluorescence based transcutaneous measurement of the glomerular filtration rate (GFR) in laboratory animals have been developed. They allow the measurement of GFR based on the elimination kinetics of fluorescent exogenous markers. None of the studies dealt with the reproducibility of the measurements in the same animals. Therefore, the reproducibility of a transcutaneous GFR assessment method was investigated using the fluorescent renal marker FITC-Sinistrin in conscious mice in the present study. We performed two transcutaneous GFR measurements within three days in five groups of mice (Balb/c, C57BL/6, SV129, NMRI at 3-4 months of age, and a group of 24 months old C57BL/6). Data were evaluated regarding day-to-day reproducibility as well as intra- and inter-strain variability of GFR and the impact of age on these parameters. No significant differences between the two subsequent GFR measurements were detected. Fastest elimination for FITC-Sinistrin was detected in Balb/c with significant differences to C57BL/6 and SV129 mice. GFR decreased significantly with age in C57BL/6 mice. Evaluation of GFR in cohorts of young and old C57BL/6 mice from the same supplier showed high consistency of GFR values between groups. Our study shows that the investigated technique is a highly reproducible and reliable method for repeated GFR measurements in conscious mice. This gentle method is easily used even in old mice and can be used to monitor the age-related decline in GFR.

Breath-hold target localization with simultaneous kilovoltage/megavoltage cone-beam computed tomography and fast reconstruction.

PURPOSE: Hypofractionated high-dose radiotherapy for small lung tumors has typically been based on stereotaxy. Cone-beam computed tomography and breath-hold techniques have provided a noninvasive basis for precise cranial and extracranial patient positioning. The cone-beam computed tomography acquisition time of 60 s, however, is beyond the breath-hold capacity of patients, resulting in respiratory motion artifacts. By combining megavoltage (MV) and kilovoltage (kV) photon sources (mounted perpendicularly on the linear accelerator) and accelerating the gantry rotation to the allowed limit, the data acquisition time could be reduced to 15 s. METHODS AND MATERIALS: An Elekta Synergy 6-MV linear accelerator, with iViewGT as the MV- and XVI as the kV-imaging device, was used with a Catphan phantom and an anthropomorphic thorax phantom. Both image sources performed continuous image acquisition, passing an angle interval of 90° within 15 s. For reconstruction, filtered back projection on a graphics processor unit was used. It reconstructed 100 projections acquired to a 512 × 512 × 512 volume within 6 s. RESULTS: The resolution in the Catphan phantom (CTP528 high-resolution module) was 3 lines/cm. The spatial accuracy was within 2-3 mm. The diameters of different tumor shapes in the thorax phantom were determined within an accuracy of 1.6 mm. The signal-to-noise ratio was 68% less than that with a 180°-kV scan. The dose generated to acquire the MV frames accumulated to 82.5 mGy, and the kV contribution was <6 mGy. CONCLUSION: The present results have shown that fast breath-hold, on-line volume imaging with a linear accelerator using simultaneous kV-MV cone-beam computed tomography is promising and can potentially be used for image-guided radiotherapy for lung cancer patients in the near future.

Fast kilovoltage/megavoltage (kVMV) breathhold cone-beam CT for image-guided radiotherapy of lung cancer.

Long image acquisition times of 60-120 s for cone-beam CT (CBCT) limit the number of patients with lung cancer who can undergo volume image guidance under breathhold. We developed a low-dose dual-energy kilovoltage-megavoltage-cone-beam CT (kVMV-CBCT) based on a clinical treatment unit reducing imaging time to < or =15 s. Simultaneous kVMV-imaging was achieved by dedicated synchronization hardware controlling the output of the linear accelerator (linac) based on detector panel readout signals, preventing imaging artifacts from interference of the linac's MV-irradiation and panel readouts. Optimization was performed to minimize the imaging dose. Single MV-projections, reconstructed MV-CBCT images and images of simultaneous 90 degrees kV- and 90 degrees MV-CBCT (180 degrees kVMV-CBCT) were acquired with different parameters. Image quality and imaging dose were evaluated and compared to kV-imaging. Hardware-based kVMV synchronization resulted in artifact-free projections. A combined 180 degrees kVMV-CBCT scan with a total MV-dose of 5 monitor units was acquired in 15 s and with sufficient image quality. The resolution was 5-6 line pairs cm(-1) (Catphan phantom). The combined kVMV-scan dose was equivalent to a kV-radiation scan dose of approximately 33 mGy. kVMV-CBCT based on a standard linac is promising and can provide ultra-fast online volume image guidance with low imaging dose and sufficient image quality for fast and accurate patient positioning for patients with lung cancer under breathhold.