Dzmitry Stsepankou

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.

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 linacs 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.

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.

Evaluation of robustness of maximum likelihood cone-beam CT reconstruction with total variation regularization

The objective of this paper is to evaluate an iterative maximum likelihood (ML) cone-beam computed tomography (CBCT) reconstruction with total variation (TV) regularization with respect to the robustness of the algorithm due to data inconsistencies. Three different and (for clinical application) typical classes of errors are considered for simulated phantom and measured projection data: quantum noise, defect detector pixels and projection matrix errors. To quantify those errors we apply error measures like mean square error, signal-to-noise ratio, contrast-to-noise ratio and streak indicator. These measures are derived from linear signal theory and generalized and applied for nonlinear signal reconstruction. For quality check, we focus on resolution and CT-number linearity based on a Catphan phantom. All comparisons are made versus the clinical standard, the filtered backprojection algorithm (FBP). In our results, we confirm and substantially extend previous results on iterative reconstruction such as massive undersampling of the number of projections. Errors of projection matrix parameters of up to 1° projection angle deviations are still in the tolerance level. Single defect pixels exhibit ring artifacts for each method. However using defect pixel compensation, allows up to 40% of defect pixels for passing the standard clinical quality check. Further, the iterative algorithm is extraordinarily robust in the low photon regime (down to 0.05 mAs) when compared to FPB, allowing for extremely low-dose image acquisitions, a substantial issue when considering daily CBCT imaging for position correction in radiotherapy. We conclude that the ML method studied herein is robust under clinical quality assurance conditions. Consequently, low-dose regime imaging, especially for daily patient localization in radiation therapy is possible without change of the current hardware of the imaging system.

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.

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.

CathI – Training System for PTCA. A Step Closer to Reality

The number of minimally invasive cardiological interventions has increased over the last few years and therefore computer based training systems find growing interest. They offer a better learning schedule compared to traditional master-apprentice models due to the repeatability of the learning situation and the possibility to learn individual tasks.

Automatic artifact removal from GFR measurements

Abstract Measurement of renal function in awake rats or mice can be accomplished by an intelligent plaster device that fits on the back of animals. The device performs a percutaneous measurement of the kinetics of a labeled fluorescent dye exclusively eliminated by the kidney. During the measurement, relative motion between plaster and skin leads to a variation of the illumination conditions, which emerge as artifacts in the data. In this paper, a novel strategy to detect and eliminate artifacts is suggested. The method combines cluster analysis and nonlinear regression with a priori knowledge about signal morphology to correct data. The performance of the proposed method is demonstrated on real and simulated data. Simulations were performed on data with two artifact amplitude ranges: (1) shifts in the recorded data with amplitude exceeding 3% of the signal amplitude for a combined duration of 10% of the total measurement time and (2) shifts greater than 3% for approximately 30% of the total measurement time. Prior to artifact removal, the MAE was calculated to be 10.3% and 21.9%, respectively. Following artifact removal using the proposed method, results showed that, when determining the half-life, the mean absolute error (MAE) was 0.88% for range type 1 and 10.4% for the more substantial range of the type 2 artifacts. When examining real data, the mean difference (bias) while determining the half-life was 7.5%. Results show that novel technique outperforms a number of state-of-the-art techniques when removing artifacts from the signal recorded while an animal is allowed to move freely. In this case, the signal acquires shifts and random changes with large amplitudes, which make it impossible to use standard methods.

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.