Juergen Hesser

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.

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.

Low-cost flexible thin-film detector for medical dosimetry applications.

The purpose of this study is to characterize dosimetric properties of thin film photovoltaic sensors as a platform for development of prototype dose verification equipment in radiotherapy. Towards this goal, flexible thin‐film sensors of dose with embedded data acquisition electronics and wireless data transmission are prototyped and tested in kV and MV photon beams. Fundamental dosimetric properties are determined in view of a specific application to dose verification in multiple planes or curved surfaces inside a phantom. Uniqueness of the new thin‐film sensors consists in their mechanical properties, low‐power operation, and low‐cost. They are thinner and more flexible than dosimetric films. In principle, each thin‐film sensor can be fabricated in any size (mm2 – cm2 areas) and shape. Individual sensors can be put together in an array of sensors spreading over large areas and yet being light. Photovoltaic mode of charge collection (of electrons and holes) does not require external electric field applied to the sensor, and this implies simplicity of data acquisition electronics and low power operation. The prototype device use for testing consists of several thin film dose sensors, each of about 1.5 cm×5 cm area, connected to simple readout electronics. Sensitivity of the sensors is determined per unit area and compared to EPID sensitivity, as well as other standard photodiodes. Each sensor independently measures dose and is based on commercially available flexible thin‐film aSi photodiodes. Readout electronics consists of an ultra low‐power microcontroller, radio frequency transmitter, and a low‐noise amplification circuit implemented on a flexible printed circuit board. Detector output is digitized and transmitted wirelessly to an external host computer where it is integrated and processed. A megavoltage medical linear accelerator (Varian Tx) equipped with kilovoltage online imaging system and a Cobalt source are use to irradiate different thin‐film detector sensors in a Solid Water phantom under various irradiation conditions. Different factors are considered in characterization of the device attributes: energies (80 kVp, 130 kVp, 6 MV, 15 MV), dose rates (different ms × mA, 100–600 MU/min), total doses (0.1 cGy‐500 cGy), depths (0.5 cm–20 cm), irradiation angles with respect to the detector surface (0°‐180°), and IMRT tests (closed MLC, sweeping gap). The detector response to MV radiation is both linear with total dose (~1‐400 cGy) and independent of dose rate (100‐600 Mu/min). The sensitivity per unit area of thin‐film sensors is lower than for aSi flat‐panel detectors, but sufficient to acquire stable and accurate signals during irradiations. The proposed thin‐film photodiode system has properties which make it promising for clinical dosimetry. Due to the mechanical flexibility of each sensor and readout electronics, low‐cost, and wireless data acquisition, it could be considered for quality assurance (e.g., IMRT, mechanical linac QA), as well as real‐time dose monitoring in challenging setup configurations, including large area and 3D detection (multiple planes or curved surfaces). PACS number: 87.56.Fc

Nonlinear image restoration methods for marker extraction in 3D fluorescent microscopy

Localization of biological markers in images obtained by fluorescent microscopy is a relevant problem in biological research. Due to blurring from imaging and noise, the analysis of supra-molecular structures can be improved by image restoration. In this paper, we compare various deblurring algorithms with and without regularization. In the first group we consider the EM (Expectation Maximization) and the JVC (Jansson-van-Cittert) algorithms and examine the effect of the Tikhonov and the TV (Total Variation) regularization in the second group. The last approach uses the I-divergence as similarity measure. As solution method for our new I-divergence--TV model we propose a non-linear projective conjugate gradient algorithm with inexact linear search. Optimal regularization parameters were found by the shape analysis of corresponding L-curves.

A new optimization method using a compressed sensing inspired solver for real-time LDR-brachytherapy treatment planning

This work discusses a novel strategy for inverse planning in low dose rate brachytherapy. It applies the idea of compressed sensing to the problem of inverse treatment planning and a new solver for this formulation is developed. An inverse planning algorithm was developed incorporating brachytherapy dose calculation methods as recommended by AAPM TG-43. For optimization of the functional a new variant of a matching pursuit type solver is presented. The results are compared with current state-of-the-art inverse treatment planning algorithms by means of real prostate cancer patient data. The novel strategy outperforms the best state-of-the-art methods in speed, while achieving comparable quality. It is able to find solutions with comparable values for the objective function and it achieves these results within a few microseconds, being up to 542 times faster than competing state-of-the-art strategies, allowing real-time treatment planning. The sparse solution of inverse brachytherapy planning achieved with methods from compressed sensing is a new paradigm for optimization in medical physics. Through the sparsity of required needles and seeds identified by this method, the cost of intervention may be reduced.

Optimal parameters for clinical implementation of breast cancer patient setup using Varian DTS software

Digital tomosynthesis (DTS) was evaluated as an alternative to cone‐beam computed tomography (CBCT) for patient setup. DTS is preferable when there are constraints with setup time, gantry‐couch clearance, and imaging dose using CBCT. This study characterizes DTS data acquisition and registration parameters for the setup of breast cancer patients using nonclinical Varian DTS software. DTS images were reconstructed from CBCT projections acquired on phantoms and patients with surgical clips in the target volume. A shift‐and‐add algorithm was used for DTS volume reconstructions, while automated cross‐correlation matches were performed within Varian DTS software. Triangulation on two short DTS arcs separated by various angular spread was done to improve 3D registration accuracy. Software performance was evaluated on two phantoms and ten breast cancer patients using the registration result as an accuracy measure; investigated parameters included arc lengths, arc orientations, angular separation between two arcs, reconstruction slice spacing, and number of arcs. The shifts determined from DTS‐to‐CT registration were compared to the shifts based on CBCT‐to‐CT registration. The difference between these shifts was used to evaluate the software accuracy. After findings were quantified, optimal parameters for the clinical use of DTS technique were determined. It was determined that at least two arcs were necessary for accurate 3D registration for patient setup. Registration accuracy of 2 mm was achieved when the reconstruction arc length was > 5° for clips with HU ≥ 1000°; larger arc length (≥ 8°) was required for very low HU clips. An optimal arc separation was found to be ≥ 20° and optimal arc length was 10°. Registration accuracy did not depend on DTS slice spacing. DTS image reconstruction took 10–30 seconds and registration took less than 20 seconds. The performance of Varian DTS software was found suitable for the accurate setup of breast cancer patients. Optimal data acquisition and registration parameters were determined. PACS numbers: 87.57.‐s, 87.57.nf, 87.57.nj

Prov2ONE: An Algorithm for Automatically Constructing ProvONE Provenance Graphs

Provenance traces history within workflows and enables researchers to validate and compare their results. Currently, modelling provenance in ProvONE is an arduous task and lacks an automated approach. This paper introduces a novel algorithm, called Prov2ONE that automatically generates the ProvONE prospective provenance for scientific workflows defined in BPEL4WS. The same prospective ProvONE graph is updated with the relevant retrospective provenance, preventing provenance to be captured in various non-standard provenance models and thus enabling research communities to share, compare and analyze workflows and its associated provenance. Finally, using the Prov2ONE algorithm, a ProvONE provenance graph for the nanoscopy workflow is generated.

An Optimized Generic Client Service API for Managing Large Datasets within a Data Repository

Exponential growth in scientific research data demands novel measures for managing the extremely large datasets. In particular, due to advancements in high-resolution microscopy, the nanoscopy scientific research community is producing datasets up to the range of multiple TeraBytes (TB). Systematically acquired datasets of biological specimens are composed of multiple high-resolution images, in the range of 150-200 TB. The management of these extremely large datasets requires an optimized Generic Client Service (GCS) API with an integration into a data repository system. The novel API proposed in this paper provides an abstract interface that connects various disparate systems. The API is optimized to provide an efficient and automated ingest, download of the data and management of its metadata. The ingest and download processes are based on well-defined workflows stated in this paper. The base metadata model for comprehensive description of the datasets is also stated in the paper. The API is seamlessly integrated with a digital data repository system, namely KIT Data Manager to make it adaptable for a wide range of communities. Finally, a simple and easy to use command line tool is realized based on GCS API to manage large datasets of nanoscopy research community.