Daniel Opp

Use of electric cell–substrate impedance sensing to assess in vitro cytotoxicity

In vitro assessment of cytotoxicity based on electrochemical impedance spectroscopy (EIS) needs more quantitative methods to analyze the alteration of cell morphology and motility, and hence the potential risk to human health. Here, we applied electric cell-substrate impedance sensing (ECIS) to evaluate dose-dependent responses of human umbilical vein endothelial cells exposed to cytochalasin B. To detect subtle changes in cell morphology, the frequency-dependent impedance data of the cell monolayer were measured and analyzed with a theoretical cell-electrode model. To detect the alternation of cell micromotion in response to cytochalasin B challenge, time-series impedance fluctuations of cell-covered electrodes were monitored and the values of power spectrum, variance, and variance of the increments were calculated to verify the difference. While a dose-dependent relationship was generally observed from the overall resistance of the cell monolayer, the analysis of frequency-dependent impedance and impedance fluctuations distinguished cytochalasin B levels as low as 0.1 microM. Our results show that cytochalasin B causes a decrease of junctional resistance between cells, an increase of membrane capacitance, and the reduction in micromotion.

Evaluation of a biplanar diode array dosimeter for quality assurance of step-and-shoot IMRT.

In this paper, we describe and characterize a novel biplanar diode array, and demonstrate its applicability to dosimetric QA of step‐and‐shoot IMRT. It is the first commercially available device of its kind specifically designed for performing measurements at varying gantry angles. The detector consists of a cylindrical PMMA phantom with two orthogonal detector boards. There are a total of 1069 p‐type 1 mm wide diode detectors covering the measurement area of 20×20cm2 in each of the measurement planes. The orthogonal detector arrays ensure that the dose modulation information is not lost regardless of the beam incidence angle. For absolute calibration, the dose to the reference detector is calculated at the appropriate SSD and radiological depth by the treatment planning system and is scaled by the measured accelerator output. The directly measured rotational response on the central axis shows the maximum variation of approximately ± 3% in the narrow ±1º angular intervals centered on the detector boards. This variation is reduced to less than ± 2% outside of the four similarly centered ± 5% angular intervals. For all detectors, the difference between the measured and the calculated dose for a plan with 12 equally spaced beams is −0.2±0.9%. Of eleven IMRT plans, ten passed the γ (3%,3 mm) criterion at or above 95%, while one passed at 92%. The biplanar diode array is a useful tool for IMRT QA, allowing for essentially instantaneous online analysis of absolute dose errors in 3D. PACS number: 87.55Qr

Evaluation of a 3D Diode Array Dosimeter for Helical Tomotherapy Delivery QA

The Delta4 biplanar diode array dosimeter was validated for helical tomotherapy delivery QA. The basic detector characteristics were found to be satisfactory in terms of short-term reproducibility (0.1%), linearity (<0.1%), dose rate dependence (0.4%), and absolute calibration accuracy (0.4% in the center of the phantom compared with the independently calibrated diode). Relative calibration of the arrays was verified by comparison with film and by rotating the detector 180°. The dosimeter response to rotational irradiation changed by no more than 0.2% when one of the detector boards was replaced by the homogeneous phantom material. The daily output correction factor can be derived from a Delta4 measurement in a uniform cylindrical field. The γ(3%, 3 mm) passing rate (absolute dose) was above 90% for all 9 evaluated clinical plans, and above 96% for all but one. The mean passing rate was 97 ± 2.7%. The plans varied in modulation factor, pitch, and calculation grid size. For best results, the phantom needs to be aligned carefully, preferably by megavoltage computed tomography imaging.

Validation of measurement-guided 3D VMAT dose reconstruction on a heterogeneous anthropomorphic phantom

3DVH software (Sun Nuclear Corp., Melbourne, FL) is capable of generating a volumetric patient VMAT dose by applying a volumetric perturbation algorithm based on comparing measurement‐guided dose reconstruction and TPS‐calculated dose to a cylindrical phantom. The primary purpose of this paper is to validate this dose reconstruction on an anthropomorphic heterogeneous thoracic phantom by direct comparison to independent measurements. The dosimetric insert to the phantom is novel, and thus the secondary goal is to demonstrate how it can be used for the hidden target end‐to‐end testing of VMAT treatments in lung. A dosimetric insert contains a 4 cm diameter unit‐density spherical target located inside the right lung (0.21g/cm3 density). It has 26 slots arranged in two orthogonal directions, milled to hold optically stimulated luminescent dosimeters (OSLDs). Dose profiles in three cardinal orthogonal directions were obtained for five VMAT plans with varying degrees of modulation. After appropriate OSLD corrections were applied, 3DVH measurement‐guided VMAT dose reconstruction agreed 100% with the measurements in the unit density target sphere at 3%/3 mm level (composite analysis) for all profile points for the four less‐modulated VMAT plans, and for 96% of the points in the highly modulated C‐shape plan (from TG‐119). For this latter plan, while 3DVH shows acceptable agreement with independent measurements in the unit density target, in the lung disagreement with experiment is relatively high for both the TPS calculation and 3DVH reconstruction. For the four plans excluding the C‐shape, 3%/3mm overall composite analysis passing rates for 3DVH against independent measurement ranged from 93% to 100%. The C‐shape plan was deliberately chosen as a stress test of the algorithm. The dosimetric spatial alignment hidden target test demonstrated the average distance to agreement between the measured and TPS profiles in the steep dose gradient area at the edge of the 2 cm target to be 1.0±0.7,0.3±0.3, and 0.3±0.3mm for the IEC X, Y, and Z directions, respectively. PACS number: 87.55Qr

Motion as a perturbation: Measurement-guided dose estimates to moving patient voxels during modulated arc deliveries

PURPOSE To present a framework for measurement-guided VMAT dose reconstruction to moving patient voxels from a known motion kernel and the static phantom data, and to validate this perturbation-based approach with the proof-of-principle experiments. METHODS As described previously, the VMAT 3D dose to a static patient can be estimated by applying a phantom measurement-guided perturbation to the treatment planning system (TPS)-calculated dose grid. The fraction dose to any voxel in the presence of motion, assuming the motion kernel is known, can be derived in a similar fashion by applying a measurement-guided motion perturbation. The dose to the diodes in a helical phantom is recorded at 50 ms intervals and is transformed into a series of time-resolved high-density volumetric dose grids. A moving voxel is propagated through this 4D dose space and the fraction dose to that voxel in the phantom is accumulated. The ratio of this motion-perturbed, reconstructed dose to the TPS dose in the phantom serves as a perturbation factor, applied to the TPS fraction dose to the similarly situated voxel in the patient. This approach was validated by the ion chamber and film measurements on four phantoms of different shape and structure: homogeneous and inhomogeneous cylinders, a homogeneous cube, and an anthropomorphic thoracic phantom. A 2D motion stage was used to simulate the motion. The stage position was synchronized with the beam start time with the respiratory gating simulator. The motion patterns were designed such that the motion speed was in the upper range of the expected tumor motion (1-1.4 cm∕s) and the range exceeded the normally observed limits (up to 5.7 cm). The conformal arc plans for X or Y motion (in the IEC 61217 coordinate system) consisted of manually created narrow (3 cm) rectangular strips moving in-phase (tracking) or phase-shifted by 90° (crossing) with respect to the phantom motion. The XY motion was tested with the computer-derived VMAT MLC sequences. For all phantoms and plans, time-resolved (10 Hz) ion chamber dose was collected. In addition, coronal (XY) films were exposed in the cube phantom to a VMAT beam with two different starting phases, and compared to the reconstructed motion-perturbed dose planes. RESULTS For the X or Y motions with the moving strip and geometrical phantoms, the maximum difference between perturbation-reconstructed and ion chamber doses did not exceed 1.9%, and the average for any motion pattern∕starting phase did not exceed 1.3%. For the VMAT plans on the cubic and thoracic phantoms, one point exhibited a 3.5% error, while the remaining five were all within 1.1%. Across all the measurements (N = 22), the average disagreement was 0.5 ± 1.3% (1 SD). The films exhibited γ(3%∕3 mm) passing rates ≥90%. CONCLUSIONS The dose to an arbitrary moving voxel in a patient can be estimated with acceptable accuracy for a VMAT delivery, by performing a single QA measurement with a cylindrical phantom and applying two consecutive perturbations to the TPS-calculated patient dose. The first one accounts for the differences between the planned and delivered static doses, while the second one corrects for the motion.

Cross-validation of two commercial methods for volumetric high-resolution dose reconstruction on a phantom for non-coplanar VMAT beams.

BACKGROUND AND PURPOSE Delta(4) (ScandiDos AB, Uppsala, Sweden) and ArcCHECK with 3DVH software (Sun Nuclear Corp., Melbourne, FL, USA) are commercial quasi-three-dimensional diode dosimetry arrays capable of volumetric measurement-guided dose reconstruction. A method to reconstruct dose for non-coplanar VMAT beams with 3DVH is described. The Delta(4) 3D dose reconstruction on its own phantom for VMAT delivery has not been thoroughly evaluated previously, and we do so by comparison with 3DVH. MATERIALS AND METHODS Reconstructed volumetric doses for VMAT plans delivered with different table angles were compared between the Delta(4) and 3DVH using gamma analysis. RESULTS The average γ (2% local dose-error normalization/2mm) passing rate comparing the directly measured Delta(4) diode dose with 3DVH was 98.2 ± 1.6% (1SD). The average passing rate for the full volumetric comparison of the reconstructed doses on a homogeneous cylindrical phantom was 95.6 ± 1.5%. No dependence on the table angle was observed. CONCLUSIONS Modified 3DVH algorithm is capable of 3D VMAT dose reconstruction on an arbitrary volume for the full range of table angles. Our comparison results between different dosimeters make a compelling case for the use of electronic arrays with high-resolution 3D dose reconstruction as primary means of evaluating spatial dose distributions during IMRT/VMAT verification.

Evaluating dosimetric accuracy of flattening filter free compensator-based IMRT: Measurements with diode arrays

PURPOSE Compensator-based IMRT coupled with the high dose rate flattening filter free (FFF) beams offers an intriguing possibility of delivering an intensity modulated radiation field in just a few seconds. As a first step, the authors evaluate the dosimetric accuracy of the treatment planning system (TPS) FFF beam model with compensators. METHODS A 6 MV FFF beam from a TrueBeam accelerator (Varian Medical Systems, Palo Alto CA) was modeled in PINNACLE TPS (v. 9.0, Philips Radiation Oncology, Fitchburg WI). Flat brass slabs from 0.3 to 7 cm thick and an 18° brass wedge were used to adjust the beam model. A 2D (MAPCHECK) and 3D (ARCCHECK) diode arrays (Sun Nuclear Corp, Melbourne FL), were investigated for use with the compensator FFF beams. Corrections for diode sensitivity caused by the spectral changes in the beam were introduced. Four compensator plans based on the AAPM TG-119 report were developed. A composite ion chamber measurement, beam by beam MAPCHECK measurements, and a composite ARCCHECK measurement were performed. The array results were analyzed with the same thresholds as in TG-119 report-3%/3 mm with global dose normalization-as well as with the more stringent combinations of the gamma analysis criteria. RESULTS The FFF beam shows a greater variation of the effective attenuation coefficient with brass thickness due to the prevalence of the low energy photons compared to the conventional 6X beam. As a result, a compromise had to be made while trying to achieve dose agreement for a combination of field sizes, brass thicknesses, and measurement depths (≥5 cm in water). An agreement of measured and calculated dose to within 1% was observed for brass thicknesses up to 2 cm. For the 3 cm slab, an error of up to 2.8% was noted for the field sizes above 10 × 10 cm(2), and up to 3.8% for the 5 × 5 cm(2) field. Both diode arrays exhibit a substantial sensitivity drop as the compensator thickness increases, reaching 10% for a 7 cm brass slab. A simple correction based on the brass thickness along the ray was introduced to counteract this effect. Pooled for five profiles, the average ratio of uncorrected and corrected MAPCHECK to ion chamber readings are 0.966 and 1.008, respectively. With the proper correction, all MAPCHECK measurement to calculation comparisons exhibit 100% γ(3%/3 mm) passing rates with global dose-error normalization. For the TG-119-type plans, the average γ(2%/2 mm) passing rate with local normalization is 94% (range 87.8%-98.3%). The lower ARCCHECK γ-analysis passing rates (corrected for diode sensitivity) are predictable based on the observed PDD discrepancies. However, with the 3%/3 mm thresholds and global normalization, the average γ-analysis passing rate is 96.4% (range 89.9%-100%). CONCLUSIONS MAPCHECK analysis demonstrates high passing rates with the stringent γ(2%/2 mm) and local normalization criteria combination. The geometry of the ARCCHECK array creates a stress test for the FFF TPS model because of the shallow depth of the entrance diodes and large air cavity. Hence, the ARCCHECK γ-analysis passing rates are lower than with the MAPCHECK, while still on par with TG-119.

Measurement-guided volumetric dose reconstruction for helical tomotherapy

It was previously demonstrated that dose delivered by a conventional linear accelerator using IMRT or VMAT can be reconstructed — on patient or phantom datasets — using helical diode array measurements and a technique called planned dose perturbation (PDP). This allows meaningful and intuitive analysis of the agreement between the planned and delivered dose, including direct comparison of the dose‐volume histograms. While conceptually similar to modulated arc techniques, helical tomotherapy introduces significant challenges to the PDP formalism, arising primarily from TomoTherapy delivery dynamics. The temporal characteristics of the delivery are of the same order or shorter than the dosimeters update interval (50 ms). Additionally, the prevalence of often small and complex segments, particularly with the 1 cm Y jaw setting, lead to challenges related to detector spacing. Here, we present and test a novel method of tomotherapy‐PDP (TPDP) designed to meet these challenges. One of the novel techniques introduced for TPDP is organization of the subbeams into larger subunits called sectors, which assures more robust synchronization of the measurement and delivery dynamics. Another important change is the optional application of a correction based on ion chamber (IC) measurements in the phantom. The TPDP method was validated by direct comparisons to the IC and an independent, biplanar diode array dosimeter previously evaluated for tomotherapy delivery quality assurance. Nineteen plans with varying complexity were analyzed for the 2.5 cm tomotherapy jaw setting and 18 for the 1 cm opening. The dose differences between the TPDP and IC were 1.0%±1.1% and 1.1%±1.1%, for 2.5 and 1.0 cm jaw plans, respectively. Gamma analysis agreement rates between TPDP and the independent array were: 99.1%±1.8% (using 3% global normalization/3 mm criteria) and 93.4%±7.1% (using 2% global/2 mm) for the 2.5 cm jaw plans; for 1 cm plans, they were 95.2%±6.7% (3% G/3) and 83.8%±12% (2% G/2). We conclude that TPDP is capable of volumetric dose reconstruction with acceptable accuracy. However, the challenges of fast tomotherapy delivery dynamics make TPDP less precise than the IMRT/VMAT PDP version, particularly for the 1 cm jaw setting. PACS number: 87.55Qr

Commissioning compensator-based IMRT on the Pinnacle treatment planning system

We present a systematic approach to commissioning of the compensator‐based IMRT in Pinnacle treatment planning system for commercially manufactured brass compensators. Some model parameters for the beams modulated by the variable‐thickness compensators can only be associated with a single compensator thickness. To intelligently choose that thickness for beam modeling, we empirically determined the most probable filter thickness occurring within the modulated portion of the compensators typically used in clinics. We demonstrated that a set of relative output factors measured with the brass slab of most probable thickness (2 cm) differs from the traditionally used open field set, and leads to improved agreement between measurements and calculations, particularly for the larger field sizes. By iteratively adjusting the modifier scatter factor and filter density, the calculated effective attenuation of the flat filters was brought to within 2% of the ion chamber measurement for the clinically‐relevant range of filter thicknesses, depths and filed sizes. Beam hardening representation in Pinnacle provides for adequate depth dose modeling beyond the depth of about 5 cm. Disagreement at shallower depth for the large field sizes is likely due to the algorithms inability to account for the low‐energy scattered photons generated in the filter. The average ion chamber point dose error at isocenter for ten clinical compensator‐based IMRT plans was under 1%. A biplanar 3D diode dosimeter was calibrated and validated for use with the compensators. The average gamma analysis (3%/3 mm) passing rate for ten IMRT plans was 98.9%± 1.0%. The device is particularly attractive because it easily generates dose comparisons at both the fraction and beam levels. Overlaying dose profiles for individual beams would easily uncover any errors in compensator orientation. PACS number: 87.55Qr

Evaluation of inhomogeneity correction factors for 6 MV flattening filter-free beams with brass compensators

The 6 MV flattening filter‐free (FFF) beam has been commissioned for use with compensators at our institution. This novel combination promises advantages in mitigating tumor motion due to the reduced treatment time made possible by the greatly increased dose rate of the FFF beam. Given the different energy spectrum of the FFF beam and the beam hardening effect of the compensator, the accuracy of the treatment planning system (TPS) model in the presence of low‐density heterogeneities cannot be assumed. Therefore, inhomogeneity correction factors (ICF) for an FFF beam attenuated by brass slabs were measured and compared to the TPS calculations in this work. The ICF is the ratio of the point dose in the presence of inhomogeneity to the dose in the same point in a homogeneous medium. The ICFs were measured with an ion chamber at a number of points in a flat water‐equivalent slab phantom containing a 7.5 cm deep heterogeneity (air or 0.27 g/cm3 wood). Comparisons for the FFF beam were carried out for the field sizes from 5×5 to 20×20 cm2 with the brass slabs ranging from 0 to 5 cm in thickness. For a low‐density wood heterogeneity in a slab phantom, with the exception of the point 1 cm beyond the proximal buildup interface, the TPS handles the inhomogeneity correction with the brass‐filtered 6 MV FFF beam at the requisite 2% error level. The combinations of field sizes and compensator thicknesses when the error exceeds 2% (2.6% maximum) are not likely to be experienced in clinical practice. In terms of heterogeneity corrections, the beam model is adequate for clinical use. PACS number: 87.56.ng