Hans-Soenke Jans

A study on the magnetic resonance imaging (MRI)-based radiation treatment planning of intracranial lesions.

The aim of this study is to develop a magnetic resonance imaging (MRI)-based treatment planning procedure for intracranial lesions. The method relies on (a) distortion correction of raw magnetic resonance (MR) images by using an adaptive thresholding and iterative technique, (b) autosegmentation of head structures relevant to dosimetric calculations (scalp, bone and brain) using an atlas-based software and (c) conversion of MR images into computed tomography (CT)-like images by assigning bulk CT values to organ contours and dose calculations performed in Eclipse (Philips Medical Systems). Standard CT + MRI-based and MRI-only plans were compared by means of isodose distributions, dose volume histograms and several dosimetric parameters. The plans were also ranked by using a tumor control probability (TCP)-based technique for heterogeneous irradiation, which is independent of radiobiological parameters. For our 3 T Intera MRI scanner (Philips Medical Systems), we determined that the total maximum image distortion corresponding to a typical brain study was about 4 mm. The CT + MRI and MRI-only plans were found to be in good agreement for all patients investigated. Following our clinical criteria, the TCP-based ranking tool shows no significant difference between the two types of plans. This indicates that the proposed MRI-based treatment planning procedure is suitable for the radiotherapy of intracranial lesions.

Radiopharmacological evaluation of 6-deoxy-6-[18F]fluoro-D-fructose as a radiotracer for PET imaging of GLUT5 in breast cancer.

INTRODUCTION Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6-deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. METHODS Uptake of 6-[(18)F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [(18)F]FDG. Biodistribution of 6-[(18)F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor-bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [(18)F]FDG. 6-[(18)F]FDF metabolism was investigated in mouse blood and urine. RESULTS 6-[(18)F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30±4% (n=9) and 12±1% (n=7) ID/mg protein 6-[(18)F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[(18)F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65±0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75±0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76±0.05; n=3] compared to EMT-6 tumors (SUV=1.23±0.09; n=3). Interestingly, [(18)F]FDG uptake was significantly different in MCF-7 tumors (SUV(15 min) 0.74±0.12 to SUV(120 min) 0.80±0.15; n=3) versus EMT-6 tumors (SUV(15 min) 1.01±0.33 to SUV(120 min) 1.80±0.25; n=3). 6-[(18)F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. CONCLUSION Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6-[(18)F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors.

Properties of noise in positron emission tomography images reconstructed with filtered-backprojection and row-action maximum likelihood algorithm.

Noise levels observed in positron emission tomography (PET) images complicate their geometric interpretation. Post-processing techniques aimed at noise reduction may be employed to overcome this problem. The detailed characteristics of the noise affecting PET images are, however, often not well known. Typically, it is assumed that overall the noise may be characterized as Gaussian. Other PET-imaging-related studies have been specifically aimed at the reduction of noise represented by a Poisson or mixed Poisson + Gaussian model. The effectiveness of any approach to noise reduction greatly depends on a proper quantification of the characteristics of the noise present. This work examines the statistical properties of noise in PET images acquired with a GEMINI PET/CT scanner. Noise measurements have been performed with a cylindrical phantom injected with 11C and well mixed to provide a uniform activity distribution. Images were acquired using standard clinical protocols and reconstructed with filtered-backprojection (FBP) and row-action maximum likelihood algorithm (RAMLA). Statistical properties of the acquired data were evaluated and compared to five noise models (Poisson, normal, negative binomial, log-normal, and gamma). Histograms of the experimental data were used to calculate cumulative distribution functions and produce maximum likelihood estimates for the parameters of the model distributions. Results obtained confirm the poor representation of both RAMLA- and FBP-reconstructed PET data by the Poisson distribution. We demonstrate that the noise in RAMLA-reconstructed PET images is very well characterized by gamma distribution followed closely by normal distribution, while FBP produces comparable conformity with both normal and gamma statistics.

Synthesis, characterisation and evaluation of a novel copper-64 complex with selective uptake in EMT-6 cells under hypoxic conditions

The radiometal (64)Cu is now widely used in the development of diagnostic imaging agents for positron emission tomography (PET). The present study has led to the development and evaluation of a novel chelating agent for (64)Cu: the new monothiourea tripodal ligand 1-benzoyl-3-{6-[(bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-2-yl}-thiourea (MTUBo). X-ray crystallographic analysis has shown this ligand forms a mononuclear complex with copper(II) and co-ordinates via a trigonal bipyramidal N4S array of donor atoms. Promisingly, cell uptake studies revealed that (64)Cu-MTUBo selectively accumulates in EMT-6 cells incubated under hypoxic conditions which may result from its relatively high Cu(II/I) redox potential. Small-animal PET imaging and ex vivo biodistribution studies in EMT-6 tumor bearing BALB/c mice revealed significant tumor uptake after 1 h p.i., yielding tumor-to-muscle (T/M) and tumor-to-blood (T/B) ratios of 8.1 and 1.1, respectively. However, injection of (64)Cu-acetate resulted in similar uptake indicating that the observed uptake was most likely non-specific. Despite showing high in vitro stability, it is likely that in vivo the complex undergoes transchelation to proteins within the blood in a relatively short timeframe. For comparison, the hypoxia imaging agent (64)Cu-ATSM was also evaluated in the same murine tumor model and showed about 60% higher tumor uptake than (64)Cu-MTUBo.

In Vitro and In Vivo Evaluation of [18F]F-GAZ, a Novel Oxygen-Mimetic Azomycin-Glucose Conjugate, for Imaging Hypoxic Tumor

Several F-18-labeled 2-nitroimidazole (azomycin) derivatives have been proposed for imaging hypoxia using positron emission tomography (PET). Their cell penetration is based on passive diffusion, which limits their intracellular concentration maxima. The purpose of this study was to investigate the uptake of N-(2-[(18)F]fluoro-3-(6-O-glucosyl)propyl-azomycin ([(18)F]F-GAZ), a new azomycin-glucose conjugate, in vitro and in vivo. [(18)F]F-GAZ was synthesized from its tetraacetyl nosylate precursor by nucleophilic radiofluorination. [(18)F]F-GAZ was evaluated in vivo in EMT-6 tumor-bearing Balb/C mice utilizing the PET and biodistribution analysis. In vitro uptake of [(18)F]FDG by EMT-6 cells was measured in the presence of unlabeled F-GAZ, 2-FDG, and D-glucose. [(18)F]F-GAZ was rapidly cleared from all tissues, including the blood pool and kidneys, with ultimate accumulation in the urinary bladder. Uptake of tracer doses of [(18)F]F-GAZ into EMT-6 tumors was fast, reaching a standardized uptake value of 0.66±0.05 within 5-6 minutes postinjection (p.i.), and decreased to 0.24±0.04 by 60 minutes p.i. (n=6). A tumor-muscle ratio of 1.87±0.18 was observed after 60 minutes. Total uptake of [(18)F]F-GAZ in tumors (60 minutes) amounted to 1.25%±0.15% ID/g versus 0.61%±0.14% ID/g (n=4) in muscle. Similar biodistribution and excretion were observed using carrier-added (100 mg/kg) doses of F-GAZ. In vitro, D-glucose and unlabeled 2-FDG were two orders of magnitude more potent than F-GAZ as competitive inhibitors of [(18)F]FDG uptake into EMT-6 cells. Besides its interaction with glucose transporters, F-GAZ seems to be not transported in the presence of glucose. Furthermore, [(18)F]F-GAZ is unlikely to be effective as a hypoxia imaging agent. The low in vivo toxicity and substantial retention in tumor observed at high doses of F-GAZ do provide rationale for further testing as a radiosensitizer for external beam radiation therapy of radioresistant, hypoxic tumors.

Sci‐Fri PM: Planning‐02: MRI‐based radiation treatment planning for an MRI‐linac system

At Cross Cancer Institute, we are investigating a novel MRI-linac system consisting of a bi-planar 0.2 T permanent magnet coupled with a 6 MV Linac. The system can freely revolve axially around the patient to deliver dose from any desired angle. For such a system, the radiation treatment planning procedure is expected to rely on the MR images only, i.e. MRI Simulation. Replacing the current CT/CT+MRI-based RTP procedure with MRI Simulation will eliminate the need for the planning CT scanning sessions (no additional x-ray exposure) and consequently the image fusion between MRI and planning CT. In this work, we propose a comprehensive MRI-based RTP procedure for an MRI-Linac system. Specifically, the method consists of a) data acquisition, b) analysis and correction of image artifacts caused by the scanner-related and patient-induced distortions, c) segmentation of organ structures relevant to dosimetric calculations (e.g. soft tissue, bone, air), d) conversion of MR images into CT-like images by assigning bulk electron density values to organ contours defined at step c), e) dose calculations in external magnetic field, and f) plan evaluation. Monte Carlo simulations were performed to determine the linac-MRI scanners magnetic field induced effects on the dose deposited patterns using patient data. Specifically, we investigated the dosimetric differences between the corresponding MRI-based RT plans simulated at zero and 0.2 T. We found that the maximum percent differences for brain studies were within 4%. Most of these differences occurred at the inferior field edge and superficially at beam exits.

TH‐C‐230A‐03: A Complete MR‐Based Treatment Planning Procedure for Radiotherapy of Intracranial Lesions

Purpose: The purpose of this study is to develop a complete treatment planning procedure for radiotherapy of brain lesions based solely on magnetic resonance imaging.Method and Materials: The MR‐based treatment planning procedure relies on converting the MRimages into CT‐like images by assigning electron density information to organ structures (i.e. brain, bone and scalp). First step in the process is to correct the MRimages for 3D geometrical distortions by applying a novel distortion correction procedure. The next stage is to segment the datasets into anatomical structures by using an automatic segmentation tool suited for MRbrainimages. Once the MRimages contain both the target volume and the electron density information, they are ready to be used for dose calculations. The resulting CT+MR and MR‐based plans were compared in terms of isodose distributions, DVHs and NTCP/TCPs. A plan ranking TCP‐based method for heterogeneous irradiation, which does not require the knowledge of radiobiological parameters, is used. Results: For all patients investigated, we found that MR‐based plans (1.5T and 3T) are in good agreement (within 1%) with their corresponding CT+MR‐based plans in terms of PTV dose coverage, DVHs and NTCP/TCPs. We compared tumor contours drawn on both 1.5T and 3T MRimages in terms of shape, volumes and their impact on CRT plans. For all patients the delineation of the tumor was simpler for 3T images due to higher contrast. For some patients the tumor volumes drawn on the 3T images were up to 60% higher than on 1.5T images. RT plan ranking shows that the 3T plans are significantly better than 1.5T ones. Conclusion: The proposed MR‐based treatment planning procedure was found to perform as good as the current clinical procedure based on CT+MR. Due to a higher contrast the tumor may be significantly better delineated on 3T images.

SU‐E‐I‐67: Monte Carlo Evaluation of CT‐Scanner Scatter Dose to Operator and Comparison with Measurements

Purpose: To investigate the scatter dose received by a CT‐scanner operator from walls and ceiling as a function of the height of the shielding barrier between the operator and the scanner. To compare Monte Carlo(MC) simulated data with measurement. Methods: MC simulations were performed, using the Penelope algorithm. The CTscanner and a typical, lead‐shielded control console were modeled in cylindrical coordinates. An x‐ray photon spectrum of 120 kVp impinging on a water‐phantom was modeled and the resulting scatter dose profile obtained in CT suite and operator room. This simulation was repeated with varying heights of the lead shield: between 6 ft. and 15ft (height of the concrete ceiling). Finally measurements were obtained of a cross section of the scatter dose profile in the operator room, using a 64 slice CTscanner (Toshiba Aquilion), a water‐equivalent phantom and an NaI‐based survey meter; the measured dose profiles are compared with the simulated ones. Dose reduction at the operator console resulting from increased wall height was measured and compared to simulation. Results: Simulating the extension of the lead shield from a height of 6 ft. all the way to the ceiling resulted in dose reduction at the operator console of two orders of magnitude. Measured dose profiles show good qualitative agreement with the simulated profiles. Measured dose reduction for increased barrier height was larger than simulated, likely owing to the simplified geometry used in simulating the CTscanner and room geometry. Conclusions: Additional contribution of dose scattered at the ceiling and back wall of an operator console can be significant; its varying contribution is given as a function of barrier height. MC simulation provides good qualitative agreement with the measurement. Improved modeling of the CT‐suite is likely needed to enhance quantitative agreement.

TU‐EE‐A3‐02: Evaluation of a 2D‐3D Registration Method for External Beam Radiation Therapy

Purpose: To implement and validate a 2D‐3D registration method for determining 3D patient position in external beam radiotherapy using orthogonal EPIDimages and megavoltage digitally reconstructedradiographs (MDRRs). To test the methods dependence on cost function, image pre‐processing and parameter space sample density, and determine the dependence of registered rotations on setup translations and vice versa. Method and Materials: Orthogonal EPIDimage of a humanoid phantom in different poses (3D rotations and translations) were acquired in anterior‐posterior and latero‐lateral view. The EPIDimages were registered with a data base of orthogonal MDRRs, calculated as projection images through the phantoms CT data set at rotation angles within ±5°. Registration results were compared for three different cost functions (least‐squares, cross‐correlation and mutual information), different image pre‐processing techniques (unsharp masking, histogram matching) and for isolated and combined rotations and translations. The influence of setup translations on registration results for rotations, and vice versa, was investigated and compared with a simple model. Results:Image pre‐processing improves registration precision by more than a factor 2. Three dimensional translations were registered with better than 0.5 mm (one standard deviation) when no rotations were present. Three‐dimensional rotations registered with a precision of better than 0.2° (1 SD) when no translations were present. Combined rotations and translations of up to 4° and 15 mm were registered with a precision of better than 0.4° and 0.7 mm respectively. Mutual information resulted in the most precise registration. Setup translations influence registered rotations, mostly following a simple theoretical model, but not vice versa. Conclusion: Precise registration requires image pre‐processing and benefits from interpolation of the parameter space. Influence of object translation on registration of out‐of‐plane rotations can be significant; these “pseudo rotations” can be corrected using the theoretical model when only one projection image is used for registration (e.g. fluoroscopy).

Sci‐Sat AM (1) General‐04: Quantitative impact of 3D inter fractional patient setup errors on TCP/NTCP

Patient setup errors in external beam radiation therapy are a cause for differences between planned dose distribution and the one delivered to the patient. A changed dose distribution results in a changed tissue response, expressed as tumor control probability (TCP) and normal tissue complication probability (NTCP). A method was developed to calculate the changes of TCP and NTCP resulting from measured patient setup errors. Patient position was measured with a 2D‐3D registration method using orthogonal EPIDimages of the patient in treatment position. Setup errors were expressed as 6 degrees of freedom (rigid body translations and rotations); non‐rigid transformations and internal organ motion was not considered. The measured setup errors were used to change beam angles and couch position in a copy of the original treatment plan, such that an equivalent beams‐eye‐view of the patient was achieved for each treatment beam. The dose distribution for this modified treatment plan was then calculated. This procedure was repeated in additional copies of the original treatment plan for each fraction in which patient position had been measured. Once the treatment was completed, dose distributions for all measured fractions were added and the dose‐volume‐histograms (DVHs) were calculated for each region of interest. The DVHs in turn served as a basis for the calculation of TCP and NTCP. This method was applied to two prostate patients, whose position was measured during six fractions of their treatment. The setup errors did not change the TCP, but NTCP of the rectum increased by 9.0% and 2.2% respectively.