Modeling in vivo relative biological effectiveness in particle therapy for clinically relevant endpoints.

BACKGROUND: The relative biological effectiveness (RBE) of particle therapy compared to photon radiotherapy is known to be variable but the exact dependencies are still subject to debate. In vitro data suggested that RBE is to a large extend independent of ion type if parametrized by the beam quality Q. This study analyzed the RBE dependence of pre-clinical data on late toxicity with an emphasis on the beam quality. MATERIAL AND METHODS: Published pre-clinical RBE dose-response data of the spinal cord following one and two fractions of photon and carbon ion irradiation were compiled. The beam quality for each treatment condition was obtained from Monte Carlo simulations. The αp and ßp parameters of the linear-quadratic (LQ) model for particle irradiation were determined from the pre-clinical data and was provided as a function of Q. An introduced model proposed αp to increase linearly with Q and ßp to remain constant. RBE values predicted by the model were compared to the published data. RESULTS: The αp parameter was highly correlated with Q (R2 = 0.96) with a linear slope of 0.019 Gy-1. No significant variation of ßp with Q was found. RBE and Q were also highly correlated (R2 = 0.98) for one and two fractions. The (extrapolated) RBE at Q = 0 (theoretical photon limit) for one and two fractions was 1.22 and significantly larger than 1 (p = .004). The model reproduced the dependence of RBE on fractionation well. CONCLUSIONS: Fraction dose and beam quality Q were sufficient to describe the RBE variability for a late toxicity model within a carbon ion treatment field. Assuming the independence of the identified RBE parameters on the ion type might suggest the translation of variable (pre-) clinical RBE data from carbon ion to proton therapy.

Proton radiography for inline treatment planning and positioning verification of small animals.

INTRODUCTION: As proton therapy becomes increasingly well established, there is a need for high-quality clinically relevant in vivo data to gain better insight into the radiobiological effects of proton irradiation on both healthy and tumor tissue. This requires the development of easily applicable setups that allow for efficient, fractionated, image-guided proton irradiation of small animals, the most widely used pre-clinical model. MATERIAL AND METHODS: Here, a method is proposed to perform dual-energy proton radiography for inline positioning verification and treatment planning. Dual-energy proton radiography exploits the differential enhancement of object features in two successively measured two-dimensional (2D) dose distributions at two different proton energies. The two raw images show structures that are dominated by energy absorption (absorption mode) or scattering (scattering mode) of protons in the object, respectively. Data post-processing allowed for the separation of both signal contributions in the respective images. The images were evaluated regarding recognizable object details and feasibility of rigid registration to acquired planar X-ray scans. RESULTS: Robust, automated rigid registration of proton radiography and planar X-ray images in scattering mode could be reliably achieved with the animal bedding unit used as registration landmark. Distinguishable external and internal features of the imaged mouse included the outer body contour, the skull with substructures, the lung, abdominal structures and the hind legs. Image analysis based on the combined information of both imaging modes allowed image enhancement and calculation of 2D water-equivalent path length (WEPL) maps of the object along the beam direction. DISCUSSION: Fractionated irradiation of exposed target volumes (e.g., subcutaneous tumor model or brain) can be realized with the suggested method being used for daily positioning and range determination. Robust registration of X-ray and proton radiography images allows for the irradiation of tumor entities that require conventional computed tomography (CT)-based planning, such as orthotopic lung or brain tumors, similar to conventional patient treatment.

Towards ion beam therapy based on laser plasma accelerators.

Only few ten radiotherapy facilities worldwide provide ion beams, in spite of their physical advantage of better achievable tumor conformity of the dose compared to conventional photon beams. Since, mainly the large size and high costs hinder their wider spread, great efforts are ongoing to develop more compact ion therapy facilities. One promising approach for smaller facilities is the acceleration of ions on micrometre scale by high intensity lasers. Laser accelerators deliver pulsed beams with a low pulse repetition rate, but a high number of ions per pulse, broad energy spectra and high divergences. A clinical use of a laser based ion beam facility requires not only a laser accelerator providing beams of therapeutic quality, but also new approaches for beam transport, dosimetric control and tumor conformal dose delivery procedure together with the knowledge of the radiobiological effectiveness of laser-driven beams. Over the last decade research was mainly focused on protons and progress was achieved in all important challenges. Although currently the maximum proton energy is not yet high enough for patient irradiation, suggestions and solutions have been reported for compact beam transport and dose delivery procedures, respectively, as well as for precise dosimetric control. Radiobiological in vitro and in vivo studies show no indications of an altered biological effectiveness of laser-driven beams. Laser based facilities will hardly improve the availability of ion beams for patient treatment in the next decade. Nevertheless, there are possibilities for a need of laser based therapy facilities in future.

Using statistical measures for automated comparison of in-beam PET data.

PURPOSE: Positron emission tomography (PET) is considered to be the state of the art technique to monitor particle therapy in vivo. To evaluate the beam delivery the measured PET image is compared to a predicted ß(+)-distribution. Nowadays the range assessment is performed by a group of experts via visual inspection. This procedure is rather time consuming and requires well trained personnel. In this study an approach is presented to support human decisions in an automated and objective way. METHODS: The automated comparison presented uses statistical measures, namely, Pearson's correlation coefficient (PCC), to detect ion beam range deviations. The study is based on 12 in-beam PET patient data sets recorded at GSI and 70 artificial beam range modifications per data set. The range modifications were 0, 4, 6, and 10 mm water equivalent path length (WEPL) in positive and negative beam directions. The reference image to calculate the PCC was both an unmodified simulation of the activity distribution (Test 1) and a measured in-beam PET image (Test 2). Based on the PCCs sensitivity and specificity were calculated. Additionally the difference between modified and unmodified data sets was investigated using the Wilcoxon rank sum test. RESULTS: In Test 1 a sensitivity and specificity over 90% was reached for detecting modifications of ±10 and ±6 mm WEPL. Regarding Test 2 a sensitivity and specificity above 80% was obtained for modifications of ±10 and -6 mm WEPL. The limitation of the method was around 4 mm WEPL. CONCLUSIONS: The results demonstrate that the automated comparison using PCC provides similar results in terms of sensitivity and specificity compared to visual inspections of in-beam PET data. Hence the method presented in this study is a promising and effective approach to improve the efficiency in the clinical workflow in terms of particle therapy monitoring by means of PET.

Quantitative assessment of radionuclide production yields in in-beam and offline PET measurements at different proton irradiation facilities.

Objective. Reliable radionuclide production yield data are a prerequisite for positron-emission-tomography (PET) basedin vivoproton treatment verification. In this context, activation data acquired at two different treatment facilities with different imaging systems were analyzed to provide experimentally determined radionuclide yields in thick targets and were compared with each other to investigate the impact of the respective imaging technique.Approach.Homogeneous thick targets (PMMA, gelatine, and graphite) were irradiated with mono-energetic proton pencil-beams at two distinct energies. Material activation was measured (i)in-beamduring and after beam delivery with a double-head prototype PET camera and (ii)offlineshortly after beam delivery with a commercial full-ring PET/CT scanner. Integral as well as depth-resolvedß+-emitter yields were determined for the dominant positron-emitting radionuclides11C,15O,13N and (in-beamonly)10C.In-beamdata were used to investigate the qualitative impact of different monitoring time schemes on activity depth profiles and their quantitative impact on count rates and total activity.Main results.Production yields measured with thein-beamcamera were comparable to or higher compared to respectiveofflineresults. Depth profiles of radionuclide-specific yields obtained from thedouble-headcamera showed qualitative differences to data acquired with thefull-ringcamera with a more convex profile shape. Considerable impact of the imaging timing scheme on the activity profile was observed for gelatine only with a range variation of up to 3.5 mm. Evaluation of the coincidence rate and the total number of observed events in the considered workflows confirmed a strongly decreasing rate in targets with a large oxygen fraction.Significance. The observed quantitative and qualitative differences between the datasets underline the importance of a thorough system commissioning. Due to the lack of reliable cross-section data, in-house phantom measurements are still considered a gold standard for careful characterization of the system response and to ensure a reliable beam range verification.

Reduction of clinical safety margins in proton therapy enabled by the clinical implementation of dual-energy CT for direct stopping-power prediction.

PURPOSE: To quantifiy the range uncertainty in proton treatment planning using dual-energy computed tomography (DECT) for a direct stopping-power prediction (DirectSPR) algorithm and its clinical implementation. METHODS AND MATERIALS: To assess the overall uncertainty in stopping-power ratio (SPR) prediction of a DirectSPR implementation calibrated for different patient geometries, the influencing factors were categorized in imaging, modeling as well as others. The respective SPR uncertainty was quantified for lung, soft tissue and bone and translated into range uncertainty for several tumor types. The amount of healthy tissue spared was quantified for 250 patients treated with DirectSPR and the dosimetric impact was evaluated exemplarily for a representative brain-tumor patient. RESULTS: For bone, soft tissue and lung, an SPR uncertainty (1σ) of 1.6%, 1.3% and 1.3% was determined for DirectSPR, respectively. This allowed for a reduction of the clinically applied range uncertainty from currently (3.5% + 2 mm) to (1.7% + 2 mm) for brain-tumor and (2.0% + 2 mm) for prostate-cancer patients. The 150 brain-tumor and 100 prostate-cancer patients treated using DirectSPR benefitted from sparing on average 2.6 mm and 4.4 mm of healthy tissue in beam direction, respectively. In the representative patient case, dose reduction in organs at risk close to the target volume was achieved, with a mean dose reduction of up to 16% in the brainstem. Patient-specific DECT-based treatment planning with reduced safety margins was successfully introduced into clinical routine. CONCLUSIONS: A substantial increase in range prediction accuracy in clinical proton treatment planning was achieved by patient-specific DECT-based SPR prediction. For the first time, a relevant imaging-based reduction of range prediction uncertainty on a 2% level has been achieved.

Improvement of radiation-mediated immunosuppression of human NSCLC tumour xenografts in a nude rat model.

Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC) xenografts in a nude rat model irradiation (2 + 2 Gy) from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Impact of range uncertainty on clinical distributions of linear energy transfer and biological effectiveness in proton therapy.

PURPOSE: Increased radiation response after proton irradiation, such as late radiation-induced toxicity, is determined by high dose and elevated linear energy transfer (LET). Steep dose-averaged LET (LETd ) gradients and elevated LETd occur at the end of proton range and might be particularly sensitive to uncertainties in range prediction. Therefore, this study quantified LETd distributions and the impact of range uncertainty in robust dose-optimized proton treatment plans and assessed the biological effect in normal tissues and tumors of patients. METHODS: For each of six cancer patients (two brain, head-and-neck, and prostate), two nominal treatment plans were robustly dose optimized using single- and multi-field optimization, respectively. For each plan, two additional scenarios with ±3.5% range deviation relative to the nominal plan were derived by global rescaling of stopping-power ratios. Dose and LETd distributions were calculated for each scenario using the beam parameters of the corresponding nominal plan. The variability in relative biological effectiveness (RBE) and probability of late radiation-induced brain toxicity (PIC ) was assessed. RESULTS: The optimization technique (single- vs multi-field) had a negligible impact on the LETd distributions in the clinical target volume (CTV) and in most organs at risk (OARs). LETd distributions in the CTV were rather homogeneous with arithmetic mean of LETd below 3.2 keV/µm and robust against range deviations. The RBE variability within the CTV induced by range uncertainty was small (≤0.05, 95% confidence interval). In OARs, LETd hotspots (>7 keV/µm) occurred and LETd distributions were inhomogeneous and sensitive to range deviations. LETd hotspots and the impact of range deviations were most prominent in OARs of brain tumor patients which translated in RBE values exceeding 1.1 in all brain OARs. The near-maximum predicted PIC in healthy brain tissue of brain tumor patients was smaller than 5% and occurred adjacent to the CTV. Range deviations induced absolute differences in PIC up to 1.2%. CONCLUSIONS: Robust dose optimization generates LETd distributions in the target volume robust against range deviations. The current findings support using a constant RBE within the CTV. The impact of range deviations on the considered probability of late radiation-induced toxicity in brain tissue was limited for robust dose-optimized treatment plans. Incorporation of LETd in robust optimization frameworks may further reduce uncertainty related to the RBE-weighted dose estimation in normal tissues.

Refinement of the Hounsfield look-up table by retrospective application of patient-specific direct proton stopping-power prediction from dual-energy CT.

BACKGROUND AND PURPOSE: Proton treatment planning relies on an accurate determination of stopping-power ratio (SPR) from x-ray computed tomography (CT). A refinement of the heuristic CT-based SPR prediction using a state-of-the-art Hounsfield look-up table (HLUT) is proposed, which incorporates patient SPR information obtained from dual-energy CT (DECT) in a retrospective patient-cohort analysis. MATERIAL AND METHODS: SPR datasets of 25 brain-tumor patients, 25 prostate-cancer patients, and three nonsmall cell lung-cancer (NSCLC) patients were calculated from clinical DECT scans with the comprehensively validated DirectSPR approach. Based on the median frequency distribution of voxelwise correlations between CT number and SPR within the irradiated volume, a piecewise linear function was specified (DirectSPR-based adapted HLUT). Differences in dose distribution and proton range were assessed for the nonadapted and adapted HLUT in comparison to the DirectSPR method, which has been shown to be an accurate and reliable SPR estimation method. RESULTS: The application of the DirectSPR-based adapted HLUT instead of the nonadapted HLUT reduced the systematic proton range differences from 1.2% (1.1 mm) to -0.1% (0.0 mm) for brain-tumor patients, 1.7% (4.1 mm) to 0.2% (0.5 mm) for prostate-cancer patients, and 2.0% (2.9 mm) to -0.1% (0.0 mm) for NSCLC patients. Due to the large intra- and inter-patient tissue variability, range differences to DirectSPR larger than 1% remained for the adapted HLUT. CONCLUSIONS: The incorporation of patient-specific correlations between CT number and SPR, derived from a retrospective application of DirectSPR to a broad patient cohort, improves the SPR accuracy of the current state-of-the-art HLUT approach. The DirectSPR-based adapted HLUT has been clinically implemented at the University Proton Therapy Dresden (Dresden, Germany) in 2017. This already facilitates the benefits of an improved DECT-based tissue differentiation within clinical routine without changing the general approach for range prediction (HLUT), and represents a further step toward full integration of the DECT-based DirectSPR method for treatment planning in proton therapy.

4D in-beam positron emission tomography for verification of motion-compensated ion beam therapy.

PURPOSE: Clinically safe and effective treatment of intrafractionally moving targets with scanned ion beams requires dedicated delivery techniques such as beam tracking. Apart from treatment delivery, also appropriate methods for validation of the actual tumor irradiation are highly desirable, In this contribution the feasibility of four-dimensionally (space and time) resolved, motion-compensated in-beam positron emission tomography (4DibPET) was addressed in experimental studies with scanned carbon ion beams. METHODS: A polymethyl methracrylate block sinusoidally moving left-right in beam's eye view was used as target. Radiological depth changes were introduced by placing a stationary ramp-shaped absorber proximal of the moving target. Treatment delivery was compensated for motion by beam tracking. Time-resolved, motion-correlated in-beam PET data acquisition was performed during beam delivery with tracking the moving target and prolonged after beam delivery first with the activated target still in motion and, finally, with the target at rest. Motion-compensated 4DibPET imaging was implemented and the results were compared to a stationary reference irradiation of the same treatment field. Data were used to determine feasibility of 4DibPET but also to evaluate offline in comparison to in-beam PET acquisition. RESULTS: 4D in-beam as well as offline PET imaging was found to be feasible and offers the possibility to verify the correct functioning of beam tracking. Motion compensation of the imaged beta(+)-activity distribution allows recovery of the volumetric extension of the delivered field for direct comparison with the reference stationary condition. Observed differences in terms of lateral field extension and penumbra in the direction of motion were typically less than 1 mm for both imaging strategies in comparison to the corresponding reference distributions. However, in-beam imaging retained a better spatial correlation of the measured activity with the delivered dose. CONCLUSIONS: 4DibPET is a feasible and promising method to validate treatment delivery of scanned ion beams to moving targets. Further investigations will focus on more complex geometries and treatment planning studies with clinical data.

[Radio- and photosensitization of plasmid DNA by DNA binding ligand propidium iodide: Investigation of Auger electron induction and detection of Cherenkov-emission]. / Radio- und Photosensitivierung von Plasmid-DNA durch den DNA-bindenden Liganden Propidiumiodid: Untersuchungen zur Auger-Elektronen-Induktion und zum Nachweis von Cherenkov-Strahlung.

PURPOSE: We investigated whether propidium iodide (PI) enhances DNA damaging effects of ionizing and non-ionizing radiation species (X-rays, alpha-, beta-, auger electron emission and light of various wavelengths, respectively). This biophysical experimental setting allowed us, furthermore, to investigate whether Cherenkov emission can be detected by photodynamic effects and increased DNA damage. MATERIAL AND METHODS: Conformation changes of plasmid DNA were detected and quantified by gelelectrophoresis and fluorescence imaging. Hydrogen peroxide, stannous dichloride, and dimethylsulfoxide were used as chemical modulators, Tc-99m, Re-188, Ra-223, and x-ray (32 kV and 200 kV) reflected radiotoxicity and light (λ = 254 nm, 366 nm and 530-575 nm) induced phototoxicity. RESULTS: Radiotracers and x-rays induced dose dependent DNA damage. PI did not serve as radiosensitizer in radioisotopes, while a low effect was detected in X-rays. The phototoxicity was dependent on the wavelengths of light. Light with a wavelength range of 530-575 nm in combination with PI resulted in direct DNA damage. The yield of Cherenkov emission was far below the photon emission of light irradiation and not distinguishable from general radiotoxicity. CONCLUSIONS: PI binds to plasmid DNA, is not chemotoxic, and increases radiotoxicity only to minor extent. Phototoxicity and its stimulation by PI is dependent on the wavelength of the light. No kind of energy deposition was capable of inducing an Auger electron cascade. Furthermore, no increase in DNA damage induced by photodynamic effects from Cherenkov emission was detectable.

Predicting In Vitro Cancer Cell Survival Based on Measurable Cell Characteristics.

Variation in cellular characteristics may determine tumor response and, consequently, patient survival in radiation therapy. However, patient-specific prediction of cellular radiation response is currently unavailable for treatment planning. Thus, the importance of developing a novel approach based on clinically accessible parameters prior to treatment (e.g., by biopsy) is high. The goal of this study was to predict in vitro cancer cell survival through the p53mutation status and the number of chromosomes (NoC). To predict cell survival, we modified a mechanistic radiation response model incorporating DNA repair and cell death, originally designed for normal human cells. Cell-specific parameters of 24 cell lines originating from two laboratories (OncoRay, Dresden, Germany and HIMAC, Chiba, Japan) were considered for modeling. In a first step, we obtained estimates of the only unknown model input parameter genome size (GS) by fitting cell survival simulations onto experimental data. We then analyzed measured and published input model parameters (NoC, p53-mutation status and cell-cycle distribution) to assess their impact on measured and simulated parameters (modeled GS, and measured α, ß, SF2 and γ-H2AX). The resulting data suggested a linear correlation between NoC and modeled GS (R2 > 0.93) allowing for estimating GS based on NoC. Applying the estimated GS resulted in predicted cell survival that matched measured data mostly within the experimental uncertainty. The measured radiobiological value ß increased quadratically with the cell's modeled GS irrespective of other cell-specific parameters. The measured α and SF2 split into two groups, depending on the cells' p53-mutation status, both linearly increasing and decreasing, respectively, with modeled GS. Model predictions of foci numbers were, on average, in agreement with published γ-H2AX measurement data. In conclusion, knowledge of clinically accessible parameters (p53-mutation status and NoC) may support patient stratification in radiotherapy based on cell-specific survival prediction testable in prospective clinical trials.

Processing of prompt gamma-ray timing data for proton range measurements at a clinical beam delivery.

In proton therapy, patients benefit from the precise deposition of the dose in the tumor volume due to the interaction of charged particles with matter. Currently, the determination of the beam range in the patient's body during the treatment is not a clinical standard. This lack causes broad safety margins around the tumor, which limits the potential of proton therapy. To overcome this obstacle, different methods are under investigation aiming at the verification of the proton range in real time during the irradiation. One approach is the prompt gamma-ray timing (PGT) method, where the range of the primary protons is derived from time-resolved profiles (PGT spectra) of promptly emitted gamma rays, which are produced along the particle track in tissue. After verifying this novel technique in an experimental environment but far away from treatment conditions, the translation of PGT into clinical practice is intended. Therefore, new hardware was extensively tested and characterized using short irradiation times of 70 ms and clinical beam currents of 2 nA. Experiments were carried out in the treatment room of the University Proton Therapy Dresden. A pencil beam scanning plan was delivered to a target without and with cylindrical air cavities of down to 5 mm thickness. The range shifts of the proton beam induced due to the material variation could be identified from the corresponding PGT spectra, comprising events collected during the delivery of a whole energy layer. Additionally, an assignment of the PGT data to the individual pencil beam spots allowed a spot-wise analysis of the variation of the PGT distribution mean and width, corresponding to range shifts produced by the different air cavities. Furthermore, the paper presents a comprehensive software framework which standardizes future PGT analysis methods and correction algorithms for technical limitations that have been encountered in the presented experiments.

Additional PET/CT in week 5-6 of radiotherapy for patients with stage III non-small cell lung cancer as a means of dose escalation planning?

BACKGROUND AND PURPOSE: Loco-regional failure after radiotherapy with total doses of 60-70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints. MATERIALS AND METHODS: Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription). RESULTS: There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability. CONCLUSIONS: Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted.

In-beam PET measurements of biological half-lives of 12C irradiation induced beta+-activity.

One of the long-standing problems in carbon-ion therapy is the monitoring of the treatment, i.e. of the delivered dose to a given tissue volume within the patient. Over the last 8 years, in-beam positron emission tomography (PET) has been used at the experimental carbon ion treatment facility at the Gesellschaft fur Schwerionenforschung (GSI) Darmstadt and has become a valuable quality assurance tool. In order to determine and evaluate the correct delivery of the patient dose, a simulation of the positron emitter distribution has been compared to the measurement. One particular effect is the blurring as well as the reduction of the measured activity distribution via washout. The objective of this study is the investigation of tissue dependent effective half-lives from patient data. We find no significant dependence of the effective half-life on the Hounsfield unit but on the local dose. The biological half-life within the high dose region is longer than in the low dose region. Furthermore, the influence of the overall treatment time on the kinetics of the positron emitter is reported. There are indications for a metabolic response of the tissue on the irradiation. Taking into account the biological half-life in the simulation leads to an improvement of the quality of the PET-images in some cases.

Attenuation correction of four dimensional (4D) PET using phase-correlated 4D-computed tomography.

The image quality in a conventional positron emission tomography (PET)/computed tomography (CT) scanner is degraded by respiratory motion because of erroneous attenuation correction when three-dimensional image acquisition is used. To overcome this problem, time-resolved data acquisition (4D) is required. For this, a Siemens Biograph 16 PET/CT scanner has been modified and its normal capability has been extended to a true 4D-PET/4D-CT imaging device including phase-correlated attenuation correction. To verify the correct functionality of this device, experiments on a respiratory motion phantom that allowed movement in two dimensions have been performed. The measurements showed good spatial correlation as well as good time synchronization between the PET and CT data. Furthermore, the motion pattern of the phantom and the shape of the activity distribution have been examined, and the volume of the reconstructed PET images has been analyzed. The results demonstrate the feasibility of such a procedure, and we therefore recommend that 4D-PET data should be reconstructed using 4D-CT data, which can be acquired on the same machine.

Research Facility for Radiobiological Studies at the University Proton Therapy Dresden.

PURPOSE: In order to take full advantage of proton radiotherapy, the biological effect of protons in normal and tumor tissue should be investigated and understood in detail. The ongoing discussion on variable relative biological effectiveness along the proton depth dose distribution (eg, Paganetti 2015), and also the administration of concomitant treatments, demands dedicated in vitro trials that prepare the translation into the clinics. Therefore, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and a clinical 6 MV photon linear accelerator (Linac) as reference. METHODS: The experimental proton beam at the University Proton Therapy Dresden is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm2 proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different sample geometries along the proton path. RESULTS: Depth-dose profiles within the phantom and dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro experiments. Cell survival test experiments were performed to demonstrate the feasibility of such experiments. CONCLUSION: In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry facilitate irradiation in an aqueous environment and are transferable to other proton, photon and ion beam facilities. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro experiments. The close vicinity to the radiotherapy and radiobiology departments provides access to clinical linacs and the interdisciplinary basis for further translational steps.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Direct time-of-flight for quantitative, real-time in-beam PET: a concept and feasibility study.

We extrapolate the impact of recent detector and scintillator developments, enabling sub-nanosecond coincidence timing resolution (tau), onto in-beam positron emission tomography (in-beam PET) for monitoring charged-hadron radiation therapy. For tau < or = 200 ps full width at half maximum, the information given by the time-of-flight (TOF) difference between the two opposing gamma-rays enables shift-variant, artefact-free in-beam tomographic imaging by means of limited-angle, dual-head detectors. We present the corresponding fast, TOF-based and backprojection-free, 3D reconstruction algorithm that, coupled with a real-time data acquisition and a fast detector encoding scheme, allows the sampled beta+-activity to be visualized in the object during the course of the irradiation. Despite the very low statistics scenario typical of in-beam PET, real-treatment simulations show that in-beam TOF-PET enables high-precision images to be obtained in real-time, either with closed-ring or with fixed, dual-head in-beam TOF-PET systems. The latter greatly alleviates the installation of in-beam PET at radiotherapeutic sites.

[An experimental positron emission tomograph for education]. / Ein Positronen-emissions-Tomograph für die Ausbildung.

Positron emission tomography (PET) has become a key technology for molecular imaging in clinical practice, as well as in medical, biological and pharmaceutical research. This increases the necessity for a practical introduction to PET in students with a corresponding specialization. For this purpose, the PET scanner 'PET-TW 05' was set up to demonstrate both the principles of computer tomography (CT) as well as the basics of PET. Moreover, the technical requirements and the signal processing needed for a PET system are shown in a simplified but comprehensive way. This article illustrates the layout of the tomography and provides an overview on the signal processing, as well as on the details of data acquisition and processing. The measuring procedure is described. The results for a measurement with a simple source configuration (five 22Na sources) are also presented. Finally, the characteristic parameters and the educational goals of the tomograph are summarized.