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Background: Proton radiography (PR) uses highly energetic proton beams to create images where energy loss is the main contrast mechanism. Water-equivalent path length (WEPL) measurements using flat panel PR (FP-PR) have potential for in vivo range verification. However, an accurate WEPL measurement via FP-PR requires irradiation with multiple energy layers, imposing high imaging doses. Purpose: A FP-PR method is proposed for accurate WEPL determination based on a patient-specific imaging field with a reduced number of energies (n) to minimize imaging dose. Methods: Patient-specific FP-PRs were simulated and measured for a head and neck (HN) phantom. An energy selection algorithm estimated spot-wise the lowest energy required to cross the anatomy (Emin) using a water-equivalent thickness map. Starting from Emin, n was restricted to certain values (n = 26, 24, 22, …, 2 for simulations, n = 10 for measurements), resulting in patient-specific FP-PRs. A reference FP-PR with a complete set of energies was compared against patient-specific FP-PRs covering the whole anatomy via mean absolute WEPL differences (MAD), to evaluate the impact of the developed algorithm. WEPL accuracy of patient-specific FP-PRs was assessed using mean relative WEPL errors (MRE) with respect to measured multi-layer ionization chamber PRs (MLIC-PR) in the base of skull, brain, and neck regions. Results: MADs ranged from 2.1 mm (n = 26) to 21.0 mm (n = 2) for simulated FP-PRs, and 7.2 mm for measured FP-PRs (n = 10). WEPL differences below 1 mm were observed across the whole anatomy, except at the phantom surfaces. Measured patient-specific FP-PRs showed good agreement against MLIC-PRs, with MREs of 1.3 ± 2.0%, −0.1 ± 1.0%, and −0.1 ± 0.4% in the three regions of the phantom. Conclusion: A method to obtain accurate WEPL measurements using FP-PR with a reduced number of energies selected for the individual patient anatomy was established in silico and validated experimentally. Patient-specific FP-PRs could provide means of in vivo range verification.

Objective. Point detector measurements in proton fields are perturbed by the volume effect originating from geometrical volume-averaging within the extended detector’s sensitive volume and density perturbations by non-water equivalent detector components. Detector specific lateral dose response functions K(x) can be used to characterize the volume effect within the framework of a mathematical convolution model, where K(x) is the convolution kernel transforming the true dose profile D(x) into the measured signal profile of a detector M(x). The aim of this work is to investigate K(x) for detectors in proton beams. Approach. The K(x) for five detectors were determined by iterative deconvolution of measurements of D(x) and M(x) profiles at 2 cm water equivalent depth of a narrow 150 MeV proton beam. Monte Carlo simulations were carried out for two selected detectors to investigate a potential energy dependence, and to study the contribution of volume-averaging and density perturbation to the volume effect. Main results. The Monte Carlo simulated and experimentally determined K(x) agree within 2.1% of the maximum value. Further simulations demonstrate that the main contribution to the volume effect is volume-averaging. The results indicate that an energy or depth dependence of K(x) is almost negligible in proton beams. While the signal reduction from a Semiflex 3D ionization chamber in the center of a gaussian shaped field with 2 mm sigma is 32% for photons, it is 15% for protons. When measuring the field with a microDiamond the trend is less pronounced and reversed with a signal reduction for protons of 3.9% and photons of 1.9%. Significance. The determined K(x) can be applied to characterize the influence of the volume effect on detectors measured signal profiles at all clinical proton energies and measurement depths. The functions can be used to derive the actual dose distribution from point detector measurements.

Cellular responses to DNA double-strand breaks (DSBs) not only promote genomic integrity in healthy tissues, but also largely determine the efficacy of many DNA-damaging cancer treatments, including X-ray and particle therapies. A growing body of evidence suggests that activation of the mechanisms that detect, signal and repair DSBs may depend on the complexity of the initiating DNA lesions. Studies focusing on this, as well as on many other radiobiological questions, require reliable methods to induce DSBs of varying complexity, and to visualize the ensuing cellular responses. Accelerated particles of different energies and masses are exceptionally well suited for this task, due to the nature of their physical interactions with the intracellular environment, but visualizing cellular responses to particle-induced damage - especially in their early stages - at particle accelerator facilities, remains challenging. Here we describe a straightforward approach for real-time imaging of early response to particle-induced DNA damage. We rely on a transportable setup with an inverted fluorescence confocal microscope, tilted at a small angle relative to the particle beam, such that cells can be irradiated and imaged without any microscope or beamline modifications. Using this setup, we image and analyze the accumulation of fluorescently-tagged MDC1, RNF168 and 53BP1—key factors involved in DSB signalling—at DNA lesions induced by 254 MeV α-particles. Our results provide a demonstration of technical feasibility and reveal asynchronous initiation of accumulation of these proteins at different individual DSBs.

To optimize beam delivery and conformality of proton therapy, MRI integration has been proposed. Therefore, we investigated if proton irradiation in a magnetic field would change biological responses. Our data in cancer cell lines and stem cell-derived organoid models suggest that a magnetic field does not modify the biological response. (C) 2019 Elsevier B.V. All rights reserved.

International audience; The R2E project at CERN has tested a few commercial SRAMs and a custom-designed SRAM, whose data are complementary to various scientific publications. The experimental data include low- and high-energy protons, heavy ions, thermal, intermediate- and high-energy neutrons, high-energy electrons and high-energy pions.

Real-time range verification of particle beams is important for optimal exploitation of the tissue-sparing advantages of particle therapy. Positron Emission Tomography (PET) of the beam-induced positron emitters such as 15O (T1/2 = 122 s) and 11C (T1/2 = 1223 s) has been used for monitoring of therapy in both clinical and preclinical studies. However, the half-lives of these nuclides preclude prompt feedback, i.e., on a sub-second timescale, on dose delivery. The in vivo verification technique relying on the in-beam PET imaging of very short-lived positron emitters such as 12N (T1/2 = 11 ms), recently proposed and investigated in feasibility experiments with a proton beam, provides millimeter precision in range measurement a few tens of milliseconds after the start of an irradiation. With the increasing interest in helium therapy, it becomes relevant to study the feasibility of prompt feedback using PET also for helium beams. A recent study has demonstrated the production of very short-lived nuclides (T1/2 = 10 ms attributed to 12N and/or 13O) during irradiation of water and graphite with helium ions. This work is aimed at investigating the range verification potential of imaging these very short-lived nuclides. PMMA targets were irradiated with a 90 AMeV 4He pencil beam consisting of a series of pulses of 10 ms beam-on and 90 ms beam-off. Two modules of a modified Siemens Biograph mCT PET scanner (21 × 21 cm2), installed 25 cm apart, were used to image the beam-induced PET activity during the beam-off periods. For the irradiation of PMMA, we identify the very short-lived activity earlier observed to be 12N (T1/2 = 11.0 ms). The range precision determined from the 12N activity profile that is measured after just one beam pulse was found to be 9.0 and 4.1 mm (1σ) with 1.3 × 1074He ions per pulse and 6.6 × 1074He ions per pulse, respectively. When considering 4.0 × 1074He ions, which is about the intensity of the most intense distal layer spot in a helium therapy plan, a range verification precision in PMMA of 5.7 mm (1σ) can be realized. The range precision scales approximately with the inverse square root of the number of 4He ions, i.e., the relative statistical accuracy of the number of coincidence events. Thus, when summing data over about 10 distal layer spots, this study shows good prospects for obtaining 1.8 mm (1σ) precision in range verification, within 50 ms after the start of a helium irradiation by in-beam PET imaging (scanner 29% solid angle) of 12N.

Compared to photon therapy, proton therapy allows a better conformation of the dose to the tumor volume with reduced radiation dose to co-irradiated tissues. In vivo verification techniques including positron emission tomography (PET) have been proposed as quality assurance tools to mitigate proton range uncertainties. Detection of differences between planned and actual dose delivery on a short timescale provides a fast trigger for corrective actions. Conventional PET-based imaging of 15O (T1/2 = 2 min) and 11C (T1/2 = 20 min) distributions precludes such immediate feedback. We here present a demonstration of near real-time range verification by means of PET imaging of 12N (T1/2 = 11 ms). PMMA and graphite targets were irradiated with a 150 MeV proton pencil beam consisting of a series of pulses of 10 ms beam-on and 90 ms beam-off. Two modules of a modified Siemens Biograph mCT PET scanner (21 × 21 cm2 each), installed 25 cm apart, were used to image the beam-induced PET activity during the beam-off periods. The modifications enable the detectors to be switched off during the beam-on periods. 12N images were reconstructed using planar tomography. Using a 1D projection of the 2D reconstructed 12N image, the activity range was obtained from a fit of the activity profile with a sigmoid function. Range shifts due to modified target configurations were assessed for multiples of the clinically relevant 108 protons per pulse (approximately equal to the highest intensity spots in the pencil beam scanning delivery of a dose of 1 Gy over a cubic 1 l volume). The standard deviation of the activity range, determined from 30 datasets obtained from three irradiations on PMMA and graphite targets, was found to be 2.5 and 2.6 mm (1σ) with 108 protons per pulse and 0.9 and 0.8 mm (1σ) with 109 protons per pulse. Analytical extrapolation of the results from this study shows that using a scanner with a solid angle coverage of 57%, with optimized detector switching and spot delivery times much smaller than the 12N half-life, an activity range measurement precision of 2.0 mm (1σ) and 1.3 mm (1σ) within 50 ms into an irradiation with 4 × 107 and 108 protons per pencil beam spot can be potentially realized. Aggregated imaging of neighboring spots or, if possible, increasing the number of protons for a few probe beam spots will enable the realization of higher precision range measurement.

Therapy with helium ions is currently receiving significantly increasing interest because helium ions have a sharper penumbra than protons and undergo less fragmentation than carbon ions and thus require less complicated dose calculations. For any ion of interest in hadron therapy, the accuracy of dose delivery is limited by range uncertainties. This has led to efforts by several groups to develop in vivo verification techniques, including positron emission tomography (PET), for monitoring of the dose delivery. Beam-on PET monitoring during proton therapy through the detection of short-lived positron emitters such as N-12 (T-1/2 = 11 ms), an emerging PET technique, provides an attractive option given the achievable range accuracy, minimal susceptibility to biological washout and provision of near prompt feedback. Extension of this approach to helium ions requires information on the production yield of relevant short-lived positron emitters. This study presents the first measurements of the production of short-lived positron emitters in water, graphite, calcium and phosphorus targets irradiated with 59 MeV/u He-3 and 50 MeV/u He-4 beams. For these targets, the most produced short-lived nuclides are O-13/N-12 (T-1/2 = 8.6/11 ms) on water, O-13/N-12 on graphite, Ti-43/Sc-41/Sc-42 (T-1/2 = 509-680 ms) on calcium, P-28 (T-1/2 = 268 ms) on phosphorus. A translation of the results from elemental targets to PMMA and representative tissues such as adipose tissue, muscle, compact and cortical bone, shows the dominance of O-13/N-12 in at least the first 20 s of an irradiation with He-4 and somewhat longer with He-3. As the production of O-13/N-12 in a He-3 irradiation is 3-4 times higher than in a He-4 irradiation, from a statistical point of view, range verification using O-13/N-12 PET imaging will be about 2 times more precise for a He-3 irradiation compared to a He-4 irradiation.

In vivo verification of dose delivery in proton therapy by means of positron emission tomography (PET) or prompt gamma imaging is mostly based on fast scintillation detectors. The digital silicon photomultiplier (dSiPM) allows excellent scintillation detector timing properties and is thus being considered for such verification methods. We present here the results of the first investigation of radiation damage to dSiPM sensors in a proton therapy radiation environment. Radiation hardness experiments were performed at the AGOR cyclotron facility at the KVI-Center for Advanced Radiation Technology, University of Groningen. A 150-MeV proton beam was fully stopped in a water target. In the first experiment, bare dSiPM sensors were placed at 25 cm from the Bragg peak, perpendicular to the beam direction, a geometry typical for an in situ implementation of a PET or prompt gamma imaging device. In the second experiment, dSiPM-based PET detectors containing lutetium yttrium orthosilicate scintillator crystal arrays were placed at 2 and 4 m from the Bragg peak, perpendicular to the beam direction; resembling an in-room PET implementation. Furthermore, the experimental setup was simulated with a Geant4-based Monte Carlo code in order to determine the angular and energy distributions of the neutrons and to determine the 1-MeV equivalent neutron fluences delivered to the dSiPM sensors. A noticeable increase in dark count rate (DCR) after an irradiation with about 108 1-MeV equivalent neutrons/cm2 agrees with observations by others for analog SiPMs, indicating that the radiation damage occurs in the single photon avalanche diodes and not in the electronics integrated on the sensor chip. It was found that in the in situ location, the DCR becomes too large for successful operation after the equivalent of a few weeks of use in a proton therapy treatment room (about 5× 103 protons). For PET detectors in an in-room setup, detector performance was unchanged even after an irradiation equivalent to three years of use in a treatment room (3× 1015 protons).

Because of strong indications of multiple counting by the multi-channel scaler (MCS) during most of the experiments described in Dendooven et al (2015 Phys. Med. Biol. 60 8923–47), the production of short-lived positron emitters in the stopping of 55 MeV protons in water, carbon, phosphorus and calcium was remeasured. The new results are reported here. With proper single counting of the MCS, the new production rates are 1.1 to 2.9 times smaller than reported in Dendooven et al (2015 Phys. Med. Biol. 60 8923–47). The omission of the conversion from MCS time bin to time unit in the previous data analysis was corrected, leading to an increase of the production rate by a factor of 2.5 or 10 for some nuclides. The most copiously produced short-lived nuclides and their production rates relative to the relevant long-lived nuclides are: 12N (T 1/2 = 11 ms) on carbon (5.3% of 11C), 29P (T 1/2 = 4.1 s) on phosphorus (23% of 30P) and 38mK (T 1/2 = 0.92 s) on calcium (173% of 38gK). The number of decays integrated from the start of an irradiation as a function of time during the irradiation of PMMA and 4 tissue materials has been determined. For (carbon-rich) adipose tissue, 12N dominates up to 70 s. On bone tissue, 38mK dominates the beam-on PET counts from 0.2–0.7 s until about 80–110 s. Considering nuclides created on phosphorus and calcium, the short-lived ones provide 8 times more decays than the long-lived ones during a 70 s irradiation. Bone tissue will thus be much better visible in beam-on PET compared to PET imaging after an irradiation. From the estimated number of 12N PET counts, we conclude that, for any tissue, except carbon-poor ones, 12N PET imaging potentially provides equal quality proton range information as prompt gamma imaging with an optimized knife-edge slit camera.

PURPOSE: A reduction in the dose, irradiated volume, and sensitivity of, in particular, normal tissue stem cells is needed to advance radiation therapy. This could be obtained with the use of particles for radiation therapy. However, the radiation response of normal tissue stem cells is still an enigma. Therefore, in the present study, we developed a model to investigate the in vitro response of stem cells to particle irradiation.METHODS AND MATERIALS: We used the immortalized human salivary gland (HSG) cell line resembling salivary gland (SG) cells to translate the radiation response in 2-dimensional (2D) to 3-dimensional (3D) conditions. This response was subsequently translated to the response of SG stem cells (SGSCs). Dispersed single cells were irradiated with photons or carbon ions at different linear energy transfers (LETs; 48.76 ± 2.16, 149.9 ± 10.8, and 189 ± 15 keV/μm). Subsequently, 2D or 3D clonogenicity was determined by counting the colonies or secondary stem cell-derived spheres in Matrigel. γH2AX immunostaining was used to assess DNA double strand break repair.RESULTS: The 2D response of HSG cells showed a similar increase in dose response to increasing higher LET irradiation as other cell lines. The 3D response of HSG cells to increasing LET irradiation was reduced compared with the 2D response. Finally, the response of mouse SGSCs to photons was similar to the 3D response of HSG cells. The response to higher LET irradiation was reduced in the stem cells.CONCLUSIONS: Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.

The development of a proton radiography system to improve the imaging of patients in proton beam therapy is described. The system comprises gridpix based time projection chambers, which are based on the Timepix chip designed by the Medipix collaboration, for tracking the protons. This type of detector was chosen to have minimal impact on the actual determination of the proton tracks by the tracking detectors. To determine the residual energy of the protons, a $BaF _{2}$ crystal with a photomultiplier tube is used. We present data taken in a feasibility experiment with phantoms that represent tissue equivalent materials found in the human body. The obtained experimental results show a good agreement with the performed simulations.

Purpose: Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function. Experimental Design: Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification. Results: Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses Conclusions: We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation.

BACKGROUND AND PURPOSE: In thoracic irradiation, the maximum radiation dose is restricted by the risk of radiation-induced cardiopulmonary damage and dysfunction limiting tumor control. We showed that radiation-induced sub-clinical cardiac damage and lung damage in rats mutually interact and that combined irradiation intensifies cardiopulmonary toxicity. Unfortunately, current clinical practice does not include preventative measures to attenuate radiation-induced lung or cardiac toxicity. Here, we investigate the effects of the ACE inhibitor captopril on radiation-induced cardiopulmonary damage.MATERIAL AND METHODS: After local irradiation of rat heart and/or lungs captopril was administered orally. Cardiopulmonary performance was assessed using biweekly breathing rate measurements. At 8weeks post-irradiation, cardiac hemodynamics were measured, CT scans and histopathology were analyzed.RESULTS: Captopril significantly improved breathing rate and cardiopulmonary density/structure, but only when the heart was included in the radiation field. Consistently, captopril reduced radiation-induced pleural and pericardial effusion and cardiac fibrosis, resulting in an improved left ventricular end-diastolic pressure only in the heart-irradiated groups.CONCLUSION: Captopril improves cardiopulmonary morphology and function by reducing acute cardiac damage, a risk factor in the development of radiation-induced cardiopulmonary toxicity. ACE inhibition should be evaluated as a strategy to reduce cardiopulmonary complications induced by radiotherapy to the thoracic area.

The specifications of a new heavy ion irradiation facility for masses up to xenon at 30 MeV/u in air at KVI-CART will be presented. The facility is planned to become operational in the beginning of 2018.

In vivo dose delivery verification in proton therapy can be performed by positron emission tomography (PET) of the positron-emitting nuclei produced by the proton beam in the patient. A PET scanner installed in the treatment position of a proton therapy facility that takes data with the beam on will see very short-lived nuclides as well as longer-lived nuclides. The most important short-lived nuclide for proton therapy is 12N (Dendooven et al 2015 Phys. Med. Biol. 60 8923–47), which has a half-life of 11 ms. The results of a proof-of-principle experiment of beam-on PET imaging of short-lived 12N nuclei are presented. The Philips Digital Photon Counting Module TEK PET system was used, which is based on LYSO scintillators mounted on digital SiPM photosensors. A 90 MeV proton beam from the cyclotron at KVI-CART was used to investigate the energy and time spectra of PET coincidences during beam-on. Events coinciding with proton bunches, such as prompt gamma rays, were removed from the data via an anti-coincidence filter with the cyclotron RF. The resulting energy spectrum allowed good identification of the 511 keV PET counts during beam-on. A method was developed to subtract the long-lived background from the 12N image by introducing a beam-off period into the cyclotron beam time structure. We measured 2D images and 1D profiles of the 12N distribution. A range shift of 5 mm was measured as 6 ± 3 mm using the 12N profile. A larger, more efficient, PET system with a higher data throughput capability will allow beam-on 12N PET imaging of single spots in the distal layer of an irradiation with an increased signal-to-background ratio and thus better accuracy. A simulation shows that a large dual panel scanner, which images a single spot directly after it is delivered, can measure a 5 mm range shift with millimeter accuracy: 5.5 ± 1.1 mm for 1 × 108 protons and 5.2 ± 0.5 mm for 5 × 108 protons. This makes fast and accurate feedback on the dose delivery during treatment possible.

We apply a Monte Carlo based integral rectangular parallel-piped (IRRP) approach to evaluate the impact of heavy ion reaction products on the Galactic Cosmic Ray (GCR) Single Event Effect (SEE) rate, concluding that owing to their similar high-energy (> 100 MeV/n) SEE cross section and much larger abundance, protons are expected to be the dominating contributor. In addition, a broad set of components, ions and energies is used to explore the sub-LET threshold experimental region for standard ground-level heavy ion test energies, identifying an overall decreasing trend in the 10-80 MeV/n range due to the decreased contribution of complete and break-up fusion, and pointing out the limitations associated to the application of Monte Carlo SEE models in this energy interval.

Purpose: Radiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation.Methods and Materials: Cells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1.Results: As expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation.Conclusions: Our results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage. (C) 2012 Elsevier Inc.

Purpose: To investigate whether occurance of early radiation effects in lung tissue depends on local close only.Methods and Materials: Twenty-five percent. 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field dose-response curves were obtained 8 weeks after irradiation. The pathohistology of parenchymal inflammation, infiltrates, fibrosis, and vascular damage and the relative expression of proinflammatory cytokines interleukin (IL)-1 alpha, transforming growth factor-beta. IL-6, and tumor necrosis factor-alpha were assessed.Results: For all histologic endpoints, irradiated dose- and volume-dependent in-field and out-of-field effects were observed, albeit with different dynamics. Of note, the out-of-field effects for vascular damage were very similar to the in-field effects. Interestingly, only IL-6 showed a clear dose-dependent increase in expression both in-field and out-of-field, whereas the expression levels of IL-1 alpha, transforming growth factor-beta, and tumor necrosis factor-alpha were either very low or without a clear dose-volume relation. As such, none of the radiation effects studied depended only on local dose to the tissue.Conclusion: The effects of radiation to lung tissue do not only depend on local dose to that tissue. Especially at high-volume irradiation, lung damage seems to present globally rather than locally. The accuracy of predictive modeling may be improved by including nonlocal effects. (C) 2011 Elsevier Inc.

Purpose: Compared to photons, using particle radiation in radiotherapy reduces the dose and irradiated volume of normal tissues, potentially reducing side effects. The biological effect of dose deposited by particles such as carbon ions, however, differs from that of dose deposited by photons. The inaccuracy in models to estimate the biological effects of particle radiation remains the most important source of uncertainties in particle therapy. Improving this requires high-precision studies on biological effects of particle radiation. Therefore, the authors aimed to develop a facility for reproducible and high-precision carbon-ion irradiation of cells in culture. The combined dose nonuniformity in the lateral and longitudinal direction should not exceed {+-}1.5%. Dose to the cells from particles than other carbon ions should not exceed 5%. Methods: A uniform lateral dose distribution was realized using a single scatter foil and quadrupole magnets. A modulator wheel was used to create a uniform longitudinal dose distribution. The choice of beam energy and the optimal design of these components was determined using GEANT4 and SRIM Monte Carlo simulations. Verification of the uniformity of the dose distribution was performed using a scintillating screen (lateral) and a water phantom (longitudinal). The reproducibility of dose delivery between experiments was assessedmore » by repeated measurements of the spatial dose distribution. Moreover, the reproducibility of dose-response measurements was tested by measuring the survival of irradiated HEK293 cells in three independent experiments. Results: The relative contribution of dose from nuclear reaction fragments to the sample was found to be

Purpose Radiotherapy with helium ions is receiving considerable interest because helium ions combine advantages of both protons and carbon ions. Like other ions, range uncertainties limit the accuracy of dose delivery, thus demanding in vivo verification techniques. Previous studies [1] , [2] show the feasibility of in-beam PET monitoring of proton therapy using very short-lived positron emitters such as 12N ( T 1 / 2 = 11 ms). The extension of this approach to helium ions requires information on the production yield of these positron emitters. Given the absence of such information, we investigated the production of positron emitters for monitoring of helium therapy. Methods The cyclotron at KVI-CART was used to bombard water, graphite and calcium phosphate targets with 3He and 4He beams having a range in water of 22 mm (E = 59 and 50 MeV/u respectively). Nuclide production was assessed via the detection of the 511 keV annihilation gammas using a sodium iodide detector (NaI). The beam was delivered in beam-on/beam-off pulses to identify the PET nuclides via half-life analysis. Results The production of short-lived PET nuclides was observed in all irradiated targets. The irradiation of water and graphite targets shows a decay with a half-life of about 10 ms, indicating the production of 12N and/or 13O. The production of this short-lived component is 8.3 × 10 - 4 per 4He and 1.2 × 10 - 3 per 3He. On the water target also 18Ne ( T 1 / 2 = 1.67 s) and 19Ne ( T 1 / 2 = 17.2 s) were observed with 4He beam, whereas only 18Ne is seen with 3He. With the 4He beam on calcium phosphate target, a half-life contribution of 0.898 ± 0.039 s was observed. Since several short-lived nuclides, including 43Ti, 42Sc and 18Ne are expected, the contribution may result from one or more of these nuclides. Conclusions More detailed quantification of the production per helium ion will be given during the presentation. The large production of a 10 ms component, about 50% higher than for protons1; is promising for real-time verification of helium therapy.

Purpose: Optimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage results in density changes that have been measured by computed tomography (CT) imaging noninvasively, but not yet on a localized scale. Therefore, the aim of the present study was to develop a method for quantification of local radiation-induced lung tissue damage using CT.Methods and Materials: CT images of the thorax were made 8 and 26 weeks after irradiation of 100%, 75%, 50%, and 25% lung volume of rats. Local lung tissue structure (S(L)) was quantified from local mean and local standard deviation of the CT density in Hounsfield units in 1-mm(3) subvolumes. The relation of changes in S(L) (Delta S(L)) to histologic changes and breathing rate was investigated. Feasibility for clinical application was tested by applying the method to CT images of a patient with non-small-cell lung carcinoma and investigating the local dose-effect relationship of Delta S(L).Results: In rats, a clear dose-response relationship of Delta S(L) was observed at different time points after radiation. Furthermore, Delta S(L) correlated strongly to histologic endpoints (infiltrates and inflammatory cells) and breathing rate. In the patient, progressive local dose-dependent increases in Delta S(L) were observed.Conclusion: We developed a method to quantify local radiation-induced tissue damage in the lung using CT. This method can be used in the development of more accurate predictive models for normal tissue complications. (C) 2010 Elsevier Inc.

Purpose: To assess in a rat model whether adding a subtolerance dose in a region adjacent to a high-dose irradiated subvolume of the parotid gland influences its response (bath-and-shower effect).Methods and Materials: Irradiation of the whole, cranial 50%, and/or the caudal 50% of the parotid glands of Wistar rats was performed using 150-MeV protons. To determine suitable (i.e., subtolerance) dose levels for a bath-dose, both whole parotid glands were irradiated with 5 to 25 Gy. Subsequently groups of Wistar rats received 30 Gy to the caudal 50% (shower) and 0 to 10 Gy to the cranial 50% (bath) of both parotid glands. Stimulated saliva flow rate (function) was measured before and up to 240 days after irradiation.Results : Irradiation of both glands up to a dose of 10 Gy did not result in late loss of function and is thus regarded subtolerance. Addition of a dose bath of I to 10 Gy to a high-dose in the caudal 50% of the glands resulted in enhanced function loss.Conclusion: Similar to the spinal cord, the parotid gland demonstrates a bath and shower effect, which may explain the less-than-expected sparing of function after IMRT. (C) 2009 Elsevier Inc.

Radiotherapy and particle therapy treatment planning require accurate knowledge of the electron density and elemental composition of the tissues in the beam path to predict the local dose deposition. We describe a method for the analysis of dual energy computed tomography (DECT) images that provides the electron densities and effective atomic numbers of tissues. The CT measurement process is modelled by system weighting functions, which apply an energy dependent weighting to the parameterization of the total cross section for photon interactions with matter. This detailed parameterization is based on the theoretical analysis of Jackson and Hawkes and deviates, at most, 0.3% from the tabulated NIST values for the elements H to Zn. To account for beam hardening in the object as present in the CT image we implemented an iterative process employing a local weighting function, derived from the method proposed by Heismann and Balda. With this method effective atomic numbers between 1 and 30 can be determined. The method has been experimentally validated on a commercially available tissue characterization phantom with 16 inserts made of tissue substitutes and aluminium that has been scanned on a dual source CT system with tube potentials of 100 kV and 140 kV using a clinical scan protocol. Relative electron densities of all tissue substitutes have been determined with accuracy better than 1%. The presented DECT analysis method thus provides high accuracy electron densities and effective atomic numbers for radiotherapy and especially particle therapy treatment planning.

After a short overview of the methods applied for measuring the neutron-skin thickness, we present the recent experimental results for the neutron-skin thicknesses of the 112–124 Sn even-even isotopes and of 208 Pb. We have used inelastic alpha scattering to excite the giant dipole resonance (GDR). The cross section of this process depends strongly on ΔR np /R, the relative neutron-skin thickness. We have also measured the excitation of the spin-dipole resonance (SDR) to deduce the neutron-skin thickness since the summed L=1 strength of the SDR is sensitive to it. The results obtained are in good agreement with the previous experimental and theoretical ones.

At Kernfysisch Versneller Institute, optical properties of injection transport beam were studied. Measurements of beam size and emittance determined by "varying quadrupole method" are compared with calculations including fringe fields up to the third order with the COSYINFINITY code. Calculations and measurements qualitatively match; the calculations reflect the observed large beam losses. On the basis of the calculations new settings have been determined, resulting in a significant increase of the transmission. To achieve full transmission a complete redesign of the beam line is needed, in particular of the bending magnets.

Positron emission tomography is so far the only method for in-vivo dose delivery verification in hadron therapy that is in clinical use. A PET scanner placed in the treatment position (in-situ) will be able to obtain the highest number of counts, as it minimizes the decay of the positron emitting nuclei before the scan is started as well as reduces the effect of biological washout. We investigated the influence of the scan protocol, i.e. the moment when a scan in done in relation to the treatment delivery, on the ability to measure unacceptable deviations from the treatment plan. We developed a Geant4-based Monte-Carlo framework for proton therapy simulations. Four patient cases are studied: two head-and-neck, one sarcoma near the spine, and one breast cancer case. For each irradiation field, the production of the following PET isotopes is calculated: 15O, 11C, 10C, 14O, 30P, 38K, and 13N. The time sequence of the pencil beam scanning irradiation, the decay of the PET isotopes during the irradiation, and biological washout are included in the simulation. The production of these nuclei is then used to calculate a PET image for two scan protocols: a scan of 120 seconds after the first field, or a scan of 120 seconds after the last field. To mimic a typical scanner spatial resolution, the images are blurred using a Gaussian blurring function with 4 mm FWHM. Deviations from the treatment plan are simulated by shifting the patient 4 mm perpendicular to the field angle, or by increasing the patient density by 3%. The PET image is then simulated again for each scanning protocol. The ability of each protocol to detect these deviations from the treatment plan is investigated by comparing the planned and the modified PET image. Several analysis methods are used: line profiles coupled to the field-directions, structural similarity index analysis [1], and gamma index analysis. [2] Preliminary data shows that a difference in density is best detected by starting the scan directly after the first field. However, shifts perpendicular to the field directions are better detected when the scan is done after the last field, due to the increased activity and counting-rate.

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the doselimiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the doselimiting toxicity.Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects.Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD.Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment. (C) 2016 Elsevier Inc. All rights reserved.

In order to determine the clinical benefit of positron emission tomography (PET) for dose delivery verification in proton therapy, we performed a patient case study comparing in-situ with in-room time-of-flight (TOF) PET. For the in-situ option, we consider both a (limited-angle) clinical scanner and a dual-head scanner placed close to the patient.

A novel emittance meter has been developed to measure the four-dimensional, transverse phase-space distribution of a low-energy ion beam using the pepper-pot technique. A characteristic feature of this instrument is that the pepper-pot plate, which has a linear array of holes in the vertical direction, is scanned horizontally through the ion beam. This has the advantage that the emittance can also be measured at locations along the beam line where the beam has a large horizontal divergence. A set of multi-channel plates, scintillation screen and ccd camera is used as a position-sensitive ion detector allowing a large range of beam intensities that can be handled. This paper describes the design, construction and operation of the instrument as well as the data analysis used to reconstruct the 4D phase-space distribution of an ion beam. Measurements on a 15 keV He+ beam are used as an example., Comment: Paper to be published; 15 pages, 7 figures

Purpose: The application of the two‐dimensional ionization chamber array Octavius 729xdr (PTW‐Freiburg, Germany) in proton beam dosimetry, consisting of 729 vented ionization chambers arranged in a 27 × 27 cm2 matrix, equivalent to the 2D‐Array 729 used for photon beams1, is investigated. Methods: Measurements were carried out with a double scattered 150 MeV proton beam at the AGOR cyclotron at the KVI (Rijksuniversiteit, Groningen — Netherlands). A water bellow with adjustable depth ranging from 10 to 300 mm was placed in the beam line directly behind the collimator for built‐up. The stability, linearity and output factors of the array for circular fields produced using collimators with sizes of 3, 5,7 and 10 cm in diameter were investigated. PDD profiles with a Farmer chamber (type 30010, PTW‐Freiburg, Germany) and the array were measured by stepwise increasing the water bellow's depth. Results: The variation in measurement signal of the 729xdr array was less than 0.2 % after preirradiation with 2 Gy. The linearity of the array was found to be excellent. Output factors showed the expected small variations for circular field sizes. PDDs measured with the array and a Farmer chamber showed good agreement in the region of the Bragg peak with the array slightly underestimating the dose in the built‐up region. Conclusion: The first measurements with the Octavius 729xdr array show the potential of a two‐dimensional ionization chamber array in proton beam dosimetry. The dosimetric properties and the applications of the array in clinical dosimetry will be investigated in more detail in future studies.References1B. Poppe, A. Blechschmidt, A. Djouguela, “Two‐dimensional ionization chamber arrays for IMRT plan verification,” Med. Phys. 33, 1005–1015 (2008)

We outline our plans to construct a soft X-ray Free Electron Laser (FEL) located at KVI, University of Groningen, The Netherlands. This new facility will be based on a 2.1 GeV normal-conducting electron linac followed by an undulator and will produce X-ray laser light with wavelengths down to 0.8 nm. The electron linac will be driven by a RF photo-injector and X-band acceleration structures with an acceleration gradient of 100 MV/m. Longitudinal coherence of the laser beam will be established by using appropriate seeding techniques. The entire length of the FEL will be on the order of 100 meters. The facility will primarily be of interest for fundamental research in atomic, molecular and optical physics, material science and (bio)chemistry, but will also be open for other users e.g. from industry.

6 pages, 2 tables, 4 figures.--PACS nrs.: 21.45.-v; 23.40.-s; 27.20.+n; 21.60.De.--Printed version published Aug 3, 2009, Two complementary experimental techniques have been used to extract precise branching ratios to unbound states in 12C from 12N and 12B β-decays. In the first the three α-particles emitted after β-decay are measured in coincidence in separate detectors, while in the second method 12N and 12B are implanted in a detector and the summed energy of the three α-particles is measured directly. For the narrow states at 7.654 MeV (0+) and 12.71 MeV (1+) the resulting branching ratios are both smaller than previous measurements by a factor of  2. The experimental results are compared to no-core shell model calculations with realistic interactions from chiral perturbation theory, and inclusion of three-nucleon forces is found to give improved agreement., This research was supported by the Academy of Finland (No.project 44875), by the Spanish Agency CICYT (No. FPA2005-02379) and the MEC Consolider project CSD2007-00042, by the Belgian IAP P6/23 project and FWO-Vlaanderen, by the European Union sixth Framework Programme “EURONS” (No. 506065), by the Swedish Research Council and the Knut and Alice Wallenberg foundation, by LLNL (Contract DE-AC52-07NA27344 and DE-FC02-07ER41457) and by DE-FG02-87ER40371.

The nuclear structure of states in C-12 have been a subject of interest for both theory and experiment since the early days of nuclear physics. Many open questions remain, especially concerning the existence and properties of 0(+) and 2(+) states in the triple alpha continuum. A series of experiments have been performed using beta-decay of N-12 and B-12 to probe these states. The latest experiment was performed at KVI using an implantation method, measuring the sum energy of the three alpha-particles directly. Preliminary results from this experiment will be presented.

The KVI is conducting radiobiology research using protons up to 190 MeV from the superconducting AGOR cyclotron in collaboration with the University Medical Center Groningen (UMCG) since 1998. Using the same set-up, we have started irradiations for radiation hardness studies of detectors and components for the European Space Agency (ESA) and industrial parties. For these irradiations, we use either mono-energetic protons or a simulated solar flare energy spectrum with fluxes up to 5 x 108 protons cm(-2) s(-1). Furthermore, tests of radiation effects such as single event upsets, are being performed with intensities down to a few particles/s. Different energies are achieved by degrading the primary beam energy. We are currently developing the capability for heavy ion irradiations in air with beams up to Xe at beam energies between 15 and 45 MeV per nucleon. Performing the irradiations in air simplifies handling and monitoring of the device under test. The high energy allows penetration to the active layer of electronic devices, without modifications to the chip housing. The different ions provide a wide range in LET. (c) 2007 Elsevier B.V. All rights reserved.