In this work, we present experimental results of a prompt gamma camera for real-time proton beam range verification. The detection system features a pixelated Cerium doped lutetium based ...scintillation crystal, coupled to Silicon PhotoMultiplier arrays, read out by dedicated electronics. The prompt gamma camera uses a knife-edge slit collimator to produce a 1D projection of the beam path in the target on the scintillation detector. We designed the detector to provide high counting statistics and high photo-detection efficiency for prompt gamma rays of several MeV. The slit design favours the counting statistics and could be advantageous in terms of simplicity, reduced cost and limited footprint. We present the description of the realized gamma camera, as well as the results of the characterization of the camera itself in terms of imaging performance. We also present the results of experiments in which a polymethyl methacrylate phantom was irradiated with proton pencil beams in a proton therapy center. A tungsten slit collimator was used and prompt gamma rays were acquired in the 3-6 MeV energy range. The acquisitions were performed with the beam operated at 100 MeV, 160 MeV and 230 MeV, with beam currents at the nozzle exit of several nA. Measured prompt gamma profiles are consistent with the simulations and we reached a precision (2σ) in shift retrieval of 4 mm with 0.5 × 10(8), 1.4 × 10(8) and 3.4 × 10(8) protons at 100, 160 and 230 MeV, respectively. We conclude that the acquisition of prompt gamma profiles for in vivo range verification of proton beam with the developed gamma camera and a slit collimator is feasible in clinical conditions. The compact design of the camera allows its integration in a proton therapy treatment room and further studies will be undertaken to validate the use of this detection system during treatment of real patients.
Treatments delivered by proton therapy are affected by uncertainties on the range of the beam within the patient, requiring medical physicists to add safety margins on the penetration depth of the ...beam. To reduce these margins and deliver safer treatments, different projects are currently investigating real-time range control by imaging prompt gammas emitted along the proton tracks in the patient. This study reports on the feasibility, development and test of a new concept of prompt gamma camera using a slit collimator to obtain a one-dimensional projection of the beam path on a scintillation detector. This concept was optimized, using the Monte Carlo code MCNPX version 2.5.0, to select high energy photons correlated with the beam range and detect them with both high statistics and sufficient spatial resolution. To validate the Monte Carlo model, spectrometry measurements of secondary particles emitted by a PMMA target during proton irradiation at 160 MeV were realized. An excellent agreement with the simulations was observed when using subtraction methods to isolate the gammas in direct incidence. A first prototype slit camera using the HiCam gamma detector was consequently prepared and tested successfully at 100 and 160 MeV beam energies. Results confirmed the potential of this concept for real-time range monitoring with millimetre accuracy in pencil beam scanning mode for typical clinical conditions. If we neglect electronic dead times and rejection of detected events, the current solution with its collimator at 15 cm from the beam axis can achieve a 1-2 mm standard deviation on range estimation in a homogeneous PMMA target for numbers of protons that correspond to doses in water at the Bragg peak as low as 15 cGy at 100 MeV and 25 cGy at 160 MeV assuming pencil beams with a Gaussian profile of 5 mm sigma at target entrance.
Prompt-gamma emission detection is a promising technique for hadrontherapy monitoring purposes. In this regard, obtaining prompt-gamma yields that can be used to develop monitoring systems based on ...this principle is of utmost importance since any camera design must cope with the available signal. Herein, a comprehensive study of the data from ten single-slit experiments is presented, five consisting in the irradiation of either PMMA or water targets with lower and higher energy carbon ions, and another five experiments using PMMA targets and proton beams. Analysis techniques such as background subtraction methods, geometrical normalization, and systematic uncertainty estimation were applied to the data in order to obtain absolute prompt-gamma yields in units of prompt-gamma counts per incident ion, unit of field of view, and unit of solid angle. At the entrance of a PMMA target, where the contribution of secondary nuclear reactions is negligible, prompt-gamma counts per incident ion, per millimetre and per steradian equal to (124 ± 0.7stat ± 30sys) × 10(-6) for 95 MeV u(-1) carbon ions, (79 ± 2stat ± 23sys) × 10(-6) for 310 MeV u(-1) carbon ions, and (16 ± 0.07stat ± 1sys) × 10(-6) for 160 MeV protons were found for prompt gammas with energies higher than 1 MeV. This shows a factor 5 between the yields of two different ions species with the same range in water (160 MeV protons and 310 MeV u(-1) carbon ions). The target composition was also found to influence the prompt-gamma yield since, for 300/310 MeV u(-1) carbon ions, a 42% greater yield ((112 ± 1stat ± 22sys) × 10(-6) counts ion(-1) mm(-1) sr(-1)) was obtained with a water target compared to a PMMA one.
We have demonstrated that recombinant hepatitis E vaccine suitable for clinical evaluation was highly immunogenic and efficacious in preventing hepatitis E and even infection in rhesus macaques ...following intravenous challenge with three different genotypes of hepatitis E virus (HEV). Two doses of vaccine were essential for optimal protection; the two-dose regimen was more important than the formulation of the vaccine for achieving efficacy. The titers of anti-HEV that were protective in this study were quantified against a World Health Organization (WHO) standard. This permits direct comparison of the results with other studies. The results of this pre-clinical trial of a candidate hepatitis E vaccine strongly suggest that it will be highly efficacious for preventing hepatitis E in the field trial of this vaccine that is currently in progress in Nepal.
The development of a vaccine for tuberculosis requires a combination of antigens and adjuvants capable of inducing appropriate and long-lasting T cell immunity. We evaluated Mtb72F formulated in ...AS02A in the cynomolgus monkey model. The vaccine was immunogenic and caused no adverse reactions. When monkeys were immunized with bacillus Calmette-Guérin (BCG) and then boosted with Mtb72F in AS02A, protection superior to that afforded by using BCG alone was achieved, as measured by clinical parameters, pathology, and survival. We observed long-term survival and evidence of reversal of disease progression in monkeys immunized with the prime-boost regimen. Antigen-specific responses from protected monkeys receiving BCG and Mtb72F/AS02A had a distinctive cytokine profile characterized by an increased ratio between 3 Th1 cytokines, IFN-γ, TNF, and IL-2 and an innate cytokine, IL-6. To our knowledge, this is an initial report of a vaccine capable of inducing long-term protection against tuberculosis in a nonhuman primate model, as determined by protection against severe disease and death, and by other clinical and histopathological parameters.
Purpose:
To measure the acoustic signal generated by a pulsed proton spill from a hospital‐based clinical cyclotron.
Methods:
An electronic function generator modulated the IBA C230 isochronous ...cyclotron to create a pulsed proton beam. The acoustic emissions generated by the proton beam were measured in water using a hydrophone. The acoustic measurements were repeated with increasing proton current and increasing distance between detector and beam.
Results:
The cyclotron generated proton spills with rise times of 18 μs and a maximum measured instantaneous proton current of 790 nA. Acoustic emissions generated by the proton energy deposition were measured to be on the order of mPa. The origin of the acoustic wave was identified as the proton beam based on the correlation between acoustic emission arrival time and distance between the hydrophone and proton beam. The acoustic frequency spectrum peaked at 10 kHz, and the acoustic pressure amplitude increased monotonically with increasing proton current.
Conclusions:
The authors report the first observation of acoustic emissions generated by a proton beam from a hospital‐based clinical cyclotron. When modulated by an electronic function generator, the cyclotron is capable of creating proton spills with fast rise times (18 μs) and high instantaneous currents (790 nA). Measurements of the proton‐generated acoustic emissions in a clinical setting may provide a method for in vivo proton range verification and patient monitoring.
The safety, immunogenicity, and protective efficacy of two non-replicating antigen-based vaccines and one live-attenuated virus (LAV) vaccine for dengue type-2 (dengue-2) virus were evaluated in the ...rhesus macaque model. The non-replicating vaccines consisted of whole, purified inactivated virus (PIV) and a recombinant subunit protein containing the amino-(N)-terminal 80% of envelope protein (r80E), each formulated with one of five different adjuvants. Each formulation was administered to three animals on a 0, 3-month schedule. Following the primary immunizations, 37 of 39 animals demonstrated dengue-2 virus neutralizing antibodies. After the booster immunizations all animals had dengue neutralizing antibodies with peak titers ranging from 1:100 to 1:9700. The highest neutralizing antibody titers were observed in the groups that received r80E antigen formulated with AS04, AS05, or AS08 adjuvant, and PIV formulated with AS05 or AS08 adjuvant. These newer adjuvants are based on alum, fraction QS-21 of saponin, and monophosphoryl lipid A (MPL). Protection was evaluated by dengue-2 virus challenge 2 months after the booster by the measurement of circulating virus (viremia) and post-challenge immune responses. Several groups exhibited nearly complete protection against viremia by bioassay, although there was evidence for challenge virus replication by Taqman™ and immunological assays. None of the vaccines conferred sterile immunity.
Prompt-gamma profile was measured at WPE-Essen using 160 MeV protons impinging a movable PMMA target. A single collimated detector was used with time-of-flight (TOF) to reduce the background due to ...neutrons. The target entrance rise and the Bragg peak falloff retrieval precision was determined as a function of incident proton number by a fitting procedure using independent data sets. Assuming improved sensitivity of this camera design by using a greater number of detectors, retrieval precisions of 1 to 2 mm (rms) are expected for a clinical pencil beam. TOF improves the contrast-to-noise ratio and the performance of the method significantly.
Prompt γ-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera ...system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2σ). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt γ-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit.
The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ(S) of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in a ...time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ(S) is determined from the difference between the μ(-) disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2 × 10(10) μ(-) decays, from which we extract the capture rate Λ(S) = (714.9 ± 5.4(stat) ± 5.1(syst)) s(-1) and derive the proton's pseudoscalar coupling g(P)(q(0)(2) = -0.88 m(μ)(2)) = 8.06 ± 0.55.
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