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The International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD) is the premier global scientific symposium dedicated to the exchange, advancement and dissemination of the latest research on the pneumococcus, one of the world’s deadliest bacterial pathogens. Since the first ISPPD was held in 1998, substantial progress has been made to control pneumococcal disease, for instance, more than half of surviving infants (78.6 million) from 143 countries now have access to the life-saving pneumococcal conjugate vaccine (PCV). The 11th ISPPD (ISPPD-11) was held in Melbourne, Australia in April 2018 and the proceedings of the symposium are captured in this report.Twenty years on from the first ISPPD, there remain many challenges and unanswered questions such as the continued disparity in disease incidence in Indigenous populations, the slow roll-out of PCV in some regions such as Asia, the persisting burden of disease in adults, serotype replacement and diagnosis of pneumococcal pneumonia. ISPPD-11 also put the spotlight on cutting-edge science including metagenomic, transcriptomic, microscopy, medical imaging and mathematical modelling approaches. ISPPD-11 was highly diverse, bringing together 1184 delegates from 86 countries, representing various fields including academia, primary healthcare, pharmaceuticals, biotechnology, policymakers and public health.

Introduction Particle therapy emerged as a principal innovative technology for tumor treatment. However, it requires verification to exploit its full potential. Various approaches based on prompt gamma radiation were developed for range verification. Prompt gamma-ray timing (PGT), which determines the range of the therapeutic particles from time distributions of produced secondary gamma-rays, is a promising candidate for this as it is collimator-free and can be easily integrated into existing clinical beam deliveries [1]. However, phase instabilities between the accelerating radio frequency (RF) and the actual proton arrival time make phase monitoring indispensable [2]. In recent years, different concepts for proton bunch monitors (PBM) were developed [3,4]. The two most promising candidates are presented here. Materials and Methods A diamond detector with high radiation hardness and excellent time resolution was positioned close to the beam degrader. Protons scattered there were used to determine the phase correlation between RF and proton arrival time under realistic clinical conditions. The second monitor is a direct phasing tap on the low-level RF module of the IBA Proteus®C230 isochronous cyclotron. The correlation of both PBMs to the actual phase was checked in a scattering setup where protons from a pencil beam scattered in a thin polythene foil and then were coincidentally detected by CeBr₃-scintillators. The kinematics of this reaction makes the determination of the proton arrival time independent of the beam's bunch time spread. Results Both PBMs strongly correlate with the phase shift between the arrival time of the proton bunch and the RF. A model based on an over-damped, harmonic oscillator was able to describe the time-dependent change in the phase position and its correction by a control circuit with sufficient accuracy. Thus, the phase instabilities in the PGT data could be successfully corrected, enabling the improved measurement accuracy. Summary The phase instability of the proton bunch is the source of the greatest uncertainty of the PGT method [2]. Two PBMs were studied to correct these instabilities. PBM(s) complement the measurement setup, which should increase the sensitivity of the method and facilitate the translation of the PGT approach into clinical application. Literature [1] C. Golnik et al.: Range assessment in particle therapy based on prompt γ-ray timing measurements, Phys. Med. Biol. 59 (2014) 5399. [2] T. Werner et al.: Processing of prompt gamma-ray timing data for proton range measurements at a clinical beam delivery, Phys. Med. Biol. 64 (2019) 105023. [3] F. Permatasari: Development of a Clinically Applicable Technique for Range Verification in Proton Therapy Based on the PGT Method, PhD thesis, TU Dresden, in preparation. [4] R.-D. Werner: Charakterisierung eines schnellen Diamantdetektors als PBM für die Reichweiteverifikation in der Protonentherapie, Masterarbeit, Universität Halle-Wittenberg, 2021.

The NeuLAND (New Large-Area Neutron Detector) plastic scintillator based time of flight detector for 0.2-1.6 GeV neutrons is currently under construction at the Facility for Antiproton and Ion Research (FAIR), Darmstadt, Germany. In its final configuration, NeuLAND will consist of 3,000 2.7 m long plastic scintillator bars that are read out on each end by fast timing photomultipliers. Here, data from a comprehensive study of an alternative light readout scheme using silicon photomultipliers (SiPM) are reported. For this purpose, a typical NeuLAND bar was instrumented on each end with a prototype of the same geometry as a 1” photomultiplier tube, including four 6×6 mm2 SiPMs, amplifiers, high voltage supply, and micro- controller. Tests were carried out using the 35 MeV electron beam from the ELBE superconducting linac with its ps-level time jitter in two different modes of operation, namely parasitic mode with one electron per bunch and single-usermode with 1-60 electrons per bunch, using Acqiris fast digitizers. In addition, offline tests using cosmic rays and the NeuLAND data acquisition scheme were carried out. Typical time resolutions of σ≤120 ps were found for ≥ 95% efficiency, improving on previous work at ELBE and exceeding the NeuLAND timing goal of σ be 70-200 s-1, comparable with the unavoidable cosmic-ray induced background. The dataset contains the with the Acqiris Digitzier recorded waveforms and analysis scripts for interpretation of the data. Also GEANT4 simulations of the light propagation in a NeuLAND bar and the electron beam propagation are included.

Treatment verification is a key element in future online-adaptive particle therapy. As a light-weight, collimator-free technique, Prompt γ-Ray Timing is a promising candidate for this purpose. The development of such a system for clinical application is challenging due to instabilities in the accelerator phase relation. We present two proton bunch monitors which are capable of measuring and ultimately correct for these instabilities. Firstly, a diamond detector to be placed at the beam energy degrader was investigated. It was found to exhibit an excellent time resolution 82(6) ps and to be able to monitor the phase instability with sufficient precision in a realistic geometry. Secondly, a phase pick-up installed in the low level radio frequency module of the accelerator was used. The data acquired with this monitor showed a very good agreement with the diamond detector with smaller statistical fluctuations. In conclusion, both proton bunch monitors were shown to resolve phase instabilities in Prompt γ-Ray Timing and are expected to strengthen the potential of this system for clinical application.

Range verification is an important prerequisite to unfold the full potential of the finite range of proton beams and to improve treatment precision. The prompt gamma-ray timing (PGT) technique offers a non-invasive approach for range verification using the measured time distribution of the prompt gamma rays produced in the patient. PGT dispenses with a heavy collimator and can be integrated into existing treatment gantries. However, the high sensitivity of this technique to any instabilities in the proton bunch periodicity is a major challenge and demands online monitoring of the proton bunch arrival time. Therefore, we have developed a proton bunch monitor (PBM) comprising fast-scintillating fibers with a double-sided silicon photomultiplier readout. Placing the PBM in the beam halo allows the direct measurement of the proton arrival time at clinical beam intensities while maintaining a processable trigger rate. In a proof-of-principle experiment with a thick acrylic glass target and defined cylindrical air cavities as well as tissue equivalent inserts, a direct monitoring of proton bunches was carried out together with a PGT measurement. With the use of the PBM, another important step towards the clinical translation of the PGT method was taken.

Ein Multipixel-Photodetektor weist elektrisch parallel geschaltete erste Avalanche-Photodioden mit jeweils einer Lichteintrittsfläche und elektrisch parallel geschaltete zweite Avalanche-Photodioden mit jeweils einer Lichteintrittsfläche auf. Die Lichteintrittsfläche jeder ersten Avalanche-Photodiode ist gleich oder größer einer Referenzfläche. Die Lichteintrittsfläche jeder zweiten Avalanche-Photodiode ist kleiner als die Referenzfläche. Die Lichteintrittsflächen der ersten und zweiten Avalanche-Photodioden bilden Teilflächen eines Belichtungsfeldes des Multipixel-Photodetektors.

Treatment verification is expected to improve targeting precision in particle therapy. A promising technique to achieve this goal is the detection of prompt gamma rays emitted along the particle tracks inside the patient. The range of the particle beam can be inferred by determining the time distribution of these gamma-rays relative to the radio frequency of the accelerator, a method commonly referred to as Prompt Gamma-Ray Timing. However, the translation of this method into a clinical setting is currently hindered by instabilities of the phase relation between the arrival of the proton bunches and the radio frequency of the accelerator. These instabilities include two effects, which have been studied at the clinical treatment facility of the University Proton Therapy Dresden. Firstly, a long-term drift of the proton bunch phase relative to the radio frequency in the order of several hundred picoseconds per hour was observed, which may be caused by small temperature changes in the cyclotron’s magnet resulting in magnetization variations in its iron parts. Secondly, strongly damped oscillations in the mean of measured prompt gamma-ray timing spectra with an amplitude in the order of few hundred picoseconds occur for about two seconds after each change of the particle energy during pencil beam scanning. This oscillation is caused by ramping the acceleration voltage back to its nominal value, which is reduced between energy layers to minimize the dark current of the accelerator and the resulting excess dose to the patient. While the former effect is only of secondary importance for the treatment due to its comparably long time scale, the phase oscillation has a considerable negative impact on the accuracy of the Prompt Gamma-Ray Timing method, which has to detect time shifts in the order of a few picoseconds for the detection of millimeter range changes. Therefore, the development of a method to monitor the arrival time of the proton bunches independently from the accelerator radio frequency, a so-called proton bunch monitor, is crucial. To this end, a bunch monitor prototype was developed consisting of scintillating fibers placed in the halo of the proton beam. The fibers were read out on both ends by silicon photomultipliers. A thick acrylic glass target with cylindrical air cavities of varying thickness and different tissue-equivalent inserts was irradiated with protons of clinically relevant energies and typical beam currents. The mean proton arrival time, determined from the time spectra of the proton bunch monitor, was used to correct the prompt gamma-ray timing spectra acquired by Ø2”x2”CeBr3 high-resolution scintillation detectors. This correction allowed to resolve differences in the prompt-gamma ray timing spectra acquired with the different cavities and inserts. In conclusion, the developed proton bunch monitor was successfully integrated to the Prompt Gamma-Ray Timing method and is expected to enable the clinical application of this method for clinical treatment verification in particle therapy.

The development of a switch circuit to gate charge sensitive preamplifiers for use at pulsed radiation sources will be presented.This development was used for the 16O(n,alpha)13C reaction measurement with a Double Frisch Grid Ionization Chamber (DFGIC) at the neutron time-of-flight facility CERN nTOF in Geneva, Switzerland. The so-called gamma-flash, which is produced in the spallation target of the nTOF facility can saturate charge sensitive preamplifiers and prevent signals from being registered in the detection system. The switch circuit made it possible for the first time to perform a measurement with the DFGIC with gamma-flash gated off at nTOF in November 2018. Nano-second gating of charge sensitive preamplifiers has a wide range of applicability at pulsed radiation sources, where short burst of radiation must be gated off to avoid saturation, e.g. with HPGe detectors for gamma-ray detection. Nano-second gating requires the stray-capacitance of the wideband reflective switch to be compensated to avoid a strong signal during the switch operation. Spectral analysis of the switch circuit shows that additional noise is insignificant.

Statusreport SiPM readout for NeuLAND (saturation effects, dark rate and time resolution measurements)

Particle therapy constitutes a promising and rapidly developing method in modern cancer treatment. In order to exploit its full potential, however, it requires detailed dose verification. Although the applicability of in-beam positron emission tomography and prompt gamma rays has already been demonstrated in patients, range verification is not yet part of the clinical routine in particle therapy. This is due to not only the methodological limitations of previous systems, but also to commercial, clinical and physical boundary conditions. In pencil beam scanning, the state-of-the-art treatment method in particle therapy, the number of secondary particles (essentially positrons, prompt gamma rays and fast neutrons) available per spot (Δt = 10 ms to 100 ms) is limited. This leads to statistical accuracy limits for verification systems exploiting these secondary particles as range probes. The development of a clinically useable treatment verification system requires gathering as much information about the local dose, as possible. The instantaneous fluence rate of prompt gamma rays reaching 5×10⁶ cm‾²s‾¹ to 10⁸ cm‾²s‾¹ challenges modern data acquisitions connected to monolithic inorganic scintillators with typical sizes used in present verification systems. In order to reduce the detector load, and also with regard to the ever higher intensities of next generation medical accelerators, future systems have to be more granular. Multi-Feature Treatment Verification combines and extends established methods (prompt gamma-ray imaging, spectroscopy, timing, etc.) in order to achieve higher reliability and performance. This idea was taken up by the NOVO project and expanded by a multi-particle approach. The NOVO (i.e. N eutron and gamma ray imaging with quasi-monolithic organic detector arrays – a novel, holistic approach to real-time range assessment-based treatment verification in particle therapy) consortium is a large collaboration of medical, nuclear and detector physicists, nuclear engineers, and mathematicians, which aim to develop a holistic realtime treatment verification system in particle therapy. Elements of a potential multi-feature/multi-particle treatment verification multi-channel system were characterized in a double time-of-flight experiment at the pulsed photo-neutron source nELBE (neutrons @ Electron Linac for beams with high Brilliance and low Emittance). The essential properties (time resolution, light yield, detection efficiency and pulse shape discrimination) of an EJ-276 plastic scintillator were determined. The very first experimental results show that the time resolution (ΔT < 400 ns) of a 20 × 20 × 200 mm³ EJ-276 plastic scintillator with double-sided readout will reach the high demands of such a proposed range verification system. However, the determined quality of the pulse-shape discrimination, the energy resolution and the quite high neutron detection threshold of above 200 keV show that the light yield of this type of scintillator is not high enough to be used in a multi-feature-based treatment verification system. Particle transport calculations with MCNP6 and GEANT4 were performed to confirm the experimental results of a single detector element. Furthermore, they also show a promising measurement accuracy of a multi-channel overall system.