The increasing burden of testicular seminomas and non-seminomas in adolescents and young adults (AYAs): incidence, treatment, disease-specific survival and mortality trends in the Netherlands between 1989 and 2019.

BACKGROUND: Testicular cancer incidence among adolescents and young adults (AYAs, aged 18-39 years at diagnosis) is increasing worldwide and most patients will survive the initial disease. Still, detailed epidemiological information about testicular cancer among AYAs is scarce. This study aimed to provide a detailed overview of testicular cancer trends in incidence, treatment, long-term relative survival and mortality by histological subtype among AYAs diagnosed in the Netherlands between 1989 and 2019. MATERIALS AND METHODS: Data of all malignant testicular cancers (ICD-code C62) were extracted from the Netherlands Cancer Registry. Mortality data were retrieved from Statistics Netherlands. European age-standardized incidence and mortality rates with average annual percentage change statistics and relative survival estimates up to 20 years of follow-up were calculated. RESULTS: A total of 12 528 testicular cancers were diagnosed between 1989 and 2019. Comparing 1989-1999 to 2010-2019, the incidence increased from 4.4 to 11.4 for seminomas and from 5.7 to 11.1 per 100 000 person-years for non-seminomas. Rising trends were most prominent for localized disease. Radiotherapy use in localized testicular seminomas declined from 78% in 1989-1993 to 5% in 2015-2019. Meanwhile, there was a slight increase in chemotherapy use. Most AYAs with localized seminomas and non-seminomas received active surveillance only (>80%). Overall, relative survival estimates remained well above 90% even at 20 years of follow-up for both seminomas and non-seminomas. Mortality rates declined from 0.5 to 0.4 per 100 000 person-years between 1989-1999 and 2010-2019. CONCLUSIONS: The incidence of seminoma and non-seminoma testicular cancers significantly increased in AYAs in the Netherlands between 1989 and 2019. There was a shift towards less-aggressive treatment regimens without negative survival effects. Relative survival estimates remained well above 90% at 20 years of follow-up in most cases. Testicular cancer mortality was already low, but has improved further over time, which makes survivorship care an important issue for these young adults.

Long-term second primary cancer risk in adolescent and young adult (15-39 years) cancer survivors: a population-based study in the Netherlands between 1989 and 2018.

BACKGROUND: Few studies have comprehensively investigated the long-term second cancer risk among adolescent and young adult (AYA, aged 15-39 years) cancer survivors. This study investigated the long-term second cancer risk by including the full range of first and second cancer combinations with at least 10 observations in the Netherlands between 1989 and 2018. MATERIALS AND METHODS: First and second primary cancer data of all 6-month AYA cancer survivors were obtained from the nationwide population-based Netherlands Cancer Registry. Excess cancer risk compared to the general population was assessed with standardized incidence ratio (SIR) and absolute excess risk (AER) statistics up to 25 years after diagnosis. Cumulative incidences were estimated, using death as a competing risk factor. Analyses were carried out with and without applying multiple cancer rules. RESULTS: The cohort included 99 502 AYA cancer survivors. Male survivors had a 2-fold higher risk of developing any cancer compared to the general population, whereas this was around 1.3-fold in females. AERs were 17.5 and 10.1 per 10 000 person-years for males and females. The long-term excess risk of cancer was significantly higher for most first and second primary cancer combinations, but comparable and lower risk estimates were also observed. Application of the multiple cancer rules resulted in a noticeable risk underestimation in melanoma, testicular, and breast cancer survivors. Risk outcomes remained similar in most cases otherwise. The cumulative incidence of second cancer overall increased over time up to 8.9% in males and 10.3% in females at 25 years' follow-up. Highest long-term cumulative incidences were observed among lymphoma survivors (13.3% males and 18.9% females). CONCLUSIONS: AYA cancer survivors have a higher cancer risk compared to the general population for most cancers up to 25 years after their initial cancer diagnosis. Additional studies that investigate risk factors for the specific cancer type combinations are needed to develop personalized follow-up strategies.

Dosimetric and biologic intercomparison between electron and proton FLASH beams.

BACKGROUND AND PURPOSE: The FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at an average dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by eFLASHvs. pFLASH has yet been performed and constitutes the aim of the present study. MATERIALS AND METHODS: The electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥110 Gy/s eFLASH and pFLASH) dose rates. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed using previously validated dosimetric approaches and experimental murine models. RESULTS: The difference between the average absorbed dose measured at Gantry 1 with PSI reference dosimeters and with CHUV/IRA dosimeters was -1.9 % (0.1 Gy/s) and + 2.5 % (110 Gy/s). The neurocognitive capacity of eFLASH and pFLASH irradiated mice was indistinguishable from the control, while both eCONV and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained after an ablative dose of 20 Gy delivered with the two beams at CONV and FLASH dose rates. Tumor rejection upon rechallenge indicates that anti-tumor immunity was activated independently of the beam-type and the dose-rate. CONCLUSION: Despite major differences in the temporal microstructure of proton and electron beams, this study shows that dosimetric standards can be established. Normal brain protection and tumor control were produced by the two beams. More specifically, normal brain protection was achieved when a single dose of 10 Gy was delivered in 90 ms or less, suggesting that the most important physical parameter driving the FLASH sparing effect might be the mean dose rate. In addition, a systemic anti-tumor immunological memory response was observed in mice exposed to high ablative dose of electron and proton delivered at CONV and FLASH dose rate.

Dosimetric and biologic intercomparison between electron and proton FLASH beams.

Background and purpose: The FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at a mean dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by e vs. pFLASH has yet been performed and constitutes the aim of the present study. Materials and methods: The electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥100 Gy/s eFLASH and pFLASH) irradiation. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed with previously validated models. Results: Doses measured at Gantry1 were in agreement (± 2.5%) with reference dosimeters calibrated at CHUV/IRA. The neurocognitive capacity of e and pFLASH irradiated mice was indistinguishable from the control while both e and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained with the two beams and was similar between e and pFLASH vs. e and pCONV. Tumor rejection was similar indicating that T-cell memory response is beam-type and dose-rate independent. Conclusion: Despite major differences in the temporal microstructure, this study shows that dosimetric standards can be established. The sparing of brain function and tumor control produced by the two beams were similar, suggesting that the most important physical parameter driving the FLASH effect is the overall time of exposure which should be in the range of hundreds of milliseconds for WBI in mice. In addition, we observed that immunological memory response is similar between electron and proton beams and is independent off the dose rate.

Short- and long-term impact of cancer on employment and financial outcomes of adolescents and young adults (AYAs): a large population-based case-control registry study in the Netherlands.

BACKGROUND: Adolescent and young adult (AYA) cancer survivors, 18-39 years at initial cancer diagnosis, often self-report negative consequences of cancer (treatment) for their career. Less is known, however, about the objective impact of cancer on employment and financial outcomes. This study examines the employment and financial outcomes of AYA cancer survivors with nationwide population-based registry data and compares the outcomes of AYAs with cancer with an age- and sex-matched control population at year of diagnosis, 1 year later (short-term) and 5 years later (long-term). PATIENTS AND METHODS: A total of 2527 AYAs, diagnosed in 2013 with any invasive tumor type and who survived for 5 years, were identified from the Netherlands Cancer Registry (clinical and demographic data) and linked to Statistics Netherlands (demographic, employment and financial data). AYAs were matched 1 : 4 with a control population based on age and sex (10 108 controls). Analyses included descriptive statistics, chi-square tests, independent samples t-tests, McNemar tests and logistic regression. RESULTS: AYA cancer survivors were significantly less often employed compared with their controls 1 year (76.1% versus 79.5%, P < 0.001) and 5 years (79.3% versus 83.5%, P < 0.001) after diagnosis, and received more often disability benefits (9.9% versus 3.1% 1 year after diagnosis, P < 0.001; 11.2% versus 3.8% 5 years after diagnosis, P < 0.001). Unemployed AYAs were more often diagnosed with higher disease stages (P < 0.001), treated with chemotherapy (P < 0.001), radiotherapy (P < 0.001) or hormone therapy (P < 0.05) and less often with local surgery (P < 0.05) compared with employed AYAs 1 and 5 years after diagnosis. CONCLUSION: Based on objective, nationwide, population-based registry data, AYAs' employment and financial outcomes are significantly affected compared with age- and sex-matched controls, both short and long-term after cancer diagnosis. Providing support regarding employment and financial outcomes from diagnosis onwards may help AYAs finding their way (back) into society.

Faraday cup for commissioning and quality assurance for proton pencil beam scanning beams at conventional and ultra-high dose rates.

Recently, proton therapy treatments delivered with ultra-high dose rates have been of high scientific interest, and the Faraday cup (FC) is a promising dosimetry tool for such experiments. Different institutes use different FC designs, and either a high voltage guard ring, or the combination of an electric and a magnetic field is employed to minimize the effect of secondary electrons. The authors first investigate these different approaches for beam energies of 70, 150, 230 and 250 MeV, magnetic fields between 0 and 24 mT and voltages between -1000 and 1000 V. When applying a magnetic field, the measured signal is independent of the guard ring voltage, indicating that this setting minimizes the effect of secondary electrons on the reading of the FC. Without magnetic field, applying the negative voltage however decreases the signal by an energy dependent factor up to 1.3% for the lowest energy tested and 0.4% for the highest energy, showing an energy dependent response. Next, the study demonstrates the application of the FC up to ultra-high dose rates. FC measurements with cyclotron currents up to 800 nA (dose rates of up to approximately 1000 Gy s-1) show that the FC is indeed dose rate independent. Then, the FC is applied to commission the primary gantry monitor for high dose rates. Finally, short-term reproducibility of the monitor calibration is quantified within single days, showing a standard deviation of 0.1% (one sigma). In conclusion, the FC is a promising, dose rate independent tool for dosimetry up to ultra-high dose rates. Caution is however necessary when using a FC without magnetic field, as a guard ring with high voltage alone can introduce an energy dependent signal offset.

A static beam delivery device for fast scanning proton arc-therapy.

Arc-therapy is a dose delivery technique regularly applied in photon radiation therapy, and is currently subject of great interest for proton therapy as well. In this technique, proton beams are aimed at a tumor from different continuous ranges of incident directions (so called 'arcs'). This technique can potentially yield a better dose conformity around the tumor and a very low dose in the surrounding healthy tissue. Currently, proton-arc therapy is performed by rotating a proton gantry around the patient, adapting the normally used dose-delivery method to the arc-specific motion of the gantry. Here we present first results from a feasibility study of the conceptual design of a new static fast beam delivery device/system for proton-arc therapy, which could be used instead of a gantry. In this novel concept, the incident angle of proton beams can be set rapidly by only changing field strengths of small magnets. This device eliminates the motion of the heavy gantry and related hardware. Therefore, a reduction of the total treatment time is expected. In the feasibility study presented here, we concentrate on the concept of the beam transport. Based on several simple, but realistic assumptions and approximations, proton tracking calculations were performed in a 3D magnetic field map, to calculate the beam transport in this device and to investigate and address several beam-optics challenges. We propose and simulate corresponding solutions and discuss their outcomes. To enable the implementation of some usually applied techniques in proton therapy, such as pencil beam scanning, energy modulation and beam shaping, we present and discuss our proposals. Here we present the concept of a new idea to perform fast proton arc-scanning and we report on first results of a feasibility study. Based on these results, we propose several options and next steps in the design.

Mean excitation energy determination for Monte Carlo simulations of boron carbide as degrader material for proton therapy.

Boron carbide is a material proposed as an alternative to graphite for use as an energy degrader in proton therapy facilities, and is favoured due to its mechanical robustness and promise to give lower lateral scattering for a given energy loss. However, the mean excitation energy of boron carbide has not yet been directly measured. Here we present a simple method to determine the mean excitation energy by comparison with the relative stopping power in a water phantom, and from a comparison between experimental data and simulations we derive a value for it of 83.1 ± 2.8 eV suitable for use in Monte-Carlo simulation. This is consistent with the existing ICRU estimate (84.7 eV with 10-15% uncertainty) that is based on indirect Bragg additivity calculation, but it has a substantially smaller uncertainty. The method described can be readily applied to predict the ionisation loss of other boron carbide materials in which the atomic constituent ratio may vary, and allows this material to be reliably used as an alternative to graphite, diamond or beryllium.

Geometry optimisation of graphite energy degrader for proton therapy.

INTRODUCTION: Cyclotron-based proton therapy facilities use an energy degrader of variable thickness to deliver beams of the different energies required by a patient treatment plan; scattering and straggling in the degrader give rise to an inherent emittance increase and subsequent particle loss in the downstream energy-selection system (ESS). Here we study alternative graphite degrader geometries and examine with Monte-Carlo simulations the induced emittance growth and consequent particle transmission. METHODS: We examined the conventional multiple-wedge degrader used in the Paul Scherrer Institute PROSCAN proton therapy system, the equivalent parallel-sided degrader, and a single block degrader of equivalent thickness. G4Beamline Monte-Carlo tracking of protons was benchmarked against measurements of the existing degrader for proton energies from 75 to 230 MeV, and used to validate simulations of the alternative geometries. RESULTS: Using a careful calculation of the beam emittance growth, we determined that a single-block degrader placed close to the collimators of the ESS is expected to deliver significantly larger transmission, up to 17% larger at 150 MeV. At the lowest deliverable of 75 MeV there is still a clear improvement in beam transmission. CONCLUSIONS: Whilst dose rates are not presently limited on the PROSCAN system at higher energies, a single-block degrader offers the ability to access either lower energies for treatment or a larger dose rate at 75 MeV in case transmission optimisation is desired. Single-block degraders should be considered for the delivery of low-energy protons from a cyclotron-based particle therapy system.

Uncertainty quantification analysis and optimization for proton therapy beam lines.

Since many years proton therapy is an effective treatment solution against deep-seated tumors. A precise quantification of sources of uncertainty in each proton therapy aspect (e.g. accelerator, beam lines, patient positioning, treatment planning) is of profound importance to increase the accuracy of the dose delivered to the patient. Together with Monte Carlo techniques, a new research field called Uncertainty Quantification (UQ) has been recently introduced to verify the robustness of the treatment planning. In this work we present the first application of UQ as a method to identify typical errors in the transport lines of a cyclotron-based proton therapy facility and analyze their impact on the properties of the therapeutic beams. We also demonstrate the potential of UQ methods in developing optimized beam optics solutions for high-dimensional problems. Sensitivity analysis and surrogate models offer a fast way to exclude unimportant parameters frcomplex optimization problems such as the design of a superconducting gantry performed at Paul Scherrer Institute in Switzerland.

Dynamic beam current control for improved dose accuracy in PBS proton therapy.

The step-and-shoot method of pencil beam scanning delivers the dose on a 3D grid in the target volume, with one dimension defined by the proton energy. While the dose per pencil beam may vary substantially within an iso-energy layer, the beam current typically remains constant. In this static operation mode, the inherent latency of the beam switch-off mechanism results in a lower limit for the deliverable spot dose, which may prevent the application of some of the low-weighted spots prescribed by the treatment planning system. To overcome this limitation, we introduced dynamic beam current control at the PSI Gantry 2, an innovative new approach successfully commissioned and in clinical operation since fall 2017. The control system was enhanced with a direct link to the vertical deflector located at the centre of the cyclotron. This connection allows much faster beam current changes (~0.1 ms) and hence opens up the possibility of dynamically reducing the current for individual low-dose spots. We demonstrate that with this new dynamic operation mode, all spots are delivered as planned without compromising treatment time. We show by two independent and complementary methods that the delivered dose distribution is improved.

Large energy acceptance gantry for proton therapy utilizing superconducting technology.

When using superconducting (SC) magnets in a gantry for proton therapy, the gantry will benefit from some reduction in size and a large reduction in weight. In this contribution we show an important additional advantage of SC magnets in proton therapy treatments. We present the design of a gantry with a SC bending section and achromatic beam optics with a very large beam momentum acceptance of [Formula: see text]15% (corresponding to about [Formula: see text]30% in the energy domain). Due to the related very large energy acceptance, approximately 70% of the treatments can be performed without changing the magnetic field for synchronization with energy modulation. In our design this is combined with a 2D lateral scanning system and a fast degrader mounted in the gantry, so that this gantry will be able to perform pencil beam scanning with very rapid energy variations at the patient, allowing a significant reduction of the irradiation time. We describe the iterative process we have applied to design the magnets and the beam transport, for which we have used different codes. COSY Infinity and OPAL have been used to design the beam transport optics and to track the particles in the magnetic fields, which are produced by the magnets designed in Opera. With beam optics calculations we have derived an optimal achromatic beam transport with the large momentum acceptance of the proton pencil beam and we show the agreement with particle tracking calculations in the 3D magnetic field map. A new cyclotron based facility with this gantry will have a significantly smaller footprint, since one can refrain from the standard degrader and energy selection system behind the cyclotron. In the treatments, this gantry will enable a very fast proton beam delivery sequence, which may be of advantage for treatments in moving tissue.

The impact of pencil beam scanning techniques on the effectiveness and efficiency of rescanning moving targets.

Therapeutic pencil beams are typically scanned using one of the following three techniques: spot scanning, raster scanning or line scanning. While providing similar dose distributions to the target, these three techniques can differ significantly in their delivery time sequence. Thus, we can expect differences in effectiveness and time efficiency when trying to mitigate interplay effects using rescanning. At the Paul Scherrer Institute, we are able to irradiate treatment plans using either of the three delivery techniques. Hence, we can compare them directly with identical underlying machine parameters such as energy switching time or minimum/maximum beam current. For this purpose, we selected three different liver targets, optimized plans for spots, and converted them to equivalent raster and line scanning plans. In addition to the scanning technique, we varied the underlying motion curve, starting phase, prescription dose and rescanning strategy, which resulted in a total of 1584 4D dose calculations and 49 measurements. They indicate that rescanning becomes effective when achieving a high number of rescans for every dose element. Fixed minimum spot weights for spot and raster scanning machines often hamper this. By introducing adaptive scaling of the beam current within iso-energy layers for line scanning, we can flexibly lower the minimum weight whenever required and achieve higher rescanning capability. Averaged over all scenarios studied, volumetric rescanning is significantly more effective than layered provided the same number of rescans are applied. Fast lateral scanning contributes to the efficiency of rescanning. We observed that in any given time window, we can always perform more rescans using raster or line scanning compared to spot scanning irradiations. Thus, we conclude that line scanning represents a promising technique for rescanning by combining both effectiveness and efficiency.

[Fatal intoxication with nicotine for e-cigarette]. / Fatale intoxicatie met nicotine voor e-sigaret.

BACKGROUND: Since the introduction of the electronic e-cigarette a few years ago, its use has greatly increased. The liquid formulations used in these e-cigarettes contain nicotine in high concentrations; ingestion of these liquids can be fatal. CASE DESCRIPTION: A 42-year-old male was admitted to the Intensive Care ward due to cardiac arrest. The patient had ingested highly concentrated liquid nicotine, originating from a vial with liquid for e-cigarettes. When the ambulance personnel found the patient he did not have a pulse; following CPR and administration of adrenaline his pulse returned. Upon admission, the plasma nicotine level was high at 3.0 mg/l (reference values for a smoker are 0.01-0.05 mg/l) and the patient's neurological function was poor. The patient was treated symptomatically, but eventually died of a postanoxic encephalopathy. CONCLUSION: Nicotine e-liquids are highly concentrated. Intentional ingestion can lead to toxic levels of nicotine which are associated with cardiac arrhythmias or arrest. Because even a few millilitres can be lethal, nicotine intoxication due to e-liquid ingestion should be considered potentially life-threatening.

A beam monitoring and validation system for continuous line scanning in proton therapy.

Line scanning represents a faster and potentially more flexible form of pencil beam scanning than conventional step-and-shoot irradiations. It seeks to minimize dead times in beam delivery whilst preserving the possibility of modulating the dose at any point in the target volume. Our second generation proton gantry features irradiations in line scanning mode, but it still lacks a dedicated monitoring and validation system that guarantees patient safety throughout the irradiation. We report on its design and implementation in this paper. In line scanning, we steer the proton beam continuously along straight lines while adapting the speed and/or current frequently to modulate the delivered dose. We intend to prevent delivery errors that could be clinically relevant through a two-stage system: safety level 1 monitors the beam current and position every 10 µs. We demonstrate that direct readings from ionization chambers in the gantry nozzle and Hall probes in the scanner magnets provide required information on current and position, respectively. Interlocks will be raised when measured signals exceed their predefined tolerance bands. Even in case of an erroneous delivery, safety level 1 restricts hot and cold spots of the physically delivered fraction dose to ±[Formula: see text] (±[Formula: see text] of [Formula: see text] biologically). In safety level 2-an additional, partly redundant validation step-we compare the integral line profile measured with a strip monitor in the nozzle to a forward-calculated prediction. The comparison is performed between two line applications to detect amplifying inaccuracies in speed and current modulation. This level can be regarded as an online quality assurance of the machine. Both safety levels use devices and functionalities already installed along the beamline. Hence, the presented monitoring and validation system preserves full compatibility of discrete and continuous delivery mode on a single gantry, with the possibility of switching between modes during the application of a single field.

A comprehensive and efficient daily quality assurance for PBS proton therapy.

There are several general recommendations for quality assurance (QA) measures, which have to be performed at proton therapy centres. However, almost each centre uses a different therapy system. In particular, there is no standard procedure for centres employing pencil beam scanning and each centre applies a specific QA program. Gantry 2 is an operating therapy system which was developed at PSI and relies on the most advanced technological innovations. We developed a comprehensive daily QA program in order to verify the main beam characteristics to assure the functionality of the therapy delivery system and the patient safety system. The daily QA program entails new hardware and software solutions for a highly efficient clinical operation. In this paper, we describe a dosimetric phantom used for verifying the most critical beam parameters and the software architecture developed for a fully automated QA procedure. The connection between our QA software and the database allows us to store the data collected on a daily basis and use it for trend analysis over longer periods of time. All the data presented here have been collected during a time span of over two years, since the beginning of the Gantry 2 clinical operation in 2013. Our procedure operates in a stable way and delivers the expected beam quality. The daily QA program takes only 20 min. At the same time, the comprehensive approach allows us to avoid most of the weekly and monthly QA checks and increases the clinical beam availability.

First experimental results of motion mitigation by continuous line scanning of protons.

Mitigation of organ motion in active, scanning proton therapy is a challenge. One of the easiest methods to implement is re-scanning, where a treatment plan is applied several times with accordingly smaller weights. As a consequence, motion effects are averaged out. For discrete spot scanning, a major drawback of this method is the treatment time, which increases linearly with the number of re-scans. Continuous line scanning, on the other hand, eliminates the dead time between the positioning of each beam, and in this work, continuous line scanning has been investigated experimentally from the point of view of dose, penumbral width and its effectiveness for re-scanning. As shown by measurements in a homogeneous phantom, dose distributions delivered by continuous line scanning were comparable with those of discrete spot scanning for both geometric and realistic targets, with only a modest degradation of lateral penumbra in the direction of scanning. In addition, delivered dose levels have also been found to agree well between discrete and line scanning. With continuous line scanning, however, more re-scans could be applied without the artefacts seen in discrete spot scanning, with motions of up to 1 cm peak-to-peak amplitude being mitigated by 10 re-scans. For larger motion, in the interest of reducing the volume of irradiated normal tissue re-scanning should be combined with other motion mitigation techniques such as gating or breath-hold.

Proton beam monitor chamber calibration.

The first goal of this paper is to clarify the reference conditions for the reference dosimetry of clinical proton beams. A clear distinction is made between proton beam delivery systems which should be calibrated with a spread-out Bragg peak field and those that should be calibrated with a (pseudo-)monoenergetic proton beam. For the latter, this paper also compares two independent dosimetry techniques to calibrate the beam monitor chambers: absolute dosimetry (of the number of protons exiting the nozzle) with a Faraday cup and reference dosimetry (i.e. determination of the absorbed dose to water under IAEA TRS-398 reference conditions) with an ionization chamber. To compare the two techniques, Monte Carlo simulations were performed to convert dose-to-water to proton fluence. A good agreement was found between the Faraday cup technique and the reference dosimetry with a plane-parallel ionization chamber. The differences-of the order of 3%-were found to be within the uncertainty of the comparison. For cylindrical ionization chambers, however, the agreement was only possible when positioning the effective point of measurement of the chamber at the reference measurement depth-i.e. not complying with IAEA TRS-398 recommendations. In conclusion, for cylindrical ionization chambers, IAEA TRS-398 reference conditions for monoenergetic proton beams led to a systematic error in the determination of the absorbed dose to water, especially relevant for low-energy proton beams. To overcome this problem, the effective point of measurement of cylindrical ionization chambers should be taken into account when positioning the reference point of the chamber. Within the current IAEA TRS-398 recommendations, it seems advisable to use plane-parallel ionization chambers-rather than cylindrical chambers-for the reference dosimetry of pseudo-monoenergetic proton beams.

The effectiveness of combined gating and re-scanning for treating mobile targets with proton spot scanning. An experimental and simulation-based investigation.

Organ motion is one of the major obstacles in radiotherapy and charged particle therapy. Even more so, the theoretical advantages of dose distributions in scanned ion beam therapy may be lost due to the interplay between organ motion and beam scanning. Several techniques for dealing with this problem have been devised. In re-scanning, the target volume is scanned several times to average out the motion effects. In gating and breath-hold, dose is only delivered if the tumour is in a narrow window of position. Experiments have been performed to verify if gating and re-scanning are effective means of motion mitigation. Dose distributions were acquired in a lateral plane of a homogeneous phantom. For a spherical target volume and regular motion gating was sufficient. However, for realistic, irregular motion or a patient target volume, gating did not reduce the interplay effect to an acceptable level. Combining gating with re-scanning recovered the dose distributions. The simplest re-scanning approach, where a treatment plan is duplicated several times and applied in sequence, was not efficient. Simulations of different combinations of gating window sizes and re-scanning schemes revealed that reducing the gating window is the most efficient approach. However, very small gating windows are not robust for irregular motion.

Characterization of SM201, an anti-hFcγRIIB antibody not interfering with ligand binding that mediates immune complex dependent inhibition of B cells.

The monoclonal antibody SM201 specifically recognizes the human inhibitory FcγRIIB without showing cross-reactivity to the related but activating FcγRIIA. The epitope recognized by SM201 is located outside the IgG-binding site of FcγRIIB. As a result, the antibody does not interfere with hIgG binding to the receptor. It was therefore hypothesized that SM201 may amplify the inhibitory signaling of FcγRIIB after coligation of B cell receptor (BCR) and FcγRIIB by immune complexes (ICs). Mechanistic and functional studies were conducted in established B cell lines as well as in primary B cells from healthy donors to substantiate the anticipated working principle. Using an experimental setup mimicking IC binding, we were able to demonstrate that SM201 enhances the extent of ITIM phosphorylation of FcγRIIB. The antibody works synergistically with ICs and the mode of action is strictly dependent on their presence. Additionally, SM201 did not induce apoptosis, cellular depletion or NK cell activation, which indicates an advantageous safety profile. This establishes an innovative approach for the treatment of antibody-mediated autoimmune diseases.