Variable Relative Biological Effectiveness in Proton Treatment Planning

Protonen töten Zellen wirksamer ab als Photonen. Die klinisch verwendete konstante relative biologische Wirksamkeit (RBW) für Protonen vernachlässigt jedoch erste klinische Evidenz einer RBW-Variabilität, die vom linearen Energietransfer (LET) abhängt. Diese Arbeit trägt dazu bei, die RBW-Variabilität in Protonen-Bestrahlungsplänen zu berücksichtigen, um potenzielle Nebenwirkungen zu vermindern. Zuerst wurde ein erhöhtes Risiko für RBW-induzierte Nebenwirkungen bei Hirntumorpatienten festgestellt. Dies konnte jedoch nicht systematisch durch klinische Planungsstrategien reduziert werden. Zweitens ergab eine multizentrische europäische Studie, dass die zentrums-spezifischen, nicht standardisierten LET-Berechnungen erheblich voneinander abweichen. Eine harmonisierte LET-Definition wurde vorgeschlagen und reduzierte die Variabilität zwischen den Zentren auf ein klinisch akzeptables Niveau, was künftig eine einheitliche Dokumentation des Therapieergebnisses ermöglicht. Abschließend wurden vier Strategien zur RBW-Reduktion in der Planoptimierung bei Hirntumorpatienten angewandt, die das Risiko für Nekrose und Erblindung erheblich reduzierten. LET-Optimierung in Hochdosisregionen erscheint besonders geeignet, um die Sicherheit der Patientenbehandlung künftig weiter zu verbessern.:List of Figures vii List of Tables viii List of Acronyms and Abbreviations ix 1 Introduction 1 2 Theoretical background 3 2.1 Proton interactions with matter 4 2.2 Biological effect of radiation 8 2.2.1 Linear-quadratic model 8 2.2.2 Relative biological effectiveness 9 2.3 Proton beam delivery and field formation 13 2.4 Treatment planning 14 2.4.1 Patient modelling and structure definition 15 2.4.2 Treatment plan optimisation 16 2.4.3 Treatment plan evaluation 19 2.5 Proton therapy uncertainties and mitigation strategies 22 2.5.1 Clinical mitigation strategies 23 2.5.2 Optimisation approaches beyond absorbed dose 26 3 Variable biological effectiveness in PBS treatment plans 29 3.1 LET and RBE recalculations of proton treatment plans with RayStation 30 3.1.1 Monte Carlo dose engine 30 3.1.2 Monte Carlo scoring extensions 32 3.1.3 Graphical user interface 33 3.2 LET assessment and the role of range uncertainties 36 3.2.1 Patient cohort and treatment plan creation 37 3.2.2 Simulation of range deviations 38 3.2.3 Treatment plan recalculation settings 39 3.2.4 Resulting impact of range deviations 40 3.3 Patient recalculations in case of side effects 46 3.3.1 Image registration and range prediction 48 3.3.2 Retrospective treatment plan assessment 49 3.4 Benefit of an additional treatment field 50 3.4.1 Patient and treatment plan information 50 3.4.2 Results of variable RBE recalculations 51 3.5 Discussion 51 3.6 Summary 59 4 Status of LET and RBE calculations in European proton therapy 61 4.1 Study design 62 4.1.1 Treatment planning information 64 4.1.2 Data processing and treatment plan evaluation 67 4.2 Treatment plan comparisons in the water phantom 68 4.2.1 Absorbed dose evaluation 69 4.2.2 Centre-specific LET calculations 69 4.2.3 Harmonised LET calculations 71 4.3 Treatment plan comparisons in patient cases 72 4.3.1 Dose-averaged linear energy transfer for protons 73 4.3.2 Centre-specific RBE models and parameters 76 4.4 Discussion 77 4.5 Summary 82 5 Biological treatment plan optimisation 83 5.1 Treatment plan design 84 5.1.1 Clinical goals 86 5.1.2 Novel treatment plan optimisation approaches 87 5.2 Treatment plan quality assessment with a constant RBE 90 5.3 Assessment of NTCP reductions with a variable RBE 90 5.4 Discussion 95 5.5 Conclusion 100 6 Summary 103 7 Zusammenfassung 107 Bibliography 111 Danksagung 137Protons are more effective in cell killing than photons. However, the clinically applied constant proton relative biological effectiveness (RBE) neglects emerging clinical evidence for RBE variability driven by the linear energy transfer (LET). This thesis aims to safely account for RBE variability in proton treatment plans to mitigate potential side effects. First, an elevated risk for RBE induced overdosage was found in brain tumour patients. However, this could not be mitigated systematically by clinical planning strategies. Second, a multicentric European study revealed that centre-specific non-standardised LET calculations differed substantially. A harmonised LET definition was proposed which reduced the inter-centre variability to a clinically acceptable level and allows for future consistent outcome reporting. Finally, four strategies to include RBE variability in treatment plan optimisation were applied to brain tumour patients, which considerably reduced the estimated risk for necrosis and blindness. Of these, LET optimisation in high dose regions may be suited for clinical practice to further enhance patient safety in view of a variable RBE.:List of Figures vii List of Tables viii List of Acronyms and Abbreviations ix 1 Introduction 1 2 Theoretical background 3 2.1 Proton interactions with matter 4 2.2 Biological effect of radiation 8 2.2.1 Linear-quadratic model 8 2.2.2 Relative biological effectiveness 9 2.3 Proton beam delivery and field formation 13 2.4 Treatment planning 14 2.4.1 Patient modelling and structure definition 15 2.4.2 Treatment plan optimisation 16 2.4.3 Treatment plan evaluation 19 2.5 Proton therapy uncertainties and mitigation strategies 22 2.5.1 Clinical mitigation strategies 23 2.5.2 Optimisation approaches beyond absorbed dose 26 3 Variable biological effectiveness in PBS treatment plans 29 3.1 LET and RBE recalculations of proton treatment plans with RayStation 30 3.1.1 Monte Carlo dose engine 30 3.1.2 Monte Carlo scoring extensions 32 3.1.3 Graphical user interface 33 3.2 LET assessment and the role of range uncertainties 36 3.2.1 Patient cohort and treatment plan creation 37 3.2.2 Simulation of range deviations 38 3.2.3 Treatment plan recalculation settings 39 3.2.4 Resulting impact of range deviations 40 3.3 Patient recalculations in case of side effects 46 3.3.1 Image registration and range prediction 48 3.3.2 Retrospective treatment plan assessment 49 3.4 Benefit of an additional treatment field 50 3.4.1 Patient and treatment plan information 50 3.4.2 Results of variable RBE recalculations 51 3.5 Discussion 51 3.6 Summary 59 4 Status of LET and RBE calculations in European proton therapy 61 4.1 Study design 62 4.1.1 Treatment planning information 64 4.1.2 Data processing and treatment plan evaluation 67 4.2 Treatment plan comparisons in the water phantom 68 4.2.1 Absorbed dose evaluation 69 4.2.2 Centre-specific LET calculations 69 4.2.3 Harmonised LET calculations 71 4.3 Treatment plan comparisons in patient cases 72 4.3.1 Dose-averaged linear energy transfer for protons 73 4.3.2 Centre-specific RBE models and parameters 76 4.4 Discussion 77 4.5 Summary 82 5 Biological treatment plan optimisation 83 5.1 Treatment plan design 84 5.1.1 Clinical goals 86 5.1.2 Novel treatment plan optimisation approaches 87 5.2 Treatment plan quality assessment with a constant RBE 90 5.3 Assessment of NTCP reductions with a variable RBE 90 5.4 Discussion 95 5.5 Conclusion 100 6 Summary 103 7 Zusammenfassung 107 Bibliography 111 Danksagung 13

Multi-sector Service Use by Children in Contact with Ontario Mental Health Agencies

Children and youth frequently receive services for mental health issues from multiple service sectors but little is known about the rates of multi-sector involvement over time. Thus, the prevalence of multi-sector service use for children in contact with Ontario mental health agencies, and the influence of demographic, familial, and need variables on child multi-sector involvement, were examined. Secondary data analyses were performed on chart reviews of clients (N=355; 67% boys; ages 4 to 13) from six mental health agencies. Approximately two-thirds of clients had multi-sector involvement. In cross-sectional analyses, risk factors predicted increased likelihood of multi-sector involvement, whereas protective factors predicted decreased likelihood. In longitudinal analyses, increased risk/need at time 1 did not predict likelihood of multi-sector involvement at time 2. Ensuring a match between a client’s degree of need and services used may prevent misallocation of mental health resources

Efficient Teleportation between Remote Single-Atom Quantum Memories

We demonstrate teleportation of quantum bits between two single atoms in distant laboratories. Using a time-resolved photonic Bell-state measurement, we achieve a teleportation fidelity of (88.0+/-1.5)%, largely determined by our entanglement fidelity. The low photon collection efficiency in free space is overcome by trapping each atom in an optical cavity. The resulting success probability of 0.1% is almost 5 orders of magnitude larger than in previous experiments with remote material qubits. It is mainly limited by photon propagation and detection losses and can be enhanced with a cavity-based deterministic Bell-state measurement.Comment: 7 pages, 4 figures, 1 tabl

Money Demand in Europe: Evidence from the Past

The conditions under which European monetary policy is likely to be conducted are investigated by means of multi-variate time series modelling using aggregated data of all eleven European Monetary Union member states. A cointegration analysis identifies two stable long-run relationships within a set of five key macroeconomic variables, one of which can be interpreted as a money demand function and a second one as a long term real interest rate (Fisher parity). Our findings indicate that monetary authorities might well be able to base their policy on the existence of a money demand. Particular emphasis is given both to the data sources and their aggregation, by providing a transparent account of our calculation procedure, which is not yet common in the existing literature.

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We report on a comparative study of spin Hall related effects and magnetoresistance in YIG|Pt and YIG|Ta bilayers. These combined measurements allow to estimate the characteristic transport parameters of both Pt and Ta layers juxtaposed to YIG: the spin mixing conductance $G_{\uparrow \downarrow}$ at the YIG$|$normal metal interface, the spin Hall angle $\Theta_{SH}$, and the spin diffusion length $\lambda_{sd}$ in the normal metal. The inverse spin Hall voltages generated in Pt and Ta by the pure spin current pumped from YIG excited at resonance confirm the opposite signs of spin Hall angles in these two materials. Moreover, from the dependence of the inverse spin Hall voltage on the Ta thickness, we extract the spin diffusion length in Ta, found to be $\lambda_{sd}^\text{Ta}=1.8\pm0.7$ nm. Both the YIG|Pt and YIG|Ta systems display a similar variation of resistance upon magnetic field orientation, which can be explained in the recently developed framework of spin Hall magnetoresistance.Comment: 8 pages, 5 figures, 1 tabl

Detection of the microwave spin pumping using the inverse spin Hall effect

We report electrical detection of the dynamical part of the spin pumping current emitted during ferromagnetic resonance (FMR) using the inverse Spin Hall Effect (ISHE). The experiment is performed on a YIG$|$Pt bilayer. The choice of YIG, a magnetic insulator, ensures that no charge current flows between the two layers and only pure spin current produced by the magnetization dynamics are transferred into the adjacent strong spin-orbit Pt layer via spin pumping. To avoid measuring the parasitic eddy currents induced at the frequency of the microwave source, a resonance at half the frequency is induced using parametric excitation in the parallel geometry. Triggering this nonlinear effect allows to directly detect on a spectrum analyzer the microwave component of the ISHE voltage. Signals as large as 30 $\mu$V are measured for precession angles of a couple of degrees. This direct detection provides a novel efficient means to study magnetization dynamics on a very wide frequency range with great sensitivity

Supersymmetry and precision data after LEP2

We study one loop supersymmetric corrections to precision observables. Adding LEP2 e ebar --> f fbar cross sections to the data-set removes previous hints for SUSY and the resulting constraints are in some cases stronger than direct bounds on sparticle masses. We consider specific models: split SUSY, CMSSM, gauge mediation, anomaly and radion mediation. Beyond performing a complete one-loop analysis, we also develop a simple approximation, based on the Shat, That, W, Y `universal' parameters. SUSY corrections give W,Y > 0 and mainly depend on the left-handed slepton and squark masses, on M_2 and on mu.Comment: 16 page