Computed Tomography (CT) imaging is an important step in treatment planning for proton therapy. The conversion from Hounsfield Unit (HU) to stopping power ratio (SPR) accounts for more than half of the 3.5% error that is considered in treatment planning. The aim of the study is to investigate the efficacy of photon-counting CT (PCCT) for predicting the SPR in proton therapy. Its performance will be compared to single-energy CT (SECT) and dual-energy CT (DECT).

Fresh tissue samples—steak, ground beef, and bone marrow—were secured in 3D-printed holders to minimize air inclusion and maintain tissue stability during measurements. These
samples were secured in a head and a body configuration of a phantom and CT scans were conducted using standard clinical protocols. SPR values were derived from the CT data
using automated DirectSPR software for the DECT and PCCT scans, and converted from HUs to SPR using a Hounsfield look up table (HLUT) for the SECT scans. Results were validated
against actual SPR measurements obtained via proton beam measurements.

Two measurement series have been performed. For the validation of the first measurement series, proton beam energies of 150 and 175 MeV both resulted in an SPR value of 1.00 for the
ground beef sample. For the steak sample, SPR values of 1.02 and 1.03 were found. The CT-based SPR predictions resulted in errors up to 1.5% for ground beef and 3.5% for steak. For
the validation of the second measurement series, SPR values for ground beef (0.89-0.92), steak (0.96-0.98), and bone marrow (0.87-0.91) were obtained. The percentage error between the CT-based SPR predictions and the validation measurements showed no substantial differences between the CT-modalities, except for SECT providing lower SPRs for the bone marrow samples than DECT and PCCT. The validation measurements of the second series resulted in lower SPR values than found in literature and the first
series, indicating possible methodological inconsistencies. Factors such as sample heterogeneities and measurement errors might have contributed to these inconsistencies, but do not account for these inconsistencies completely. These results highlight the need
for further research with standardized phantoms and animal tissue samples to evaluate PCCT’s true potential in combination with DirectSPR prediction.

From this study it cannot be concluded that PCCT demon-
strates an advantage over SECT and DECT as CT-modality for
the HU-SPR conversion in proton therapy treatment planning

Female breast cancer is the second most common cancer worldwide. A promising novel technique to treat early-stage breast cancer is the use of thermo-brachy therapy. This thesis analysed the effect of the cancer biomarker glutathione (GSH) on the magnetic hyperthermal effects of iron oxide nanoparticles. The synthesised nanoparticles with a diameter of 10±4 nm have been coated with cysteine and treated with hydrogen peroxide leading to their aggregation upon cross-linking. As the GSH concentration is higher around cancerous cells (10 μM instead of 3 μM), these nanoparticles would be more monodispersed as GSH could break the disulfide bonds between the cysteines. Since aggregated nanoparticles exhibit lower heating efficiencies, it was assumed that this method would allow for (partially) selective heating of the tumour. The addition of 10 μM GSH resulted in an 11% higher heating efficiency compared to 3 μM GSH when analysing the coated nanoparticles in an alternating magnetic field. However, a GSH concentration of 10 mM (intracellular GSH concentration in cancerous cells) gave a decrease in heating efficiency. Another methodology was proposed as well. Uncoated nanoparticles were encapsulated in a ZIF-8 framework. This framework is less stable in environments with a lower pH value and higher GSH concentration, which is the case in the tumour microenvironment. This methodology gave a 27% higher heating efficiency in a tumour-related GSH concentration and pH value. The differences with both the cysteine and ZIF-8-based methods are yet too small to limit thermal damage to healthy tissue. Modelling the diffusion and its influence on the temperature change, gave very local heating near the injection site due to slow diffusion. Therefore, while this thesis provided insights into the heating efficiencies in tumour-related conditions with both methodologies, addressing the current limitations can lead to significant advancements.

¹⁶¹Tb is considered a promising alternative to ¹⁷⁷Lu in the treatment of neuroendocrine tumors and prostate cancer. It is produced via neutron irradiation of ¹⁶⁰Gd targets and its subsequent separation from said targets. Current separation methods have limitations so a fast removal method of the Gd bulk is desired. Such a method is developed in this research using solvent extraction techniques. Three extractants were investigated, the one with the highest potential, DEHPA, was used to optimize the extraction. This yielded a Tb extraction efficiency of 98.6 ± 0.2 % and a Gd extraction efficiency of 85.7 ± 5.5 % followed by a Tb back-extraction efficiency of 98.2 ± 0.1 % and a Gd back-extraction efficiency of more than 98.2 ± 0.1 %. The Tb/Gd separation was increased by adding the reverse size selective chelator MACROPA to the aqueous phase to preferentially complex Gd in the aqueous phase. This yielded a Tb and Gd extraction efficiency of 95.0 ± 0.2 % and 53.1 ± 3.0 % respectively. The ratio between total EEs of Tb and Gd after three subsequent extractions was approximately 10 demonstrating the potential of using sequential extractions to remove a bulk of Gd from Tb. The procedure of doing consecutive extractions must however be further optimized as nearly 80% of Tb was not extracted. Finally, it was shown that the resulting solution after bulk Gd removal can still be further purified using an ion exchange column. In future research, it is highly advised to investigate the recycling of Gd and MACROPA from the aqueous phase after extraction to allow for further irradiation of the Gd and re-usability of the MACROPA.

To reduce the probability of complications in proton therapy, while maintaining a high tumor control probability, adaptive treatment can be applied. In adaptive treatments, the treatment plans are frequently assessed and adjusted to, for example, account for anatomical changes. Ideally, daily adaptive treatment would be implemented, where every day a repeat scan is made and the treatment plan is adjusted. However, due to computational limitations, daily adaptive treatment is not possible yet. Quality assurance (QA) is a vital part of the proton therapy workflow. Intending to implement daily adaptive treatment, fast-working quality assurance tools are necessary. The goal of this thesis is to calibrate and adapt a deterministic proton transport algorithm to reconstruct the delivered dose using log files, which can be compared to the planned dose as a QA tool.

To achieve this, Yet anOther Dose Algorithm (YODA) was calibrated to the popular planning software RayStation, by optimizing the input parameters of YODA to minimize the difference in dose between YODA and RayStation for a 0° gantry angle single spot in a homogeneous water phantom. From this calibration, beam data library (BDL) files were created for cases without a range shifter and with range shifters of thicknesses 2 cm, 3 cm and 5 cm and planned spot energies ranging from 70 MeV to 190 MeV. An approximation to improve the inclusion of the effect of nuclear interactions was added to YODA. The lowest passing rate found was 99.47% for a 190 MeV spot without a range shifter, therefore the calibration was successful. The passing rate decreased for high energies, likely due to the crude approximation to deal with nuclear interactions. Other ways to include
the effect of nuclear interaction should be investigated to further improve the calibration results. After the calibration was complete, three experiments were performed.

First, simple treatment plan comparisons were performed using the BDL files and a homogeneous water phantom, including plans containing a single spot irradiated from gantry angles ranging from 10° to 90°. To account for the angled beams, a beam splitting algorithm was used. It was observed that the BDL files are specific for the isocenter to CT volume surface distance, as the boundary conditions of YODA are at the CT volume surface while the treatment plans define spots at the isocenter in air. To include this effect, the BDLs should contain beamlet parameters at the isocenter, from which the beamlet parameters at the CT volume surface can be calculated. The calibration procedure for the spatial spread, angular spread and correlation needs to be adjusted. Alternatives to the beam splitting algorithm should be investigated, as this algorithm inadequately reflects reality when a beam enters the CT volume under an angle.

Second, YODA assumes that spots are laterally symmetrical, however, in reality, spots are ellipse-shaped. To solve this, the asymmetrical spot solution to the Fermi-Eyges equation was derived. The difference in integrated Fermi-Eyges flux between the symmetrical and asymmetrical spot was calculated for realistic combinations of lateral spread, angular spread and correlation. The mean error in integrated Fermi-Eyges flux, relative to the maximum, induced by assuming lateral spot symmetry, around the central beam axis is significant, as it ranges from 0.6853% to 3.071% at the entrance of the CT volume and from 0.4710% to 4.957% at the Bragg peak. Therefore the asymmetrical spot solution should be implemented, after which, YODA should be re-calibrated

Third, the error induced by systematic errors in the log file was investigated. The plan contains a target cube centered in the homogeneous water phantom irradiated by a 0° gantry angle beam. By perturbing each energy layer randomly using a uniform distribution, where the maximum perturbation was 0.8 mm in spot position, 1% for MU and 0.1% for energy, the magnitude of the dose difference was calculated. The mean differences in dose in the target cube induced by randomly perturbing each energy layer were 0.1204% ± 0.0408% in x, 0.1700% ± 0.0324% in z, 0.2592% ± 0.1595% in MU and 0.4802% ± 0.1558% in energy. These differences are small compared to the error induced by assuming symmetrical spots, note that the differences in spatial spread were an order of magnitude bigger than the perturbation in spot position. Before this investigation on the effect of systematic errors can continue, the asymmetrical spot solution needs to be implemented and the problems discovered with angled beams should be solved.

The calibration was successful, and additional extensions and alterations have been identified to further improve YODA before it can be used as the described patient-specific quality assurance tool.

Cancer is one of the leading causes of death in the world. Because of this, there are many novel methods to treat it being currently researched. One of the answers from the nuclear medicine perspective is Radionuclide Therapy, where alpha or beta emitters are applied, with the goal to selectively irradiate tumours in the body. A promising radionuclide researched for Radionuclide Therapy is Holmium-166, which is a beta emitter with a short half-life of 26.8 hours, which is useful for the treatment of large metastases. A method to ensure an effective treatment with Holmium-166 is the use of a Dysprosium-166/Holmium-166 in vivo generator, as the dose delivered to patients per administered dose is two times higher with the in vivo generator rather than the direct use of Holmium-166. However, carriers used in Radionuclide Therapy, which usually involve the formation of a chelator-metal complex are not effective for the in vivo generator due to the release of auger electrons during the decay process leading to the destruction of the chelator-metal complex. A promising non-chelator method designed by Liu et al. at the Applied Radiation and Isotopes research team at TU Delft involves the radiolabelling of micelles. This thesis sought to evaluate the use of micelles, radiolabelled with this mechanism as an effective carrier for the Dysprosium-166/Holmium-166 in vivo generator. For this, micelles made of Polycaprolactone-block-Polyethylene Oxide and Polylactic Acidblock-Polyethylene oxide were evaluated based on the obtained radiolabelling efficiency and their stability when challenged with diethylenetriaminepentaacetic acid (DTPA). The results in this study show that the radiolabelling method used to encapsulate Dysprosium relies on the diffusion of Dysprosium hydroxides into the micelle core, followed by precipitation as the right concentration is reached inside the micelles. The best results obtained by this study occur when radiolabelling Polylactic Acid-block-Polyethylene Oxide (PLA-PEO) micelles, and then adding phosphate ions at a concentration of 3 × 10−8𝑀, 30 minutes after the addition of the active Dysprosium. Although more tuning is required on the radiolabelling mechanism to make micelles the most effective carriers of the 166Dy/166Ho in vivo generator, promising first steps were made to begin this process

The severe accident at the Fukushima-Daiichi Nuclear Power Station in 2011 has shown the necessity to study the impact of the release of hazardous fission products. This work investigates the Ba-Cs-Sr-Mo-O system, which contains some of the most abundantly produced fission products, as well as fission products that carry a great health risk on release. The study of this system is broken up into four subsystems: Ba-Sr-O, Ba-Mo-O, Sr-Mo-O and Ba-Cs-Mo-O. A literature study into the ternary Ba-Sr-O system, including existing thermodynamic models, showed the formation of no stoichiometric ternary compounds due to the mutual miscibility of Ba and Sr. Despite this mutual solubility, a miscibility gap is shown to be present in the solid region of the binary BaO-SrO phase diagram below a certain temperature. Thermogravimetric differential scanning calorimetry (TGDSC) investigations of the BaMoO₄ – MoO₃, SrMoO₄ – MoO₃ and BaMoO₄ – Cs₂MoO₄ pseudo-binary systems revealed likely compositions for the eutectic equilibria at 0.792 ≤ x(MoO₃) ≤ 0.80, 0.806 ≤ x(MoO₃) ≤ 0.82 and 0.909 ≤ x(Cs₂MoO₄) ≤ 0.976, respectively. These measurements also allowed for the development and optimisation of a new thermodynamic model of the BaMoO₄ – Cs₂MoO₄ system using the CALPHAD (Calculation of Phase Diagram) method. Syntheses of BaMoO₄, BaMo₃O₁₀, Ba₂MoO₅ and BaCs₂(MoO₄)₂ were successfully completed. A partially successful synthesis method was developed for Ba₃MoO₆ that needs further optimisation. The novel synthesis of Ba₂MoO₅ allowed for solution calorimetry measurements to be performed, leading to the determination of its standard enthalpy of formation Δ_fH°_m(298.15K, Ba₂MoO₅) = -(2169.0 ± 14.7) kJ/mol. Vapour pressure studies of BaMoO₄ by means of Knudsen EffusionMass Spectrometry (KEMS) gave insight into the composition of the vapour formed above BaMoO₄ after vaporisation. The results showed extensive influence of fragmentation reactions and only a small amount of congruent evaporation, indicated by the high partial pressure of BaO(g) and other binary molecules. A partial reduction of the BaMoO₄ sample to BaMoO₃ could have occurred, but this cannot be confirmed due to the full evaporation of the KEMS sample. Further studies are required to investigate a potential reduction.

Treatment of early stage breast cancer is generally invasive to a patient's daily life while being treated. Therefore, to diminish the physical and psychological impact during and after recovery, a newly proposed minimally invasive therapy for early-stage breast cancer treatment is proposed. Within this study, this proposed treatment is modelled to gain more knowledge of the behavior of the treatment material in tissue. The treatment includes magnetic thermal ablation, which is combined with permanent Low Dose Rate (LDR) brachytherapy, both performed simultaneously.
The goal of the treatment is to diminish the physical and psychological impact during treatment and after recovery, since it requires only a single medical intervention. The treatment material consists of radioactive palladium-103 superparamagnetic iron-oxide nanoparticles (Pd-103 SPIONs) incorporated in a solid gel, forming a seed that is implanted into the tumor. To investigate the effectiveness and limitations of the combined therapy, computational simulations were performed in Matlab using the Finite Element Method (FEM).
These simulations allowed for the prediction of the treatment results, by calculating the temperature distribution based on Pennes' bioheat equation, the nanoparticle concentration distribution and the dose distribution over time. The sensitivity of the results to the relevant physical properties and optimization parameters was analyzed. The latter resulted in a recommended optimization approach that ultimately could be used for treatment planning. First, an initial simulation was performed using property values from literature. Then, the temperature and dose results were tested on their sensitivity to model parameter changes. The temperature model was found to be most sensitive to changes in the nanoparticle heat source value Qnp, to an increased heat conduction coefficient k and to a decreased blood perfusion rate wb. The cumulative dose results are sensitive to both the initial concentration ci and to a decreased diffusion coefficient D. It is concluded that accurate values for these temperature and concentration model parameters are necessary to perform relevant simulations.
Furthermore, the possible optimization parameters were identified. For dose optimization, these parameters are the activity of the nanoparticles A, which is not easily modified, and the initial nanoparticle concentration in the seeds ci, which affects the temperature distribution as well. The temperature distribution specific variables that were found, are the strength of the magnetic field H and the time t of magnetic field application, which both can be adjusted during the treatment. The seed location and number of seeds are two additional adjustable variables used for optimization of both temperature and dose distribution. Lastly, it was concluded that the internal radiation part of the treatment is limiting in the reaching treatment goals and in number of optimization possibilities, compared to the thermal ablation part. Therefore, treatment optimization should be performed on the dose distribution first. Because most limitations of the models are a result of the 2D representation and because these limitations strongly affect the outcomes of the models, it is recommended to transform these models to 3D. These limitations make it impossible to do proper treatment planning with the 2D model, which requires a 3D view of the results. With all these findings, this study has contributed by providing basic knowledge of the state-of-the-art early stage breast cancer combined therapy, bringing it one step closer to clinical implementation.

Cancer remains responsible for a large part of deaths worldwide. At present most treatments for cancer still give rise to unwanted side-effects. In this thesis, a treatment that combines both chemo- and radiotherapy to reduce the side-effects of chemotherapy is reported. Instead of allowing the drug to spread through the whole body and also targeting fast dividing healthy cells, a chemotherapeutic drug is encapsulated in a polymeric nanocarrier. In addition, the nanocarrier encapsulates another molecule, a photosensitizer. The photosensitizer can be activated by visible light to produce singlet oxygen and in previous experiments was shown to be able to induce release when exposed to ionizing radiation. In a yet unknown process this will act as a switch, leading to the polymeric nanocarrier releasing the chemodrug. This allows inducing a more precise release at the tumor by focusing the radiation locally. To enhance the local radiation effect, gold nanoparticles are introduced in the nanocarrier in addition to the other particles present.
In this research the first steps in validating this type of treatment were taken by
investigating the release of the chemotherapeutic drug upon irradiation of the
nanocarriers, as well as testing the viability of human glioblastoma cancer cells
containing the nanocarriers before and after irradiation. New methods to measure.
the release from the nanocarriers were tested, different radiation types were
investigated, and two different cell viability assays were used. The results indicate no clear effect of the gold nanoparticles on the release of the nanocarriers, but the interesting interaction between the different particles in the nanocarriers invites for further studies

Calcium is an important mineral which the body uses to maintain strong bones and carry out many important bodily functions. According to the Dutch nutrition center people in the Netherlands consume 80-90% of their calcium through milk and other milk products. Often times people will further ’process’ milk for other food products. Examples of these include boiling milk to make hot chocolate or freezing it for ice-cream. These temperature changes can have great influence on the bio-availability of the Calcium. The goal of this thesis was to find the effect of temperature on the bio-availability of Calcium in milk. This was done through 2 experiments. Dialysing skim bovine milk at temperatures between 4-90°C and heating or cooling the bovine milk to temperatures between -18°C-95°C and then dialysing at room temperature. The dialysis separates the soluble and insoluble phase of milk allowing for the calculation of percentage soluble calcium which is a good indicator for bio-availability of calcium in milk. It was found that there is a linear relationship between the temperature of the milk and the percentage soluble Calcium, the higher the temperature of the milk the lower the amount of bio-available calcium in the milk. Furthermore when looking at the heated milk it was found that heating to 60°C and above all showed a similar drop in percentage soluble calcium indicating some permanent loss of bio-available calcium. This permanent loss is however lower than what can be observed to be lost in the milk whilst hot indicating that a portion of the calcium that becomes insoluble upon heating returns to the soluble phase once returned to its original temperature.

Calcium is an important nutrient for both young and elderly people which can, among others, stimulate healthy bone growth and prevent osteoporosis. Therefore, nutrition with sufficient calcium is of great importance. The highest calcium nutrient density for all foods can be found in bovine milk, which contains on average 1.2 g Ca / L. To increase the amount of bioavailable calcium, milk can be fortified by the addition of different calcium salts. In this research the bioavailability and exchangeability of calcium in unfortified and fortified skimmed milk was studied by in vitro methods using equilibrium dialysis and ultracentrifugation to separate different fractions in milk. Radioactive 45Ca was used to follow the exchange behaviour of calcium between the three different fractions in milk: casein micelles, serum proteins, and soluble calcium. For unfortified milk it was found that 34.9 ± 2.2% of the calcium was present in the soluble phase, 9.1 ± 0.6% was bound to serum proteins, and 56 ± 1.6% was present in the casein micelles, which confirmed the results in literature. In addition, with the investigation of the exchange behaviour of 45Ca, it was confirmed that ~40% of calcium in casein micelles is hardly exchanged.To investigate the influence of calcium fortification on the calcium equilibrium in milk, six different calcium salts were selected to be synthesized: calcium chloride, calcium carbonate, calciumgluconate, tri-calcium di-citrate, calcium lactate, and tri-calcium phosphate. Of these, calcium chloride, calcium carbonate, calcium gluconate, and tri-calcium di-citrate were successfully synthesized. Further experiments were performed with calcium chloride and calcium carbonate, intrinsically labelled with 45Ca. From fractionation with ultracentrifugation, it was concluded that addition of calcium chloride led to an increase of calcium in the soluble phase, which might indicate an increase in bioavailability. Fortification of milk with 45Ca labelled calciumcarbonate did not lead to an exchange of 45Ca with the calcium present in milk, indicating that calcium carbonate is unlikely to make calcium in milk more bioavailable. In conclusion, a better understanding of the solubility and exchangeability of Ca in milk and the influence of milk fortification with calcium chloride and calcium carbonate is obtained by using 45Ca as a tracer.

Radionuclides are important in the diagnosis and treatment of, amongst others, cancer. A promising therapy is targeted radionuclide therapy, where the radionuclide is brought to the tumor by a targeting specific
vector. Bringing the radionuclide directly to the tumor, should reduce the dose to the healthy tissue. For targeted radionuclide therapy, a radionuclide with a high specific activity is required. Some radionuclides,
with promising half-lives and decay energies, are currently not produced with the required specific activity. This problem occurs mainly for radionuclides that are produced via (n,γ) reactions in nuclear reactors. For radionuclides that are produced via this reaction, it is nearly impossible to do a chemical separation between the target material and the produced radionuclide, because these are of the same element. This is why new production routes have to be investigated. In this thesis a feasibility study has been done for a new production method, which should increase the specific activity of radionuclides that are produced via a (n,γ) reaction. For this production method, the target material is labeled with a chelator. Due to the Szilard-Chalmers effect the bond with the chelator will be broken, when the target material is activated by a neutron. This enables the separation of the produced radionuclide from the target complex and therefore, the extraction of the radionuclide. The production method will be loop-based, in order to enable continuous activation of the target material and extraction of the radionuclide. Furthermore, the loop-based design should minimize the effect of radiolysis and relabeling. The loop will be placed close to the reactor core. In this thesis, the elements holmium and lutetium have been used. It has been determined which chelator is most suitable to label with holmium and lutetium. Furthermore, the stability of this complex has been investigated for: higher temperatures, time and the effect of the γ-radiation. The effect of the γ-radiation was determined because this results in radiolysis. The extraction of the radionuclide has also been investigated. These parameters have been used in the calculation of the possible achievable specific activity of 166Ho and 177Lu, when using this loop-based production method. Labeling was possible with the chelator DOTA, which resulted in a stable complex, even for higher temperatures. Labeling happened fast, which also results in fast relabeling. The effect of radiolysis, due to the γ-radiation, was determined by fitting the experimental data. The fit gave negative values for short irradiation times, which is not possible. Therefore, two possible fits were made, which did not give negative results. The first fit was shifted over the y-axis and for the second fit the negative values were assigned to be zero....

The Organ on Chip (OoC) market is fast-growing and has the promise to drastically reduce the cost of developing drugs and the need for animal testing. However, the growth could be obstructed by the difficulties of scaling up production of developed prototypes. Most OoC prototypes are not suited for mass production because of the material used, namely polydimethylsiloxane (PDMS). In this thesis a roadmap for the OoC prototyping process is proposed, which can be carried out in small labs without expensive equipment, and which can be directly scaled up to mass production. In the proposed roadmap the polymer cyclic olefin copolymer (COC) is used instead of PDMS. Expensive etching processes typically used to fabricate a mold are replaced by stereolithography printing and soft lithography. The final parts of the chip are soft embossed and for assembly thermal fusion bonding is suggested. These steps require relatively simple equipment, namely a stereolithography printer, a spin coater, a fume hood, and basic lab ware. Next to that, a press for embossing and bonding is required. Such a press is designed, fabricated, calibrated, and tested in this thesis. The press enables embossing and bonding experiments with high repeatability on a simple desktop and can be fabricated in roughly 2 - 3 days in a workshop with standard materials costing no more than € 250,-. Temperature of the compression platens can be controlled within 0.25oC precise up to 180oC. Compression forces up to 3.5 kN can be applied and an accuracy of ±32 N and ±80 N for forces up to respectively 1.3 kN and 2.0 kN can be reached. The performance of the press is tested by carrying out embossing experiments, which yielded replication accuracies comparable with literature for channels of 170 µm deep and 1 mm wide. Next to that, a protocol is produced for spin coating COC films with controllable thickness between 7.5 and 14 µm on top of a COC substrate.

The recently discovered negative health effects of Gd(III) complexes based magnetic resonance imaging (MRI) contrast agents have stirred interest into the development of alternatives based on Mn(II) complexes
due to its biocompatibility, and hence less health concerns. One important aspect of investigation on contrast agents in general, and Mn(II) complexes in particular, is an accurate determination of their concentrations in solution. Therefore, in this study a known approach of determining the concentration of paramagnetic species in solution, via the Bulk Magnetic Susceptibility (BMS) shift, is applied for Mn(II) and the feasibility of the method is evaluated. A proof of principle using Gd-DOTP concentrations in the range 0.7 – 6.6 mM Gd(III) to verify the applied BMS method was successfully performed. Subsequently, BMS measurements were performed with MnDOTA as well as free Mn(II) and the obtained concentrations were verified with ICP-OES. A good agreement between the two methods was found within the concentration range of 0.4 - 15.1 mM Mn(II) for both MnDOTA and free Mn(II). Although, BMS measurements showed slightly higher concentrations than those found by ICP-OES for both Mn-DOTA and free Mn(II). Additionally, the deviations between ICP-OES and BMS were greater for free Mn(II) compared to Mn-DOTA. Experiments for determining the accuracy of the BMS method showed a 2.5% upward systematic error. The random error decreased from 20% for 0.27 mM Mn(II) to almost 0% for 4.0 mM Mn(II) and higher concentrations. In conclusion, the BMS method proved to be accurate for determining Mn(II) concentrations and has
promising prospects for future research into Mn(II) complexes. However, deviations between ICP-OES and BMS measurements need further investigations. Key words: Bulk Magnetic Susceptibility shift, contrast agent, Mn(II) complexes.

The scope of a radiotherapy treatment is to induce damage to tumor cells by irradiating them with ionizing radiation. The radiation should target the tumor as visible in images, also called the macroscopic disease. There is, however, a risk of small, invisible groups of cancer cells in the area surrounding the macroscopic tumor, the microscopic disease. For an optimal clinical outcome of radiotherapy, the microscopic disease needs to be irradiated as well. In current treatment planning, the macroscopic tumor is extended with a margin to better ensure full disease coverage. Because there is uncertainty in the extent of the microscopic disease, also the margin definition is uncertain. Moreover, in current planning, the same margin is used for all patients, and there is no patient-specific exploration of the trade-offs between dose extensions to cover potentially present microscopic disease vs radiation-induced toxicity because of enhanced dose in organs at risk (OARs) surrounding the tumor. This study aimed to explore whether the margin concept could be replaced by more advanced, individualized approaches for irradiation of volumes just outside the macroscopic tumor. All plans were generated automatically to avoid bias by human planners and to reduce workload. Two novel treatment planning approaches were investigated. The first focused on increasing dose coverage of the microscopic disease while at the same time controlling the resulting increased dose to the healthy tissues surrounding the macroscopic tumor, including OARs. Several treatment plans were generated to explore a range of trade-offs between dose in microscopic disease and dose in OARs. The results showed that for optimal microscopic disease irradiation, both low and high OAR doses needed to worsen. However, the most significant increase in microscopic disease coverage could be obtained when accepting higher OAR low doses, that is generally less important for induction of negative side-effects.
In the second approach, an expected Tumor Control Probability (expected TCP) cost function was used to control dose delivery in areas close to the macroscopic tumor. Basis of the expected TCP model was a function describing the probability of finding microscopic disease at a specific distance from the macroscopic tumor. The results again demonstrated opportunities to increase dose to areas close to the tumor, at the cost of enhanced doses in OARs. In conclusion, both approaches had a positive impact on microscopic disease dose coverage. However, improved irradiation of the microscopic disease was always at a price of enhanced dose in OARs. Complementary studies, involving clinicians, need to be carried out to investigate if and how the approaches could be used to replace the current planning with fixed margins.

Introduction:  Despite the vast amount of optimization algorithms, radiotherapy treatment planning remains a manual, time-consuming and iterative process. To increase plan standardization, we clinically use Pinnacle's autoplanner for several disease sites. However, this introduces new challenges: first, the autoplanner is not perfect and still requires substantial interaction from the radiotherapy technician (RTT). Second, it is difficult to judge whether a plan has indeed the most optimal trade-o_ between cure and toxicity, since the RTT has not worked the plan. Knowledge-based planning (KBP) could serve as a quality assurance tool to resolve these problems. It uses historical data (anatomical and dosimetric) from previous plans, to predict the likely dose distribution for the current patient. In this study, we construct an initial, simplistic KBP model that serves as the clinical practice. We then investigate of a variety of KBP modelling approaches to predict rectum dose-volume histograms (DVHs), in order to complement the current clinical practice in prostate cancer. Methods:  For model evaluation, we formulate a clinical tolerance criterion (TC) bandwidth based on a ground-truth set of existing radiotherapy plans. We evaluate on the overall prediction accuracy (RMS), the fraction of correctly predicted DVH bins (TC_α), anαd on the fraction of patients that have ≥ 90% of their DVH correctly predicted (TC_β). We use the overlap volume histogram (OVH) to encode for organ geometrical information, and use reduced order modelling (ROM) to capture the most important characteristics of the DVH and OVH. Optimization methods we use are Principal Component Analysis (PCA) eigenvalue RMS minimization, direct DVH RMS minimization, and TC_α and TC_β maximization. Results:  Analyses of the KBP clinical practice yielded training and testing errors of 81.4% and 80.8% for TC_α and 53.3% and 51.1% for TC_{β, with an RMS of 4.80 and 4.94 volume percentage [%]. Eigenvalue-optimization resulted TCα of 86.5% and 82.4%, and TCβ of 68.8% and 59.1%, with respective RMS of 2.82 % and 3.22 %. Direct DVH-optimization yielded TCα of 86.7% and 81.9%, and TCβ of 69.4% and 61.4%, with similar RMS. TCα and TCβ maximizers resulted TCα training and testing errors of 92.1% and 78.5%, and TCβ training and testing errors of and 84.3% and 53.4% respectively. Discussion:  The investigated models yielded significant improvements for direct eigenvalue- and DVH optimization methods. We have also been able to perform optimizations for the clinical goal metrics, showing promising results in training data. Because TCα- and TCβ- maximizers were unable generalize to perform well for unseen data, it is believed these metrics are too sensitive to be trained reliably, and more consistent data may be required for these optimizers to produce reliable test errors. Based on our findings, we advice the clinical practice to extend KBP-approaches to optimize for DVH-least squares.}