[en] Background and Purpose: Indications of the existence of long repair half-times on the order of 2-4 h for late-responding human normal tissues have been obtained from continuous hyperfractionated accelerated radiotherapy (CHART). Recently, these data were used to explain, on the basis of the biologically effective dose (BED), the potential superiority of fractionated high-dose rate (HDR) with large fraction sizes of 5-7 Gy over continuous low-dose rate (LDR) irradiation at 0.5 Gy/h in cervical carcinoma. We investigated the optimal fraction size in HDR brachytherapy and its dependency on treatment choices (overall treatment time, number of HDR fractions, and time interval between fractions) and treatment conditions (reference low-dose rate, tissue repair characteristics). Methods and Materials: Radiobiologic model calculations were performed using the linear-quadratic model for incomplete mono-exponential repair. An irradiation dose of 20 Gy was assumed to be applied either with HDR in 2-12 fractions or continuously with LDR for a range of dose rates. HDR and LDR treatment regimens were compared on the basis of the BED and BED ratio of normal tissue and tumor, assuming repair half-times between 1 h and 4 h. Results: With the assumption that the repair half-time of normal tissue was three times longer than that of the tumor, hypofractionation in HDR relative to LDR could result in relative normal tissue sparing if the optimum fraction size is selected. By dose reduction while keeping the tumor BED constant, absolute normal tissue sparing might therefore be achieved. This optimum HDR fraction size was found to be largely dependent on the LDR dose rate. On the basis of the BED_NT/TUM ratio of HDR over LDR, 3 x 6.7 Gy would be the optimal HDR fractionation scheme for replacement of an LDR scheme of 20 Gy in 10-30 h (dose rate 2-0.67 Gy/h), while at a lower dose rate of 0.5 Gy/h, four fractions of 5 Gy would be preferential, still assuming large differences between tumor and normal tissue repair half-times and equal overall treatment time. For the same fraction size, an even larger normal tissue sparing can be obtained by prolongation of the HDR overall treatment time. Conclusion: Radiobiologic model calculations presented here aim to demonstrate that hypofractionation in HDR might have its opportunities for widening the therapeutic window, but definitely has its limits. For each specific combination of the parameters, a theoretical optimal HDR fraction size with regard to relative or absolute normal tissue sparing can be estimated, but because of uncertainty in the biologic parameters, these hypofractionation schemes cannot be generalized for all HDR brachytherapy indications

[en] Purpose: Investigation of normal tissue sparing in pulsed brachytherapy (PB) relative to continuous low-dose rate irradiation (CLDR) by adjusting pulse frequency based on tissue repair characteristics. Method: Using the linear quadratic model, the relative effectiveness (RE) of a 20 Gy boost was calculated for tissue with an α/β ratio ranging from 2 to 10 Gy and a half-time of sublethal damage repair between 0.1 and 3 h. The boost dose was considered to be delivered either in a number of pulses varying from 2 to 25, or continuously at a dose rate of 0.50, 0.80, or 1.20 Gy/h. Results: The RE of 20 Gy was found to be identical for PB in 25 pulses of 0.80 Gy each h and CLDR delivered at 0.80 Gy/h for any α/β value and for a repair half-time > 0.75 h. When normal tissue repair half-times are assumed to be longer than tumor repair half-times, normal tissue sparing can be obtained, within the restriction of a fixed overall treatment time, with higher dose per pulse and longer period time (time elapsed between start of pulse n and start of pulse n + 1). An optimum relative normal tissue sparing larger than 10% was found with 4 pulses of 5 Gy every 8 h. Hence, a therapeutic gain might be obtained when changing from CLDR to PB by adjusting the physical dose in such a way that the biological dose on the tumor is maintained. The normal tissue-sparing phenomenon can be explained by an increase in RE with longer period time for tissue with high α/β ratio and fast or intermediate repair half-time, and the RE for tissue with low α/β ratio and long repair half-time remains almost constant. Conclusion: Within the benchmark of the LQ model, advantage in normal tissue-sparing is expected when matching the pulse frequency to the repair kinetics of the normal tissue exposed. A period time longer than 1 h may lead to a reduction of late normal tissue complications. This theoretical advantage emphasizes the need for better knowledge of human tissue-repair kinetics

[en] Background and purpose: Radiobiological studies suggest equivalent biological effects between continuous low dose rate brachytherapy (CLDR) and pulsed brachytherapy (PB) when pulses are applied without interruption every hour. However, radiation protection and institute-specific demands requested the design of a practical PB protocol substituting the CLDR boost in breast cancer patients. An office hours scheme was designed, considering the CLDR dose rate, the overall treatment time, pulse frequency and tissue repair characteristics. Radiobiological details are presented as well as the logistics and technical feasibility of the scheme after treatment of the first 100 patients. Materials and methods: Biologically effective doses (BEDs) were calculated according to the linear quadratic model for incomplete repair. Radiobiological parameters included an α/β value of 3 Gy for normal tissue late effects and 10 Gy for early normal tissue or tumour effects. Tissue repair half-time ranged from 0.1 to 6 h. The reference CLDR dose rate of 0.80 Gy/h was obtained retrospectively from analysis of patients' data. The treatment procedure was evaluated with regard to variations in implant characteristics after treatment of 100 patients. Results: A PB protocol was designed consisting of two treatment blocks separated by a night break. Dose delivery in PB was 20 Gy in two 10 Gy blocks and, for application of the 15 Gy boost, one 10 Gy block plus one 5 Gy block. The dose per pulse was 1.67 Gy, applied with a period time of approximately 1.5 h. An inter-patient variation of 30% (1 SD) was observed in the instantaneous source strength. Taking also the spread in implant size into account, the net variation in pulse duration amounted to 38%. Conclusion: An office hours PB boost regimen was designed for substitution of the CLDR boost in breast-conserving therapy on the basis of the BED. First treatment experience shows the office hour regimen to be convenient to the patients and no technical perturbations were encountered

[en] The isotope labelled monocyclic ketones 5 and 8, postulated precursors to the presumably acetogenic naphthylisoquinoline alkaloids, have been synthesized for biogenetic experiments to Ancistrocladaceae and Dioncophyllaceae plants. Key step of the preparation of 1-(2'-[carbonyl-¹⁴C] acetyl-3',5'-dibenzyloxyphenyl-2-propanone ([¹⁴C]-13 is the C-acetylation of the arylpropanone 10 with the mixed pivalic acetic anhydride ([¹⁴C]-11). The resulting pyrylium salt [¹⁴C]-12, which is stable and can be stored, is cleaved directly before the feeding experiment to give the diketone [¹⁴C]-13 and deprotected to give the free phenolic target molecule [¹⁴C]-5. This synthetic route is applicable also to the preparation of 1-(2'-[¹³C₂]acetyl-3'hydroxyphenyl)-2-propanone ([¹³C₂]-5) for biosynthetic experiments with NMR analysis. For the preparation of the oxygen-poorer ¹³C-labelled diketone 1-(2'-[methyl-¹³C] acetyl-3'-hydr oxyphenyl)-2-propanone [¹³C]-8, an 'indanone-route' has been elaborated. (Author)

[en] Background and purpose: To compare intensity-modulated treatment plans of patients with head and neck cancer generated by forward and inverse planning. Materials and methods: Ten intensity-modulated treatment plans, planned and treated with a step and shoot technique using a forward planning approach, were retrospectively re-planned with an inverse planning algorithm. For this purpose, two strategies were applied. First, inverse planning was performed with the same beam directions as forward planning. In addition, nine equidistant, coplanar incidences were used. The main objective of the optimisation process was the sparing of the parotid glands beside an adequate treatment of the planning target volume (PTV). Inverse planning was performed both with pencil beam and Monte Carlo dose computation to investigate the influence of dose computation on the result of the optimisation. Results: In most cases, both inverse planning strategies managed to improve the treatment plans distinctly due to a better target coverage, a better sparing of the parotid glands or both. A reduction of the mean dose by 3-11 Gy for at least one of the parotid glands could be achieved for most of the patients. For three patients, inverse planning allowed to spare a parotid gland that had to be sacrificed by forward planning. Inverse planning increased the number of segments compared to forward planning by a factor of about 3; from 9-15 to 27-46. No significant differences for PTV and parotid glands between both inverse planning approaches were found. Also, the use of Monte Carlo instead of pencil beam dose computation did not influence the results significantly. Conclusion: The results demonstrate the potential of inverse planning to improve intensity-modulated treatment plans for head and neck cases compared to forward planning while retaining clinical utility in terms of treatment time and quality assurance

[en] The minimum margins required to compensate for random geometric uncertainties in the delivery of radiotherapy treatment were determined for a spherical Clinical Target Volume, using an analytic model for the cumulative dose. Margins were calculated such that the minimum dose in the target would be no less than 95% of the prescribed dose for 90% of the patients. The dose distribution model incorporated two Gaussians, and could accurately represent realistic dose profiles for various target sizes in lung and water. It was found that variations in target size and tissue density lead to significant changes in the minimum margin required for random errors. The random error margin increased with tissue density, and decreased with target size. The required margins were similar for dose distributions of spherical and cylindrical symmetry. Significant dose outside the spherical high dose region, as could result from multiple incident beams, lead to an increased margin for the larger targets. We could confirm that the previously proposed margin of 0.7 times the standard deviation of the random errors is safe for standard deviations up to 5 mm, except for very small targets in dense material

[en] Lithium-ion cells are temperature sensitive: operation outside the optimal operating range causes premature aging and correspondingly reduces vehicle range and battery system lifetime. In order to meet consumer demands for electric and hybrid-electric vehicle performance, especially in adverse climates, a battery thermal management system (BTMS) is often required. This work presents a novel experimental method for analyzing BTMS using three sample cooling plate concepts. For each concept, the input parameters (ambient temperature, coolant temperature and coolant flow rate) are varied and the resulting effect on the average temperature and temperature distribution across and between cells is compared. Additionally, the pressure loss along the coolant path is utilized as an indicator of energy efficiency. Using the presented methodology, various cooling plate layouts optimized for production alternative techniques are compared to the state of the art. It is shown that these production-optimized cooling plates provide sufficient thermal performance with the additional benefit of mechanical integration within the battery and/or vehicle system. It is also shown that the coolant flow influences battery cell thermal behavior more than the solid material and that pressure drop is more sensitive to geometrical changes in the cooling plate than temperature changes at the module.

[en] For the detection of hidden objects by low-frequency electromagnetic imaging the linear sampling method works remarkably well despite the fact that the rigorous mathematical justification is still incomplete. In this work, we give an explanation for this good performance by showing that in the low-frequency limit the measurement operator fulfils the assumptions for the fully justified variant of the linear sampling method, the so-called factorization method. We also show how the method has to be modified in the physically relevant case of electromagnetic imaging with divergence-free currents. We present numerical results to illustrate our findings, and to show that similar performance can be expected for the case of conducting objects and layered backgrounds

[en] To study dose-effect relations of prostate implants with I-125 seeds, accurate knowledge of the dose distribution in the prostate is essential. Commonly, a post-implant computed tomography (CT) scan is used to determine the geometry of the implant and to delineate the contours of the prostate. However, the delineation of the prostate on CT slices is very cumbersome due to poor contrast between the prostate capsule and surrounding tissues. Transrectal Ultrasound (TRUS) on the other hand offers good visualization of the prostate but poor visualization of the implanted seeds. The purpose of this study was to investigate the applicability of combining CT with 3D TRUS by means of image fusion. The advantage of fused TRUS-CT imaging is that both prostate contours and implanted seeds will be well visible. In our clinic, post-implant imaging was realized by simultaneously acquiring a TRUS scan and a CT scan. The TRUS transducer was inserted while the patient was on the CT couch and the CT scan was made directly after the TRUS scan, with the probe still in situ. With the TRUS transducer being visible on both TRUS and CT images, the geometrical relationship between both image sets could be defined by registration on the transducer. Having proven the applicability of simultaneous imaging, the accuracy of this registration method was investigated by additional registration on visible seeds, after preregistration on the transducer. In 4 out of 23 investigated cases an automatic grey value registration on seeds failed for each of the investigated cost functions, and in 2 cases for both cost functions, due to poor visibility of the seeds on the TRUS scan. The average deviations of the seed registration with respect to the transducer registration were negligible. However, in a few individual cases the deviations were significant and probably due to movement of the patient between TRUS and CT scan. In case of a registration on the transducer it is important to avoid patient movement in-between the TRUS and CT scan and to keep the time in-between the scans as short as possible. It can be concluded that fusion of a CT scan and a simultaneously made TRUS scan by means of a three-dimensional (3D) transducer is feasible and accurate when performing a registration on the transducer, if necessary, fine-tuned by a registration on seeds. These fused images are likely to be of great value for post-implant dose distribution evaluations

[en] The purpose of this work was the development of a probabilistic planning method with biological cost functions that does not require the definition of margins. Geometrical uncertainties were integrated in tumor control probability (TCP) and normal tissue complication probability (NTCP) objective functions for inverse planning. For efficiency reasons random errors were included by blurring the dose distribution and systematic errors by shifting structures with respect to the dose. Treatment plans were made for 19 prostate patients following four inverse strategies: Conformal with homogeneous dose to the planning target volume (PTV), a simultaneous integrated boost using a second PTV, optimization using TCP and NTCP functions together with a PTV, and probabilistic TCP and NTCP optimization for the clinical target volume without PTV. The resulting plans were evaluated by independent Monte Carlo simulation of many possible treatment histories including geometrical uncertainties. The results showed that the probabilistic optimization technique reduced the rectal wall volume receiving high dose, while at the same time increasing the dose to the clinical target volume. Without sacrificing the expected local control rate, the expected rectum toxicity could be reduced by 50% relative to the boost technique. The improvement over the conformal technique was larger yet. The margin based biological technique led to toxicity in between the boost and probabilistic techniques, but its control rates were very variable and relatively low. During evaluations, the sensitivity of the local control probability to variations in biological parameters appeared similar for all four strategies. The sensitivity to variations of the geometrical error distributions was strongest for the probabilistic technique. It is concluded that probabilistic optimization based on tumor control probability and normal tissue complication probability is feasible. It results in robust prostate treatment plans with an improved balance between local control and rectum toxicity, compared to conventional techniques