A. de Leeuw

Age of the Badenian salinity crisis; impact of Miocene climate variability on the circum-Mediterranean region

Massive evaporites were deposited in the Central European Paratethys Sea during the Badenian salinity crisis (BSC). The scarcity of absolute age data has hampered a thorough understanding of these salt deposits. Here we present a robust chronology for this catastrophic event by 40 Ar/ 39 Ar dating of volcanic tuffs below and within the Badenian salts in southern Poland. The onset of BSC evaporite deposition is dated at 13.81 ± 0.08 Ma and the entire event is estimated to have lasted 200–600 k.y. Correlation to oxygen isotope records shows that the BSC evaporites were just preceded by glacial event Mi-3b, suggesting a causal relationship. The corresponding sea-level fall most likely restricted the open marine connection to the Mediterranean, thereby trapping the salt in the deep Paratethys basins.

Radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate cancer: preliminary results

To report an interim clinical evaluation of combined external beam irradiation (EBRT) and interstitial or regional hyperthermia in the treatment of locally advanced prostate cancer.

Development of a regional hyperthermia treatment planning system

A flexible and fast regional hyperthermia treatment planning system for the Coaxial TEM System has been devised and is presented. Using Hounsfield Unit based thresholding and manually outlining of the tumour, a 40 cm CT data set (slice thickness 5 mm) is segmented and down scaled to a resolution of 1 cm, requiring only 30 min. The SAR model is based on the finite-difference time-domain (FDTD) method. The number of time steps to achieve numerical stability has been determined and was found to be 7000. Various optimizations of the SAR model have been applied, resulting in a relatively short computation time of 3.7 h (memory requirements 121 MB) on a Pentium III, 450 MHz standard personal computer, running GNU/Linux. The model has been validated using absolute value(Ez) measurements in a standard phantom inserted in the Coaxial TEM Applicator under different conditions and a good agreement was found. Hyperthermia treatment planning in combination with the homemade visualization tools have provided much insight in the regional hyperthermia treatment with the Coaxial TEM Applicator.A flexible and fast regional hyperthermia treatment planning system for the Coaxial TEM System has been devised and is presented. Using Hounsfield Unit based thresholding and manually outlining of the tumour, a 40cm CT data set (slice thickness 5mm) is segmented and down scaled to a resolution of 1cm, requiring only 30min. The SAR model is based on the finite-difference time-domain (FDTD) method. The number of time steps to achieve numerical stability has been determined and was found to be 7000. Various optimizations of the SAR model have been applied, resulting in a relatively short computation time of 3.7h (memory requirements 121MB) on a Pentium III, 450MHz standard personal computer, running GNU/Linux. The model has been validated using |Ez| measurements in a standard phantom inserted in the Coaxial TEM Applicator under different conditions and a good agreement was found. Hyperthermia treatment planning in combination with the homemade visualization tools have provided much insight in the regional hyperthermia treatment with the Coaxial TEM Applicator.

Regional hyperthermia applicator design using FDTD modelling

Recently published results confirm the positive effect of regional hyperthermia combined with external radiotherapy on pelvic tumours. Several studies have been published on the improvement of RF annular array applicator systems with dipoles and a closed water bolus. This study investigates the performance of a next-generation applicator system for regional hyperthermia with a multi-ring annular array of antennas and an open water bolus. A cavity slot antenna is introduced to enhance the directivity and reduce mutual coupling between the antennas. Several design parameters, i.e. dimensions, number of antennas and operating frequency, have been evaluated using several patient models. Performance indices have been defined to evaluate the effect of parameter variation on the specific absorption rate (SAR) distribution. The performance of the new applicator type is compared with the Coaxial TEM. Operating frequency appears to be the main parameter with a positive influence on the performance. A SAR increase in tumour of 1.7 relative to the Coaxial TEM system can be obtained with a three-ring, six-antenna per ring cavity slot applicator operating at 150 MHz.

Treatment planning for capacitive regional hyperthermia

Capacitively coupled hyperthermia devices are widely in use, mainly in Asian countries. In this paper, a comprehensive treatment planning system, including a Specific Absorption Rate (SAR) and thermal model for capacitively coupled hyperthermia, is described and demonstrated using a heterogeneous patient model. In order to accurately model a hyperthermia treatment, simulation at high resolution is mandatory. Using the quasi-static approximation, the electromagnetic problem can be solved at high resolution with acceptable computational effort. The validity of the quasi-static approximation is demonstrated by comparing the Maxwell solution of a phantom problem to the quasi-static approximation. Modelling of capacitive hyperthermia of the prostate reveals the difficulty of heating deep-seated tumours in the pelvic area. Comparison of the SAR distribution in the heterogeneous patient model and a patient shaped agar phantom shows a shielding effect of the pelvic bone and the influence of the fat-muscle distribution. It is shown that evaluation of capacitive hyperthermia with agar phantoms leads to overly optimistic conclusions. Therapeutic relevant tumour temperatures can only be obtained by permitting temperature extrema in normal tissue. This concurs with clinical practice, where treatment-limiting hot spots restrict the tumour temperature. It is demonstrated that the use of very cold overlay bolus bags has only a very superficial effect. The presented model can be used for individual treatment planning and optimization, for the evaluation of capacitive applicator modifications and comparison with other devices.

Quality assurance in various radiative hyperthermia systems applying a phantom with LED matrix

The Amsterdam phantom with LED-matrix is applied as an instrument in testing the performance of four types of radiative deep-body hyperthermia systems, which are in clinical use in Germany and The Netherlands. The devices tested were Essens BSD-1000, Berlins BSD-2000, Utrechts Coaxial TEM applicator and Amsterdams Four-waveguide-array. Photographs were taken of the matrix of dipoles loaded with light-emitting diodes (LED) to visualize the distribution of the RF power deposition or specific absorption rate (SAR) in the aperture midplane. The utility of the phantom with LED matrix for various types of radiative hyperthermia systems is demonstrated. Within this preliminary study, the influence of important parameters on the SAR-pattern in the aperture midplane was demonstrated. After corrections on the phase relation of the applicators a central focus in the SAR distribution could be realized in all systems and could also be moved in any direction. The patterns of the central focus changed in its absolute values and its proportions depending on the relative relations of phase and amplitude of the lateral applicators with respect to the top and bottom applicator. Frequency dependency was recognized for the central focus of the BSD-1000 as well as for the irradiation pattern of a single applicator for the BSD-2000. In the Coaxial TEM applicator it was demonstrated that the dimension of the open water bolus influenced the absolute value of SAR in the aperture midplane.

Determination and validation of the actual 3D temperature distribution during interstitial hyperthermia of prostate carcinoma.

To determine the thermal dose of a hyperthermia treatment, knowledge of the three-dimensional (3D) temperature distribution is mandatory. The aim of this paper is to validate an interstitial hyperthermia treatment planning system with which the full 3D temperature distribution can be obtained in individual patients. Within a phase I study, 12 patients with prostate cancer were treated with interstitial hyperthermia using our multi electrode current source interstitial hyperthermia treatment (MECS IHT) system. The temperature distribution was measured from within the heating devices and by additional thermometry. The perfusion level was estimated and the heating implant reconstructed. The steady-state temperature distribution was calculated using our interstitial hyperthermia treatment planning system. The simulated temperature distribution was validated by individually comparing the measured and simulated thermo-sensors, both for the thermometry integrated with the heating applicators and the additional thermometry. The entire procedure was also performed on a no-flow agar-agar phantom. It was shown that the calculated temperature distribution of an individual patient during MECS interstitial hyperthermia is very heterogeneous. The validation indicates that the calculated temperature elevations match the measurements within approximately 1 degrees C. Possible improvements are more precise reconstruction, incorporation of discrete vasculature and using a temperature-dependent, heterogeneous perfusion distribution. Further technical improvements of the MECS-IHT system may also result in better temperature calculations.

On verification of hyperthermia treatment planning for cervical carcinoma patients.

Purpose: The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SARcalc) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients. Methods: Hyperthermia treatments were performed using the 70 MHz AMC-4 waveguide system. Temperatures were measured using multisensor thermocouple probes. One invasive thermometry catheter in the cervical tumour and two non-invasive catheters in the vagina were used. For optimal tissue contact and fixation of the catheters, a gynaecological tampon was inserted, moisturized with distilled water (4 treatments), or saline (6 treatments) for better thermal contact. During one treatment no tampon was used. At the start of treatment the temperature rise (ΔTmeas) after a short power pulse was measured, which is proportional to SARmeas. The SARcalc along the catheter tracks was extracted from the calculated SAR distribution and compared with the ΔTmeas-profiles. Results: The correlation between ΔTmeas and SARcalc was on average R = 0.56 ± 0.28, but appeared highly dependent on the wetness of the tampon (preferably with saline) and the tissue contact of the catheters. Correlations were strong (R ∼ 0.85–0.93) when thermal contact was good, but much weaker (R ∼ 0.14–0.48) for cases with poor thermal contact. Conclusion: Good correlations between measurements and calculations were found when tissue contact of the catheters was good. The main difficulties for accurate verification were of clinical nature, arising from improper use of the gynaecological tampon. Poor thermal contact between thermocouples and tissue caused measurement artefacts that were difficult to correlate with calculations.

Comparison of intra-luminal versus intra-tumoural temperature measurements in patients with locally advanced prostate cancer treated with the coaxial TEM system: report of a feasibility study

A study was performed on regional hyperthermia for patients with locally advanced prostate carcinoma. The primary objective was to analyse the thermometry data with an emphasis on the possibility of replacing invasive thermometry by tumour-related intra-luminal thermometry. Fourteen patients were treated with a combination of conformal external beam radiotherapy (70 Gy) and hyperthermia. Hyperthermia was delivered using the Coaxial TEM system, one treatment per week, to a total of five treatments. Thermometry was performed in bladder, urethra, rectum and esophagus. Invasive thermometry in the prostate was carried out during one or two treatments for each patient by placing transperineally a central and a peripheral catheter. Heterogeneous temperature distributions were measured in the prostate. The mean average invasive temperature range was 1.1°C. Due to the temperature heterogeneity and a limited number of thermometry sensors (mean 7, range 2-13), large variability between treatments and patients existed regarding achieved temperatures and dose. The mean invasive T 90 was 40.2 - 0.6°C and T 50 was 40.8 - 0.6°C. The mean Cum min T 90 >40.5°C per treatment was 22 (range 0-50). Importantly, intra-luminal temperatures did not reliably predict invasively measured temperatures. Invasive thermometry, therefore, remains compulsory to calculate a thermal dose for an individual patient. Changes in temperature during treatment, measured by the urethral sensors, corresponded well with changes in temperature measured by the individual invasive sensors. Similar comparison of rectal temperature changes with intra-prostatic temperature changes was not as predictive. The similarity in temperature changes between the urethral and interstial sites, suggests that urethral temperatures are sufficient for treatment optimization. The SAR profile did not correspond with the temperature profile indicating heterogeneous perfusion. Although regional hyperthermia in combination with external beam radiotherapy for locally advanced prostate carcinoma is clinically feasible, the question on the importance of invasive thermometry remains.

Quasistatic zooming for regional hyperthermia treatment planning

Due to current computer limitations, specific absorption rate (SAR) distributions in regional hyperthermia treatment planning (HTP) are limited to centimetre resolution. However, since patient anatomy is highly structured on a millimetre scale, millimetre-resolution SAR modelling is required. A method called quasistatic zooming has been developed to obtain a high-resolution SAR distribution within a volume of interest (VOI): using the low-resolution E-field distribution and the high-resolution patient anatomy, the high-resolution SAR distribution is computed within a small zoom volume Q (small compared with the wavelength in water (lambda(w))). Repeating this procedure yields the zoomed-resolution SAR distribution in an arbitrary VOI. To validate this method for a VOI that is not small compared with lambda(w), high-resolution finite-difference time-domain (FDTD) modelling is needed. Since this is impractical for a clinical applicator, a computer model of a small applicator has been created. A partial patient anatomy is inserted into the applicator and both high- and low-resolution SAR distributions are computed for this geometry. For the same geometry, zoomed-resolution SAR distributions are computed with different sizes of Q. To compare the low- and zoomed-resolution SAR distributions with the high-resolution one, the correlation and averaged absolute difference are computed. These numbers are improved considerably using zooming (correlation 58% to 92%; averaged absolute difference 43% to 20%). These results appear to be independent of the size of Q, up to 0.3 lambda(w). Quasistatic zooming is a valuable tool in high-resolution regional HTP.