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Development and Laboratory Testing of a Noninvasive Intracranial Focused Hyperthermia System Irene S. Karanasiou, Member, IEEE, Konstantinos T. Karathanasis, Anastasios Garetsos, and Nikolaos K. Uzunoglu, Fellow, IEEE
Abstract—During the past two decades, a great deal of research has been carried out with the aim of developing effective techniques for hyperthermia treatment, primarily using RF, microwave, and ultrasound energy. A system for deep brain hyperthermia treatment, designed to also provide passive measurements of temperature and/or conductivity variations inside the human body, is presented in this paper. The proposed system comprises both therapeutic and diagnostic modules, operating in a totally contactless way, based on the use of an ellipsoidal beamformer to achieve focusing on the areas under treatment and monitoring. In previous publications, the performance of the system’s diagnostic module in phantom, animal, and human studies has been reported. In the current research, new theoretical and experimental results using the therapeutic hyperthermia module of the system are presented. The main scope of the theoretical analysis is the improvement of the system’s focusing attributes. Moreover, phantom experimental results verify the proof of concept. Both computation and phantom measurement results show that deep focused brain hyperthermia may be achievable with adequate spatial resolution and sensitivity using the proposed methodology, subject to the appropriate combination of operation frequency and low-loss dielectric material used as filling in the ellipsoidal. Index Terms—Ellipsoidal conductive reflector, focusing properties, hyperthermia, microwave radiometry, noninvasive contactless methodology.
I. INTRODUCTION ANCER, being one of the leading causes of death worldwide for several decades, is not a single disease, but comprises more than 200 illnesses. Hence, research for diagnosis, treatment, and prevention of cancer is of great interest. Especially in bioengineering, research interest in new modalities for diagnostic and therapeutic purposes continuously grows. Hyperthermia, also called thermal therapy or thermotherapy, is a type of cancer treatment mainly under study in clinical trials and not widely available. Hyperthermia is mainly considered as
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Manuscript received September 27, 2007; revised April 7, 2008. First published August 15, 2008; current version published September 5, 2008. This work was supported under Project PENED 2003(03ED/226). The project was co-financed by 80% of public expenditure through EC–European Social Fund, by 20% of public expenditure of the Ministry of Development, and by the private sector under Measure 8.3 of the operational program “COMPETITIVENESS” of the Third Community Support Programme. The authors are with the National Technical University of Athens, GR15780 Athens, Greece (e-mail:
[email protected];
[email protected]. ntua.gr;
[email protected];
[email protected];
[email protected]. ntua.gr). Color versions of one or more of the figures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identifier 10.1109/TMTT.2008.2002227
an experimental treatment in the U.S. for late-stage patients with advanced or recurrent tumors, but it has gained some acceptance in Europe and Japan during the last decade [1]–[3]. During hyperthermia sessions, body tissues are exposed to high temperatures, resulting in damaging cancer cells, usually with minimal injury to healthy tissue [4].1 Research has shown that by killing cancer cells and damaging proteins and structures within cells, hyperthermia may shrink tumors [5]. This therapy is often used in conjunction with chemotherapy and radiotherapy since the cytotoxic effect of drugs, as well as the cell-destroying ability of ionizing radiation is enhanced by hyperthermia [6], [7]. Thus, the objective of hyperthermia treatment is to raise the temperature in the tumor volume above 42 C–43 C for a sufficient period of time in order to achieve cell death or render the cells more sensitive to ionizing radiation and chemical toxins [8]. Several methods of hyperthermia have been under study the past few years including local, regional, and whole-body hyperthermia [9]–[15]. Clinical studies have shown local hyperthermia to be effective in the treatment of various types of cancer [1], [10], [16], [17], as well as breast cancer [18]–[20] when used as an adjuvant playing a supplementary treatment role to radiation and/or chemotherapy. The length of treatment and cell and tissue characteristics in conjunction with the temperature distribution achieved during a hyperthermia session determine the effectiveness of the treatment [4], [5]. A very crucial part of the hyperthermia methodology is the temperature monitoring of the tumor and surrounding tissue in order to ensure the desired heating of the relevant areas [9], [11], [13]. In practice, this monitoring procedure is invasive (insertion of thermometric devices into the treatment area) and performed using local anesthesia. Specifically, regarding the use of hyperthermia for the treatment of brain tumors, the methodology has long been known to improve the results of other treatments for brain tumors. Heating a tumor in the brain to a temperature between 42 C–45 C can enhance the effects of both chemotherapy and radiation therapy [21], [22], as happens in other body tumors. The advantage of heating the suffering brain region is that hyperthermic toxic effects are independent of the cell-cycle phase. Since brain cells do not regenerate, there is no cell-cycle phase for the normal brain cells. The advantage of hyperthermia lies in dividing growing tumor cells. In fact, anatomic and metabolic conditions that restrict the success of other modalities of treatment, such as anoxia and poor vascularization, may 1U.S. National Cancer Institute, Bethesda, MD. [Online]. Available: http:// www.cancer.gov/
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enhance the effect of hyperthermia. The main difficulty in the therapeutic application of this modality has been the lack of an effective mode of application. Various experiments involving whole body and whole or half brain hyperthermia have been accompanied by unacceptable cerebral oedema. The only method that has been employed with good results, until now, is invasive interstitial microwave hyperthermia treatment of brain tumors [9], [11], [13] with control of spatial temperature uniformity within a centimeter [3], [23]–[26]. This is normally performed in conjunction with interstitial brachytherapy and uses the same stereotactically implanted tubes for access by microwave antennas. The improvement in survival of patients with gliomas treated by hyperthermia in addition to brachytherapy was statistically very significant (94 weeks median survival versus 53 weeks for controls) [27]. It has also been shown that exposing 90% of the tumor to a temperature of more than 41.2 C has a better therapeutic effect [28]. The problem with interstitial hyperthermia is that it requires transcranial implantation of average three guiding tubes into the tumor. Each implantation has 1% risk of hemorrhage or infection. The tubes also remain for only a short time—effectively preventing repeated treatments. Repeated hyperthermia, unlike radiotherapy, does not lead to a cumulative toxic effect to normal cells. During the past decades, extensive research on the development of hyperthermia treatment methodologies has been carried out in our laboratory (e.g., [29]–[32]) focusing mainly on contact hyperthermia applicators and devices. In this paper, a novel noninvasive and contactless method for inducing focal brain hyperthermia to obtain preferential heating is proposed, also providing noninvasive real-time temperature monitoring of the areas under treatment. The proposed system is based on the Microwave Radiometry Imaging System, developed in the Microwave and Fiber Optics Laboratory, National Technical University of Athens, Athens, Greece [33]–[41]. The operating principle of both the therapeutic (hyperthermia) and the diagnostic (temperature monitoring with radiometry) modules of the system is based on the use of an ellipsoidal conductive wall cavity for beamforming and focusing on the brain areas of interest. The aforementioned radiometry imaging modality has been used for the past four-and-one-half years in various experiments with the view to assess the system as a potential intracranial imaging device [33]–[41]. The system is able to provide realtime temperature and/or conductivity variation measurements in water phantoms and animals and potentially in subcutaneous biological tissues. Both spatial resolution and detection depth provided by the system have been estimated through detailed theoretical analysis and validation experimental process using phantoms and animals [33]–[41]. In the 1.3–3.5-GHz range, imaging of the head model areas placed at the ellipsoid’s focus is feasible with a variety of detection/penetration depths (ranging from 2 to 4.5 cm) and spatial resolution (ranging from less than 1 cm to over 3 cm), depending on the frequency used. The system’s temperature resolution ranges from 0.5 C to less than 1 C in phantom and small animal experiments.
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Importantly, the system has been used in experiments involving the participation of human volunteers with the view to explore the possibility of noninvasively measuring variations of brain activation possibly attributed to local conductivity changes. Indeed, the results indicate the potential value of using focused microwave radiometry to identify brain activation possibly involved or affected in operations induced by particular psychophysiological tasks [34]. Based on the promising experimental results of our research thus far, we aim at combining the existing diagnostic module with a hyperthermia treatment component. Using a modality for focusing an external microwave source, such as the one proposed herein, primarily aims at increasing the power deposited at a deep target. To avoid harming healthy tissue, the target power density level must be greater than the power density at the tissue surface or at any other position in the tissue volume. Even though focusing yields, in general, much greater heating of targeted areas, focusing alone may still be impractical because of excessive heating of healthy intervening tissue. In theoretical and phantom studies, uniform SAR distributions inside a tumor occurred in setups where the source surrounded the volume (e.g., [42] and [43]). Computational methods to estimate the temperature pattern inside irradiated tissue in such setups have also been developed (e.g., [42]). Of course, appropriate frequencies and source distributions must be utilized and tested in practice to validate the effectiveness of each proposed technique. The main difficulty of noninvasive microwave hyperthermia is focusing electromagnetic power at a depth in high water content biological tissue. This tissue includes muscle, blood, and organ tissue and has relatively high dielectric constant and conductivity. It absorbs power quickly while rapidly attenuating waves propagating through it, preventing deep wave penetration [44]. In particular, brain tissue being very complicated both in structure and electromagnetic properties renders noninvasive deep brain hyperthermia even more difficult. Although use of noninvasive microwave hyperthermia to treat cancer is problematic in many human body structures, careful selection of the source electric field distribution may generate a tightly focused global power density maximum at deep areas within the brain [44]. With this view, in the proposed methodology, the preferential focusing of heating is attempted through a new approach by using an external RF microwave source in conjunction with the ellipsoidal reflector. The treatment area is placed on one ellipsoidal focus, whereas the irradiating antenna is placed on the conjugate focal point. The energy emitted by the latter is converged on the brain area under treatment. The system characteristics depend mainly on the operation frequency used. The main objective of our research presented in this paper is to theoretical study configurations that improve the focusing properties of the system and to perform experiments that substantiate the system performance. In the following sections, the proposed methodology and a theoretical simulation study exhibiting the system focusing properties at various operating frequencies are presented. The optimization of the system’s attributes are theoretically tested, utilizing lossless media of different dielectric constant values placed in the ellipsoidal cavity or around the human head model. Additionally, phantom experimental results performed in the framework of the cur-
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rent research—verifying theory and proof of concept—are described in detail. This paper concludes with a discussion including the assessment of theoretical and experimental results, presenting the potential of the system, and finally, with overall conclusions. II. SYSTEM DESCRIPTION The proposed focused deep brain hyperthermia system consists of an ellipsoidal cavity with an opening aperture to host the human head to receive the focused brain hyperthermia. The ellipsoidal cavity is axis-symmetric with 1.5-m length of large axis and 1.2-m length of small axis. It is an exact replica of the ellipsoidal cavity of the previously mentioned Microwave Radiometry Imaging System [33]–[35]. The new cavity has been cut transversally to the major axis at a distance of 5 cm of the focal plane (currently having a length of large horizontal axis: 1.25 m) and the subtracted shell is currently not being used. On one hand, this action has been taken in order to have better access to the interior of the cavity, ensuring easier positioning and monitoring during the experimental procedure. It has been already demonstrated through theoretical analysis [33]–[41] that the system’s focusing properties are not affected by this alteration compared to those achieved using the whole cavity volume. Additionally, the subtracted shell part has been designed and constructed in such a way that allows effective sealing of the ellipsoidal dome when it is filled with any dielectric material in any form (liquid, foam, or powder in small particles). It is of concave shape, nonconductive, and ensures isolation of the material in the interior of the cavity. The inner surface of the ellipsoidal walls has an overlay of a highly conductive nickel coating to achieve a good reflection of incident electromagnetic waves. The cavity has been externally covered with aluminum sheets to increase isolation. Each irradiation is performed by placing the area of interest (of a phantom at present) on one focal area, while the transmitting dipole antenna is placed on the other geometrical focus of the ellipsoid (Fig. 1). Hence, the ellipsoidal cavity is excited by a dipole antenna, while it is foreseen that the human head should be placed properly on the conjugate focus with the aim to achieve focusing on the area under treatment. At present, the energy for heating is provided by a magnetron generator operating at 2450 MHz with microwave energy of 200 W connected to the dipole antenna [see Fig. 1(b)]. Temperature monitoring of the heated area will be performed after each irradiation using the microwave radiometry methodology with the same ellipsoidal setup, as has been described in the past [34], [35], [41]. The combination of the two systems in one may be achieved by using two different antennas or even the same antenna for monitoring and heating. Specifically, the cavity is constructed in such way that two antennas may be placed at the same focal point (not at the same time point, but subsequently); one from an opening at the side of the cavity and one from an opening on the top. Current research by our group aims at optimizing the combination of therapeutic and diagnostic techniques in the existing setup (e.g., use of the same antenna applicator for heating and measuring after implementing appropriate cooling of the receiving antenna). Finally, the two methodologies may be combined by integrating two ellipsoidal cavities in one construction with one common focal
Fig. 1. (a) Block diagram of the hyperthermia system. (b) Ellipsoidal conductive wall cavity (rear view) of the hyperthermia system. (c) Ellipsoidal conductive wall cavity and the applicator connected to the Magnetron generator providing microwave energy of 200 W at the frequency of 2450 MHz.
area. The subject or phantom could be placed at that common area, while the receiving and heating antennas would be placed accordingly at the other foci of the two cavities. The temperature monitoring module has been extensively studied both theoretically and experimentally providing promising results as stated above [33]–[41]. Additionally, in experimentation including human volunteers, the system functionality has also been studied from a functional brain imaging perspective, resulting in the interesting outcome that the system may pick up brain activation attributed to cortex conductivity changes at microwave frequencies [34], [36]. In the current research, only the therapeutic module of the system is studied. III. THEORETICAL MODELING AND SIMULATION OF THE ELLIPSOIDAL CAVITY FOCUSED DEEP BRAIN HYPERTHERMIA DEVICE A. Methods During the past few years, extensive electromagnetic analysis has been performed by our group using both semianalytical methods based on Green’s function theory and a finite-element method (FEM) simulation tool [33], [34], [38], [39]. The previous theoretical results show that focusing can be achieved in the brain areas of interest with a variety of dimensions of the focusing region and penetration depths related to the operation frequencies used [33], [34], [38], [39]. Various approaches towards the optimization of the system focusing properties have been explored: use of high dielectric constant, but low-loss dielectric materials around the radiating antenna, as well as a number
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of dielectric layers placed around the human head in order to achieve better matching on the head–air interface [45]. The results of these analyses have shown improvement of the system focusing properties. Indeed, through the comparison of the electric field distributions, yielded in the various simulation scenarios, it could be derived that with the usage of stepped index materials the bounds of the focusing area are better delimited and defined, whereas the penetration depth is also improved [45]. The thickness of the dielectric materials also seems to play an important role with the usage of thinner layers proving to be more effective. Nevertheless, these approaches, even if they ameliorate spatial resolution and penetration depth, do not adequately ensure spatial sensitivity in terms of displacement of the treatment area with respect to the ellipsoid’s focal area [45]. The aim toward the development of a practically useful tool is to be able to treat a specific area at a specific depth inside the human head placed at the ellipsoidal reflector’s focus. By moving this area from the focus and placing another part of the human brain (or body in general) that needs treatment at the focal area, the energy will be solely accumulated on the tissue placed at the focus where the maximum energy of the system is converged. Thus, besides spatial resolution, spatial sensitivity is, in practice, of great value. The current research takes into consideration recent research results and past experience and also the fact that, in practice, the main operation requirements of a deep brain hyperthermia system are: 1) adequate spatial resolution; 2) spatial sensitivity; and 3) penetration depth in order to heat the treatment area without overheating or damaging healthy tissue. Consequently, it aims at exploring various setups toward successfully heating only the brain area placed on the ellipsoidal focal point where maximum convergence of the energy emitted from the other focus is achieved. It should be emphasized that as “focused deep hyperthermia” the ability to irradiate a specified brain region in terms of its position and size is defined. More specifically what we need to achieve is the ability to irradiate with microwave energy a pre-specified brain volume of spherical shape with its radius and center controllable by the operator of the proposed deep brain hyperthermia system. This means that the tumor volume (e.g., glioblastoma) will receive maximum microwave energy (development maximum heating effect), while the healthy tissues will receive minimum deposition of microwave energy. In the current study, the simulations carried out consist of modeling the proposed ellipsoidal cavity hyperthermia applicator by fully taking into account all electromagnetic and geometrical properties and characteristics. The analysis of the electromagnetic problem is approached numerically using commercial simulation software, which solves Maxwell’s equations using an FEM. The solution domain is meshed into a set of tetrahedral elements. The characteristics of the generated mesh are crucial to obtaining a reliable well-converged solution. The human head is simulated by a double layered sphere (i.e., brain and skull). Dielectric permittivity and conductivity values are those of the respective human head tissues at the corresponding frequencies. Specifically the inner sphere simulates the brain and the outer spherical layer represents the skull, each having the corresponding permittivity and conductivity values. The head model considered was for the worst case,
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assuming the greatest tissue loss characteristics—for each frequency—in the largest possible sphere for which a central global maximum could be found. The configuration is excited by a dipole antenna operating at 2.45 GHz or broadband double discone antenna operating at 1–4 GHz. The theoretical analysis that was carried out and is herein presented is threefold: • brief review of the focusing properties of the hyperthermiaradiometry system; • investigation on the use of a “matching” dielectric layer on the head surface; • investigation of low-loss material with various permittivity characteristics to fill the ellipsoidal in conjunction with the possibility of developing a smaller more portable system, maximizing in parallel the focusing capabilities of the device. Extensive calculation of the penetration of microwave energy into the human head in the proposed ellipsoidal cavity hyperthermia applicator has been carried out. Comparison of the computational simulation results of the microwave energy penetration and deposition into the human head for various setups, and radiation frequencies illustrate the system attributes. B. Numerical Results In this section, simulations at various frequencies are presented with the view to evaluate the performance of the system in each of the above-mentioned cases. The constructed ellipsoidal reflector is a structure created by revolution of an ellipse around its major axis and it has been modeled in the same manner. The initial mesh and the following mesh adaptations are carried out by the program. Convergence is assessed by monitoring the convergence of the -parameters (i.e., transmission and reflection) from iteration to iteration. In some cases, in order to minimize the computational cost, a half or quarter of the ellipsoid was used for the calculations, exploiting in this way the electrical symmetry of the model in two planes. The head model that was used is a double-layered sphere comprising two types of head tissues; the inner sphere of 9-cm radius, representing average brain tissue, whereas the outer spherical shell has a radius of 10 cm, representing the skull tissue, all having the respective conductivity and permittivity values [46] at the various operation frequencies. The values of permittivity and conductivity of brain and skull at various frequencies are listed in Table I. For the case of brain tissue, a mean value of grey and white matter is considered for the simulations. The excitation frequencies used in the simulation scenarios are in the bandwidth of 1–4 GHz, which is also the dynamic range of operating frequencies of the sensitive radiometric receivers of the diagnostic module of the system [33]–[41]. The extensive calculation that has been carried out concerns the following cases discussed in Sections III-B.1–3. 1) Ellipsoid Focusing Properties at Various Operating Frequencies: Initially, the focusing properties of the system are studied through simulations of the cavity-antenna setup without the presence of the human head model. In Figs. 2 and 3, the field distribution inside the ellipsoidal is depicted at
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TABLE I PERMITTIVITY AND CONDUCTIVITY VALUES OF HEAD TISSUES AT VARIOUS FREQUENCIES
Fig. 4. (a) Electric field distribution inside the ellipsoidal at the presence of a head model at 1 GHz (center head on focus). (b) Magnification of head model.
Fig. 2. Ellipsoid focusing properties at: (a) 1 GHz. (b) Detail of field distribution at focal area.
Fig. 5. Electric field distribution inside the ellipsoidal at the presence of a head model at 2 GHz (center head placed on focus).
Fig. 3. (a) Ellipsoid focusing properties at 2 GHz. (b) Detail of field distribution at focal area.
1 and 2 GHz, respectively. It is well observed that focusing on the ellipsoid’s geometrical focal point is achieved in both cases with or without the use of the whole ellipsoidal reflector; despite the large opening and the conductive wall cavity part missing, the system properties are not affected. These results are totally compliant with numerical and simulation results obtained in the past using the entire ellipsoidal setup [33], [34]. It is well observed that the energy emitted by the antenna placed on one focus merges on the other geometrical focal point of the ellipsoidal reflector. At 1 GHz, there is a rather large 3-dB focusing region of approximately 5 cm, whereas this is reduced at 2 GHz by almost 50%. In the continuing study, the same configuration has been used, but at the presence of a spherical human head model with its center placed at the ellipsoid’s focal point. In Figs. 4 and 5, the electric field distribution at the presence of the human head model is depicted. Focusing on the head center is achieved at the lower frequency since the penetration depth is quite large. At 2 GHz, the penetration depth is of the order of 3 cm. Once again, the results are similar to those obtained in the past [33], [34]. Another important aspect of the current analysis is the focusing sensitivity of the system—with respect to the energy
Fig. 6. (a) Electric field distribution at 1 GHz (head center placed 5 cm away from focus). (b) Magnification of head model.
merged on the ellipsoid’s focus—when moving the center of the human head model from the ellipsoid’s geometrical focus. The results of the simulation performed at 1 GHz when the head center is moved 5 cm away from the focus towards the ellipsoid center are shown in Fig. 6. A small shift of the merged energy from the focal area is observed; the maximum electric field was expected to be observed on the right circle marker of Fig. 6(b), where the ellipsoid’s focal point is placed, whereas the left marker denotes the head center. This phenomenon is mainly attributed to the spherical geometry of the head model and the penetration depth in conjunction with the resonance phenomena generated in the inhomogeneous spherical head model. Simulation results at the presence of the human head model placed at the ellipsoid’s geometrical focus at 2.45 GHz are also presented. This simulation was performed in order to compare the theoretical results with the experimental part described in Section III-B.2. The penetration depth is of the order of approximately 3 cm, and the averaged normalized SAR value is presented in Fig. 7.
KARANASIOU et al.: DEVELOPMENT AND LABORATORY TESTING OF NONINVASIVE INTRACRANIAL FOCUSED HYPERTHERMIA SYSTEM
Fig. 7. SAR distribution at 2.45 GHz (head center placed at focus).
Fig. 8. (a) Ellipsoid focusing properties at 1 GHz inside human head model with matching layer. (b) Detail of field distribution inside head model.
Fig. 9. (a) Ellipsoid focusing properties at 2.45 GHz inside human head model without matching layer. (b) With the use of the matching layer with "r = 6.
2) Use of a Matching Dielectric Layer Placed Around the Head Model: In an attempt to enhance the penetration of the microwave radiation emitted by a double discone antenna source (placed on one focus), a matching layer (cap) of 1.5-cm thickand ness is utilized with dielectric constant . The aim is to change in a smoother stepped manner the reflection index on the head–air interface and, thus, enhance the penetration of the microwave energy inside the human head. This low-loss dielectric material has been selected because it is commercially available and we intend to use it in future experiments. The proposed matching layer is designed to be worn by the human participants (e.g., special caps comprising layers filled with the powder of the dielectric material). The matching layer affords a reduction in diffraction effects on the head–air interface. It is well observed that the penetration depth has been enhanced at both frequencies (Figs. 8 and 9). Especially at 1 GHz, the use of the dielectric matching material significantly reduces the occurrence of other auxiliary hot spots besides the focus inside the head model (Figs. 4 and 8).
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Fig. 10. SAR distribution at 1 GHz inside the reduced sized ellipsoidal (head center moved 8 cm away from focus along x-axis). (a) With air inside the ellipsoid. (b) With dielectric filling "r = 6.
This solution does not seem to provide complete manipulation of the system’s focusing sensitivity with respect to the displacement from the system’s focal region, as discussed above. Nevertheless, the focusing region may be changed by placing another brain area at the focus. This setup will be experimentally studied and evaluated in detail in the near future. 3) Size Reduction and Dielectric Filling of Ellipsoidal Cavity: With the view to enhance the focusing properties of the proposed system in terms of spatial resolution, penetration depth, and spatial sensitivity—based on the above mentioned findings—simulations with ellipsoid reflectors of various dimensions filled with low-loss dielectric material have been carried out at various operating frequencies. With this approach, we aim to achieve improved penetration and focusing inside the human head and to achieve better control of the deposited electromagnetic energy. Initially, the ellipsoidal reflector’s volume has been reduced by a factor of 25%, was filled with a dielectric material of , and excited at 1 GHz. Simulation results using the original ellipsoidal filled with and excited at 415 MHz were then carried out. Finally, a half-sized cavity, filled with a high value low-loss permittivity material has been examined at 432 and 915 MHz. A smaller (by a factor of 25% having a major axis: 112.5 cm and a minor axis: 90 cm) ellipsoid in conjunction with an operating frequency at 1 GHz is being utilized. The conductive wall dielectric macavity is filled with a low-loss terial with permittivity value . The center of the human head model has been placed 8 cm away from the focal point along the -axis (closer to the emitting antenna). In Fig. 10(b), the normalized SAR values inside the human head model are depicted. A clear hot spot can be observed deep in the human head model approximately 4 cm away along the -axis from the geometrical ellipsoid focus with a volume of 3.5 cm . The use of the dielectric-filling material clearly results in avoiding the introduction of auxiliary foci or “hot spots” and in parallel in improving the scattering effects on the head–air interface. The energy is not concentrated at the ellipsoid’s focus point as expected, but at a distance of 4 cm. This is due to the quite large penetration of the electromagnetic energy at 1 GHz inside the head model. The beneficial outcome from using a dielectric filling inside the ellipsoidal is clearly exhibited by comparing the normalized specific absorption rate (SAR) values of
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Fig. 11. SAR distribution at 1 GHz inside the reduced-sized ellipsoidal with dielectric filling "r = 6 when: (a) head center moved 8 cm away from focus along x-axis and 5 cm along z -axis and (b) head center moved 8 cm away from focus along x-axis and 8 cm along z -axis.
Fig. 10(a) and (b), which are four times larger in the case of the dielectric filling than the air filling at the same convergence point inside the human head model. In order to further explore the system’s spatial sensitivity with respect to the displacement of the center of the human head model from the ellipsoid’s focal point, where the maximum peak of the emitted energy is converged, two more configurations were simulated: initially, the center of the head model is moved 8 cm away from focus along the -axis and 5 cm along the -axis and then displaced 8 cm away from focus along the -axis and 8 cm along the -axis. Once again, a clear hot spot can be observed at a 4-cm distance from the geometrical focus along the -axis and at 8 cm along the -axis from the geometrical ellipsoid focus with a volume of 3.5 cm without the presence of any auxiliary “hot spots” [see Fig. 11(a)]. In the second case, since the head has been placed totally away from the focal area of the ellipsoid, the energy penetrating the human head model is low without creating any hot spots inside it [see Fig. 11(b)]. These simulations exhibit the enhanced spatial sensitivity of the proposed configuration, showing the system’s focusing capabilities attributed to the ellipsoidal reflector. The ellipsoidal reflector (having its actual dimensions) is then filled with a dielectric material of permittivity equal to and operating frequency of 415 MHz. Similar displacement positions of the human head model from the ellipsoid’s focus have been used so these results could be compared to the above findings. The energy is concentrated deep in the human head model approximately 4 cm away along the -axis from the geometrical ellipsoid focus, but having a much larger volume of the order of 10 cm (Fig. 12). The use of the low-loss dielectric-filling material clearly results in avoiding the introduction of auxiliary foci and in parallel in improving the scattering effects on the head–air interface. The energy is not concentrated at the ellipsoid’s focus area as expected, but at an area shifted by 4 cm along the -axis. This is due to the even larger penetration of the electromagnetic energy at the lower frequency of 415 MHz inside the head model.
Fig. 12. (a) SAR distribution at 415 MHz. (b) Electric field distribution at 415 MHz with dielectric filling "r = 10 when head center moved 8 cm away from focus along x-axis.
Fig. 13. SAR distribution at 415 MHz with dielectric filling "r = 10 when: (a) head center moved 8 cm away from focus along x-axis and 5 cm along z -axis and (b) head center moved 8 cm away from focus along x-axis and 8 cm along z -axis.
As expected, at 415-MHz frequency, the penetration depth increases, as the simulation results also show, whereas the spatial resolution of the system deteriorates, compared to the operating frequency of 1 GHz. This finding can be observed in Fig. 13 where the results of two additional simulations are depicted. It is observed that by moving the human head around the focal area, the region on which the energy is converged inside the human head model does not significantly change. Even in the case where the human head is placed off focus, a significant amount of energy is still converged at a specific area inside the head model. The hot spot becomes smaller (approximately 7 cm ) since the whole head model is placed away form the focus, but nevertheless it still exists. This is due to the operation frequency used exhibiting poor spatial resolution and sensitivity with the result that the energy focusing area cannot be spatially manipulated as desired. Hence, this finding supports the conclusion that the system’s spatial resolution and sensitivity are seriously impaired at operating frequencies much lower than 1 GHz when using the existing ellipsoidal reflector with dielecand tric fillings with permittivity values approximately lower. Nevertheless, the above configuration could be considered in cases with large penetration depths and rather large treatment areas.
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C. Conclusions of Computational Study
Fig. 14. Focusing capability of a half-sized ellipsoidal cavity. Computation results in the case of a half-sized ellipsoidal cavity filled with TiO ("r = 80) at 432 MHz. (right) Detailed figure of focusing area.
Fig. 15. Computation results in the case of a half-sized ellipsoidal cavity filled with TiO ("r = 80) at 915 MHz. (right) Detailed figure of focusing area.
The values of the dielectric material used in the above simulations were chosen based on commercial availability and relatively low price with the view to provide a future viable enhancement of the existing configuration. Nevertheless, in the framework of the current research, a variety of lossless dielectric fillings of the ellipsoidal cavity have also been used in simulations; their permittivity values ranged between 20–40. The results using such dielectric materials resulted in a similar or less promising outcome compared to the ones that are presented in this paper. Along similar lines of thought and based on the previously reported findings, but with the view of proposing a more portable solution, a half-sized ellipsoidal cavity is considered. A low-loss, but very high-permittivity dielectric filling has been used in simulations at two operating frequencies, i.e., 432 and 915 MHz (see Figs. 14 and 15). The dielectric material and loss factor in used is TiO2 (permittivity value the order of 10 ). In the case of a small cavity, the use of a high-permittivity medium is mandatory in order to maintain the focusing and beamforming properties of the ellipsoidal reflector at low microwave operating frequencies in the range of those used in hyperthermia and microwave radiometry. The center of the human head model is placed at the ellispoid’s focus point. It is well observed that a hot spot can once again be created deep in the human head model in conjunction with a significant decrease of the reflection and scattering effects on the head–air interface (see Figs. 14 and 15). The spatial resolution, as well as the dimensions of the hot spot, are dependent mainly on the operating frequency used, as has also been observed in previous results.
Extensive calculation carried out shows that by varying the radiation frequency, the dielectric materials for the ellipsoidal cavity filling, and the human head position, the desired controllability of the size and position of the region to be heated may be achieved. The computed results performed in the current research were extensive, covering a wide range of parameters of radiation frequency and dielectric material, as well as position of the human head model and cavity size. The most representative results exhibiting the system’s attributes are presented in this paper. The primary conclusion of the extensive computational study that has been carried out is the difficulty of achieving deep brain hyperthermia in the case of an air-filled cavity, while more satisfactory performance is achieved when using cavities filled with low-loss dielectric material and matching layers around the human head model. The results demonstrate that standing waves may be formed within the skull during transcranial microwave radiation, leading to nonuniform skull heating when matching materials around the human head or filling media inside the cavity are not used. However, the results also show that these effects can be sufficiently controlled to allow therapeutic microwave to be focused in the cranial base region of the brain without causing thermal damage to the scalp, skull, or outer surface of the brain. With the appropriate combination of ellipsoidal size, dielectric matching materials, and operation frequencies, the system could be potentially used for hyperthermia treatment. The same findings apply to the implementation of a more portable system as the simulation results have demonstrated. Future studies will be conducted using more realistic human head models to account for differences in head size, shape, tissue layers, etc. that affect SAR distribution. Moreover, changes in blood flow induced by hyperthermia that can influence the response of a tumor to heat are not considered in the current analysis. Nevertheless, when the underlying mechanisms responsible for the antitumor effects of a combined treatment (hyperthermia with either radiotherapy or chemotherapy) are considered, either an increase or a decrease in blood flow could potentially contribute to the cytotoxic effect [47]. IV. EXPERIMENTAL PROCEDURES AND RESULTS The performance of the system’s diagnostic module designed and developed for brain imaging has been previously studied in phantom, animal, and human tests, illustrating promising results [33]–[39]. In the framework of the current research, the hyperthermia module—as described in Section II—is tested through phantom experimentation. The microwave radiation used in the experiments was at 2450 MHz with a total power of 200 W. The first phantom used was a cylindrical glass container (10-cm height, 6-cm radius), filled with a gel-based saline solution, having the electromagnetic properties of average brain tissue at 2450 MHz (Fig. 16). The latter is the operating frequency of the magnetron generator used to feed the radiating dipole antenna. The results of this experiment show that the temperature of the area placed at the focus of the ellipsoid was found to be 1 C higher after a 3-min irradiation than that
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Fig. 18. Experimental setup: the ellipsoidal conductive wall cavity and the infrared camera. Fig. 16. Front view of the conductive wall cavity of the proposed brain hyperthermia system.
Fig. 19. Side view of phantom using the infrared camera: Dark areas show phantom regions that have higher temperature after irradiation (side view). Fig. 17. Experimental setup: the ellipsoidal conductive wall cavity and the phantom placed at the focal area.
measured before heating in a volume of approximately 8 cm [41]. Following the initial promising results, a larger phantom has been used in order to more realistically model the dimensions of the human head. A split cylindrical phantom method has been employed to study the focusing properties of the air-filled ellipsoidal cavity brain hyperthermia applicator. The main purpose of this initial experimentation is to verify the proof of concept with the existing configuration. Two hemispherical phantoms of 12-cm radius filled with a gel-based saline solution (showing similar loss and permittivity dielectric properties with the human head at the operating frequency used) were prepared. The split phantom comprised two hemispherical parts that contained the gel-based saline solution; a plastic thin film separated their contents, and after each experiment, was removed to observe the results and effects of each irradiation (Fig. 17). The system focusing properties with the existing setup are studied using infrared camera measurement techniques. After a 2-min irradiation, the split phantom was removed, opened, and imaged by an infrared camera (Thermal Camera PIU, PYSER-SGI) measuring the temperature distribution by observing the 8–12- m infrared radiation (Fig. 18). The procedure was repeated five times with similar results in terms of temperature rise (approximately 1 C), verifying previous experimental results and spatial resolution in the order of 3 cm. In Figs. 19–21, the measured results using the infrared camera are depicted.
Fig. 20. (a) Top view of phantom using infrared camera. (b) Actual phantom (one hemisphere). The areas where the temperature is higher after radiation can be clearly observed.
Fig. 21. Third hot spot observed at the area placed on the ellipsoid’s focus (top view).
Initially, the geometrical center of the cylindrical phantom was placed exactly at the ellipsoidal focus point, which was spatially defined by the crossing of three laser beams. The phantom
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was irradiated by the dipole antenna placed at the other focus of the conductive wall dome, which was connected to the magnetron generator. After the 2-min irradiation, the phantom was split into two parts and was then visually observed and monitored using the thermo-camera. The theoretical simulation results presented in Section III show that, for this configuration, i.e., when a human head model with its center placed at the ellipsoid focal point is irradiated at 2.45 GHz, only part of the electromagnetic energy penetrates it up to a depth of approximately 3 cm (see Fig. 7). The dark-colored areas in the figure illustrate all the phantom regions exhibiting higher temperature after irradiation. By observing Fig. 19, which shows the image from the infrared camera, the simulation results are completely verified by the experiment. It is clearly observed that the phantom viewed and monitored from the side exhibits only one hot spot at the area expected by the simulation results with a penetration depth of 3 cm and a volume of approximately 4 cm . The phantom was subsequently turned by 180 and once again with its center placed at the focus of the ellipsoidal and the irradiation was repeated for 2 min. The results were identical to those reported above and are depicted in Fig. 20. It can be clearly observed that two dark areas exist, namely, two hot spots as expected; one from the previous experiment and a new one at its antipodal. Indeed, the actual photograph of the split phantom illustrates the two parts where the gel-based saline solution has been melted by the heating caused by the electromagnetic energy. Finally, a part of the circumference of the phantom was placed at the focal region and the experiment was once more repeated. A new hot spot, close to the previous ones, could once again be readily found by visual observation and by using the infrared camera (Fig. 21). The measured results fully verify the computations showing the limited capability of radiation to penetrate the phantom head in the case of an air-filled cavity at 2.45 GHz. The computational and phantom results show that the system in its present state selectively heats areas at the superficial regions of a human head model at 2.45 GHz in a totally noninvasive manner. V. DISCUSSION AND CONCLUSIONS The combination of a microwave radiometry device with a hyperthermia treatment module using the same focusing operation principal was herein investigated with the view to develop a tool that may provide noninvasive treatment and monitoring, which can be repeated as often as necessary without significant risk, giving the possibility of useful and further enhancement of radiosurgery. The proposed hybrid system is completely novel, passive, harmless, and low cost. In this paper, the focusing properties of the ellipsoidal beamformer-based hyperthermia system was investigated through a simulation and experimental study. The design and construction of the conductive wall cavity used for focusing on the areas of the human head under treatment is based on the Microwave Radiometry Imaging System developed during the past few years by our group [33]–[41]. A new cavity has been constructed, being an actual replica of the above mentioned one with a single difference: a larger opening at the
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ellipsoid’s focal plane, permitting the entrance of the human body inside the cavity in a horizontal (lying) position. In this paper, three approaches in order to optimize the focusing properties of the hybrid system have been presented. Electromagnetic analysis has been performed using a finite-element simulation methodology at various operating frequencies. Initially, the simulation scenario comprised the configuration of an ellipsoidal cavity excited by a double discone antenna at the presence of a human head model, placed at an arbitrary point with respect to the ellipsoid’s focal point. The electric field distribution was calculated and compared to the second simulation scenario with the use of lossless dielectric materials placed inside the cavity. The primary conclusion of the extensive computational study that has been carried out is the difficulty in achieving deep brain hyperthermia in case of an air-filled cavity, while satisfactory performance is achieved by the use of cavities filled with low-loss dielectric materials and dielectric matching materials placed around the human head model. A smaller more portable system may also be developed, comprising similar attributes with the use of high-permittivity low-loss dielectric fillings in the interior of the ellipsoidal cavity. Moreover, the experiment of heating a specific 3-D region of a phantom at 2450 MHz performed in the framework of the current research has shown promising results. A rise of 1 C has been achieved in the region of interest (volume of 6 cm approximately), while the temperature of the surroundings remained unchanged. The results have also been monitored using an infrared camera. The measurement results fully verify the simulation study. In conclusion, in this paper, a brain hyperthermia system also comprising a passive brain temperature monitoring module has been presented. Simulation results and experiments reveal the system’s potential as a possible future clinical tool. Both computation and phantom measurement results show that deep focused brain hyperthermia is achievable with adequate spatial resolution and sensitivity using the proposed methodology subject to the appropriate combination of operation frequency and low-loss dielectric material used as filling in the ellipsoidal. Since interstitial hyperthermia can double prognosis, it is logical to assume that the proposed new method, if shown to be sufficiently accurate after further and in-depth investigation, could also work. Future research, including mainly phantom, animal, and human experiments, implementing the above focusing optimization techniques, will illustrate the value of the current study and actual treatment efficacy, quantified in terms of the thermal dose delivered to the target. This further investigation could result in potentially creating a complementary totally noninvasive therapeutic and diagnostic brain imaging tool. With the great advantage of being noninvasive, which allows it to be repeated as often as necessary without significant risk and with an acceptable cost, it could possibly add to the treatment protocol of brain malignancy in the future. REFERENCES [1] J. Overgaard, D. G. Gonzalez, M. C. C. M. Hulshof, G. Arcangeli, O. Dahl, O. Mella, and S. M. Bentzen, “Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma,” Lancet, vol. 345, pp. 540–543, Mar. 1995.
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[2] J. Overgaard, D. G. Gonzalez, M. C. C. M. Hulshof, G. Arcangeli, O. Dahl, O. Mella, and S. M. Bentzen, “Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma—A multicentre randomized trial by the European Society for Hyperthermic Oncology,” Int. J. Hypertherm., vol. 12, no. 1, pp. 3–20, Jan.–Feb. 1996. [3] H. Kuwano, K. Sumiyoshi, M. Watanabe, N. Sadanaga, T. Nozoe, M. Yasuda, and K. Sugimachi, “Preoperative hyperthermia combined with chemotherapy and irradiation for the treatment of patients with esophageal carcinoma,” Tumori, vol. 81, pp. 18–22, Jan.–Feb. 1995. [4] J. van der Zee, “Heating the patient: A promising approach?,” Ann. Oncol., vol. 13, no. 8, pp. 1173–1184, Aug. 2002. [5] B. Hildebrandt, P. Wust, O. Ahlers, A. Dieing, G. Sreenivasa, T. Kerner, R. Felix, and H. Riess, “The cellular and molecular basis of hyperthermia,” Crit. Rev. Oncol. Hematol., vol. 43, no. 1, pp. 33–56, Jul. 2002. [6] M. H. Seegenschmiedt, P. Fessenden, and C. C. Vernon, Thermoradiotherapy and Thermochemotherapy. Berlin, Germany: Springer-Verlag, 1995, vol. 1, Biol., Physiol., Phys. [7] J. H. Suh and G. H. Barnett, “Brachytherapy for brain tumor,” Hematol. Oncol. Clin. North Amer., vol. 13, no. 3, pp. 635–650, Jun. 1999. [8] R. B. Roemer, “Engineering aspects of hyperthermia therapy,” Annu. Rev. Biomed. Eng., vol. 1, pp. 347–376, Aug. 1999. [9] P. Wust, B. Hildebrandt, G. Sreenivasa, B. Rau, J. Gellermann, H. Riess, R. Felix, and P. M. Schlag, “Hyperthermia in combined treatment of cancer,” Lancet Oncol., vol. 3, no. 8, pp. 487–497, Aug. 2002. [10] H. R. Alexander, “Isolation perfusion,” in Cancer: Principles and Practice of Oncology, V. T. DeVita, Jr., S. Hellman, and S. A. Rosenberg, Eds., 6th ed. Philadelphia, PA: Lippincott, Williams, Wilkins, 2001, vol. 1 and 2. [11] M. H. Falk and R. D. Issels, “Hyperthermia in oncology,” Int. J. Hypertherm., vol. 17, no. 1, pp. 1–18, Jan. 2001. [12] M. W. Dewhirst, F. A. Gibbs, Jr., R. B. Roemer, and T. V. Samulski, “Hyperthermia,” in Clinical Radiation Oncology, L. L. Gunderson and J. E. Tepper, Eds., 1st ed. New York: Churchill Livingstone, 2000. [13] D. S. Kapp, G. M. Hahn, and R. W. Carlson, “Principles of hyperthermia,” in Cancer Medicine, R. C. Bast, Jr., D. W. Kufe, and R. E. Pollock, Eds., 5th ed. Hamilton, ON, Canada: B.C. Decker, 2000. [14] A. L. Feldman, S. K. Libutti, J. F. Pingpank, D. L. Bartlett, T. H. Beresnev, S. M. Mavroukakis, S. M. Steinberg, D. J. Liewehr, D. E. Kleiner, and H. R. Alexander, “Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy,” J. Clin. Oncol., vol. 21, no. 24, pp. 4560–4567, Dec. 2003. [15] E. Chang, H. R. Alexander, S. K. Libutti, R. Hurst, S. Zhai, W. D. Figg, and D. L. Bartlett, “Laparoscopic continuous hyperthermic peritoneal perfusion,” J. Amer. Coll. Surgery, vol. 193, no. 2, pp. 225–229, Aug. 2001. [16] K. A. Leopold, M. Dewhirst, T. Samulski, J. Harrelson, J. A. Tucker, S. L. George, R. K. Dodge, W. Grant, S. Clegg, L. R. Prosnitz, and J. R. Oleson, “Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft-tissue sarcomas,” Int. J. Radiat. Oncol. Biol. Phys., vol. 22, no. 5, pp. 989–998, 1992. [17] J. van der Zee, D. G. Gonzalez, G. C. van Rhoon, J. D. P. van Dijk, W. L. J. van Putten, and A. A. M. Hart, “Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: A prospective, randomised, multicentre trial,” Lancet, vol. 355, pp. 1119–1125, 2000. [18] C. C. Vernon, J. W. Hand, S. B. Field, D. Machin, J. B. Whaley, J. van der Zee, W. L. J. van Putten, G. C. van Rhoon, J. D. P. van Dijk, D. G. Gonzalez, F. F. Liu, P. Goodman, and M. Sherar, “Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials,” Int. J. Radiat. Oncol. Biol. Phys., vol. 35, no. 4, pp. 731–744, Jul. 1996. [19] J. W. Hand, D. Machin, C. C. Vernon, and J. B. Whaley, “Analysis of thermal parameters obtained during phase III trials of hyperthermia as an adjunct to radiotherapy in the treatment of breast carcinoma,” Int. J. Hypertherm., vol. 13, pp. 343–364, 1997. [20] D. S. Kapp, “Efficacy of adjuvant hyperthermia in the treatment of superficial recurrent breast cancer: Confirmation and future directions,” Int. J. Radiat. Oncol. Biol. Phys., vol. 35, pp. 1117–1121, 1996. [21] O. Dahl and O. Mella, “Enhanced effects of combined hyperthermia and chemotherapy (bleomycin, BCNU) in a neurogenic rat tumour (BT A) in vivo,” Anticancer Res., vol. 2, pp. 359–364, Nov.–Dec. 1984. [22] M. Salcman and G. M. Samaras, “Hyperthermia for brain tumours: Biophysical rationale,” Neurosurgery, vol. 4, pp. 327–335, Sep. 1981.
[23] B. Stea, J. Kittleson, and J. R. Cassady, “Treatment of malignant glioma with interstitial irradiation and hyperthermia,” Int. J. Radiat. Oncol. Biol. Phys., vol. 24, pp. 657–667, 1992. [24] T. Nakajima, D. W. Roberts, T. P. Ryan, P. J. Hoopes, C. T. Coughlin, B. S. Trembly, and J. W. Strohbehn, “Pattern of response to interstitial hyperthermia and brachytherapy for malignant intracranial tumour: A CT analysis,” Int. J. Hypertherm., vol. 9, pp. 491–502, Jul.–Aug. 1993. [25] B. Emami, C. Scott, C. A. Perez, S. Asbell, P. Swift, P. Grigsby, A. Montesano, P. Rubin, W. Curran, J. Delrowe, H. Arastu, K. Fu, and E. Moros, “Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors—A prospectively controlled randomized study by the Radiation Therapy Oncology Group,” Int. J. Radiat. Oncol. Biol. Phys., vol. 34, pp. 1097–1104, Mar. 1996. [26] P. K. Sneed, P. R. Stauffer, M. W. McDermott, C. J. Diederich, K. R. Lamborn, M. D. Prados, S. Chang, K. A. Weaver, L. Spry, M. K. Malec, S. A. Lamb, B. Voss, R. L. Davis, W. M. Wara, D. A. Larson, T. L. Phillips, and P. H. Gutin, “Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost += hyperthermia for glioblastoma multiforme,” Int. J. Radiat. Oncol. Biol. Phys., vol. 40, pp. 287–295, 1998. [27] B. Stea, K. Rossman, J. Kittelson, A. Shetter, A. Hamilton, and J. R. Cassady, “Interstitial irradiation versus interstitial thermoradiotherapy for malignant gliomas. A comparative survival analysis,” Int. J. Radiat. Oncol. Biol. Phys., vol. 30, pp. 591–600, Oct. 1994. [28] P. K. Sneed and P. H. Gutin, “Interstitial radiation and hyperthermia,” in The Gliomas, M. S. Berger and C. B. Wilson, Eds. Philadelphia, PA: Saunders, 1999, pp. 499–510. [29] K. S. Nikita and N. K. Uzunoglu, “Analysis of the power coupling from a waveguide hyperthermia applicator into a three-layered tissue model,” IEEE Trans. Microw. Theory Tech., vol. 37, no. 11, pp. 1794–1801, Nov. 1989. [30] K. S. Nikita, N. Maratos, and N. K. Uzunoglu, “Optimum excitation of phases and amplitudes in a phased array hyperthermia system,” Int. J. Hypertherm., vol. 8, no. 4, pp. 515–528, Jul.–Aug. 1992. [31] K. S. Nikita and N. K. Uzunoglu, “Coupling phenomena in concentric multi-applicator phased array hyperthermia systems,” IEEE Trans. Microw. Theory Tech., vol. 44, no. 1, pp. 65–74, Jan. 1996. [32] V. E. Kouloulias, J. R. Kouvaris, K. S. Nikita, B. C. Golematis, N. K. Uzunoglu, K. Mystakidou, C. Papavasiliou, and L. Vlahos, “Intraoperative hyperthermia in conjunction with multi-schedule chemotherapy (pre-, intra- and post-operative), by-pass surgery, and post-operative radiotherapy for the management of unresectable pancreatic adenocarcinoma,” Int. J. Hypertherm., vol. 18, no. 3, pp. 233–252, May 2002. [33] I. S. Karanasiou, N. K. Uzunoglu, and A. Garetsos, “Electromagnetic analysis of a non-invasive 3D passive microwave imaging system,” Progr. Electromagn. Res., vol. PIER 44, pp. 287–308, 2004. [34] I. S. Karanasiou, N. K. Uzunoglu, and C. Papageorgiou, “Towards functional non-invasive imaging of excitable tissues inside the human body using focused microwave radiometry,” IEEE Trans. Microw. Theory Tech., vol. 52, no. 8, pp. 1898–1908, Aug. 2004. [35] I. S. Karanasiou, N. K. Uzunoglu, S. Stergiopoulos, and W. Wong, “A passive 3D imaging thermograph using microwave radiometry,” Innov. Tech. Biol. Med., vol. 25, no. 4, pp. 227–239, 2004. [36] I. S. Karanasiou, C. Papageorgiou, and N. K. Uzunoglu, “Is it possible to measure non-invasively brain conductivity fluctuations during reactions to external stimuli with the use of microwaves?,” Int. J. Bioelectromagn., vol. 7, no. 1, pp. 356–359, 2005. [37] I. S. Karanasiou, G. Stratakos, and N. K. Uzunoglu, “Passive multiband microwave tomography for intracranial applications,” Int. J. Microw. Opt. Technol., vol. 1, no. 2, pp. 477–482, Aug. 2006. [38] I. S. Karanasiou and N. K. Uzunoglu, “Single-frequency and multiband microwave radiometry for feasible brain conductivity variation imaging during reactions to external stimuli,” Nucl. Instrum. Methods Phys. Res. A, Accel. Spectrom Detect. Assoc. Equip., vol. 569, pp. 581–586, 2006. [39] I. S. Karanasiou and N. K. Uzunoglu, “Experimental study of 3D Contactless conductivity detection using microwave radiometry: A possible method for investigation of brain conductivity fluctuations,” in Proc. 26th IEEE EMBS, San Francisco, CA, Sep. 1–5, 2004, pp. 2303–2306. [40] I. S. Karanasiou and N. K. Uzunoglu, “The inverse problem of a passive multiband microwave intracranial imaging method,” in Proc. 27th IEEE EMBS, Shanghai, China, Sep. 1–4, 2005, pp. 1642–1645. [41] I. S. Karanasiou and N. K. Uzunoglu, “Study of a brain hyperthermia system providing also passive brain temperature monitoring,” in Proc. 28th IEEE EMBS, New York, NY, Aug. 29–Sep. 3 2006, pp. 5017–5020.
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[42] J. C. Lin, S. Hirai, C. L. Chiang, W. L. Hsu, J. L. Su, and Y. J. Wang, “Computer simulation and experimental studies of SAR distributions of interstitial arrays of sleeved-slot microwave antennas for hyperthermia treatment of brain tumors,” IEEE Trans. Microw. Theory Tech., vol. 48, no. 11, pp. 2191–2198, Nov. 2000. [43] M. E. Kowalski and J. M. Jin, “Model-based optimization of phased arrays for electromagnetic hyperthermia,” IEEE Trans. Microw. Theory Tech., vol. 52, no. 8, pp. 1964–1977, Aug. 2004. [44] D. Dunn, C. M. Rappaport, and A. J. Terzuoli, Jr., “FDTD verification of deep-set brain tumor hyperthermia using a spherical microwave source distribution,” IEEE Trans. Microw. Theory Tech., vol. 44, no. 10, pp. 1769–1777, Oct. 1996. [45] G. C. Trichopoulos, I. S. Karanasiou, and N. K. Uzunoglu, “Enhancing the focusing properties of an ellipsoidal beamformer based imaging system: A simulation study,” in Proc. 28th IEEE EMBS, New York, NY, Aug. 29–Sep. 3 2006, pp. 5097–5100. [46] S. Gabriel, R. W. Lau, and C. Gabriel, “The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz,” Phys. Med. Biol., vol. 41, pp. 2251–2269, Nov. 1996. [47] D. K. Kelleher and P. Vaupel, “Vascular effects of localized hyperthermia hyperthermia,” in Cancer Treatment: A Primer, G. F. Baronzio and E. D. Hager, Eds. Berlin, Germany: Springer-Verlag, 2006, ch. 7.
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Konstantinos T. Karathanasis was born in Athens, Greece, in 1982. He received the Diploma degree in electrical and computer engineering, M.Sc. degree in biomedical engineering from the University of Patras, Patras, Greece, in 2005 and 2007, respectively, and is currently working toward the Ph.D. degree in biomedical engineering at the National Technical University of Athens (NTUA), Athens, Greece. Mr. Karathanasis has been a member of the Technical Chamber of Greece since 2005.
Anastasios Garetsos was born in Athens, Greece, in 1972. He received the Diploma degree in electrical and computer engineering from the National Technical University of Athens (NTUA), Athens, Greece, in 1997. He possesses very good experience in RF design, microcontrollers, field-programmable gate arrays (FPGAs), and servo-controllers. His research interests involve RF designing, antennas theory and techniques, biomedicine, and telemedicine. Mr. Garetsos is a member of the Technical Chamber of Greece.
Irene S. Karanasiou (M’05) was born in Athens, Greece. She received the Diploma and Ph.D. degrees in electrical and computer engineering from the National Technical University of Athens (NTUA), Athens, Greece, in 1999 and 2003, respectively. Since 1999, she has been a Researcher with the Microwave and Fiber Optics Laboratory (MFOL), NTUA. She has authored over 40 papers in refereed international journals and conference proceedings. Her research interests involve biomedical imaging techniques, bioelectromagnetism, and applications of microwaves in therapy and diagnosis. Dr. Karanasiou is a member of the IEEE Engineering in Medicine and Biology Society (EMBS) and the Technical Chamber of Greece. She was the recipient of the Thomaidio Foundation Award for her doctoral dissertation and three academic journal publications.
Nikolaos K. Uzunoglu (M’82–SM’97–F’06) was born in Constantinople, Turkey, in 1951. He received the B.Sc. degree in electronics from the Technical University of Istanbul, Istanbul, Turkey, in 1973, and the Ph.D. degree from the University of Essex, Essex, U.K., in 1976. Since 1987, he has been a Professor with the School of Electrical and Computer Engineering, National Technical University of Athens, Athens, Greece. He has authored or coauthored over 300 papers in refereed international journals and three books. His research interests include electromagnetic scattering, propagation of electromagnetic waves, fiber-optics telecommunications, and biomedical engineering. Prof. Uzunoglu was the recipient of many honorary awards including the 1981 International G. Marconi Award in telecommunications.
