Ethylcellulose-stabilized fat-tissue phantom for quality assurance in clinical hyperthermia.

BACKGROUND: Phantoms accurately mimicking the electromagnetic and thermal properties of human tissues are essential for the development, characterization, and quality assurance (QA) of clinically used equipment for Hyperthermia Treatment (HT). Currently, a viable recipe for a fat equivalent phantom is not available, mainly due to challenges in the fabrication process and fast deterioration. MATERIALS AND METHODS: We propose to employ a glycerol-in-oil emulsion stabilized with ethylcellulose to develop a fat-mimicking material. The dielectric, rheological, and thermal properties of the phantom have been assessed by state-of-the-art measurement techniques. The full-size phantom was then verified in compliance with QA guidelines for superficial HT, both numerically and experimentally, considering the properties variability. RESULTS: Dielectric and thermal properties were proven equivalent to fat tissue, with an acceptable variability, in the 8 MHz to 1 GHz range. The rheology measurements highlighted enhanced mechanical stability over a large temperature range. Both numerical and experimental evaluations proved the suitability of the phantom for QA procedures. The impact of the dielectric property variations on the temperature distribution has been numerically proven to be limited (around 5%), even if higher for capacitive devices (up to 20%). CONCLUSIONS: The proposed fat-mimicking phantom is a good candidate for hyperthermia technology assessment processes, adequately representing both dielectric and thermal properties of the human fat tissue while maintaining structural stability even at elevated temperatures. However, further experimental investigations on capacitive heating devices are necessary to better assess the impact of the low electrical conductivity values on the thermal distribution.

Suitability of eigenvalue beam-forming for discrete multi-frequency hyperthermia treatment planning.

PURPOSE: Thermal dose delivery in microwave hyperthermia for cancer treatment is expected to benefit from the introduction of ultra-wideband (UWB)-phased array applicators. A full exploitation of the combination of different frequencies to improve the deposition pattern is, however, a nontrivial problem. It is unclear whether the cost functions used for hyperthermia treatment planning (HTP) optimization in the single-frequency setting can be meaningfully extended to the UWB case. METHOD: We discuss the ability of the eigenvalue (EV) and a novel implementation of iterative-EV (i-EV) beam-forming methods to fully exploit the available frequency spectrum when a discrete set of simultaneous operating frequencies is available for treatment. We show that the quadratic power deposition ratio solved by the methods can be maximized by only one frequency in the set, therefore rendering EV inadequate for UWB treatment planning. We further investigate whether this represents a limitation in two realistic test cases, comparing the thermal distributions resulting from EV and i-EV to those obtained by optimizing for other nonlinear cost functions that allow for multi-frequency. RESULTS: The classical EV-based single-frequency HTP yields systematically lower target SAR deposition and temperature values than nonlinear HTP. In a larynx target, the proposed single-frequency i-EV scheme is able to compensate for this and reach temperatures comparable to those given by global nonlinear optimization. In a meninges target, the multi-frequency setting outperforms the single-frequency one, achieving better target coverage and 0 . 5 ∘ C higher T 90 in the tumor than single-frequency-based HTP. CONCLUSIONS: Classical EV performs poorly in terms of resulting target temperatures. The proposed single-frequency i-EV scheme can be a viable option depending on the patient and tumor to be treated, as long as the proper operating frequency can be selected across a UWB range. Multi-frequency HTP can bring a considerable benefit in regions typically difficult to treat such as the brain.

Radiobiological Evaluation of Combined Gamma Knife Radiosurgery and Hyperthermia for Pediatric Neuro-Oncology.

Combining radiotherapy (RT) with hyperthermia (HT) has been proven effective in the treatment of a wide range of tumours, but the combination of externally delivered, focused heat and stereotactic radiosurgery has never been investigated. We explore the potential of such treatment enhancement via radiobiological modelling, specifically via the linear-quadratic (LQ) model adapted to thermoradiotherapy through modulating the radiosensitivity of temperature-dependent parameters. We extend this well-established model by incorporating oxygenation effects. To illustrate the methodology, we present a clinically relevant application in pediatric oncology, which is novel in two ways. First, it deals with medulloblastoma, the most common malignant brain tumour in children, a type of brain tumour not previously reported in the literature of thermoradiotherapy studies. Second, it makes use of the Gamma Knife for the radiotherapy part, thereby being the first of its kind in this context. Quantitative metrics like the biologically effective dose (BED) and the tumour control probability (TCP) are used to assess the efficacy of the combined plan.

Maximizing the oil content in polysaccharide-based emulsion gels for the development of tissue mimicking phantoms.

Formulations based on agar and κ-carrageenan were investigated for the production of emulsion gels applicable as tissue mimicking phantoms. The effects of the polysaccharide matrix, the oil content and the presence of surfactants on the micro-/nanostructure, rheology, and mechanical and dielectric properties were investigated. Results showed a high capacity of the agar to stabilize oil droplets, producing gels with smaller (10-21 µm) and more uniform oil droplets. The addition of surfactants allowed increasing the oil content and reduced the gel strength and stiffness down to 57 % and 34 %, respectively. The permittivity and conductivity of the gels were reduced by increasing the oil content, especially in the agar gels (18.8 and 0.05 S/m, respectively), producing materials with dielectric properties similar to those of low-water content tissues. These results evidence the suitability of these polysaccharides to design a variety of tissue mimicking phantoms with a broad range of mechanical and dielectric properties.

Iterative time-reversal for multi-frequency hyperthermia.

Time-reversal (TR) is a known wideband array beam-forming technique that has been suggested as a treatment planning alternative in deep microwave hyperthermia for cancer treatment. While the aim in classic TR is to focus the energy at a specific point within the target, no assumptions are made on secondary lobes that might arise in the healthy tissues. These secondary lobes, together with tissue heterogeneity, may result in hot-spots (HSs), which are known to limit the efficiency of the thermal dose delivery to the tumor. This paper proposes a novel wideband TR focusing method that iteratively shifts the focus away from HSs and towards cold-spots from an initial TR solution, a procedure that improves tumor coverage and reduces HSs. We verify this method on two different applicator topologies and several target volume configurations. The algorithm is deterministic and runs within seconds, enabling its use for real-time applications. At the same time, it yields results comparable to those obtained with global stochastic optimizers such as Particle Swarm.

Wideband Self-Grounded Bow-Tie Antenna for Thermal MR.

The objective of this study was the design, implementation, evaluation and application of a compact wideband self-grounded bow-tie (SGBT) radiofrequency (RF) antenna building block that supports anatomical proton (1 H) MRI, fluorine (19 F) MRI, MR thermometry and broadband thermal intervention integrated in a whole-body 7.0 T system. Design considerations and optimizations were conducted with numerical electromagnetic field (EMF) simulations to facilitate a broadband thermal intervention frequency of the RF antenna building block. RF transmission (B1+ ) field efficiency and specific absorption rate (SAR) were obtained in a phantom, and the thigh of human voxel models (Ella, Duke) for 1 H and 19 F MRI at 7.0 T. B1+ efficiency simulations were validated with actual flip-angle imaging measurements. The feasibility of thermal intervention was examined by temperature simulations (f = 300, 400 and 500 MHz) in a phantom. The RF heating intervention (Pin = 100 W, t = 120 seconds) was validated experimentally using the proton resonance shift method and fiberoptic probes for temperature monitoring. The applicability of the SGBT RF antenna building block for in vivo 1 H and 19 F MRI was demonstrated for the thigh and forearm of a healthy volunteer. The SGBT RF antenna building block facilitated 19 F and 1 H MRI at 7.0 T as well as broadband thermal intervention (234-561 MHz). For the thigh of the human voxel models, a B1+ efficiency ≥11.8 µT/√kW was achieved at a depth of 50 mm. Temperature simulations and heating experiments in a phantom demonstrated a temperature increase ΔT >7 K at a depth of 10 mm. The compact SGBT antenna building block provides technology for the design of integrated high-density RF applicators and for the study of the role of temperature in (patho-) physiological processes by adding a thermal intervention dimension to an MRI device (Thermal MR).

Hydrogels as a water bolus during hyperthermia treatment.

The feasibility of using hydrogels as a water bolus during hyperthermia treatment was assessed. Three types of gels, high methoxyl (HM) pectin/alginate, xanthan/locust bean gum (LBG) and xanthan/LBG/agarose were evaluated based on their dielectric, rheological and mechanical properties. The most suitable, xanthan/LBG/agarose gel was further used as a water bolus in a hyperthermia array applicator. The gels composed of polysaccharides carrying low charge displayed dielectric properties close to those of water, while the dielectric properties of HM pectin/alginate gel was deemed unsuitable for the current application. The mechanical examination shows that the xanthan/LBG gel has a non-brittle behaviour at room temperature, in contrast to the agarose gel. The moduli of the xanthan/LBG gel weaken however considerably between the temperature range of 40 °C and 50 °C, reducing its potential to be used as water bolus. The ternary system of xanthan/LBG/agarose had advantageous behaviour as it was dominated by the thermal hysteresis typical of agarose upon temperature increase, but governed by the typical non-brittle behaviour of the xanthan/LBG at low temperatures. The final evaluation within the hyperthermia applicator showed excellent signal transmission from the antennas. The agarose/xanthan/LBG gel reduced the scattering of electromagnetic waves, enabled a tight closure between the body and the antennas, and offered a less bulky solution than the currently used water-filled plastic bags. The results presented here open up a new application area for hydrogels in improving heat delivery during hyperthermia treatment and other near-field microwave applications.

Compact self-grounded Bow-Tie antenna design for an UWB phased-array hyperthermia applicator.

Using UWB hyperthermia systems has the potential to improve the heat delivery to deep seated tumours. In this paper, we present a novel self-grounded Bow-Tie antenna design which is to serve as the basis element in a phased-array applicator. The UWB operation in the frequency range of 0.43-1 GHz is achieved by immersing the antenna in a water bolus. The radiation characteristics are improved by appropriate shaping the water bolus and by inclusion of dielectric layers on the top of the radiating arms of the antenna. In order to find the most appropriate design, we use a combination of performance indicators representing the most important attributes of the antenna. These are the UWB impedance matching, the transmission capability and the effective field size. The antenna was constructed and experimentally validated on muscle-like phantom. The measured reflection and transmission coefficients as well as radiation characteristics are in excellent agreement with the simulated results. MR image acquisitions with antenna located inside MR bore indicate a negligible distortion of the images by the antenna itself, which indicates MR compatibility.

Quality assurance guidelines for superficial hyperthermia clinical trials: I. Clinical requirements.

Quality assurance guidelines are essential to provide uniform execution of clinical trials and treatment in the application of hyperthermia. This document provides definitions for a good hyperthermia treatment and identifies the clinical conditions where a certain hyperthermia system can or cannot adequately heat the tumour volume. It also provides brief description of the characteristics and performance of the current electromagnetic (radiative and capacitive), ultrasound and infra-red heating techniques. This information helps to select the appropriate heating technique for the specific tumour location and size, and appropriate settings of the water bolus and thermometry. Finally, requirements of staff training and documentation are provided. The guidelines in this document focus on the clinical application and are complemented with a second, more technical quality assurance document providing instructions and procedure to determine essential parameters that describe heating properties of the applicator for superficial hyperthermia. Both sets of guidelines were developed by the ESHO Technical Committee with participation of senior STM members and members of the Atzelsberg Circle.

Asymmetric cationic liposomes designed for heat-activated association with cells.

Improved anticancer drugs and drug carriers are needed in combination therapies, such as hyperthermia-assisted chemotherapy. Liposomal drug carriers with advanced functions are attractive candidates for targeted accumulation and drug release in response to heat stimulus. We report on the design of liposomes with a heat-activated surface function. Our design is based on asymmetric lipid membranes with a defined gel to liquid-crystalline phase-transition temperature around 41°C. Asymmetry between the inner and the outer membrane leaflets was generated through selective PEGylation of cationic lipids in the outer membrane leaflet. In a physiological buffer, the PEGylated asymmetric liposomes had a neutral zeta potential and did not bind to planar anionic model membranes. In contrast, following upon heat-activation, binding of liposomes to the model membranes occurred. Release of a hydrophilic dye encapsulated in the asymmetric liposomes occurred at 40°C. Enhanced uptake of the asymmetric liposomes by hypopharyngeal carcinoma cells (FaDu cells) was observed when hyperthermia was applied compared to experiments performed at 37°C. These results show the potential of asymmetric liposomes for localized delivery of drugs into cells in response to (external) temperature stimulus.

Heat-activated liposome targeting to streptavidin-coated surfaces.

There is a great need of improved anticancer drugs and corresponding drug carriers. In particular, liposomal drug carriers with heat-activated release and targeting functions are being developed for combined hyperthermia and chemotherapy treatments of tumors. The aim of this study is to demonstrate the heat-activation of liposome targeting to biotinylated surfaces, in model experiments where streptavidin is used as a pretargeting protein. The design of the heat-activated liposomes is based on liposomes assembled in an asymmetric structure and with a defined phase transition temperature. Asymmetry between the inside and the outside of the liposome membrane was generated through the enzymatic action of phospholipase D, where lipid head groups in the outer membrane leaflet, i.e. exposed to the enzyme, were hydrolyzed. The enzymatically treated and purified liposomes did not bind to streptavidin-modified surfaces. When activation heat was applied, starting from 22°C, binding of the liposomes occurred once the temperature approached 33±0.5°C. Moreover, it was observed that the asymmetric structure remained stable for at least 2 weeks. These results show the potential of asymmetric liposomes for the targeted binding to cell membranes in response to (external) temperature stimulus. By using pretargeting proteins, this approach can be further developed for personalized medicine, where tumor-specific antibodies can be selected for the conjugation of pretargeting agents.

Microwave-based stroke diagnosis making global prehospital thrombolytic treatment possible.

Here, we present two different brain diagnostic devices based on microwave technology and the associated two first proof-of-principle measurements that show that the systems can differentiate hemorrhagic from ischemic stroke in acute stroke patients, as well as differentiate hemorrhagic patients from healthy volunteers. The system was based on microwave scattering measurements with an antenna system worn on the head. Measurement data were analyzed with a machine-learning algorithm that is based on training using data from patients with a known condition. Computer tomography images were used as reference. The detection methodology was evaluated with the leave-one-out validation method combined with a Monte Carlo-based bootstrap step. The clinical motivation for this project is that ischemic stroke patients may receive acute thrombolytic treatment at hospitals, dramatically reducing or abolishing symptoms. A microwave system is suitable for prehospital use, and therefore has the potential to allow significantly earlier diagnosis and treatment than today.

Design of a wideband multi-channel system for time reversal hyperthermia.

PURPOSE: To design and test a wideband multi-channel amplifier system for time reversal (TR) microwave hyperthermia, operating in the frequency range 300 MHz-1 GHz, enabling operation in both pulsed and continuous wave regimes. This is to experimentally verify that adaptation of the heating pattern with respect to tumour size can be realised by varying the operating frequency of the antennas and potentially by using Ultra-wideband (UWB) pulse sequences instead of pure harmonic signals. MATERIALS AND METHODS: The proposed system consists of 12 identical channels driven by a common reference signal. The power and phase settings are applied with resolutions of 0.1 W and 0.1°, respectively. Using a calibration procedure, the measured output characteristics of each channel are interpolated using polynomial functions, which are then implemented into a system software algorithm driving the system feedback loop. RESULTS: The maximum output power capability of the system varies with frequency, between 90 and 135 W with a relative power error of ± 6%. A phase error in the order of ± 4° has been achieved within the entire frequency band. CONCLUSIONS: The developed amplifier system prototype is capable of accurate power and phase delivery, over the entire frequency band of the system. The output power of the present system allows for an experimental verification of a recently developed TR-method on phantoms or animals. The system is suitable for further development for head and neck tumours, breast or extremity applications.

Time-reversal focusing in microwave hyperthermia for deep-seated tumors.

A fast beam-forming method for hyperthermia treatment of deep-seated tumors is described and verified. The approach is based on the time-reversal characteristics of Maxwell equations. The basic principle of the method is coupling of the electromagnetic modeling of the system with the actual application. In this modeling the wavefront of the source is propagated through a patient-specific model from a virtual antenna placed in the tumor of the model. The simulated radiated field is then captured using a computer model of the surrounding antenna system. The acquired amplitudes and phases are then used in the real antenna system. The effectiveness of this procedure is demonstrated by calculating the power absorption distribution using FDTD electromagnetic simulations of a realistic 2D breast model as well as a 2D neck model. Several design parameters, i.e. number of antennas, operating frequency and dimensions, have been evaluated by performance indicators. The promising results suggest that the development of this technique is pursued further.