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The aim of the article is to provide a summary of the work carried out in the framework of a research project funded by the Italian Ministry of Research. The main goal of the activity was to introduce multiple tools for reliable, affordable, and high-performance microwave hyperthermia for cancer therapy. The proposed methodologies and approaches target microwave diagnostics, accurate in vivo electromagnetic parameters estimation, and improvement in treatment planning using a single device. This article provides an overview of the proposed and tested techniques and shows their complementarity and interconnection. To highlight the approach, we also present a novel combination of specific absorption rate optimization via convex programming with a temperature-based refinement method implemented to mitigate the effect of thermal boundary conditions on the final temperature map. To this purpose, numerical tests were carried out for both simple and anatomically detailed 3D scenarios for the head and neck region. These preliminary results show the potential of the combined technique and improvements in the temperature coverage of the tumor target with respect to the case wherein no refinement is adopted.

Clinical effectiveness of hyperthermia treatments, in which tumor tissue is artificially heated to 40-44 °C for 60-90 min, can be hampered by a lack of accurate temperature monitoring. The need for noninvasive temperature monitoring in the head and neck region (H&N) and the potential of MR thermometry prompt us to design an MR compatible hyperthermia applicator: the MRcollar. In this work, we validate the design, numerical model, and MR performance of the MRcollar. The MRcollar antennas have low reflection coefficients (<-15 dB) and the intended low interaction between the individual antenna modules (<-32 dB). A 10 °C increase in 3 min was reached in a muscle-equivalent phantom, such that the specifications from the European Society for Hyperthermic Oncology were easily reached. The MRcollar had a minimal effect on MR image quality and a five-fold improvement in SNR was achieved using the integrated coils of the MRcollar, compared to the body coil. The feasibility of using the MRcollar in an MR environment was shown by a synchronous heating experiment. The match between the predicted SAR and measured SAR using MR thermometry satisfied the gamma criteria [distance-to-agreement = 5 mm, dose-difference = 7%]. All experiments combined show that the MRcollar delivers on the needs for MR-hyperthermia in the H&N and is ready for in vivo investigation.

Temperature monitoring plays a central role in improving clinical effectiveness of adjuvant hyperthermia. The potential of magnetic resonance thermometry for treatment monitoring purposes led to several MR-guided hyperthermia approaches. However, the proposed solutions were sub-optimal due to technological and intrinsic limitations. These hamper achieving target conformal heating possibilities (applicator limitations) and accurate thermometry (inadequate signal-to-noise-ratio (SNR)). In this work, we studied proof of principle of a dual-function hyperthermia approach based on a coil array (64 MHz, 1.5 T) that is integrated in-between a phased array for heating (434 MHz) for maximum signal receive in order to improve thermometry accuracy. Hereto, we designed and fabricated a superficial hyperthermia mimicking planar array setup to study the most challenging interactions of generic phased-array setups in order to validate the integrated approach. Experiments demonstrated that the setup complies with the superficial hyperthermia guidelines for heating and is able to improve SNR at 2-4 cm depth by 17%, as compared to imaging using the body coil. Hence, the results showed the feasibility of our dual-function MR-guided hyperthermia approach as basis for the development of application specific setups.

Background: The success of cancer hyperthermia (HT) treatments is strongly dependent on the temperatures achieved in the tumor and healthy tissues as it correlates with treatment efficacy and safety, respectively. Hyperthermia treatment planning (HTP) simulations have become pivotal for treatment optimization due to the possibility for pretreatment planning, optimization and decision making, as well as real-time treatment guidance., Materials and Methods: The same computational methods deployed in HTP are also used for in silico studies. These are of great relevance for the development of new HT devices and treatment approaches. To aid this work, 3 D patient models have been recently developed and made available for the HT community. Unfortunately, there is no consensus regarding tissue properties, simulation settings, and benchmark applicators, which significantly influence the clinical relevance of computational outcomes., Results and Discussion: Herein, we propose a comprehensive set of applicator benchmarks, efficacy and safety optimization algorithms, simulation settings and clinical parameters, to establish benchmarks for method comparison and code verification, to provide guidance, and in view of the 2021 ESHO Grand Challenge (Details on the ESHO grand challenge on HTP will be provided at https://www.esho.info/)., Conclusion: We aim to establish guidelines to promote standardization within the hyperthermia community such that novel approaches can quickly prove their benefit as quickly as possible in clinically relevant simulation scenarios. This paper is primarily focused on radiofrequency and microwave hyperthermia but, since 3 D simulation studies on heating with ultrasound are now a reality, guidance as well as a benchmark for ultrasound-based hyperthermia are also included.

Purpose: To develop a head and neck hyperthermia phased array system compatible with a 1.5 T magnetic resonance (MR) scanner for noninvasive thermometry., Methods: We designed a dielectric-parabolic-reflector antenna (DiPRA) based on a printed reflector backed dipole antenna and studied its predicted and measured performance in a flat configuration (30 mm thick water bolus and muscle equivalent layer). Thereafter, we designed a phased array applicator model ('MRcollar') consisting of 12 DiPRA modules placed on a radius of 180 mm. Theoretical heating performance of the MRcollar model was benchmarked against the current clinical applicator (HYPERcollar3D) using specific (3D) head and neck models of 28 treated patients. Lastly, we assessed the influence of the DiPRA modules on MR scanning quality., Results: The predicted and measured reflection coefficients (S 11 ) of the DiPRA module are below -20 dB. The maximum specific absorption rate (SAR) in the area under the antenna was 47% higher than for the antenna without encasing. Compared to the HYPERcollar3D, the MRcollar design incorporates 31% less demineralized water (-2.5 L), improves the predicted TC25 (target volume enclosed by 25% iso-SAR contour) by 4.1% and TC50 by 8.5%, while the target-to-hotspot quotient (THQ) is minimally affected (-1.6%). MR experiments showed that the DiPRA modules do not affect MR transmit/receive performance., Conclusion: Our results suggest that head and neck hyperthermia delivery quality with the MRcollar can be maintained, while facilitating simultaneous noninvasive MR thermometry for treatment monitoring and control.

The potential of MR thermometry (MRT) fostered the development of MRI compatible radiofrequency (RF) hyperthermia devices. Such device integration creates major technological challenges and a crucial point for image quality is the water bolus (WB). The WB is located between the patient body and external sources to both couple electromagnetic energy and to cool the patient skin. However, the WB causes MRT errors and unnecessarily large field of view. In this work, we studied making the WB MRI transparent by an optimal concentration of compounds capable of modifying T 2 * relaxation without an impact on the efficiency of RF heating. Three different T 2 * reducing compounds were investigated, namely CuSO 4 , MnCl 2 , and Fe 3 O 4 . First, electromagnetic properties and T 2 * relaxation rates at 1.5 T were measured. Next, through multi-physics simulations, the predicted effect on the RF-power deposition pattern was evaluated and MRT precision was experimentally assessed. Our results identified 5 mM Fe 3 O 4 solution as optimal since it does not alter the RF-power level needed and improved MRT precision from 0.39 ∘ C to 0.09 ∘ C. MnCl 2 showed a similar MRT improvement, but caused unacceptable RF-power losses. We conclude that adding Fe 3 O 4 has significant potential to improve RF hyperthermia treatment monitoring under MR guidance.

Purpose: Thermal dose-effect relations have demonstrated that clinical effectiveness of hyperthermia would benefit from more controlled heating of the tumor. Hyperthermia treatment planning (HTP) is a potent tool to study strategies enabling target conformal heating, but its accuracy is affected by patient modeling approximations. Homogeneous phantoms models are being used that do not match the body shape of patients in treatment position and often have unrealistic target volumes. As a consequence, simulation accuracy is affected, and performance comparisons are difficult. The aim of this study is to provide the first step toward standardization of HTP simulation studies in terms of patient modeling by introducing the Erasmus Virtual Patient Repository (EVPR): a virtual patient model database. Methods: Four patients with a tumor in the head and neck or the pelvis region were selected, and corresponding models were created using a clinical segmentation procedure. Using the Erasmus University Medical Center standard procedure, HTP was applied to these models and compared to HTP for commonly used surrogate models. Results: Although this study was aimed at presenting the EVPR database, our study illustrates that there is a non-negligible difference in the predicted SAR patterns between patient models and homogeneous phantom-based surrogate models. We further demonstrate the difference between actual and simplified target volumes being used today. Conclusion: Our study describes the EVPR for the research community as a first step toward standardization of hyperthermia simulation studies.

Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique capabilities to non-invasively measure the 3D-temperature. This study investigates MRT accuracy for MR-hyperthermia hybrid systems located at five European institutions while heating a centric or eccentric target in anthropomorphic phantoms with pelvic and spine structures. Scatter plots, root mean square error (RMSE) and Bland-Altman analysis were used to quantify accuracy of MRT compared to high resistance thermistor probe measurements. For all institutions, a linear relation between MRT and thermistor probes measurements was found with R 2 (mean ± standard deviation) of 0.97 ± 0.03 and 0.97 ± 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 ± 0.31 °C and 0.30 ± 0.20 °C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 ± 0.20 °C and 0.13 ± 0.08 °C, respectively. This first multi-institutional evaluation of MR-hyperthermia hybrid systems indicates comparable device performance and good agreement between MRT and thermistor probes measurements. This forms the basis to standardize treatments in multi-institution studies of MR-guided hyperthermia and to elucidate thermal dose-effect relations., Competing Interests: Dr. Curto reports grants from Pyrexar Medical Corp., grants from COST, during the conduct of the study; Mr. Mulder reports grants from Dutch Cancer Society, during the conduct of the study; Mr. Lamprecht reports grants from Sennewald, during the conduct of the study; grants from Elekta, grants from Siemens, outside the submitted work; Dr. Peller reports grants from Dr. Sennewald Medizintechnik GmbH, outside the submitted work; Dr. Lindner reports grants from Sennewald Medizintechnik GmbH, during the conduct of the study; Dr. Fietkau reports personal fees from Sennewald GmbH, during the conduct of the study; grants and personal fees from Merck Serono, grants and personal fees from Astra Zenica, grants and personal fees from MSD, personal fees from Novocure, personal fees from Brainlab, personal fees from Fresenius Kabi, personal fees from Bristol Byers Squibb, outside the submitted work; Dr. Zips reports financial support from Dr. Sennewald for educational events, during the conduct of the study; grants from Elekta, grants from Siemens, outside the submitted work; Dr. Paulides reports grants from Dutch Cancer Society, during the conduct of the study; Dr. van Rhoon reports grants from Dutch Cancer Society grant KWF-DDHK 2013-6072, grants from Pyrexar Medical Corp., during the conduct of the study; grants from Sensius BV, outside the submitted work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Purpose: Hyperthermia treatment quality determines treatment effectiveness as shown by the clinically derived thermal-dose effect relations. SAR based optimization factors are used as possible surrogate for temperature, since they are not affected by thermal tissue properties uncertainty and variations. Previously, target coverage (TC) at the 25% and 50% iso-SAR level was shown predictive for treatment outcome in superficial hyperthermia and the target-to-hot-spot-quotient (THQ) was shown to highly correlate with predictive temperature in deep pelvic hyperthermia. Here, we investigate the correlation with temperature for THQ and TC using an 'intermediate' scenario: semi-deep hyperthermia in the head & neck region using the HYPERcollar3D., Methods: Fifteen patient-specific models and two different planning approaches were used, including random perturbations to circumvent optimization bias. The predicted SAR indicators were compared to predicted target temperature distribution indicators T50 and T90, i.e., the median and 90th percentile temperature respectively., Results: The intra-patient analysis identified THQ, TC25 and TC50 as good temperature surrogates: with a mean correlation coefficient R 2 T50  = 0.72 and R 2 T90 =0.66. The inter-patient analysis identified the highest correlation with TC25 (R 2 T50  = 0.76, R 2 T90 =0.54) and TC50 (R 2 T50  = 0.74, R 2 T 90  = 0.56)., Conclusion: Our investigation confirmed the validity of our current strategy for deep hyperthermia in the head & neck based on a combination of THQ and TC25. TC50 was identified as the best surrogate since it enables optimization and patient inclusion decision making using one single parameter.

Clinical trials have shown that hyperthermia is a potent adjuvant to conventional cancer treatments, but the temperatures currently achieved in the clinic are still suboptimal. Hyperthermia treatment planning simulations have potential to improve the heating profile of phased-array applicators. An important open challenge is the development of an effective optimization procedure that enables uniform heating of the target region while keeping temperature below a threshold in healthy tissues. In this work, we analyzed the effectiveness and efficiency of a recently proposed optimization approach, i.e. focusing via constrained power optimization (FOCO), using 3D simulations of twelve clinical patient specific models. FOCO performance was compared against a clinically used particle swarm based optimization approach. Evaluation metrics were target coverage at the 25% iso-SAR level, target hotspot quotient, median target temperature (T50) and computational requirements. Our results show that, on average, constrained power focusing performs slightly better than the clinical benchmark ([Formula: see text]T50 [Formula: see text] °C), but outperforms this clinical benchmark for large target volumes ([Formula: see text]40 cm[Formula: see text], [Formula: see text]T50 [Formula: see text] °C). In addition, the results are achieved in a shorter time ([Formula: see text]%) and are repeatable because the approach is formulated as a convex optimization problem.

Magnetic nanoparticle-aided microwave imaging is recently gaining an increasing interest as a potential tool for breast cancer diagnostics. This is due to the peculiar features of magnetic nanoparticles, which are biocompatible, can be selectively targeted to the tumor, and may change their microwave magnetic response when modulated by a polarizing magnetic field. This latter aspect is particularly appealing, as it enables the physical separation of the microwave signal due the malignancy, targeted by the nanoparticles, from that due to healthy tissue. This increases the specificity of the diagnostic tool, in principle allowing a diagnosis based solely on the detection of the signal due to the nanoparticles response. In this respect, a proper choice of the polarizing field modulation can remarkably increase the detection performances. This paper deals with this issue, by providing the mathematical framework for such an optimization and a procedure for estimating the required quantities from a set of proper measurements. The procedure is then experimentally demonstrated by applying it to a recently developed ultrawideband radar system for the magnetic nanoparticle-aided detection of breast cancer. For such a system, the optimal magnetic field modulation is determined.