Entwicklung von RF-Technologie für die Ultrahochfeld-MRT: Optimierung und Anwendung einer Self-Grounded-Bow-Tie-Dipolantenne

Magnetic resonance imaging (MRI) is an important diagnostic imaging modality free of ionizing radiation. Sensitivity gain, signal-to-noise ratio (SNR) considerations, and changes in the tissue dependent MRI properties. Together with technical and scientific developments further research into increasing the magnetic field strength is justified, culminating in human applications at ultrahigh magnetic field (UHF, B0 ≥ 7.0 T) MRI. Elevating the field strength results in an increased radiofrequency (RF) for signal transmission and reception in MRI (= Larmor frequency, f ≈ 298 MHz at B0 = 7.0 T). The wavelength of this RF signal becomes sufficiently short when passing through tissue relative to the size of the target anatomy of the brain, upper torso, or abdomen. This phenomenon leads to constructive and deconstructive interference of the electromagnetic field (EMF) distribution, which results in a high susceptibility for non-uniformities in the magnetic RF transmission field (B1+). This detrimental excitation field distribution can cause shading, massive signal drop-off or even signal voids, and potentially offset the benefits of UHF-MRI due to compromised image quality. UHF cardiovascular MR (CMR) benefits from SNR gains and changes in the tissue dependent MRI properties, but the B1+ distribution – in addition to the wavelength dependent non-uniformities – is further compromised by a dielectrically heterogeneous tissue environment. Research on UHF-CMR focuses on the improvement of the cardiac chamber morphology quantification, myocardial T1- and T2*-mapping, fat-water imaging, and vascular imaging (4D-flow). These applications benefit from a homogenous B1+ within the heart and the vascular structure. Several published reports on the development of RF antenna array technology tailored for UHF-CMR address this challenge with ideas and achievements to enable broad clinical UHF-CMR applications in the future. The primary objective of advancing this RF technology is to achieve a uniform B1+ distribution in the heart and the vascular structure with optimizing the magnetic field pattern. The second objective is the improvement of the RF antenna’s efficiency with the reduction of the specific absorption rate (SAR), which is achieved by an optimization of the electric field pattern. The control of the electric field is furthermore conceptually appealing beyond conventional MR imaging modalities and useful for localized and targeted RF induced thermal intervention. Combining MRI with a thermal intervention modality in an integrated Thermal MR system permits direct supervision of the treatment via MR-thermometry, as well as adapting and improving the focal point quality of the RF power deposition. The Thermal MR system is a platform for comprehensive investigation of the effects of temperature on molecular, biochemical, and physiological processes, ultimately yielding insights into temperature utilization for diagnosis and therapy in vivo. EMF control of an RF antenna array depends on the radiation pattern of the antenna elements. Electrical dipoles are promising for UHF-MRI due to a linear polarized current pattern and an energy deposition perpendicular to the antenna. However, the channel count and therefore the degree of freedom for EMF shaping of previously reported antenna concepts is limited by the geometric extent and the coupling between the elements. The first section of this work addresses the design, implementation, and validation of a novel small-sized Self-Grounded Bow-Tie (SGBT) antenna, in combination with a dielectrically filled housing. The narrowband SGBT antenna variant is used in a 32-channel transmit/receive array configuration for UHF-CMR at 7.0 T. The second section focuses on the development of a modified broadband SGBT concept for the Thermal MR system. The broadband antenna increases the degree of freedom with an adaptation of the intervention frequency to improve the focal point quality (size, homogeneity, and specificity). The third section presents the implementation and validation of a signal generator in conjunction with the broadband SGBT variant introduced in section two. The device allows the generation of the intervention signal with a time dependent, channel-wise adaptation of amplitude, phase, and frequency. The work of this thesis offers a technical and conceptual framework for an increased degree of freedom for EMF shaping for a multitude of applications ranging from UHF-MRI to interventional MRI.Die Magnetresonanztomographie (MRI) ist ein wichtiges bildgebendes Diagnoseverfahren mit der Anwendung in vielen medizinischen Disziplinen. Die Forschung zu ultrahohen Magnetfeldern (UHF, B0 ≥ 7.0 T) im humanen Bereich wird durch technische und wissenschaftliche Errungenschaften getrieben und basiert auf einer höheren Sensitivität, einem verbesserten Signal-Rausch-Verhältnisses (SNR) sowie eine Veränderung der gewebsspezifischen MR Eigenschaften. Die höhere Feldstärke resultiert auch in einer erhöhten Radiofrequenz (RF) für die MRI Signalübertragung (= Larmorfrequenz, f ≈ 298 MHz bei B0 = 7.0 T). Die Wellenlänge des RF Signals im Gewebe ist dabei bezogen zur Zielanatomie (e.g. Schädel, Oberkörper und Abdomen) verkürzt was zu konstruktiven und destruktiven Interferenzen des elektromagnetischen Feldes (EMF) führt. Diese Interferenzen ergeben ein heterogenes RF Transmissionsfeld (B1+) mit Abschattungen, massiven Signalabfällen oder Signalausfällen welche die Vorteile der UHF-MRI durch eine beeinträchtigte Bildqualität schmälert. Die UHF Herz MR (CMR) profitiert von einem SNR-Gewinn sowie von veränderten gewebsspezifischen MR Eigenschaften bei höheren Feldstärken. Jedoch wird die B1+ Verteilung, neben der gegebenen RF wellenlängenabhängigen Heterogenität, durch dielektrische Gradienten im Bereich des Thorax zusätzlich beeinträchtigt. Die anwendungsbezogene Forschung und Entwicklung auf dem Gebiet der UHF-CMR konzentriert sich auf die Verbesserung der Quantifizierung der Herzkammermorphologie, des myokardialen T1- und T2*-Mappings, der Fett-Wasser-Bildgebung und der Gefäßbildgebung inklusive der Flussbildgebung (4D-Flow). Die Weiterentwicklung dieser Methoden streben eine breite klinische Anwendung an und profitieren von einer homogenen B1+ Verteilung im Herzen und in der Gefäßstruktur. Das primäre Ziel der der Forschung und Entwicklung von RF Antennenarraytechnologie ist eine Optimierung der B1+ Verteilung. Das sekundäre Ziel ist die Verbesserung der Effizienz durch die Verringerung der spezifischen Absorptionsrate (SAR) mittels einer elektrischen Feldoptimierung. Die Kontrolle des elektrischen Feldes kann aber auch über die konventionelle MR Bildgebung hinaus genutzt werden und ermöglicht konzeptionell eine lokalisierte und gezielte RF induzierte thermische Intervention. Die Kombination von MRI und thermischen Interventionen in einem integrierten Thermal MR System ermöglicht die Anpassung und Verbesserung der lokalen Intervention durch eine Supervision der Behandlung mittels MR-Thermometrie. Das Thermal MR System stellt damit eine technologische Plattform dar, welche eine umfassende Untersuchung der Auswirkungen der Temperatur auf molekulare, biochemische und physiologische Prozesse erlaubt. Letztlich kann die Plattform Erkenntnisse darüber liefern, wie die Temperatur für Diagnosen und Therapien in vivo genutzt werden kann. Die Kontrolle der EMF Verteilung durch ein RF Antennen Array ist abhängig von den Abstrahlungseigenschaften der einzelnen Antennenelemente. Elektrische Dipole stellen durch eine linear polarisierte Stromverteilung und eine Abstrahlungsrichtung orthogonal zur Antenne eine vielversprechende Option dar. Allerdings ist die Kanalzahl und damit der Freiheitsgrad für die EMF Optimierung bei bisher vorgestellten Antennenkonzepten durch die Größe und die Kopplung zwischen den Elementen begrenzt. Der erste Abschnitt dieser Arbeit befasst sich mit dem Entwurf, der Implementierung und der Validierung einer Self-Grounded Bow-Tie (SGBT) Antenne in Kombination mit einem dielektrisch gefüllten Gehäuse. Eine schmalbandige Antennenvariante wird in einer 32-Kanal Sende-/Empfangs-Array Konfiguration für UHF-CMR bei 7,0 T vorgestellt. Der zweite Abschnitt befasst sich mit der Entwicklung eines modifizierten breitbandigen SGBT-Konzepts für das Thermal MR System. Diese Antennenvariante erhöht die Freiheitsgrade für die Optimierung der elektrischen Feldverteilung um die Interventionsfrequenz und erlaubt eine Verbesserung der lokalen Erwärmung (Größe, Homogenität und Spezifität). Im dritten Abschnitt dieser Arbeit wird die Implementierung und Validierung eines Signalgenerators in Verbindung mit der im zweiten Abschnitt vorgestellten Breitbandantennenvariante vorgestellt. Der Signalgenerator erzeugt einen Interventionssignal mit der zeitabhängigen Anpassung von Amplitude, Phase und Frequenz für jeden Kanal. Die Entwicklungen und Erkenntnisse dieser Arbeit bieten einen konzeptionellen Rahmen für eine Vielzahl von realen Anwendungen, welche von der konventionellen MRI bis zu einem integrierten interventionellen Thermal MR System reichen.EC/H2020/743077/EU/Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy/ThermalM

32‐Channel self‐grounded bow‐tie transceiver array for cardiac MR at 7.0T

Purpose Design, implementation, evaluation, and application of a 32‐channel Self‐Grounded Bow‐Tie (SGBT) transceiver array for cardiac MR (CMR) at 7.0T. Methods The array consists of 32 compact SGBT building blocks. Transmission field (B1+) shimming and radiofrequency safety assessment were performed with numerical simulations and benchmarked against phantom experiments. In vivo B1+ efficiency mapping was conducted with actual flip angle imaging. The array’s applicability for accelerated high spatial resolution 2D FLASH CINE imaging of the heart was examined in a volunteer study (n = 7). Results B1+ shimming provided a uniform field distribution suitable for female and male subjects. Phantom studies demonstrated an excellent agreement between simulated and measured B1+ efficiency maps (7% mean difference). The SGBT array afforded a spatial resolution of (0.8 × 0.8 × 2.5) mm3 for 2D CINE FLASH which is by a factor of 12 superior to standardized cardiovascular MR (CMR) protocols. The density of the SGBT array supports 1D acceleration of up to R = 4 (mean signal‐to‐noise ratio (whole heart) ≥ 16.7, mean contrast‐to‐noise ratio ≥ 13.5) without impairing image quality significantly. Conclusion The compact SGBT building block facilitates a modular high‐density array that supports accelerated and high spatial resolution CMR at 7.0T. The array provides a technological basis for future clinical assessment of parallel transmission techniques.EC/H2020/743077/EU/Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy/ThermalMRBMBF, 01QE1815, Verbundprojekt: Seeing is Believing: Revolution der bildgebenden Diagnostik und Therapiekontrolle des Körperstammes durch superaufgelöste Hochfeld-Magnetresonanztomographie; Teilprojekt: Industrielle Forschung und Entwicklung lokaler Radiofrequenz-Antennen für hochauflösende Hochfeld-MRT des Körperstamme

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 (1H) MRI, fluorine (19F) 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 1H and 19F 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 1H and 19F MRI was demonstrated for the thigh and forearm of a healthy volunteer. The SGBT RF antenna building block facilitated 19F and 1H 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).BMBF, 13GW0102A, KMU-Innovativ - Verbundprojekt: Forschung für Tumortherapie mit lokalisierter Hochfrequenz-Hyperthermie: Diagnostik, Therapiesteuerung und -kontrolle mit ultrahochfeld MRT (3-IN-1:THERAHEAT) - Teilvorhaben: Erforschung von Hochfrequenzantennen für Tumortherapie mittels kontrollierter Hochfrequenz-HyperthermieEC/H2020/EU/743077/Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy/ThermalM

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Advanced Radio Frequency Applicators for Thermal Magnetic Resonance Theranostics of Brain Tumors

Thermal Magnetic Resonance (ThermalMR) is a theranostic concept that combines diagnostic magnetic resonance imaging (MRI) with targeted thermal therapy in the hyperthermia (HT) range using a radiofrequency (RF) applicator in an integrated system. ThermalMR adds a therapeutic dimension to a diagnostic MRI device. Focused, targeted RF heating of deep-seated brain tumors, accurate non-invasive temperature monitoring and high-resolution MRI are specific requirements of ThermalMR that can be addressed with novel concepts in RF applicator design. This work examines hybrid RF applicator arrays combining loop and self-grounded bow-tie (SGBT) dipole antennas for ThermalMR of brain tumors, at magnetic field strengths of 7.0 T, 9.4 T and 10.5 T. These high-density RF arrays improve the feasible transmission channel count, and provide additional degrees of freedom for RF shimming not afforded by using dipole antennas only, for superior thermal therapy and MRI diagnostics. These improvements are especially relevant for ThermalMR theranostics of deep-seated brain tumors because of the small surface area of the head. ThermalMR RF applicators with the hybrid loop+SGBT dipole design outperformed applicators using dipole-only and loop-only designs, with superior MRI performance and targeted RF heating. Array variants with a horse-shoe configuration covering an arc (270°) around the head avoiding the eyes performed better than designs with 360° coverage, with a 1.3 °C higher temperature rise inside the tumor while sparing healthy tissue. Our EMF and temperature simulations performed on a virtual patient with a clinically realistic intracranial tumor provide a technical foundation for implementation of advanced RF applicators tailored for ThermalMR theranostics of brain tumors

Design, implementation, evaluation and application of a 32-channel radio frequency signal generator for thermal magnetic resonance based anti-cancer treatment

Thermal Magnetic Resonance (ThermalMR) leverages radio frequency (RF)-induced heating to examine the role of temperature in biological systems and disease. To advance RF heating with multi-channel RF antenna arrays and overcome the shortcomings of current RF signal sources, this work reports on a 32-channel modular signal generator (SGPLL). The SGPLL was designed around phase-locked loop (PLL) chips and a field-programmable gate array chip. To examine the system properties, switching/settling times, accuracy of RF power level and phase shifting were characterized. Electric field manipulation was successfully demonstrated in deionized water. RF heating was conducted in a phantom setup using self-grounded bow-tie RF antennae driven by the SGPLL. Commercial signal generators limited to a lower number of RF channels were used for comparison. RF heating was evaluated with numerical temperature simulations and experimentally validated with MR thermometry. Numerical temperature simulations and heating experiments controlled by the SGPLL revealed the same RF interference patterns. Upon RF heating similar temperature changes across the phantom were observed for the SGPLL and for the commercial devices. To conclude, this work presents the first 32-channel modular signal source for RF heating. The large number of coherent RF channels, wide frequency range and accurate phase shift provided by the SGPLL form a technological basis for ThermalMR controlled hyperthermia anti-cancer treatment. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Dermatoskopie – 30 Jahre nach der 1. Konsensus-Konferenz

N/

Ipilimumab-induced cutaneous reactions.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>MelanA-specific vaccination.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; TKI, tyrosine kinase inhibitor; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response; CR, complete response; MAH, melanoma-associated hypopigmentation.</p