Development of multi-channel radio frequency technology for sodium and potassium magnetic resonance imaging at 7.0 Tesla: design and clinical application

Sodium (Na+) and potassium (K+) ions play key roles in the physiology and metabolism of living cells. Primary active transport, which is carried out by sodium/potassium pumps (Na+/K+-ATPase), maintains the ion concentration gradient between intra- and extracellular space. Changes in Na+ and K+ concentration (and distribution) might reflect ongoing pathological processes within a tissue what might be relevant for various types of cardiovascular and ocular disorders. Ultrahigh magnetic resonance imaging (UHF-MRI) provides new opportunities to non-invasively investigate changes in Na+ and K+ concentrations with spatial resolution and within total scan times that are reaching ranges acceptable for clinical applications. Despite an intrinsic to UHF-MRI gain in signal-to-noise ratio (SNR), nuclear magnetic resonance (NMR) signals of sodium (23Na) and potassium (39K) being detected remain very weak. The NMR sensitivity of 23Na is about 9%, while 39K is 0.05% the one of proton (1H). Therefore, radio frequency (RF) coils, which are used to capture these signals, should be optimized for a given anatomical structure in order to improve the SNR. The goal of this work is to develop two separate RF coils which would enable high-resolution in vivo 23Na MRI of the human eye and in vivo 39K MRI of the human heart at 7.0 Tesla. To achieve these goals, the six-channel transmit receive 23Na coil array and a four/two-channel 1H/39K coil array have been designed, built and tested. The performance of the developed RF coils has been evaluated using RF circuit, electromagnetic field (EMF) and specific absorption rate (SAR) simulations. Phantom as well as in vivo experiments involving several healthy volunteers have been conducted. The experiments have revealed that the developed six-channel transmit/receive coil array supports in vivo 23Na MRI of the human eye with nominal spatial resolution of (1.0 x 1.0 x 1.0) mm3 and within scan time of 10 minutes. This work also demonstrates that the proposed four/two-channel 1H/39K coil array enabled obtaining the world’s first in vivo 39K image of the human heart with nominal spatial resolution of (14.5 x 14.5 x 14.5) mm3 and within total scan time of 30 minutes. The results demonstrate that sodium content in the lens is distinguishable from sodium content in the aqueous and vitreous humor. There is strong evidence that sodium concentration in the compartments of the eye should change in diseases like cataract, glaucoma and ocular melanoma. The broad roles of this element in processes related to eye physiology suggest a range of questions for ophthalmological investigations. This work also shows that in vivo potassium MRI of the human heart is feasible. Previous reports, suggesting that potassium concentration is expected to alter in arrhythmia, ischemia or irreversible injury to miocytes, provides encouragement for future in vivo studies involving patients who suffer from various cardiovascular disorders.Natrium- (Na+) und Kaliumionen (K+) spielen kritische Rollen in der Physiologie und dem Metabolismus lebender Zellen. Der primär-aktive Transport, der den Ionenkonzentrationsgradienten zwischen intra- und extrazellulärer Maxtrix aufrecht hält, wird von Natrium/Kaliumpumpen durchgeführt. Änderungen der Na+ - und K+-Konzentration und -Verteilung könne auf pathologische Prozesse in einem Gewebe zurückzuführen sein. Dies ist sehr relevant für eine Vielzahl von Krankheiten, einschließlich Herz-Kreislauf- und Augenerkrankungen. Ultrahohe Magnetresonanztomographie (UHF-MRT) bietet neue Möglichkeiten zur nicht-invasiven Untersuchung von Änderungen in Na+- und K+-Konzentrationen mit hoher räumlicher Auflösung, die innerhalb für klinische Anwendungen akzeptabler Gesamtabtastzeiten durchgeführt werden können. Trotz eines UHF-MRT-spezifischen Anstiegs des Signal-Rausch-Verhältnisses (SNR) bleiben die nachgewiesenen kernmagnetischen Resonanzsignale (NMR) von Natrium (23Na) und Kalium (39K) sehr schwach. Die NMR-Empfindlichkeit von 23Na beträgt etwa 9%, während 39K - 0.05% des Protons (1H) beträgt. Daher sollten Hochfrequenzspulen (HF), die zur Erfassung dieser Signale verwendet werden, für eine bestimmte anatomische Struktur optimiert werden, um das SNR zu verbessern. Ziel dieser Arbeit ist es, zwei separate HF-Spulen zu entwickeln, die eine hochauflösende in vivo 23Na-MRT des menschlichen Auges und eine in vivo 39K-MRT des menschlichen Herzens bei 7.0 Tesla ermöglichen. Um diese Ziele zu erreichen, wurden das/ein 23Na-Spulenarray mit sechs Sende- und Empfangskanälen und ein 1H/39K-Spulenarray mit vier/zwei Kanälen entworfen, gebaut und getestet. Es wurden Experimente an Messphantomen sowie In-vivo-Testmessungen von mehreren gesunden Freiwilligen durchgeführt. Die Messungen haben gezeigt, dass das in dieser Arbeit entwickelte 6-Kanal-Sende- / Empfangsspulenarray in vivo 23Na MRT des menschlichen Auges mit einer nominalen räumlichen Auflösung von (1.0x1.0x1.0) mm3 innerhalb der Scanzeit von 10 Minuten ermöglicht. Diese Arbeit zeigt auch, dass es dank des 1H/39K -Spulenarray mit vier/zwei Kanälen gelang, das weltweit erste 39K -Bild des menschlichen Herzens in vivo mit einer nominalen räumlichen Auflösung von (14.5x14.5x14.5) mm3 und einer Gesamtabtastzeit von zu 30 Minuten aufzunehmen. Die Ergebnisse zeigen, dass der Natriumgehalt in der Linse vom Natriumgehalt im wässrigen und im Glaskörper unterscheidbar ist. Es gibt starke Hinweise darauf, dass sich die Natriumkonzentration in den Kompartimenten des Auges bei Erkrankungen wie Katarakt, Glaukom und okularem Melanom ändern sollte. Diese Arbeit zeigt auch, dass eine in vivo Kalium-MRT des menschlichen Herzens möglich ist. Frühere Berichte, aus denen hervorgeht, dass sich die Kaliumkonzentration voraussichtlich bei Arrhythmie, Ischämie oder irreversiblen Verletzungen der Miozyten ändert, ermutigen zukünftige In-vivo-Studien mit Patienten, die an verschiedenen Herz-Kreislauf-Erkrankungen leiden

Overall survival after reirradiation of spinal metastases – independent validation of predictive models

Background: It is unknown if survival prediction tools (SPTs) sufficiently predict survival in patients who undergo palliative reirradiation of spinal metastases. We therefore set out to clarify if SPTs can predict survival in this patient population. Methods: We retrospectively analyzed spinal reirradiations performed (n = 58, 52 patients, 44 included in analysis). SPTs for patients with spinal metastases were identified and compared to a general palliative score and to a dedicated SPT to estimate prognosis in palliative reirradiation independent of site (SPT-Nieder). Results: Consistently in all tests, SPT-Nieder showed best predictive performance as compared to other tools. Items associated with survival were general condition (KPS), liver metastases, and steroid use. Other factors like primary tumor site, pleural effusion, and bone metastases were not correlated with survival. We adapted an own score to the data which performed comparable to SPT-Nieder but avoids the pleural effusion item. Both scores showed good performance in identifying long-term survivors with late recurrences. Conclusions: Survival prediction in case of spinal reirradiation is possible with sufficient predictive separation. Applying SPTs in case of reirradiation helps to identify patients with good life expectancy who might benefit from dose escalation or longer treatment courses

Genital invasion or perigenital spread may pose a risk of marginal misses for Intensity Modulated Radiotherapy (IMRT) in anal cancer

Background: While intensity modulated radiotherapy (IMRT) in anal cancer is feasible and improves high-dose conformality, the current RTOG/AGITG contouring atlas and planning guidelines lack specific instructions on how to proceed with external genitalia. Meanwhile, the RTOG-Protocol 0529 explicitly recommends genital sparing on the basis of specific genital dose constraints. Recent pattern-of-relapse studies based on conventional techniques suggest that marginal miss might be a potential consequence of genital sparing. Our goal is to outline the potential scope and increase the awareness for this clinical issue. Methods: We present and discuss four patients with perigenital spread in anal cancer in both early and advanced stages (three at time of first diagnosis and one in form of relapse). Genital/perigenital spread was observed once as direct genital infiltration and thrice in form of perigenital lymphatic spread. Results: We review the available data regarding the potential consequences of genital sparing in anal cancer. Pattern-of-relapse studies in anal cancer after conventional radiotherapy and the current use of IMRT in anal cancer are equivocal but suggest that genital sparing may occasionally result in marginal miss. An obvious hypothesis suggested by our report is that perigenital lymphovascular invasion might be associated with manifest inguinal N+ disease. Conclusions: Local failure has low salvage rates in recent anal cancer treatment series. Perigenital spread may pose a risk of marginal misses in IMRT in anal cancer. To prevent marginal misses, meticulous pattern-of-relapse analyses of controlled IMRT-series are warranted. Until their publication, genital sparing should be applied with caution, PET/CT should be used when possible and meeting genital dose constraints should not be prioritized over CTV coverage, especially (but not only) in stage T3/4 and N+ disease

Twisted Pair Transmission Line Coil -- A Flexible, Self-Decoupled and Extremely Robust Element for 7T MRI

This study evaluates the performance of a twisted pair transmission line coil as a transceive element for 7T MRI in terms of physical flexibility, robustness to shape deformations, and interelement decoupling. Each coil element was created by shaping a twisted pair of wires into a circle. One wire was interrupted at the top, while the other was interrupted at the bottom, and connected to the matching circuit. Electromagnetic simulations were conducted to determine the optimal number of twists per length (in terms of B$_1^+$ field efficiency, SAR efficiency, sensitivity to elongation and interelement decoupling properties) and for investigating the fundamental operational principle of the coil through fields streamline visualization. A comparison between the twisted pair coil and a conventional loop coil in terms of B$_1^+$ fields, maxSAR10g, and stability of $S_{11}$ when the coil was deformed, was performed. Experimentally measured interelement coupling between individual elements of multichannel arrays was also investigated. Increasing the number of twists per length resulted in a more physically robust coil. Poynting vector streamline visualization showed that the twisted pair coil concentrated most of the energy in the near field. The twisted pair coil exhibited comparable B$_1^+$ fields and improved maxSAR10g to the conventional coil but demonstrated exceptional stability with respect to coil deformation and a strong self-decoupling nature when placed in an array configuration. The findings highlight the robustness of the twisted pair coil, showcasing its stability under shape variations. This coil holds great potential as a flexible RF coil for various imaging applications using multiple-element arrays, benefiting from its inherent decoupling.Comment: Revised version; 20 pages, 16 figures, preprin

Detection of local recurrence with 3-tesla MRI after radical prostatectomy: A useful method for radiation treatment planning?

Background/Aim: Salvage radiotherapy improves biochemical control in patients with recurrence of prostate cancer after prostatectomy. Radiotherapy target volumes of the prostatic fossa are based on empirical data and differ between different guidelines. Localization of recurrence with multiparametric magnetic resonance imaging (MRI) might be a feasible approach to localize recurrent lesions. Patients and Methods: Twenty-one patients with biochemical recurrence after radical prostatectomy were included (median prostate-specific antigen (PSA) =0.17 ng/ml). Multi-parametric MRI was performed using a 3-T MR system. Results: Lesions were detected in seven patients with a median PSA of 0.86 ng/ml (minimum= 0.31 ng/ml). Patients without detectable recurrence had a median PSA of 0.12 ng/ml. All patients with detectable lesions responded to radiotherapy. Eleven out of 14 patients without detectable recurrence also responded. Plasma flow in suspicious lesions was correlated with PSA level. Conclusion: Detection of recurrence at the prostatic fossa with our approach was possible in a minority of patients with a low PSA level. Clinical relevance of plasma flow in suspicious lesions should be further investigated

Fully automated treatment planning of spinal metastases - A comparison to manual planning of Volumetric Modulated Arc Therapy for conventionally fractionated irradiation

_Background:_ Planning for Volumetric Modulated Arc Therapy (VMAT) may be time consuming and its use is limited by available staff resources. Automated multicriterial treatment planning can eliminate this bottleneck. We compared automatically created (auto) VMAT plans generated by Erasmus-iCycle to manually created VMAT plans for treatment of spinal metastases. _Methods:_ Forty-two targets in 32 patients were analyzed. Lungs and kidneys were defined as organs at risk (OARs). Twenty-two patients received radiotherapy on kidney levels, 17 on lung levels, and 3 on both levels. _Results:_ All Erasmus-iCycle plans were clinically acceptable. When compared to manual plans, planning target volume (PTV) coverage of auto plans was significantly better. The Homogeneity Index did not differ significantly between the groups. Mean dose to OARs was lower in auto plans concerning both kidneys and the left lung. One hotspot (>110% of D50%) occurred in the spinal cord of one auto plan (33.2 Gy, D50%: 30 Gy). Treatment time was 7% longer in auto plans. _Conclusions:_ Erasmus-iCycle plans showed better target coverage and sparing of OARs at the expense of minimally longer treatment times (for which no constraint was set)

Automated VMAT planning for postoperative adjuvant treatment of advanced gastric cancer

Background: Postoperative/adjuvant radiotherapy of advanced gastric cancer involves a large planning target volume (PTV) with multi-concave shapes which presents a challenge for volumetric modulated arc therapy (VMAT) planning. This study investigates the advantages of automated VMAT planning for this site compared to manual VMAT planning by expert planners. Methods: For 20 gastric cancer patients in the postoperative/adjuvant setting, dual-arc VMAT plans were generated using fully automated multi-criterial treatment planning (autoVMAT), and compared to manually generated VMAT plans (manVMAT). Both automated and manual plans were created to deliver a median dose of 45 Gy to the PTV using identical planning and segmentation parameters. Plans were evaluated by two expert radiation oncologists for clinical acceptability. AutoVMAT and manVMAT plans were also compared based on dose-volume histogram (DVH) and predicted normal tissue complication probability (NTCP) analysis. Results: Both manVMAT and autoVMAT plans were considered clinically acceptable. Target coverage was similar (manVMAT: 96.6 ± 1.6%, autoVMAT: 97.4 ± 1.0%, p = 0.085). With autoVMAT, median kidney dose was reduced on average by > 25%; (for left kidney from 11.3 ± 2.1 Gy to 8.9 ± 3.5 Gy (p = 0.002); for right kidney from 9.2 ± 2.2 Gy to 6.1 ± 1.3 Gy (p <  0.001)). Median dose to the liver was lower as well (18.8 ± 2.3 Gy vs. 17.1 ± 3.6 Gy, p = 0.048). In addition, Dmax of the spinal cord was significantly reduced (38.3 ± 3.7 Gy vs. 31.6 ± 2.6 Gy, p <  0.001). Substantial improvements in dose conformity and integral dose were achieved with autoVMAT plans (4.2% and 9.1%, respectively; p <  0.001). Due to the better OAR sparing in the autoVMAT plans compared to manVMAT plans, the predicted NTCPs for the left and right kidney and the liver-PTV were significantly reduced by 11.3%, 12.8%, 7%, respectively (p ≤ 0.001). Delivery time and total number of monitor units were increased in autoVMAT plans (from 168 ± 19 s to 207 ± 26 s, p = 0.006) and (from 781 ± 168 MU to 1001 ± 134 MU, p = 0.003), respectively. Conclusions: For postoperative/adjuvant radiotherapy of advanced gastric cancer, involving a complex target shape, automated VMAT planning is feasible and can substantially reduce the dose to the kidneys and the liver, without compromising the target dose delivery

Postoperative elective pelvic nodal irradiation compared to prostate bed irradiation in locally advanced prostate cancer – a retrospective analysis of dose-escalated patients

Background: It is uncertain if whole-pelvic irradiation (WPRT) in addition to dose-escalated prostate bed irradiation (PBRT) improves biochemical progression-free survival (bPFS) after prostatectomy for locally advanced tumors. This study was initiated to analyze if WPRT is associated with bPFS in a patient cohort with dose-escalated (> 70 Gy) PBRT. Methods: Patients with locally advanced, node-negative prostate carcinoma who had PBRT with or without WPRT after prostatectomy between 2009 and 2017 were retrospectively analyzed. A simultaneous integrated boost with equivalent-doses-in-2-Gy-fractions (EQD-2) of 79.29 Gy or 71.43 Gy to the prostate bed was applied in patients with margin-positive (or detectable) and margin-negative/undetectable tumors, respectively. WPRT (44 Gy) was offered to patients at an increased risk of lymph node metastases. Results: Forty-three patients with PBRT/WPRT and 77 with PBRT-only were identified. Baseline imbalances included shorter surgery-radiotherapy intervals (S-RT-Intervals) and fewer resected lymph nodes in the WPRT group. WPRT was significantly associated with better bPFS in univariate (p = 0.032) and multivariate models (HR = 0.484, p = 0.015). Subgroup analysis indicated a benefit of WPRT (p = 0.029) in patients treated with rising PSA values who mostly had negative margins (74.1%); WPRT was not associated with a longer bPFS in the postoperative setting with almost exclusively positive margins (96.8%). Conclusion: We observed a longer bPFS after WPRT compared to PBRT in patients with locally advanced prostate carcinoma who underwent dose-escalated radiotherapy. In subset analyses, the association was only observed in patients with rising PSA values but not in patients with non-salvage postoperative radiotherapy for positive margins

Challenges and Contradictions of Metal Nano-Particle Applications for Radio-Sensitivity Enhancement in Cancer Therapy

From the very beginnings of radiotherapy, a crucial question persists with how to target the radiation effectiveness into the tumor while preserving surrounding tissues as undamaged as possible. One promising approach is to selectively pre-sensitize tumor cells by metallic nanoparticles. However, though the “physics” behind nanoparticle-mediated radio-interaction has been well elaborated, practical applications in medicine remain challenging and often disappointing because of limited knowledge on biological mechanisms leading to cell damage enhancement and eventually cell death. In the present study, we analyzed the influence of different nanoparticle materials (platinum (Pt), and gold (Au)), cancer cell types (HeLa, U87, and SKBr3), and doses (up to 4 Gy) of low-Linear Energy Transfer (LET) ionizing radiation (- and X-rays) on the extent, complexity and reparability of radiation-induced H2AX + 53BP1 foci, the markers of double stand breaks (DSBs). Firstly, we sensitively compared the focus presence in nuclei during a long period of time post-irradiation (24 h) in spatially (three-dimensionally, 3D) fixed cells incubated and non-incubated with Pt nanoparticles by means of high-resolution immunofluorescence confocal microscopy. The data were compared with our preliminary results obtained for Au nanoparticles and recently published results for gadolinium (Gd) nanoparticles of approximately the same size (2–3 nm). Next, we introduced a novel super-resolution approach—single molecule localization microscopy (SMLM)—to study the internal structure of the repair foci. In these experiments, 10 nm Au nanoparticles were used that could be also visualized by SMLM. Altogether, the data show that different nanoparticles may or may not enhance radiation damage to DNA, so multi-parameter effects have to be considered to better interpret the radiosensitization. Based on these findings, we discussed on conclusions and contradictions related to the effectiveness and presumptive mechanisms of the cell radiosensitization by nanoparticles. We also demonstrate that SMLM offers new perspectives to study internal structures of repair foci with the goal to better evaluate potential differences in DNA damage patterns