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Objective. Compact ion imaging systems based on thin detectors are a promising prospect for the clinical environment since they are easily integrated into the clinical workflow. Their measurement principle is based on energy deposition instead of the conventionally measured residual energy or range. Therefore, thin detectors are limited in the water-equivalent thickness range they can image with high precision. This article presents our energy painting method, which has been developed to render high precision imaging with thin detectors feasible even for objects with larger, clinically relevant water-equivalent thickness (WET) ranges. Approach. A detection system exclusively based on pixelated silicon Timepix detectors was used at the Heidelberg ion-beam therapy center to track single helium ions and measure their energy deposition behind the imaged object. Calibration curves were established for five initial beam energies to relate the measured energy deposition to WET. They were evaluated regarding their accuracy, precision and temporal stability. Furthermore, a 60 mm × 12 mm region of a wedge phantom was imaged quantitatively exploiting the calibrated energies and five different mono-energetic images. These mono-energetic images were combined in a pixel-by-pixel manner by averaging the WET-data weighted according to their single-ion WET precision (SIWP) and the number of contributing ions. Main result. A quantitative helium-beam radiograph of the wedge phantom with an average SIWP of 1.82(5) % over the entire WET interval from 150 mm to 220 mm was obtained. Compared to the previously used methodology, the SIWP improved by a factor of 2.49 ± 0.16. The relative stopping power value of the wedge derived from the energy-painted image matches the result from range pullback measurements with a relative deviation of only 0.4 %. Significance. The proposed method overcomes the insufficient precision for wide WET ranges when employing detection systems with thin detectors. Applying this method is an important prerequisite for imaging of patients. Hence, it advances detection systems based on energy deposition measurements towards clinical implementation. [ABSTRACT FROM AUTHOR]

Background: Radiation fields encountered in proton therapy (PT) and ionbeam therapy (IBT) are characterized by a variable linear energy transfer (LET), which lead to a variation of relative biological effectiveness and also affect the response of certain dosimeters. Therefore, reliable tools to measure LET are advantageous to predict and correct LET effects. Fluorescent nuclear track detectors (FNTDs) are suitable to measure LET spectra within the range of interest for PT and IBT, but so far the accuracy and precision have been challenged by sensitivity variations between individual crystals. Purpose: To develop a novel methodology to correct changes in the fluorescent intensity due to sensitivity variations among FNTDs. This methodology is based on exposing FNTDs to alpha particles in order to derive a detector-specific correction factor. This will allow us to improve the accuracy and precision of LET spectra measurements with FNTDs. Methods: FNTDs were exposed to alpha particles. Afterward, the detectors were irradiated to monoenergetic protons, 4He-, 12C-, and 16O-ions. At each step, the detectors were imaged with a confocal laser scanning microscope. The tracks were reconstructed and analyzed using in-house developed tools. Alpha-particle tracks were used to derive a detector-specific sensitivity correction factor (ks,i). Proton, 4He-, 12C-, and 16O-ion tracks were used to establish a traceable calibration curve that relates the fluorescence intensity with the LET in water (LETH2O). FNTDs from a second batch were exposed and analyzed following the same procedures, to test if ks,i can be used to extend the applicability of the calibration curve to detectors from different batches. Finally, a set of blind tests was performed to assess the accuracy of the proposed methodology without user bias. Throughout all stages, the main sources of uncertainty were evaluated. Results: Based on a sample of 100 FNTDs, our findings show a high sensitivity heterogeneity between FNTDs, with ks,i having values between 0.57 and 2.55. The fitting quality of the calibration curve, characterized by the mean absolute percentage residuals and correlation coefficient, was improved when ks,i was considered. Results for detectors from the second batch show that, if the fluorescence signal is corrected by ks,i,the differences in the predicted LETH2O with respect to the reference set are reduced from 55%, 141%, 41%, and 186% to 4.2%, 6.5%, 5.0%, and 11.0%,for protons, 4He-, 12C-, and 16O-ions, respectively. The blind tests showed that it is possible to measure the track- and doseaverage LETH2O with an accuracy of 0.3%, 16%, and 9.6% and 1.7%, 28%, and 30% for protons, 12C-ions and mixed beams, respectively. On average, the combined uncertainty of the measured LETH2O was 11%, 13%, 21%, and 26% for protons, 4He-, 12C-, and 16O-ions, respectively. These values were increased by a mean factor of 2.0 when ks,i was not applied. Conclusions: We have demonstrated for the first time that alpha particles can be used to derive a detector-specific sensitivity correction factor. The proposed methodology allows us to measure LET spectra using FNTD-technology, with a degree of accuracy and precision unreachable before with sole experimental approaches. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive methods to monitor carbon‐ion beams in patients are desired to fully exploit the advantages of carbon‐ion radiotherapy. Prompt secondary ions produced in nuclear fragmentations of carbon ions are of particular interest for monitoring purposes as they can escape the patient and thus be detected and tracked to measure the radiation field in the irradiated object. This study aims to evaluate the performance of secondary‐ion tracking to detect, visualize, and localize an internal air cavity used to mimic inter‐fractional changes in the patient anatomy at different depths along the beam axis. Methods: In this work, a homogeneous head phantom was irradiated with a realistic carbon‐ion treatment plan with a typical prescribed fraction dose of 3 Gy(RBE). Secondary ions were detected by a mini‐tracker with an active area of 2 cm2, based on the Timepix3 semiconductor pixel detector technology. The mini‐tracker was placed 120 mm behind the center of the target at an angle of 30 degrees with respect to the beam axis. To assess the performance of the developed method, a 2‐mm thick air cavity was inserted in the head phantom at several depths: in front of as well as at the entrance, in the middle, and at the distal end of the target volume. Different reconstruction methods of secondary‐ion emission profile were studied using the FLUKA Monte Carlo simulation package. The perturbations in the emission profiles caused by the air cavity were analyzed to detect the presence of the air cavity and localize its position. Results: The perturbations in the radiation field mimicked by the 2‐mm thick cavity were found to be significant. A detection significance of at least three standard deviations in terms of spatial distribution of the measured tracks was found for all investigated cavity depths, while the highest significance (six standard deviations) was obtained when the cavity was located upstream of the tumor. For a tracker with an eight‐fold sensitive area, the detection significance rose to at least nine standard deviations and up to 17 standard deviations, respectively. The cavity could be detected at all depths and its position measured within 6.5 ± 1.4 mm, which is sufficient for the targeted clinical performance of 10 mm. Conclusion: The presented systematic study concerning the detection and localization of small inter‐fractional structure changes in a realistic clinical setting demonstrates that secondary ions carry a large amount of information on the internal structure of the irradiated object and are thus attractive to be further studied for noninvasive monitoring of carbon‐ion treatments. [ABSTRACT FROM AUTHOR]

The dose conformity of carbon-ion beam radiotherapy, which allows the reduction of the dose deposition in healthy tissue and the escalation of the dose to the tumor, is associated with a high sensitivity to anatomical changes during and between treatment irradiations. Thus, the monitoring of inter-fractional anatomical changes is crucial to ensure the dose conformity, to potentially reduce the size of the safety margins around the tumor and ultimately to reduce the irradiation of healthy tissue. To do so, monitoring methods of carbon-ion radiotherapy in depth using secondary-ion tracking are being investigated. In this work, the detection and localization of a small air cavity of 2 mm thickness were investigated at different detection angles of the mini-tracker relative to the beam axis. The experiments were conducted with a PMMA head phantom at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. In a clinic-like irradiation of a single field of 3 Gy (RBE), secondary-ion emission profiles were measured by a 2 cm2 mini-tracker composed of two silicon pixel detectors. Two positions of the cavity in the head phantom were studied: in front and in the middle of the tumor volume. The significance of the cavity detection was found to be increased at smaller detection angles, while the accuracy of the cavity localization was improved at larger detection angles. Detection angles of 20° – 30° were found to be a good compromise for accessing both, the detectability and the position of the air cavity along the depth in the head of a patient. [ABSTRACT FROM AUTHOR]

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Purpose: Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon‐ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy‐dependent extrapolation of the nozzle‐measured positions to obtain the lateral beam positions in the isocenter, since the nozzle‐to‐isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. Methods: The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C‐ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini‐tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary‐ion fluence rate in the mini‐tracker rises up to 1.5 × 105 ions/s/cm2, causing strong pile‐up of secondary‐ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3 Gy (RBE) and averaged dose rate of 0.27 Gy/s at the Heidelberg Ion‐Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi‐wire proportional chamber positioned at the room isocenter. Results: The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2‐cm2 mini‐tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. Conclusions: It was demonstrated that the performance of the method for a non‐invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study. [ABSTRACT FROM AUTHOR]

The synthesis of a new type of intrinsically chiral, directly [beta],[beta]'-linked, octa-meso-aryl-substituted bisporphyrins is described, by using an optimized Suzuki-Miyaura coupling procedure. The novel axially chiral bis(tetrapyrrole) compounds are potentially useful as substrates for asymmetric catalysis, biomimetic studies on directed electron-transfer processes, for photodynamic therapy (PDT), and for chiral recognition.

Radiotherapy with protons and carbon ions enables to deliver dose distributions of high conformation to the target. Treatment with helium ions has been suggested due to their physical and biological advantages. A reliable benchmarking of the employed physics models with experimental data is required for treatment planning. However, experimental data for helium interactions is limited, in part due to the complexity and large size of conventional experimental setups. We present a novel method for the investigation of helium interactions with matter using miniaturized instrumentation based on highly integrated pixel detectors. The versatile setup consisted of a monitoring detector in front of the PMMA phantom of varying thickness and a detector stack for investigation of outgoing particles. The ion type downstream from the phantom was determined by high-resolution pattern recognition analysis of the single particle signals in the pixelated detectors. The fractions of helium and hydrogen ions behind the used targets were determined. As expected for the stable helium nucleus, only a minor decrease of the primary ion fluence along the target depth was found. E.g. the detected fraction of hydrogen ions on axis of a 220 MeV/u 4 He beam was below 6% behind 24.5 cm of PMMA. Monte-Carlo simulations using Geant4 reproduce the experimental data on helium attenuation and yield of helium fragments qualitatively, but significant deviations were found for some combinations of target thickness and beam energy. The presented method is promising to contribute to the reduction of the uncertainty of treatment planning for helium ion radiotherapy. [ABSTRACT FROM AUTHOR]

8-Oxopurines (8-oxodG and 8-oxodA) and formamidopyrimidines (FaPydG and FaPydA) are major oxidative DNA lesions involved in cancer development and aging. Their mutagenicity is believed to result from a conformational shift of the N9-C1′ glycosidic bonds from anti to syn, which allows the lesions to form noncanonical Hoogsteen-type base pairs with incoming triphosphates during DNA replication. Here we present biochemical data and what are to our knowledge the first crystal structures of carbocyclic FaPydA and FaPydG containing DNA in complex with a high-fidelity polymerase. Crystallographic snapshots show that the cFaPy lesions keep the anti geometry of the glycosidic bond during error-free and error-prone replication. The observed dG·dC→dT·dA transversion mutations are the result of base shifting and tautomerization. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions In‐vivo monitoring methods of carbon ion radiotherapy (CIRT) includes explorations of nuclear reaction products generated by carbon‐ion beams interacting with patient tissues. Our research group focuses on in‐vivo monitoring of CIRT using silicon pixel detectors. Currently, we are conducting a prospective clinical trial as part of the In‐Vivo Monitoring project (InViMo) at the Heidelberg Ion Beam Therapy Center (HIT) in Germany. We are using an innovative, in‐house developed, non‐contact fragment tracking system with seven mini‐trackers based on the Timepix3 technology developed at CERN.This article focuses on the implementation of the mini‐tracker in Monte Carlo (MC) based on FLUKA simulations to monitor secondary charged nuclear fragments in CIRT. The main objective is to systematically evaluate the simulation accuracy for the InViMo project.The implementation involved integrating the mini‐tracker geometry and the scoring mechanism into the FLUKA MC simulation, utilizing the finely tuned HIT beam line. The systematic investigation included varying mini‐tracker angles (from 15∘$15^\circ$ to 45∘$45^\circ$ in 5∘$5^\circ$ steps) during the irradiation of a head‐sized phantom with therapeutic carbon‐ion pencil beams. To evaluate our implemented FLUKA framework, a comparison was made between the experimental data and data obtained from MC simulations. To ensure the fidelity of our comparison, experiments were performed at the HIT using the parameters and setup established in the simulations.Our research demonstrates high accuracy in reproducing characteristic behaviors and dependencies of the monitoring method in terms of fragment distributions in the mini‐tracker, track angles, emission profiles, and fragment numbers. Discrepancies in the number of detected fragments between the experimental data and the data obtained from MC simulations are less than 4% for the angles of interest in the InViMo detection system.Our study confirms the potential of our simulation framework to investigate the performance of monitoring inter‐fractional anatomical changes in patients undergoing CIRT using secondary nuclear charged fragments escaping from the irradiated patient. [ABSTRACT FROM AUTHOR]

In this paper, the synthesis of a new type of intrinsically chiral, directly β,β′-linked, octa-meso-aryl-substituted bisporphyrins is described, by using an optimized Suzuki-Miyaura coupling procedure. This strategy leads to a broad variety of such axially chiral 'superbiaryls', differing in their metalation states and substitution patterns. On the basis of an efficient route to as-yet-unknown β-boronic acid esters of various meso-tetraarylporphyrins (TAPs) by a two-step bromination-borylation protocol, 18 axially chiral bisporphyrin derivatives were prepared in good to excellent yields. As compared to all other directly linked dimeric porphyrin systems, the joint presence of eight bulky meso substituents and the peripheral position of the porphyrin-porphyrin linkage is unprecedented. The axial configurations and rotational barriers of the pure atropo-enantiomers were investigated by HPLC-CD experiments on a chiral phase in combination with quantum chemical CD calculations. According to the HPLC experiments and in agreement with quantum chemical calculations by applying the dispersion-corrected BLYP method, the configurational stability of the central porphyrin-porphyrin axis strongly depends on the nature of the central metals. Cyclovoltammetric studies proved the systematic influence of the meso substituents and of the metal ions on the oxidation potentials of the bisporphyrins. The novel axially chiral bis(tetrapyrrole) compounds described here are potentially useful as substrates for asymmetric catalysis, biomimetic studies on directed electron-transfer processes, for photodynamic therapy (PDT), and for chiral recognition. [ABSTRACT FROM AUTHOR]

Objective: The highly conformal carbon-ion radiotherapy is associated with an increased sensitivity of the dose distributions to internal changes in the patient during the treatment course. Hence, monitoring methodologies capable of detecting such changes are of vital importance. We established experimental setup conditions to address the sensitivity of a monitoring approach based on secondary-fragment tracking for detecting clinically motivated air cavity dimensions in a homogeneous head-size PMMA phantom in 40 mm depth., Approach: The air cavities were positioned within the entrance channel of a treatment field of 50 mm diameter at three lateral positions. The measured secondary-fragment emission profiles were compared to a reference measurement without cavities. The experiments were conducted at the Heidelberg Ion-Beam Therapy Center in Germany at typical doses and dose rates., Main Results: Significances above a detectability threshold of 2σ for the larger cavities (20 mm diameter and 4 mm thickness, and 20 mm diameter and 2 mm thickness) across the entire treatment field. The smallest cavity of 10 mm diameter and 2 mm thickness, which is on the lower limit of clinical interest, could not be detected at any position. We also demonstrated that it is feasible to reconstruct the lateral position of the cavity on average within 2.8 mm, once the cavity is detected. This is sufficient for the clinicians to estimate medical effects of such a cavity and to decide about the need for a control imaging CT., Significance: This investigation defines well-controlled reference conditions for the evaluation of the performance of any kind of treatment monitoring method and its capability to detect internal changes within head-sized objects. Air cavities with volumes from 0.31 cm3 to 1.26 cm3 were narrowed down around the detectability threshold of this secondary-fragment-based monitoring method., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Objective. There is an increasing interest in calculating and measuring linear energy transfer (LET) spectra in particle therapy in order to assess their impact in biological terms. As such, the accuracy of the particle fluence energy spectra becomes paramount. This study focuses on quantifying energy depositions of distinct proton, helium, carbon, and oxygen ion beams using a silicon pixel detector developed at CERN to determine LET spectra in silicon. Approach. While detection systems have been investigated in this pursuit, the scarcity of detectors capable of providing per-ion data with high spatial and temporal resolution remains an issue. This gap is where silicon pixel detector technology steps in, enabling online tracking of single-ion energy deposition. The used detector consisted of a 300 µ m thick silicon sensor operated in partial depletion. Main results. During post-processing, artifacts in the acquired signals were identified and methods for their corrections were developed. Subsequently, a correlation between measured and Monte Carlo-based simulated energy deposition distributions was performed, relying on a two-step recalibration approach based on linear and saturating exponential models. Despite the observed saturation effects, deviations were confined below 7% across the entire investigated range of track-averaged LET values in silicon from 0.77 keV µ m -1 to 93.16 keV µ m -1 . Significance. Simulated and measured mean energy depositions were found to be aligned within 7%, after applying artifact corrections. This extends the range of accessible LET spectra in silicon to clinically relevant values and validates the accuracy and reliability of the measurements. These findings pave the way towards LET-based dosimetry through an approach to translate these measurements to LET spectra in water. This will be addressed in a future study, extending functionality of treatment planning systems into clinical routine, with the potential of providing ion-beam therapy of utmost precision to cancer patients., (Creative Commons Attribution license.)

In this report, we perform structure validation of recently reported RNA phosphorothioate (PT) modifications, a new set of epitranscriptome marks found in bacteria and eukaryotes including humans. By comparing synthetic PT-containing diribonucleotides with native species in RNA hydrolysates by high-resolution mass spectrometry (MS), metabolic stable isotope labeling, and PT-specific iodine-desulfurization, we disprove the existence of PTs in RNA from E. coli, S. cerevisiae, human cell lines, and mouse brain. Furthermore, we discuss how an MS artifact led to the initial misidentification of 2'-O-methylated diribonucleotides as RNA phosphorothioates. To aid structure validation of new nucleic acid modifications, we present a detailed guideline for MS analysis of RNA hydrolysates, emphasizing how the chosen RNA hydrolysis protocol can be a decisive factor in discovering and quantifying RNA modifications in biological samples., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Purpose: In carbon ion beam radiation therapy, fragmentation processes within the patient lead to changes in the composition of the particle field with increasing depth. Consequences are alterations of the resulting dose distribution and its biological effectiveness. To enable accurate treatment planning, the characteristics of the ion spectra resulting from fragmentation processes need to be known for various ion energies and target materials. In this work, we present a novel method for ion type identification using a small and highly flexible setup based on a single detector and designed to simplify measurements and overcome current shortages in available fragmentation data., Materials and Methods: The presented approach is based on the pixelated, semiconductor detector Timepix. The large number of pixels with small pitch, all individually calibrated for energy deposition, enables detection and visualization of single particle tracks. For discrimination among different ion species, the pattern recognition analysis of the detector signal is used. Fragmentation spectra resulting from a primary carbon ion beam at various depths of tissue-equivalent material were studied to identify different ion species in mixed particle fields. The performance of the method was evaluated quantitatively using reference data from an established technique., Results: All ion species resulting from carbon ion fragmentation in tissue-equivalent material could be separated. For measurements behind a 158-mm-thick water tank, the relative fractions of H, He, Be, and B ions detected agreed with corresponding reference data within the limits of uncertainty. For the relatively rare lithium ions, the agreement was within 2.3 Δ ref (uncertainty of reference)., Conclusion: For designated configurations, the presented ion type identification method enables studies of therapeutic carbon ion beams with a simple, small, and configurable detection setup. The technique is promising to enable online fragmentation studies over a wide range of beam and target parameters in the future., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (© Copyright 2017 International Journal of Particle Therapy.)