The potential of mixed carbon-helium beams for online treatment verification: a simulation and treatment planning study.

Objective.Recently, a new and promising approach for range verification was proposed. This method requires the use of two different ion species. Due to their equal magnetic rigidity, fully ionized carbon and helium ions can be simultaneously accelerated in accelerators like synchrotrons. At sufficiently high treatment energies, helium ions can exit the patient distally, reaching approximately three times the range of carbon ions at an equal energy per nucleon. Therefore, the proposal involves adding a small helium fluence to the carbon ion beam and utilizing helium as an online range probe during radiation therapy. This work aims to develop a software framework for treatment planning and motion verification in range-guided radiation therapy using mixed carbon-helium beams.Approach.The developed framework is based on the open-source treatment planning toolkit matRad. Dose distributions and helium radiographs were simulated using the open-source Monte Carlo package TOPAS. Beam delivery system parameters were obtained from the Heidelberg Ion Therapy Center, and imaging detectors along with reconstruction were facilitated by ProtonVDA. Methods for reconstructing the most likely patient positioning error scenarios and the motion phase of 4DCT are presented for prostate and lung cancer sites.Main results.The developed framework provides the capability to calculate and optimize treatment plans for mixed carbon-helium ion therapy. It can simulate the treatment process and generate helium radiographs for simulated patient geometry, including small beam views. Furthermore, motion reconstruction based on these radiographs seems possible with preliminary validation.Significance.The developed framework can be applied for further experimental work with the promising mixed carbon-helium ion implementation of range-guided radiotherapy. It offers opportunities for adaptation in particle therapy, improving dose accumulation, and enabling patient anatomy reconstruction during radiotherapy.

Comparative assessment of direct and indirect cold atmospheric plasma effects, based on helium and argon, on human glioblastoma: an in vitro and in vivo study.

Recent research has highlighted the promising potential of cold atmospheric plasma (CAP) in cancer therapy. However, variations in study outcomes are attributed to differences in CAP devices and plasma parameters, which lead to diverse compositions of plasma products, including electrons, charged particles, reactive species, UV light, and heat. This study aimed to evaluate and compare the optimal exposure time, duration, and direction-dependent cellular effects of two CAPs, based on argon and helium gases, on glioblastoma U-87 MG cancer cells and an animal model of GBM. Two plasma jets were used as low-temperature plasma sources in which helium or argon gas was ionized by high voltage (4.5 kV) and frequency (20 kHz). In vitro assessments on human GBM and normal astrocyte cell lines, using MTT assays, flow cytometry analysis, wound healing assays, and immunocytochemistry for Caspase3 and P53 proteins, demonstrated that all studied plasma jets, especially indirect argon CAP, selectively induced apoptosis, hindered tumor cell growth, and inhibited migration. These effects occurred concurrently with increased intracellular levels of reactive oxygen species and decreased total antioxidant capacity in the cells. In vivo results further supported these findings, indicating that single indirect argon and direct helium CAP therapy, equal to high dose Temozolomide treatment, induced tumor cell death in a rat model of GBM. This was concurrent with a reduction in tumor size observed through PET-CT scan imaging and a significant increase in the survival rate. Additionally, there was a decrease in GFAP protein levels, a significant GBM tumor marker, and an increase in P53 protein expression based on immunohistochemical analyses. Furthermore, Ledge beam test analysis revealed general motor function improvement after indirect argon CAP therapy, similar to Temozolomide treatment. Taken together, these results suggest that CAP therapy, using indirect argon and direct helium jets, holds great promise for clinical applications in GBM treatment.

Effects of cellular radioresponse on therapeutic helium-, carbon-, oxygen-, and neon-ion beams: a simulation study.

Objective. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges.Approach. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams.Main results. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases.Significance.From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.

Energy painting: helium-beam radiography with thin detectors and multiple beam energies.

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 ourenergy paintingmethod, 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.

Diamond detectors for dose and instantaneous dose-rate measurements for ultra-high dose-rate scanned helium ion beams.

BACKGROUND: The possible emergence of the FLASH effect-the sparing of normal tissue while maintaining tumor control-after irradiations at dose-rates exceeding several tens of Gy per second, has recently spurred a surge of studies attempting to characterize and rationalize the phenomenon. Investigating and reporting the dose and instantaneous dose-rate of ultra-high dose-rate (UHDR) particle radiotherapy beams is crucial for understanding and assessing the FLASH effect, towards pre-clinical application and quality assurance programs. PURPOSE: The purpose of the present work is to investigate a novel diamond-based detector system for dose and instantaneous dose-rate measurements in UHDR particle beams. METHODS: Two types of diamond detectors, a microDiamond (PTW 60019) and a diamond detector prototype specifically designed for operation in UHDR beams (flashDiamond), and two different readout electronic chains, were investigated for absorbed dose and instantaneous dose-rate measurements. The detectors were irradiated with a helium beam of 145.7 MeV/u under conventional and UHDR delivery. Dose-rate delivery records by the monitoring ionization chamber and diamond detectors were studied for single spot irradiations. Dose linearity at 5 cm depth and in-depth dose response from 2 to 16 cm were investigated for both measurement chains and both detectors in a water tank. Measurements with cylindrical and plane-parallel ionization chambers as well as Monte-Carlo simulations were performed for comparisons. RESULTS: Diamond detectors allowed for recording the temporal structure of the beam, in good agreement with the one obtained by the monitoring ionization chamber. A better time resolution of the order of few µs was observed as compared to the approximately 50 µs of the monitoring ionization chamber. Both diamonds detectors show an excellent linearity response in both delivery modalities. Dose values derived by integrating the measured instantaneous dose-rates are in very good agreement with the ones obtained by the standard electrometer readings. Bragg peak curves confirmed the consistency of the charge measurements by the two systems. CONCLUSIONS: The proposed novel dosimetric system allows for a detailed investigation of the temporal evolution of UHDR beams. As a result, reliable and accurate determinations of dose and instantaneous dose-rate are possible, both required for a comprehensive characterization of UHDR beams and relevant for FLASH effect assessment in clinical treatments.

Development and benchmarking of a dose rate engine for raster-scanned FLASH helium ions.

BACKGROUND: Radiotherapy with charged particles at high dose and ultra-high dose rate (uHDR) is a promising technique to further increase the therapeutic index of patient treatments. Dose rate is a key quantity to predict the so-called FLASH effect at uHDR settings. However, recent works introduced varying calculation models to report dose rate, which is susceptible to the delivery method, scanning path (in active beam delivery) and beam intensity. PURPOSE: This work introduces an analytical dose rate calculation engine for raster scanned charged particle beams that is able to predict dose rate from the irradiation plan and recorded beam intensity. The importance of standardized dose rate calculation methods is explored here. METHODS: Dose is obtained with an analytical pencil beam algorithm, using pre-calculated databases for integrated depth dose distributions and lateral penumbra. Dose rate is then calculated by combining dose information with the respective particle fluence (i.e., time information) using three dose-rate-calculation models (mean, instantaneous, and threshold-based). Dose rate predictions for all three models are compared to uHDR helium ion beam (145.7 MeV/u, range in water of approximatively 14.6 cm) measurements performed at the Heidelberg Ion Beam Therapy Center (HIT) with a diamond-detector prototype. Three scanning patterns (scanned or snake-like) and four field sizes are used to investigate the dose rate differences. RESULTS: Dose rate measurements were in good agreement with in-silico generated distributions using the here introduced engine. Relative differences in dose rate were below 10% for varying depths in water, from 2.3 to 14.8 cm, as well as laterally in a near Bragg peak area. In the entrance channel of the helium ion beam, dose rates were predicted within 7% on average for varying irradiated field sizes and scanning patterns. Large differences in absolute dose rate values were observed for varying calculation methods. For raster-scanned irradiations, the deviation between mean and threshold-based dose rate at the investigated point was found to increase with the field size up to 63% for a 10 mm × 10 mm field, while no significant differences were observed for snake-like scanning paths. CONCLUSIONS: This work introduces the first dose rate calculation engine benchmarked to instantaneous dose rate, enabling dose rate predictions for physical and biophysical experiments. Dose rate is greatly affected by varying particle fluence, scanning path, and calculation method, highlighting the need for a consensus among the FLASH community on how to calculate and report dose rate in the future. The here introduced engine could help provide the necessary details for the analysis of the sparing effect and uHDR conditions.

Development and validation of MonteRay, a fast Monte Carlo dose engine for carbon ion beam radiotherapy.

BACKGROUND: Monte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; so far however, no commercial treatment planning system (TPS) provides a fast MC for supporting clinical practice in carbon ion therapy. PURPOSE: To extend and validate the in-house developed fast MC dose engine MonteRay for carbon ion therapy, including physical and biological dose calculation. METHODS: MonteRay is a CPU MC dose calculation engine written in C++ that is capable of simulating therapeutic proton, helium and carbon ion beams. In this work, development steps taken to include carbon ions in MonteRay are presented. Dose distributions computed with MonteRay are evaluated using a comprehensive validation dataset, including various measurements (pristine Bragg peaks, spread out Bragg peaks in water and behind an anthropomorphic phantom) and simulations of a patient plan. The latter includes both physical and biological dose comparisons. Runtimes of MonteRay were evaluated against those of FLUKA MC on a standard benchmark problem. RESULTS: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. In terms of pristine Bragg peaks, mean errors between simulated and measured integral depth dose distributions were between -2.3% and +2.7%. Comparing SOBPs at 5, 12.5 and 20 cm depth, mean absolute relative dose differences were 0.9%, 0.7% and 1.6% respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of 1.2 % ± 1.1 % $1.2\% \pm 1.1\;\%$ with global 3%/3 mm 3D-γ passing rates of 99.3%, comparable to those previously reached with FLUKA (98.9%). Comparisons against dose predictions computed with the clinical treatment planning tool RayStation 11B for a meningioma patient plan revealed excellent local 1%/1 mm 3D-γ passing rates of 98% for physical and 94% for biological dose. In terms of runtime, MonteRay achieved speedups against reference FLUKA simulations ranging from 14× to 72×, depending on the beam's energy and the step size chosen. CONCLUSIONS: Validations against clinical dosimetric measurements in homogeneous and heterogeneous scenarios and clinical TPS calculations have proven the validity of the physical models implemented in MonteRay. To conclude, MonteRay is viable as a fast secondary MC engine for supporting clinical practice in proton, helium and carbon ion radiotherapy.

First evidence of in vivo effect of FLASH radiotherapy with helium ions in zebrafish embryos.

The ability to reduce toxicity of ultra-high dose rate (UHDR) helium ion irradiation has not been reported in vivo. Here, we tested UHDR helium ion irradiation in an embryonic zebrafish model. Our results show that UHDR helium ions spare body development and reduce spine curvature, compared to conventional dose rate.

Stopping-power ratio of body tissues with updated effective energies and elemental I values for treatment planning of proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions.

The stopping-power ratio (SPR) of body tissues relative to water depends on the particle energy and mean excitation energy (I value) of the tissues. Effective energies to minimize the range error in proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions and elemental I values have been updated in recent studies. We investigated the effects of these updates on SPR estimation for computed tomography-based treatment planning. The updates led to an increase of up to 0.5% in the SPRs of soft tissues, whereas they led to a decrease of up to 1.9% in the SPRs of bone tissues compared with the current clinical settings. For 44 proton beams planned for 15 randomly sampled patients, the mean water-equivalent target depth change was - 0.2 mm with a standard deviation of 0.2 mm. The maximum change was - 0.6 mm, which we consider to be insignificant in clinical practice.

Short-lived radioactive8Li and8He ions for hadrontherapy: a simulation study.

Purpose.Although charged particle therapy (CPT) for cancer treatment has grown these past years, the use of protons and carbon ions for therapy remains debated compared to x-ray therapy. While a biological advantage of protons is not clearly demonstrated, therapy using carbon ions is often pointed out for its high cost. Furthermore, the nuclear interactions undergone by carbons inside the patient are responsible for an additional dose delivered after the Bragg peak, which deteriorates the ballistic advantage of CPT. Therefore, a renewed interest for lighter ions with higher biological efficiency than protons was recently observed. In this context, helium and lithium ions represent a good compromise between protons and carbons, as they exhibit a higher linear energy transfer (LET) than protons in the Bragg peak and can be accelerated by cyclotrons. The possibility of accelerating radioactive8Li, decaying in 2α-particles, and8He, decaying in8Li byß-decay, is particularly interesting.Methods. This work aims to assess the interest of the use of8Li and8He ions for therapy by Monte Carlo simulations carried out withGeant4.Results. It was calculated that the8Li and8He decay results in an increase of the LET of almost a factor 2 in the Bragg peak compared to stable7Li and4He. This results also in a higher dose deposited in the Bragg peak without an increase of the dose in the plateau region. It was also shown that both8He and8Li can have a potential interest for prompt-gamma monitoring techniques. Finally, the feasibility of accelerating facilities delivering8Li and8He was also discussed.Conclusion. In this study, we demonstrate that both8Li and8He have interesting properties for therapy. Indeed, simulations predict that8Li and8He are a good compromise between proton and12C, both in terms of LET and dose.

Commissioning of Helium Ion Therapy and the First Patient Treatment With Active Beam Delivery.

PURPOSE: Helium ions offer intermediate physical and biological properties to the clinically used protons and carbon ions. This work presents the commissioning of the first clinical treatment planning system (TPS) for helium ion therapy with active beam delivery to prepare the first patients' treatment at the Heidelberg Ion-Beam Therapy Center (HIT). METHODS AND MATERIALS: Through collaboration between RaySearch Laboratories and HIT, absorbed and relative biological effectiveness (RBE)-weighted calculation methods were integrated for helium ion beam therapy with raster-scanned delivery in the TPS RayStation. At HIT, a modified microdosimetric kinetic biological model was chosen as reference biological model. TPS absorbed dose predictions were compared against measurements with several devices, using phantoms of different complexities, from homogeneous to heterogeneous anthropomorphic phantoms. RBE and RBE-weighted dose predictions of the TPS were verified against calculations with an independent RBE-weighted dose engine. The patient-specific quality assurance of the first treatment at HIT using helium ion beam with raster-scanned delivery is presented considering standard patient-specific measurements in a water phantom and 2 independent dose calculations with a Monte Carlo or an analytical-based engine. RESULTS: TPS predictions were consistent with dosimetric measurements and independent dose engines computations for absorbed and RBE-weighted doses. The mean difference between dose measurements to the TPS calculation was 0.2% for spread-out Bragg peaks in water. Verification of the first patient treatment TPS predictions against independent engines for both absorbed and RBE-weighted doses presents differences within 2% in the target and with a maximum deviation of 3.5% in the investigated critical regions of interest. CONCLUSIONS: Helium ion beam therapy has been successfully commissioned and introduced into clinical use. Through comprehensive validation of the absorbed and RBE-weighted dose predictions of the RayStation TPS, the first clinical TPS for helium ion therapy using raster-scanned delivery was employed to plan the first helium patient treatment at HIT.

Heliox simulations for initial management of congenital laryngotracheal stenosis.

OBJECTIVES: Congenital laryngotracheal stenosis is rare, potentially severe, and difficult to manage. Heliox is a medical gas effective in obstructive airway pathologies, given its physical properties. This study aims to model the interest of Heliox in reducing the respiratory work in congenital laryngotracheal stenosis, using numerical fluid flow simulations, before considering its clinical use. DESIGN: This is a retrospective study, performing Computational Fluid Dynamics numerical simulations of the resistances to airflow and three types of Heliox, on 3D reconstructions from CT scans of children presenting with laryngotracheal stenosis. PATIENTS: Infants and children who were managed in the Pediatric ENT department of a tertiary-care center and underwent CT scanning for laryngotracheal stenosis between 2008 and 2018 were included. RESULTS: Fourteen models of congenital laryngotracheal stenosis were performed in children aged from 16 days to 5 years, and one model of the normal trachea in a 5-year-old child. Tightest stenosis obtained the highest airway resistances, ranging from 40 to 10 kPa/L/s (up to 800 times higher than in the normal case). Heliox enabled a decrease in pressure drops and airway resistances in all stenosis cases, correlated to increasing Helium concentration. CONCLUSIONS: Heliox appears to reduce pressure drops and airway resistances in 3D models of laryngotracheal stenosis. It may represent a supportive treatment for laryngotracheal stenosis, while waiting for specialized care, thanks to the reduction of respiratory work.

Development and benchmarking of the first fast Monte Carlo engine for helium ion beam dose calculation: MonteRay.

BACKGROUND: Monte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; however, general purpose MC engines are computationally demanding and require long runtimes. For this reason, several groups have recently developed fast MC systems dedicated mainly to photon and proton external beam therapy, affording both speed and accuracy. PURPOSE: To support research and clinical activities at the Heidelberg Ion-beam Therapy Center (HIT) with actively scanned helium ion beams, this work presents MonteRay, the first fast MC dose calculation engine for helium ion therapy. METHODS: MonteRay is a CPU MC dose calculation engine written in C++, capable of simulating therapeutic proton and helium ion beams. In this work, development steps taken to include helium ion beams in MonteRay are presented. A detailed description of the newly implemented physics models for helium ions, for example, for multiple coulomb scattering and inelastic nuclear interactions, is provided. MonteRay dose computations of helium ion beams are evaluated using a comprehensive validation dataset, including measurements of spread-out Bragg peaks (SOBPs) with varying penetration depths/field sizes, measurements with an anthropomorphic phantom and FLUKA simulations of a patient plan. Improvement in computational speed is demonstrated in comparison against reference FLUKA simulations. RESULTS: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. Comparing SOBPs at 5, 12.5, and 20 cm depth, mean absolute percent dose differences were 0.7%, 0.7%, and 1.4%, respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of about 1.2% (FLUKA: 1.5%) with per voxel errors ranging from -4.5% to 4.1% (FLUKA: -6% to 3%). Computed global 3%/3 mm 3D-gamma passing rates of ∼99% were achieved, exceeding those previously reported for an analytical dose engine. Comparisons against FLUKA simulations for a patient plan revealed local 2%/2 mm 3D-gamma passing rates of 98%. Compared to FLUKA in voxelized geometries, MonteRay saw run-time reductions ranging from 20× to 60×, depending on the beam's energy. CONCLUSIONS: MonteRay, the first fast MC engine dedicated to helium ion therapy, has been successfully developed with a focus on both speed and accuracy. Validations against dosimetric measurements in homogeneous and heterogeneous scenarios and FLUKA MC calculations have proven the validity of the physical models implemented. Timing comparisons have shown significant speedups between 20 and 60 when compared to FLUKA, making MonteRay viable for clinical routine. MonteRay will support research and clinical practice at HIT, for example, TPS development, validation and treatment design for upcoming clinical trials for raster-scanned helium ion therapy.

[Is helium beneficial in a pulmonary rehabilitation program for severe COPD?] / Apport de l'hélium dans la réhabilitation respiratoire de patients BPCO sévères.

Helium is known to reduce airflow limitation. Our hypothesis was that severe COPD patients undertaking exercise would show greater improvement in endurance under a heliox mixture (80/20%) than under air alone. This hypothesis was tested in a double-blinded, randomized study. METHODS: Out of the 53 patients included, 45 were randomly assigned to two groups : Heliox (n= 23) and Air (n= 22). Patients were assessed with spirometry under air and heliox, incremental exercise test, constant workload (80% Wmax) exercise test and weekly 6-minute walk test. The two groups went through fifteen 30-minute retraining sessions in the overall framework of an identical pulmonary rehabilitation program. RESULTS: There was no significant difference in endurance improvement (Heliox : +52.5 sec, Air:+114sec, median value). FEV1 improvement under heliox exceeding 10% identified a group of 20 patients as "helium responders", who improved their endurance time by a median of 135sec compared to 50sec for the "non-responders" (non-significant difference). CONCLUSION: In patients with severe COPD, use of Heliox in exercise retraining did not produce significantly improved endurance. On the other hand, "helium responders" showed more FEV1 improvement than non-responders. Improved FEV1 under heliox should therefore be used in future studies as an inclusion criterion.

Spot-scanning hadron arc (SHArc) therapy: A proof of concept using single- and multi-ion strategies with helium, carbon, oxygen, and neon ions.

PURPOSE: To present particle arc therapy treatments using single and multi-ion therapy optimization strategies with helium (4 He), carbon (12 C), oxygen (16 O), and neon (20 Ne) ion beams. METHODS AND MATERIALS: An optimization procedure and workflow were devised for spot-scanning hadron arc therapy (SHArc) treatment planning in the PRECISE (PaRticle thErapy using single and Combined Ion optimization StratEgies) treatment planning system (TPS). Physical and biological beam models were developed for helium, carbon, oxygen, and neon ions via FLUKA MC simulation. SHArc treatments were optimized using both single-ion (12 C, 16 O, or 20 Ne) and multi-ion therapy (16 O+4 He or 20 Ne+4 He) applying variable relative biological effectiveness (RBE) modeling using a modified microdosimetric kinetic model (mMKM) with (α/ß)x values of 2, 5, and 3.1 Gy, respectively, for glioblastoma, pancreatic adenocarcinoma, and prostate adenocarcinoma patient cases. Dose, effective dose, linear energy transfer (LET), and RBE were computed with the GPU-accelerated dose engine FRoG and dosimetric/biophysical attributes were evaluated in the context of conventional particle and photon-based therapies (e.g., volumetric modulated arc therapy [VMAT]). RESULTS: All SHArc plans met the target optimization goals (3GyRBE) and demonstrated increased target conformity and substantially lower low-dose bath to surrounding normal tissues than VMAT. SHArc plans using a singleion species (12 C, 16 O, or 20 Ne) exhibited favorable LET distributions with the highest-LET components centralized in the target volume, with values ranging from ∼80-170 keV/µm, ∼130-220 keV/µm, and ∼180-350 keV/µm for 12 C, 16 O, or 20 Ne, respectively, exceeding mean target LET of conventional particle therapy (12 C:∼55, 16 O:∼75 20 Ne:∼95 keV/µm). Multi-ion therapy with SHArc delivery (SHArcMIT ) provided a similar level of target LET enhancement as SHArc compared to conventional planning, however, with additional benefits of homogenous physical dose and RBE distributions. CONCLUSION: Here, we demonstrate that arc delivery of light and heavy ion beams, using either a single-ion species (12 C, 16 O, or 20 Ne) or combining two ions in a single fraction (16 O+4 He or 20 Ne+4 He) affords enhanced physical and biological distributions (e.g., LET) compared with conventional delivery with photons or particle beams. SHArc marks the first single- and multi-ion arc therapy treatment optimization approach using light and heavy ions.

Therapeutic Gases and Inhaled Anesthetics as Adjunctive Therapies in Critically Ill Patients.

The administration of exogenous oxygen to support adequate gas exchange is the cornerstone of respiratory care. In the past few years, other gaseous molecules have been introduced in clinical practice to treat the wide variety of physiological derangement seen in critical care patients.Inhaled nitric oxide (NO) is used for its unique selective pulmonary vasodilator effect. Recent studies showed that NO plays a pivotal role in regulating ischemia-reperfusion injury and it has antibacterial and antiviral activity.Helium, due to its low density, is used in patients with upper airway obstruction and lower airway obstruction to facilitate gas flow and to reduce work of breathing.Carbon monoxide (CO) is a poisonous gas that acts as a signaling molecule involved in many biologic pathways. CO's anti-inflammatory and antiproliferative effects are under investigation in the setting of acute respiratory distress and idiopathic pulmonary fibrosis.Inhaled anesthetics are widely used in the operative room setting and, with the development of anesthetic reflectors, are now a valid option for sedation management in the intensive care unit.Many other gases such as xenon, argon, and hydrogen sulfide are under investigation for their neuroprotective and cardioprotective effects in post-cardiac arrest syndrome.With all these therapeutic options available, the clinician must have a clear understanding of the physiologic basis, therapeutic potential, and possible adverse events of these therapeutic gases. In this review, we will present the therapeutic gases other than oxygen used in clinical practice and we will describe other promising therapeutic gases that are in the early phases of investigation.

Biological Dose Optimization for Particle Arc Therapy Using Helium and Carbon Ions.

PURPOSE: To present biological dose optimization for particle arc therapy using helium and carbon ions. METHODS AND MATERIALS: Treatment planning and optimization procedures were developed for spot-scanning hadron arc (SHArc) delivery using the RayStation treatment planning system and FRoG dose engine. The SHArc optimization algorithm is applicable for charged particle beams and determines angle dependencies for spot and energy selection with three main initiatives: (i) achieve standard clinical optimization goals and constraints for target and organs at risk (OARs), (ii) target dose robustness, and (iii) increase linear energy transfer (LET) in the target volume. Three patient cases previously treated at the Heidelberg Ion-beam Therapy Center (HIT) were selected for evaluation of conventional versus arc delivery for the two clinical particle beams (helium [4He] and carbon [12C] ions): glioblastoma, prostate adenocarcinoma, and skull-base chordoma. Biological dose and dose-averaged LET (LETd) distributions for SHArc were evaluated against conventional planning techniques (volumetric modulated arc therapy [VMAT] and 2-field intensity modulated particle therapy) applying the modified microdosimetric kinetic model with (α/ß)x = 2 Gy. Clinical viability and deliverability were assessed via evaluation of plan quality, robustness, and irradiation time. RESULTS: For all investigated patient cases, SHArc treatment optimizations met planning goals and constraints for target coverage and OARs, exhibiting acceptable target coverage and reduced normal tissue volumes, with effective dose >10-GyRBE compared with conventional 2F planning. For carbon ions, LETd was increased in the target volume from ∼40-60 to ∼80-140 keV/µm for SHArc compared with conventional treatments. Favorable LETd distributions were possible with the SHArc approach, with maximum LETd in clinical target volume/gross tumor volume and potential reductions of high-LET regions in normal tissues and OARs. Compared with VMAT, SHArc affords substantial reductions in normal tissue dose (40%-70%). CONCLUSIONS: SHArc therapy offers potential treatment benefits such as increased normal tissue sparing from higher doses >10-GyRBE, enhanced target LETd, and potential reduction in high-LET components in OARs. Findings justify further development of robust SHArc treatment planning toward potential clinical translation.

Heliox Prescribing Trends for Pediatric Critical Asthma.

BACKGROUND: Children with asthma exacerbations requiring pediatric ICU (PICU) admission, known as critical asthma (CA), are prescribed a variety of therapeutic interventions including heliox. Delivered invasively and noninvasively, heliox is employed to enhance deposition of aerosolized medications, improve obstructive pulmonary pathophysiology, and avoid complications associated with invasive mechanical ventilation. We used the Virtual Pediatric Systems database to update estimates of heliox prescription and explore for relationships between heliox and mechanical ventilation frequency and duration. METHODS: We performed a retrospective cohort study using data from 97 PICUs among children 3-17 y of age admitted for CA from 2013-2019. The primary outcome was heliox prescribing rates and trends. Subgroup analyses assessed mechanical ventilation rates and duration by heliox exposure. RESULTS: Of 43,238 subjects studied, 1,070 (2.5%) were prescribed heliox. Mean heliox prescribing rates fell from 4.11% in 2013 to 2.37% in 2019. Heliox use was greater from centers in the South (2.6%) and Midwest (3.3%) as compared to the West (1.6%) and Northeast United States (1.6%, P < .001). In the subgroup assessing mechanical ventilation frequency, mechanical ventilation rates were 273/39,739 (0.7%) and greater for those provided heliox (1.9% vs 0.7%, P < .001). In the subgroup assessing mechanical ventilation duration, no differences in median mechanical ventilation duration were observed (4.94 [interquartile range [IQR] 3.04-6.36] vs 4.63 [IQR 3.11-7.30] d; P = .35) for those with and without heliox. In exploratory adjusted models, noninvasive heliox was not associated with mechanical ventilation. Mortality was rare (206/43,238 [0.47%]) and predominantly among subjects intubated prehospitalization (188/206 [91.3%]). CONCLUSIONS: Heliox as adjunctive therapy for children with CA is uncommon (2.5%) and not associated with mechanical ventilation or decreased mechanical ventilation duration in adjusted models. Updated estimates provided herein inform prospective controlled trial development to better define the role of heliox for CA.

Roadmap: helium ion therapy.

Helium ion beam therapy for the treatment of cancer was one of several developed and studied particle treatments in the 1950s, leading to clinical trials beginning in 1975 at the Lawrence Berkeley National Laboratory. The trial shutdown was followed by decades of research and clinical silence on the topic while proton and carbon ion therapy made debuts at research facilities and academic hospitals worldwide. The lack of progression in understanding the principle facets of helium ion beam therapy in terms of physics, biological and clinical findings persists today, mainly attributable to its highly limited availability. Despite this major setback, there is an increasing focus on evaluating and establishing clinical and research programs using helium ion beams, with both therapy and imaging initiatives to supplement the clinical palette of radiotherapy in the treatment of aggressive disease and sensitive clinical cases. Moreover, due its intermediate physical and radio-biological properties between proton and carbon ion beams, helium ions may provide a streamlined economic steppingstone towards an era of widespread use of different particle species in light and heavy ion therapy. With respect to the clinical proton beams, helium ions exhibit superior physical properties such as reduced lateral scattering and range straggling with higher relative biological effectiveness (RBE) and dose-weighted linear energy transfer (LETd) ranging from ∼4 keVµm-1to ∼40 keVµm-1. In the frame of heavy ion therapy using carbon, oxygen or neon ions, where LETdincreases beyond 100 keVµm-1, helium ions exhibit similar physical attributes such as a sharp lateral penumbra, however, with reduced radio-biological uncertainties and without potentially spoiling dose distributions due to excess fragmentation of heavier ion beams, particularly for higher penetration depths. This roadmap presents an overview of the current state-of-the-art and future directions of helium ion therapy: understanding physics and improving modeling, understanding biology and improving modeling, imaging techniques using helium ions and refining and establishing clinical approaches and aims from learned experience with protons. These topics are organized and presented into three main sections, outlining current and future tasks in establishing clinical and research programs using helium ion beams-A. Physics B. Biological and C. Clinical Perspectives.