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Protons and carbon ions have been extensively used for radiotherapy treatments, and in comparison to conventional radiotherapy, they allow a more conformal dose to the target tumor, especially in case of deep-seated tumors. However, the accuracy of hadron therapy treatments is affected by uncertainties in the particle range calculations. Several techniques are under development for in-vivo range verification, one of which consists on measuring the activity distributions of positron emitters, such as 10C, 11C and 15O, which are produced in the patient body during proton and carbon ion treatments. A comparison between measured and expected positron emitter activity distributions can provide information on the quality of the delivered treatment and accuracy of the particle range calculations. In this work the FLUKA production cross sections for 10C, 11C and 15O originated from proton and carbon ion beams in carbon and oxygen targets were compared with experimental data, at low and therapeutic energies.

Mono-energetic carbon ion scanning beams of 195.2 MeV/u at the Italian National Centre for Oncological Hadrontherapy (CNAO) have been used to study the microdosimetric features of an “active” carbon ion beam used in hadrontherapy. A 30x30 mm2 area has been scanned by a 6 mm beam with scanning steps of 2 mm. A mini TEPC of 0.57 mm3 has been used to perform measurements in a water phantom at different depths on the beam axis. The detector small size allowed for measuring, with good spatial resolution, also inside the relatively small Bragg peak region and inside the distal edge, where the radiation quality varies quickly. In spite of the high event rate (up to ~ 105 s-1), no pile-up effects were observed. Results showed that the frequency-mean lineal energy scaled well with the absorbed dose. Moreover, the dose-mean lineal energy itself seemed to be a good descriptor of the radiation quality.

Background and purpose: Ion beams exhibit an increased relative biological effectiveness (RBE) with respect to photons. This study determined the RBE of oxygen ion beams as a function of linear energy transfer (LET) and dose in the rat spinal cord. Materials and methods: The spinal cord of rats was irradiated at four different positions of a 6 cm spread-out Bragg-peak (LET: 26, 66, 98 and 141 keV/µm) using increasing levels of single and split oxygen ion doses. Dose-response curves were established for the endpoint paresis grade II and based on ED50 (dose at 50 % effect probability), the RBE was determined and compared to model predictions. Results: When LET increased from 26 to 98 keV/µm, ED50 decreased from 17.2 ± 0.3 Gy to 13.5 ± 0.4 Gy for single and from 21.7 ± 0.4 Gy to 15.5 ± 0.5 Gy for split doses, however, at 141 keV/µm, ED50 rose again to 15.8 ± 0.4 Gy and 17.2 ± 0.4 Gy, respectively. As a result, the RBE increased from 1.43 ± 0.05 to 1.82 ± 0.08 (single dose) and from 1.58 ± 0.04 to 2.21 ± 0.08 (split dose), respectively, before declining again to 1.56 ± 0.06 for single and 1.99 ± 0.06 for split doses at the highest LET. Deviations from RBE-predictions were model-dependent. Conclusion: This study established first RBE data for the late reacting central nervous system after single and split doses of oxygen ions. The data was used to validate the RBE-dependence on LET and dose of three RBE-models. This study extends the existing data base for protons, helium and carbon ions and provides important information for future patient treatments with oxygen ions.

Abstract Background Carbon ion radiotherapy (CIRT) yields biophysical advantages compared to photons but randomized studies for the reirradiation setting are pending. The aim of the current project was to evaluate potential clinical benefits and drawbacks of CIRT compared to volumetric modulated arc therapy (VMAT) in recurrent head and neck cancer. Methods Dose-volume parameters and local failure patterns of CIRT compared to VMAT were evaluate in 16 patients from the randomized CARE trial on head and neck cancer reirradiation. Results Despite an increased target dose, CIRT resulted in significantly reduced organ at risk (OAR) dose across all patients (− 8.7% Dmean). The dose-volume benefits were most pronounced in the brainstem (− 20.7% Dmax) and the optic chiasma (− 13.0% Dmax). The most frequent local failure was type E (extraneous; 50%), followed type B (peripheral; 33%) and type A (central; 17%). In one patient with type A biological and/or dosimetric failure after CIRT, mMKM dose recalculation revealed reduced target coverage. Conclusions CIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Local failure pattern analysis revealed further potential CIRT specific clinical benefits and potential pitfalls with regard to image-guidance and biological dose-optimization.

Abstract Background To develop an auxiliary GPU-accelerated proton therapy (PT) dose and LETd engine for the IBA Proteus®ONE PT system. A pediatric low-grade glioma case study is reported using FRoG during clinical practice, highlighting potential treatment planning insights using variable RBE dose (DvRBE) and LETd as indicators for clinical decision making in PT. Methods The physics engine for FRoG has been modified for compatibility with Proteus®ONE PT centers. Subsequently, FRoG was installed and commissioned at NPTC. Dosimetric validation was performed against measurements and the clinical TPS, RayStation (RS-MC). A head patient cohort previously treated at NPTC was collected and FRoG forward calculations were compared against RS-MC for evaluation of 3D-Γ analysis and dose volume histogram (DVH) results. Currently, treatment design at NPTC is supported with fast variable RBE and LETd calculation and is reported in a representative case for pediatric low-grade glioma. Results Simple dosimetric tests against measurements of iso-energy layers and spread-out Bragg Peaks in water verified accuracy of FRoG and RS-MC. Among the patient cohort, average 3D-Γ applying 2%/2 mm, 3%/1.5 mm and 5%/1 mm were > 97%. DVH metrics for targets and OARs between FRoG and RayStation were in good agreement, with ∆D50,CTV and ∆D2,OAR both ⪅1%. The pediatric case report demonstrated implications of different beam arrangements on DvRBE and LETd distributions. From initial planning in RayStation sharing identical optimization constraints, FRoG analysis led to plan selection of the most conservative approach, i.e., minimized DvRBE,max and LETd,max in OARs, to avoid optical system toxicity effects (i.e., vision loss). Conclusion An auxiliary dose calculation system was successfully integrated into the clinical workflow at a Proteus®ONE IBA facility, in excellent agreement with measurements and RS-MC. FRoG may lead to further insight on DvRBE and LETd implications to help clinical decision making, better understand unexpected toxicities and establish novel clinical procedures with metrics currently absent from the standard clinical TPS.

Purpose: To present novel approaches in particle therapy that could result in an improvement of patient outcome. Methods: Technological/planning and biological innovations could bring particle therapy into a new area of precision medicine. However, several hurdles have to be overcome in order to transform these R&D opportunities into clinical advantages. In this contribution, we summarize the potential advantages of novel tumor targeting, through high-LETd boosting strategies with carbon ions, over standard IMPT: LETd-optimization for IMPT plan, IMPTLET, and spot-scanning hadron arc (SHArc) therapy. Two patient cases are presented to showcase the benefit: a pancreatic cancer patient (PATA) and a recurrent glioblastoma patient (PATB). Results: For both patients, the prescription dose and target/organs at risk (OARs) optimization goals were reached for the three techniques. In standard IMPT, the maximum LETd is placed outside of the target volume and extends into normal tissues. For the gross target volume (GTV), mean LETd values were, on average, around ∼40–60 keV/µm. IMPTLET allowed an increase in the GTV minimum LETd from 38.4 keV/µm to 48.6 keV/µm, and from 55.1 to 87.1 keV/µm, for PATA and PATB, respectively. SHArc led to an enhancement of the maximum LETd in the GTV up to at least 125 keV/µm, while the minimum GTV LETd were 47.2 keV/µm and 46.1 keV/µm, respectively. For PATA, SHArc lowers the maximum LETd in the gastrointestinal tract to 47.5 keV/µm compared to 88.0 keV/µm and 83.0 keV/µm found for the IMPT and IMPTLET plans, respectively. Conclusions: Many technological and biological innovations could enhance our current clinical approach. Following the current success of the IMPTLET introduction in clinic, SHARc will represent an interesting clinical option in carbon ion therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study retrospectively investigates clinicopathological characteristics and survival outcomes of patients affected by sinonasal intestinal-type adenocarcinoma with tumor budding. Tumor budding was evaluated in 32 patients and allowed the identification of high budding (>4) and low budding (≤4) groups. High-budding patients had worse overall survival, higher relapse, and disease-caused death compared to low-budding patients. On multivariate analysis, considering tumor budding, therapy, and stage as covariates, tumor budding was found to be an independent prognostic factor net of the stage of disease and the type of therapy received. Other markers, such as p53, did not show any significant prognostic correlation in sinonasal intestinal-type adenocarcinoma, whereas no change in DNA mismatch repair protein expression was detected. These results reinforce the prognostic value of tumor budding in sinonasal intestinal-type adenocarcinoma, underline the potential impact of this parameter, and encourage its use in clinical practice. Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients' outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice. [ABSTRACT FROM AUTHOR]

Bacterial infections are usually caused by biofilms that are resistant to extreme conditions. Studies have shown that fungal extracts have the potential to inhibit biofilm formation. The aim of this study was to examine the activity of several fungal culture filtrates in inhibiting bacterial growth and biofilm formation. The fungi were identified by molecular method, and the effects of different concentrations (45%, 75%, and 90%), medium pH (6, 7, and 9), temperatures (30 and 37 °C), and incubation times (24, 48, and 72 h) of the filtrates on their anti-biofilm formation properties were investigated. Anti-biofilm assay was performed using the diffusion test and microtiter assay. The parameters examined included the diameter of the inhibition zone of each well and the optical density of the filtrate solution. Molecular identification based on ITS rDNA regions showed that the fungal isolates in this study were Schizophyllum commune (strain JSB2), Coniothyrium sp. (strain JB1-3), and Fusarium sp. (strain JBB2). Antibacterial assay showed that, among the culture filtrates obtained from all fungi, that from Fusarium sp. strain JBB2 exhibits the highest inhibitory activity. Biofilm inhibition assay further revealed optimum fungal culture filtrate activities at pH 7.

To start clinical trials with the first clinical treatment planning system supporting raster-scanned helium ion therapy, a comprehensive database of beam characteristics and parameters was required for treatment room-specific beam physics modeling at the Heidelberg Ion-Beam Therapy Center (HIT). At six different positions in the air gap along the beam axis, lateral beam profiles were systematically measured for 14 initial beam energies covering the full range of available energies at HIT. The 2D-array of liquid-filled ionization chambers OCTAVIUS from PTW was irradiated by a pencil beam focused at the central axis. With a full geometric representation of HIT’s monitoring chambers and beamline elements in FLUKA, our Monte Carlo beam model matches the measured lateral beam profiles. A second set of measurements with the detector placed in a water tank was used to validate the adjustments of the initial beam parameters assumed in the FLUKA simulation. With a deviation between simulated and measured profiles below ±0.8 mm for all investigated beam energies, the simulated profiles build part of the database for the first clinical treatment planning system for helium ions. The evolution of beamwidth was also compared to similar simulations of the clinically available proton and carbon beam. This allows a choice of treatment modality based on quantitative estimates of the physical beam properties. Finally, we investigated the influence of beamwidth variation on patient treatment plans in order to estimate the relevance and necessary precision limits for lateral beam width models.

Dose calculation algorithms based on Monte Carlo (MC) simulations play a crucial role in radiotherapy. Here, the development and benchmarking of a novel MC dose engine, MonteRay, is presented for proton therapy aiming to support clinical activity at the Heidelberg Ion Beam Therapy center (HIT) and the development of MRI (magnetic resonance imaging)-guided particle therapy. Comparisons against dosimetric data and gold standard MC FLUKA calculations at different levels of complexity, ranging from single pencil beams in water to patient plans, showed high levels of agreement, validating the physical approach implemented in the dose engine. Additionally, MonteRay has been found to match satisfactorily to FLUKA dose predictions in magnetic fields both in homogeneous and heterogeneous scenarios advocating its use for future MRI-guided proton therapy applications. Benchmarked on 150 MeV protons transported on a 2 × 2 × 2 mm3 grid, MonteRay achieved a high computational throughput and was able to simulate the histories of more than 30,000 primary protons per second on a single CPU core.

Purpose: Variable relative biological effectiveness (RBE) models allow for differences in linear energy transfer (LET), physical dose, and tissue type to be accounted for when quantifying and optimizing the biological damage of protons. These models are complex and fraught with uncertainties, and therefore, simpler RBE optimization strategies have also been suggested. Our aim was to compare several biological optimization strategies for proton therapy by evaluating their performance in different clinical cases. Methods and Materials: Two different optimization strategies were compared: full variable RBE optimization and differential RBE optimization, which involve applying fixed RBE for the planning target volume (PTV) and variable RBE in organs at risk (OARs). The optimization strategies were coupled to 2 variable RBE models and 1 LET-weighted dose model, with performance demonstrated on 3 different clinical cases: brain, head and neck, and prostate tumors. Results: In cases with low (α/β)x in the tumor, the full RBE optimization strategies had a large effect, with up to 10% reduction in RBE-weighted dose to the PTV and OARs compared with the reference plan, whereas smaller variations (

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. [ABSTRACT FROM AUTHOR]