Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT\'s clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology.

UNASSIGNED: The Marburg Ion-Beam Therapy Center (MIT) is one of two particle therapy centers in Germany that enables the treatment of patients with both protons and carbon ions. The facility was build by Siemens Healthineers and is one of only two centers worldwide built by Siemens (Marburg, Germany and Shanghai, China). The present report provides an overview of technical and clinical operations as well as research activities at MIT.
UNASSIGNED: The MIT was completed in 2011 and uses a synchrotron for accelerating protons and carbon ions up to energies of 250 MeV/u and 430 MeV/u respectively. Three treatment rooms with a fixed horizontal beam-line and one room with a 45 degree beam angle are available.
UNASSIGNED: Since the start of clinical operations in 2015, around 2.500 patients have been treated at MIT, about 40% with carbon ions and 60% with protons. Currently around 400 patients are treated each year. The majority of the patients suffered from benign and malign CNS tumors (around 40%) followed by head and neck tumors (around 23%). MIT is actively involved in clinical studies with its patients. In addition to clinical operations, there is active research at MIT in the fields of radiation biology and medical physics. The focus is on translational research to improve the treatment of H & N carcinomas and lung cancer (NSCLC). Moreover, intensive work is being carried out on the technical implementation of FLASH irradiation for research purposes.
UNASSIGNED: The MIT is one of two centers worldwide that were built by Siemens Healtineers and has been successfully in clinical operation since 2015. The service provided by Siemens is guaranteed until 2030, the future after 2030 is currently under discussion.

OBJECTIVE: Magnetic resonance (MR) images free of artefacts are of pivotal importance for MR-guided ion radiotherapy. This study investigates MR image quality for simultaneous irradiation in an experimental setup using phantom imaging as well as in-vivo imaging. Observed artefacts are described within the study and their cause is investigated with the goal to find conclusions and solutions for potential future hybrid devices. Approach: An open magnetic resonance scanner with a field strength of 0.25 T has been installed in front of an ion beamline. Simultaneous MRI and irradiation using raster scanning were performed to analyze image quality in dedicated phantoms. Magnetic field measurements were performed to assist the explanation of observed artifacts. In addition, in-vivo images were acquired by operating the magnets for beam scanning without transporting a beam. Main Results: The additional frequency component within the isocenter caused by the fringe field of the horizontal beam scanning magnet correlates with the amplitude and frequency of the scanning magnet steering and can cause ghosting artifacts in the images. These are amplified with high currents and fast operating of the scanning magnet. Applying a real-time capable pulse sequence in-vivo revealed no ghosting artifacts despite a continuously changing current pattern and a clinical treatment plan activation scheme, suggesting that the use of fast imaging is beneficial for the aim of creating high quality in-beam MR images. This result suggests, that the influence of the scanning magnets on the MR acquisition might be of negligible importance and does not need further measures like extensive magnetic shielding of the scanning magnets. Significance: Our study delimited artefacts observed in MR images acquired during simultaneous raster scanning ion beam irradiation. The application of a fast pulse sequence showed no image artefacts and holds the potential that online MR imaging in future hybrid devices might be feasible. .

Upright positioning has seen a surge in interest recently as a means to reduce radiotherapy (RT) cost, improve patient comfort, and, in selected cases, benefit treatment quality. In particle therapy, eliminating the need for a gantry can present massive reduction of upfront investment, and would drastically reduce the facility footprint. For patients with pre-existing conditions that make lying down uncomfortable, or for target sites in intimate body regions, upright RT presents a promising option toward a more comfortable, patient centred treatment. With more evidence for benefits of upright patient postures in RT emerging, several centres across the globe, mainly in particle therapy, are currently in the process of installing commercially available or prototype upright positioning devices or have already commenced treatment with upright patient postures. Yet, there remain many challenges and open questions to embed upright positioning in the modern RT workflow, no international guidelines exist to support clinical practice in upright RT, and there is a lack of professionals trained for upright patient positioning. Much work is still needed to justify the many changes necessary for upright RT. Modern image guidance is paramount to upright RT, and it is yet unclear which imaging modalities are necessary to support upright postures with the same quality as recumbent positioning. In works on prototype upright positioning systems, external alignment similar to recumbent positioning was reported for small patient or volunteer cohorts. Certain clinical advantages, such as reduced breathing motion in upright position, have been reported, but limited cohort sizes do not allow resilient conclusions on the expected treatment quality yes. Redesign of RT equipment for upright positioning, such as immobilization accessories for various body regions, is necessary, where innovations have been presented in recent literature. This review discusses the opportunities of upright RT and puts them in perspective to the current challenges.

OBJECTIVE: Neskeep®, an absorbable polyglycolic acid spacer, has been developed as the optimal material for spacer placement surgery. However, preventing its severe adhesion is a crucial concern. Therefore, we aimed to identify an effective anti-adhesion agent for Neskeep® using rat models.
METHODS: Animal experiments were performed using 60 rats, which underwent Neskeep® placement on the abdominal wall. Three types of anti-adhesion agents were employed, establishing four subgroups: Seprafilm®, INTERCEED®, AdSpray®, and only Neskeep® (control) groups. Rats were sacrificed on postoperative days 7, 14, and 28 to assess adhesion levels around the Neskeep® Macroscopic visual assessment with the Lauder score and histopathological evaluation were performed to assess the degree of adhesion.
RESULTS: There were no significant differences in the proportion of Lauder scores on days 7 and 14 between the four groups. Histological evaluation revealed no significant differences between groups at any observation time. However, the mean Lauder scores at day 28 were 5.0, 1.6, 4.0, and 4.8 in the Neskeep®, Seprafilm®, INTERCEED®, and AdSpray® groups, respectively. The proportion of milder Lauder score was significantly higher in the Seprafilm® group on day 28.
CONCLUSIONS: Seprafilm® may exhibit an anti-adhesive effect when used with Neskeep®.

Objective.Scanned particle therapy often requires complex treatment plans, robust optimization, as well as treatment adaptation. Plan optimization is especially complicated for heavy ions due to the variable relative biological effectiveness. We present a novel deep-learning model to select a subset of voxels in the planning process thus reducing the planning problem size for improved computational efficiency.Approach.Using only a subset of the voxels in target and organs at risk (OARs) we produced high-quality treatment plans, but heuristic selection strategies require manual input. We designed a deep-learning model based onP-Net to obtain an optimal voxel sampling without relying on patient-specific user input. A cohort of 70 head and neck patients that received carbon ion therapy was used for model training (50), validation (10) and testing (10). For training, a total of 12 500 carbon ion plans were optimized, using a highly efficient artificial intelligence (AI) infrastructure implemented into a research treatment planning platform. A custom loss function increased sampling density in underdosed regions, while aiming to reduce the total number of voxels.Main results.On the test dataset, the number of voxels in the optimization could be reduced by 84.8% (median) at <1% median loss in plan quality. When the model was trained to reduce sampling in the target only while keeping all voxels in OARs, a median reduction up to 71.6% was achieved, with 0.5% loss in the plan quality. The optimization time was reduced by a factor of 7.5 for the total AI selection model and a factor of 3.7 for the model with only target selection.Significance.The novel deep-learning voxel sampling technique achieves a significant reduction in computational time with a negligible loss in the plan quality. The reduction in optimization time can be especially useful for future real-time adaptation strategies.

To investigate the toxicity and survival outcomes of proton and carbon ion radiotherapy for patients with operable early-stage lung cancer who are eligible for lobectomy.
This multicenter nationwide prospective cohort study included patients with operable early-stage lung cancer. Proton and carbon ion radiotherapy was performed according to the schedule stipulated in the unified treatment policy. Progression-free survival (PFS), overall survival (OS) and treatment-related toxicities were evaluated.
A total of 274 patients were enrolled and included in efficacy and safety analyses. The most common tumor type was adenocarcinoma (44 %), while 105 cases (38 %) were not histologically confirmed or diagnosed clinically. Overall, 250 (91 %) of the 274 patients had tumors that were peripherally situated, while 138 (50 %) and 136 (50 %) patients were treated by proton and carbon ion radiotherapy, respectively. The median follow-up time for all censored patients was 42.8 months (IQR 36.7-49.0). Grade 3 or severe treatment-related toxicity was observed in 4 cases (1.5 %). Three-year PFS was 80.5 % (95 % CI: 75.7 %-85.5 %) and OS was 92.5 % (95 % CI: 89.3 %-95.8 %). Pathological confirmation and clinical stage were factors significantly associated with PFS, while tumor location and particle-ion type were not. Meanwhile, clinical stage was significantly associated with OS, but pathological confirmation, tumor location, and particle-ion type were not.
Particle therapy for operable early-stage lung cancer resulted in excellent 3-year OS and PFS in each subset. In this disease context, proton and carbon ion beam therapies are feasible alternatives to curative surgery.

BACKGROUND: Particle therapy makes a noteworthy contribution in the treatment of tumor diseases. In order to be able to irradiate from different angles, usually expensive, complex and large gantries are used. Instead rotating the beam via a gantry, the patient itself might be rotated. Here we present tolerance and compliance of volunteers for a fully-enclosed patient rotation system in a clinical magnetic resonance (MR)-scanner for potential use in MR-guided radiotherapy, conducted within a prospective evaluation study.
METHODS: A patient rotation system was used to simulate and perform magnetic resonance imaging (MRI)-examinations with 50 volunteers without an oncological question. For 20 participants, the MR-examination within the bore was simulated by introducing realistic MRI noise, whereas 30 participants received an examination with image acquisition. Initially, body parameters and claustrophobia were assessed. The subjects were then rotated to different angles for simulation (0°, 45°, 90°, 180°) and imaging (0°, 70°, 90°, 110°). At each angle, anxiety and motion sickness were assessed using a 6-item State-Trait-Anxiety-Inventory (STAI-6) and a modified Motion Sickness Assessment Questionnaire (MSAQ). In addition, general areas of discomfort were evaluated.
RESULTS: Out of 50 subjects, three (6%) subjects terminated the study prematurely. One subject dropped out during simulation due to nausea while rotating to 45°. During imaging, further two subjects dropped out due to shoulder pain from positioning at 90° and 110°, respectively. The average result for claustrophobia (0 = no claustrophobia to 4 = extreme claustrophobia) was none to light claustrophobia (average score: simulation 0.64 ± 0.33, imaging 0.51 ± 0.39). The mean anxiety scores (0% = no anxiety to 100% = maximal anxiety) were 11.04% (simulation) and 15.82% (imaging). Mean motion sickness scores (0% = no motion sickness to 100% = maximal motion sickness) of 3.5% (simulation) and 6.76% (imaging) were obtained across all participants.
CONCLUSIONS: Our study proves the feasibility of horizontal rotation in a fully-enclosed rotation system within an MR-scanner. Anxiety scores were low and motion sickness was only a minor influence. Both anxiety and motion sickness showed no angular dependency. Further optimizations with regard to immobilization in the rotation device may increase subject comfort.

BACKGROUND: A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size.
METHODS: This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4 Gy relative biological effectiveness in 12 fractions, between 2012 and 2022.
RESULTS: Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80 years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9-62.4), 74.9% (95% CI, 90.7-59.0), and 66.4% (95% CI, 83.3-49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis.
CONCLUSIONS: Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma.

Purpose: Head and neck adenoid cystic carcinoma (HNACC) is a radioresistant tumor. Particle therapy, primarily proton beam therapy and carbon-ion radiation, is a potential radiotherapy treatment for radioresistant malignancies. This study aims to conduct a meta-analysis to evaluate the impact of charged particle radiation therapy on HNACC. Methods: A comprehensive search was conducted in Pubmed, Cochrane Library, Web of Science, Embase, and Medline until December 31, 2022. The primary endpoints were overall survival (OS), local control (LC), and progression-free survival (PFS), while secondary outcomes included treatment-related toxicity. Version 17.0 of STATA was used for all analyses. Results: A total of 14 studies, involving 1297 patients, were included in the analysis. The pooled 5-year OS and PFS rates for primary HNACC were 78% (95% confidence interval [CI] = 66-91%) and 62% (95% CI = 47-77%), respectively. For all patients included, the pooled 2-year and 5-year OS, LC, and PFS rates were as follows: 86.1% (95% CI = 95-100%) and 77% (95% CI = 73-82%), 92% (95% CI = 84-100%) and 73% (95% CI = 61-85%), and 76% (95% CI = 68-84%) and 55% (95% CI = 48-62%), respectively. The rates of grade 3 and above acute toxicity were 22% (95% CI = 13-32%), while late toxicity rates were 8% (95% CI = 3-13%). Conclusions: Particle therapy has the potential to improve treatment outcomes and raise the quality of life for HNACC patients. However, further research and optimization are needed due to the limited availability and cost considerations associated with this treatment modality.