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Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response. We utilized a panel of human PDAC cell lines with diverse genetic profiles to determine their sensitivity to CIRT compared to γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity was linked to impaired DNA double-strand break (DSB) repair, particularly in cell lines with deficiencies in the homologous recombination (HR) repair pathway and/or elevated genomic instability from replication stress. Furthermore, pretreatment with the HR inhibitor B02 significantly enhanced CIRT sensitivity in a radioresistant PDAC cell line when irradiated in the spread-out Bragg peak but not at the entry position of the beam. These findings suggest that PDAC tumors with HR pathway mutations or high replication stress are more likely to benefit from CIRT while minimizing normal tissue toxicity. [ABSTRACT FROM AUTHOR]

Featured Application: Nomograms were developed to estimate 5- and 7-year biochemical recurrence-free survival in patients with high-risk prostate cancer treated with carbon-ion radiotherapy and androgen deprivation therapy. Background: The aim of this study was to develop nomograms predicting 5- and 7-year biochemical-recurrence (BCR)-free survival in high-risk prostate cancer (PCa) patients treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). Methods: We retrospectively evaluated 785 high-risk PCa patients treated with CIRT and ADT. Based on the least absolute shrinkage and selection operator model, two nomograms predicting 5- and 7-year BCR-free survival were developed and internally validated. The ability of each nomogram to predict BCR-free survival was determined by calculating the area under the survival curve (AUC). Results: The 5- and 7-year BCR-free survival rates were 92.1% and 89.3%, respectively. Age, prostate-specific antigen level, clinical T stage, and Gleason score were incorporated into the nomogram predicting 5-year BCR-free survival. In addition to these variables, the percentage of positive biopsy cores was also added to the nomogram predicting 7-year BCR-free survival. The AUC value of each nomogram showed suboptimal-to-good discrimination. Conclusions: We developed the first nomograms accurately predicting BCR-free survival in high-risk PCa patients treated with CIRT and ADT. These nomograms will enable adequate understanding and explanation of BCR-free survival to patients when clinicians use them. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, calling for enhanced research. Pancreatic ductal adenocarcinoma (PDAC) represents 70–80% of all cases and is known for its resistance to conventional therapies. Carbon-ion radiotherapy (CIRT) has emerged as a promising approach due to its ability to deliver highly localized doses and unique radiobiological properties compared to X-rays. In vitro radiobiology has relied on two-dimensional (2D) cell culture models so far; however, these are not sufficient to replicate the complexity of the in vivo tumor architecture. Three-dimensional (3D) models become a paradigm shift, surpassing the constraints of traditional models by accurately re-creating morphological, histological, and genetic characteristics as well as the interaction of tumour cells with the microenvironment. Materials and Methods: This study investigates the survival of pancreatic cancer cells in both 2D and spheroids, a 3D model, following photon, proton, and carbon-ion irradiation by means of clonogenic, MTT, spheroid growth, and vitality assays. Results: Our results demonstrate that carbon ions are more efficient in reducing cancer cell survival compared to photons and protons. In 2D cultures, carbon-ion irradiation reduced cell survival to approximately 15%, compared to 45% with photons and 30% with protons. In the 3D culture model, spheroid growth was similarly inhibited by carbon-ion irradiation; however, the overall survival rates were higher across all irradiation modalities compared to the 2D cultures. Carbon ions consistently showed the highest efficacy in reducing cell viability in both models. Conclusions: Our research highlights the pivotal role of 3D models in unraveling the complexities of pancreatic cancer radiobiology, offering new avenues for designing more effective and precise treatment protocols. [ABSTRACT FROM AUTHOR]

Background: In carbon ion radiotherapy, accurate measurement of the three‐dimensional (3D) absorbed dose distribution is critical for effectively targeting tumors. Although micellar gel dosimeters exhibit considerable potential for measuring 3D absorbed dose distributions, few studies have focused on radiotherapy using carbon ion beams. Purpose: This study investigated the applicability of the surfactant hydrogel dosimeter (SHD), a micellar gel dosimeter, to measuring a 3D dose absorbed through carbon ion beam irradiation. Methods: A cubic target region of 34 mm per side was established at a depth of 46 mm below the upper surface of an SHD specimen. Scanning irradiation was performed using a pencil beam of carbon ions at the Ion‐beam Radiation Oncology Center in Kanagawa ("i‐ROCK"), Japan, under irradiation conditions set by the treatment planning system ("Monaco for Carbon", Ver. 5.20, Elekta AB, Sweden) to create a spread‐out Bragg peak within the target. The physical dose was set to 10 Gy at the isocenter, situated at the center of the target. The SHD responsiveness was measured twice using optical computed tomography (CT) ("Vista 15", Modus Medical Devices, Canada) for three irradiated specimens, and six types of measured optical attenuation coefficient (OAC) were obtained. To assess whether the OAC represented the absorbed dose expected in the treatment plan, we compared the relative distribution of the OAC and that of the absorbed dose. Relative fraction (RF) was used to measure the difference between the relative value of the OAC and that of the absorbed dose. Moreover, the distribution of OH radical (•OH) concentration obtained by Monte Carlo simulation ("PHITS" ver. 3.24 JAEA, Japan) and that of the OAC were compared. Results: In the direction of beam travel, the relative distribution of the OAC was lower than that of the absorbed dose. This discrepancy could be attributed to a decrease in the concentration of •OH produced by irradiation owing to the recombination reaction, which does not accurately reflect the absorbed dose. By contrast, the distributions in the plane perpendicular to the beam travel were consistent. The RF increased from ± 3% to ± 13% along the beam travel direction. The small RF in the plane perpendicular to the beam travel could be attributed to the constant distribution of linear energy transfer, regardless of the irradiation position, and the generation of radicals proportionally to the absorbed dose. The increase in RF along the beam travel direction was ascribed to ring artifacts in the irradiated region. Conclusion: The measurement of the absorbed dose distribution in the beam travel direction should be improved. The observed discrepancy is attributed to the reduced reactivity of the SHD due to a high liner energy transfer near the Bragg peak. However, the absorbed dose distribution can be effectively evaluated in the plane perpendicular to the direction of beam travel. [ABSTRACT FROM AUTHOR]

Objective: Exploring the experiences and perceptions of head and neck cancer (HNC) patients undergoing proton heavy ion therapy who develop taste dysfunction during treatment to improve taste dysfunction management for these patients. Design: A qualitative study design using a descriptive phenomenological approach. Method: Conducted individual face-to-face semi-structured interviews in the Head and Neck Tumor Department of the Shanghai Proton and Heavy Ion Center from February to April 2024. Results: The experiences of patients with HNC undergoing proton and heavy ion radiotherapy revealed four key themes: the diversity of taste dysfunction (including reduced or lost perception of sweet, sour, bitter, and other tastes, as well as altered and distorted taste of certain foods); the impact of taste dysfunction on quality of life (changes in dietary habits, malnutrition and weight fluctuations, mental health, and social impacts); strategies for coping with taste dysfunction (altering dietary habits and increasing the use of seasonings to compensate for taste reduction, seeking social support, and engaging in mental health activities to manage emotional distress); and expectations from the healthcare team (need for information and support, psychological support services, and monitoring and evaluation). Conclusion: Patients with HNC undergoing proton and heavy ion therapy experience significant taste dysfunction. Therefore, during proton and heavy ion therapy for HNC, it is crucial to closely monitor and effectively manage taste dysfunction to enhance patients’ quality of life and treatment outcomes. Future research should further explore the mechanisms of taste dysfunction and develop interventions to better meet patients’ needs and improve the individualization of treatment. [ABSTRACT FROM AUTHOR]

The current research on staffing models is primarily focused on conventional external photon beam therapy, which predominantly involves using linear accelerators. This emphasizes the need for comprehensive studies to understand better and define specific particle therapy facilities' staffing requirements. In a 2022 survey of 25 particle therapy facilities in Japan with an 84% response rate, significant insights were obtained regarding workload distribution, defined as the product of personnel count and task time (person-minutes), for patient-related tasks and equipment quality assurance and quality control (QA/QC). The survey revealed that machinery QA/QC tasks were particularly demanding, with an average monthly workload of 376.9 min and weekly tasks averaging 162.1 min. In comparison, patient-related workloads focused on treatment planning, exhibiting substantial time commitments, particularly for scanning and passive scattering techniques. The average workloads for treatment planning per patient were 291.3 and 195.4 min, respectively. In addition, specific patient scenarios such as pre-treatment sedation in pediatric cases require longer durations (averaging 84.5 min), which likely include the workloads of not only the physician responsible for sedation but also the radiotherapy technology and medical physics specialists providing support during sedation and the nursing staff involved in sedation care. These findings underscore the significant time investments required for machinery QA/QC and patient-specific treatment planning in particle therapy facilities, along with the need for specialized care procedures in pediatric cases. The results of this survey also emphasized the challenges and staffing requirements to ensure QA/QC in high-precision medical environments. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion A passive dosimeter framework for the measurement of dose in carbon ion beams has yet to be characterized or implemented for regular use.This work determined the dose calculation correction factors for absorbed dose in thermoluminescent dosimeters (TLDs) in a therapeutic carbon ion beam. TLD could be a useful tool for remote audits, particularly in the context of clinical trials as new protocols are developed for carbon ion radiotherapy.TLD‐100 were irradiated in a carbon ion beam at the Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia, Italy. The dose correction factors for linearity, fading, and beam quality were characterized. Fading was characterized from 5 to 100 days post‐irradiation. For linearity, the TLDs were irradiated to absorbed doses ranging from 1 to 15 Gy in both the entrance of a high‐energy pristine carbon ion peak and the center of a 2 cm spread‐out Bragg peak. For beam quality, the TLD was irradiated to the same absorbed dose (3 Gy) in several pristine carbon ion Bragg peaks, as well as in several spread‐out Bragg peaks. Each correction factor was calculated and compared to photon correction factors. The correction factors were also compared between high and low dose‐averaged linear energy transfer (LETD) in the carbon ion beams. The absorbed dose was compared between ion chamber and TLD‐100 in the several tissue substitute phantom materials, applying the carbon ion TLD correction factors.There was no statistically significant difference in the TLD fading correction factor between photons, low LETD carbon ion beams, or high LETD carbon ion beams. The TLD linearity correction factor did differ between photons, low LETD carbon ions, and high LETD carbon ions. The beam quality correction factor was large and changed linearly with LETD. The overall uncertainty of the carbon ion absorbed dose calculation was 3.9% at the one‐sigma level, driven largely by a 3.5% uncertainty in the beam quality correction. TLD measurements were within 1.2% of ion chamber measurements in the phantom material for polyethylene, solid water (Gammex and Sun Nuclear), acrylic, blue water, and techtron HPV. TLD measurements in balsa wood were within 3.0% and cork was 6.6% low compared to ion chamber.TLD‐100 can be used for passive dosimetry in a therapeutic carbon ion beam. Importantly, the linearity and beam quality correction factors are both different from photon therapy, and dependent on LETD of the carbon ion beam. This opens the possibility of TLD use for carbon ion output audits, phantom audits, and in vivo dose measurements, but may be subject to more complicated management and slightly larger uncertainties than are achieved in photon beams. [ABSTRACT FROM AUTHOR]

Background and purpose: This study evaluates the dosimetric impact of tumor matching (TM) and bone matching (BM) in carbon ion radiotherapy for locally advanced non-small cell lung cancer. Materials and methods: Forty patients diagnosed with locally advanced non-small cell lung cancer were included in this study. TM and BM techniques were employed for recalculation based on re-evaluation computed tomography (CT) images of the patients, resulting in the generation of dose distributions: Plan-T and Plan-B, respectively. These distributions were compared with the original dose distribution, Plan-O. The percentage of the internal gross tumor volume (iGTV) receiving a prescription dose greater than 95% (V95%) was evaluated using dose-volume parameters. Statistical analysis was performed using a paired signed-rank sum test. Additionally, the study investigated the influence of tumor displacement, volume changes, and rotational errors on target dose coverage. Results: The median iGTV V95% values for the Plan-O, Plan-T, and Plan-B groups were 100%, 99.93%, and 99.60%, respectively, with statistically significant differences observed. TM demonstrated improved target dose coverage compared to BM. Moreover, TM exhibited better target coverage in case of larger tumor displacement. TM's increased adjustability in rotation directions compared to BM significantly influenced dosimetric outcomes, rendering it more tolerant to variations in tumor morphology. Conclusion: TM exhibited superior target dose coverage compared to BM, particularly in cases of larger tumor displacement. TM also demonstrated better tolerance to variations in tumor morphology. [ABSTRACT FROM AUTHOR]

Simple Summary: Gynecological mucosal melanomas are rare, aggressive, and radioresistant neoplasms for which no standardized treatment protocols currently exist. When surgery, which appears to be the gold standard, is not feasible, radiation therapy can be considered. However, mucosal melanomas exhibit specific biological hallmarks of radioresistance, and, indeed, the outcomes reported in the literature on the use of photons in this context are not encouraging. Currently, there are limited data on the use of carbon ion radiotherapy (CIRT) in this setting. The aim of this study is to evaluate, in a real-world cohort, the efficacy and tolerance of CIRT for gynecological melanomas, with the goal of expanding knowledge on the use of this radiotherapy technique in such a radioresistant and difficult-to-treat malignancy. Background/Objectives: Primary gynecological melanomas are rare malignancies with lower survival rates compared to cutaneous melanomas. Both preclinical and clinical data support the evidence that mucosal melanomas are photon-radioresistant but responsive to carbon ion radiotherapy (CIRT). The aim of this study is to assess, in a real-world cohort, the effectiveness and tolerability of radical CIRT in patients with inoperable gynecological mucosal melanoma. Methods: This is a real-world study aimed to assess the effectiveness and the safety of CIRT in this setting. We defined as the primary endpoints the objective response rate (ORR) and the clinical benefit (CB). The secondary endpoints included the actuarial local control rate (LC) assessed after 1 year and 2 years and the toxicity scored according to CTCAE v.5. Actuarial outcomes were analyzed using the Kaplan–Meier method, while potential predictors were investigated through the Log-rank test. Results: Between 2017 and 2023, eleven Caucasian patients underwent pelvic CIRT (total dose 68.8 GyRBE) for mucosal malignant melanoma of the vulva or the vagina. With a median follow-up of 18 months, we observed an ORR of 82% and a CB of 100%. LC at 1 and 2 years was 100% and 86%, respectively, and among the factors analyzed for their potential impact on LC, age < 60 years seems to be a potential predictor (p = 0.014). The treatment was well tolerated, with only one case of acute grade 3 erythema and, in the late phase, one case of grade 3 erythema and grade 3 urethral toxicity. Conclusions: CIRT was effective and safe for gynecological melanomas. Larger collaborative cohort studies and longer follow-ups are needed to take a step forward in comprehending the correct management of this disease. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion Clinical carbon ion beams offer the potential to overcome hypoxia‐induced radioresistance in pancreatic tumors, due to their high dose‐averaged Linear Energy Transfer (LETd), as previous studies have linked a minimum LETd within the tumor to improved local control. Current clinical practices at the Heidelberg Ion‐Beam Therapy Center (HIT), which use two posterior beams, do not fully exploit the LETd advantage of carbon ions, as the high LETd is primarily focused on the beams’ distal edges. Different LETd‐boosting strategies, such as Spot‐scanning Hadron Arc (SHArc), could enhance LETd distribution by concentrating high‐LETd values in potential hypoxic tumor cores while sparing organs at risk.This study aims to investigate and verify different LETd‐boosting strategies using an anthropomorphic pancreas phantom.Various LETd‐boosting strategies were investigated for a cylindrical and a pancreas‐shaped target in an anthropomorphic pancreas phantom. Treatment plans were optimized using single field optimization (SFO) or multi field optimization (MFO), with objective functions based on either physical dose (Phys), relative biological effectiveness (RBE)‐weighted dose, or a combination of RBE and LETd‐based objectives (LETopt). The LETd‐boosting planning strategies were optimized with the goal of increasing the minimum LETd in the tumor without compromising its homogeneous dose coverage. Beam configurations investigated included the two‐beam in‐house clinical standard (2‐SFOPhys, 2‐SFORBE and 2‐MFORBE‐LETopt), a three‐beam configuration (3‐MFORBE and 3‐MFORBE‐LETopt) and SHArc (SHArcPhys, SHArcRBE and SHArcRBE‐LETopt) using step‐and‐shoot delivery. The different plans were verified using an anthropomorphic pancreas phantom at HIT and compared to treatment planning system (TPS) predictions.All investigated LETd‐boosting strategies altered the LETd distribution while meeting optimization goals and constraints, resulting in varying degrees of LETd enhancement. For the cylindrical volume, the SHArc plan resulted in the highest LETd concentration in the tumor core, with the minimum LETd in the GTV scaling up to 91 keV/µm. For the pancreas‐shaped volume, however, the 3‐MFORBE‐LETopt achieved a higher minimum LETd in the GTV than SHArcRBE (75.6 and 62.3 keV/µm, respectively). When combining SHArc with LETd optimization, a minimum LETd of 76.3 keV/µm was achieved, suggesting a potential benefit from this combined approach. Most dosimetric verifications showed dose deviations to the TPS within a 5% range, for both beam‐per‐beam and total dose. LETd‐optimized and SHArc plans exhibited slightly higher mean dose deviations (2.0%—4.6%) compared to the standard RBE‐based plans (<1.5%).This study demonstrated the feasibility of enhancing LETd in pancreatic tumors using carbon ion arc delivery coupled with LETd optimization. The possibility of delivering these plans was verified through irradiation of an anthropomorphic pancreas phantom, which showed agreement between dose measurements and predictions. [ABSTRACT FROM AUTHOR]

Chordomas are rare, locally aggressive tumors that have a high rate of recurrence, especially at the skull base. This systematic review and meta-analysis aimed to analyze the efficacy and safety of proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) for skull base chordoma. We conducted a systematic search of MEDLINE, EMBASE, CENTRAL, Web of Science, and Ovid up to November 26, 2023, following the PRISMA statement. Studies involving more than 10 patients with skull base chordoma treated with PBT or CIRT were included. The outcomes analyzed were local control, overall survival, progression-free survival, and toxicities. Meta-analysis was performed using the Mantel–Haenszel method and the inverse variance method. Fourteen studies met the inclusion criteria, encompassing 1,145 patients (671 treated with PBT and 474 with CIRT). No significant difference was found between PBT and CIRT for 5-year local control (LC) and overall survival (OS). The only timepoint with a difference in local control was at 3 years, when PBT showed an advantage in local control (90% vs. 83% for CIRT; p = 0.05) and progression-free survival was similar (94% for PBT vs. 83% for CIRT; p = 0.09). Sensitivity analysis and meta-regression revealed no significant influence of predefined parameters on outcomes. Publication bias was suggested by asymmetrical funnel plots. Both PBT and CIRT are effective treatments for skull base chordoma, with comparable long-term efficacy. This meta-analysis underscores the need for individualized treatment approaches and further research to refine these therapies in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Due to the rarity of mucosal melanomas, few recent studies can be found investigating the success and side effects of therapy for this entity with large numbers of patients. In this retrospective analysis, the efficacy and toxicity of combined intensity-modulated radiotherapy (IMRT) and carbon ion therapy (C12) of mucosal melanomas were analyzed to contribute to a better understanding of this rare disease. Methods: Twenty-two patients were included from 2013 to 2022 in the Department of Radiation Oncology at Heidelberg University Hospital. 19 patients received bimodal radiotherapy consisting of radiotherapy by IMRT and carbon ion therapy (C12). 3 patients received photon only IMRT. In addition to Overall Survival (OS), local control rate (LCR), locoregional control rate (LRCR) and progression-free survival (PFS), early and late toxicity of treatment was analyzed. Bimodal radiotherapy consisted of IMRT of the primary tumor region and cervical lymph nodes in a single dose of 2 Gy up to the dose of 50.0 Gy in the basic schedule after application of a C12 boost of the primary tumor region up to 24 Gy (RBE) in a single dose of 3 Gy (RBE) up to the total dose of 74.0 Gy (RBE) in 5-6 fractions/week. Photon only radiotherapy comprised IMRT up to total doses of 66-70,4 Gy in 5 fractions/week. Results: After 2 years, overall survival, progression-free survival, local control and locoregional control were 46%, 41%, 77% and 77%, respectively. 4 out of 5 patients with local relapse showed in-field recurrence inside the C12 boost volume. The primary tumor in these patients was always located in the main nasal cavity and/or paranasal sinus. Leading acute toxicity was grade 2 mucositis (12 patients, 55%) followed by grade 1 radiation dermatitis (10 patients, 45%). The cumulative incidence of late grade 3 toxicities was 15%. Discussion: The combination of IMRT with carbon ion therapy in the treatment of mucosal melanoma provides promising local control rates with mild acute toxicity despite unfavorable patient preselection. The unfavorable overall survival as well as progression-free survival rates indicate that concomitant systemic therapies should be the subject of future research. [ABSTRACT FROM AUTHOR]

Mayo Clinic Florida will initially open with the capability to treat with a single horizontal port for carbon ion therapy. Carbon ion therapy is traditionally done using a multi fixed port treatment approach. In this study, for nine treatment sites, clinically approved treatment plan of Osaka Heavy Ion Therapy Center was compared to a treatment plan using only a horizontal port. The treatment sites evaluated in this study were prostate cancer, pancreatic cancer, cervical cancer, recurrent rectal cancer, liver cancer, head and neck cancer, bone cancer (sarcoma and chordoma), and lung cancer. As expected, the prostate plans are identical and are only included for completeness. The DVH results for the pancreas and cervical cancer were very similar. The results for recurrent rectal, head and neck, sarcoma, chordoma, and lung cancer indicate that a single horizontal port with couch roll and yaw will accommodate certain medial targets but will be challenging to treat for laterally located targets without creative mitigations. [ABSTRACT FROM AUTHOR]

Background: 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. Purpose: 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. Methods: 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. Results: 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. Conclusions: 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]

Abstract Background The potential of carbon ion radiation therapy (CIRT) as a curative treatment for localized prostate cancer (PCa) has garnered attention due to its characteristic dose distribution. We prospectively collected and analyzed over five years to investigate the outcomes of localized PCa treated with CIRT at our institution. Patients and methods The study included patients with histologically confirmed prostate adenocarcinoma. CIRT treatment was administered at a total dose of 57.6 Gy (RBE) in 16 fractions over four weeks. Uroflowmetry (UFM) and residual urine measurements were performed at various time points: before CIRT treatment, one month after starting CIRT, three months after treatment, and annually for five years starting from 1 year after the completion of CIRT. Prostate volume was measured using transrectal ultrasonography (TRUS). Results A total of 304 prostate cancer patients were analyzed. UFM parameters were significantly worsened immediately after the treatment. However, they recovered to pretreatment levels after three months and remained stable until five years post-treatment. Notably, Average flow rate showed significant improvement after three years of treatment compared to before the treatment. Prostate volume decreased to 80% of baseline in patients treated with CIRT alone and to 60–70% of baseline in those receiving combined CIRT and either short- or long-term ADT. The logistic-binomial analysis identified post-voiding residual urine volume (PVR) as a significant factor for predicting adverse events in the acute phase. Conclusions Following CIRT treatment, the voiding parameters in PCa patients significantly deteriorated immediately. However, after three months, they returned to their pre-treatment levels and remained stable for five years.

Introduction: This study used the GEANT4 Monte Carlo toolkit for radiation transport simulations in brain carbon therapy, incorporating a human phantom model to accurately assess dose delivery to targeted and non-targeted organs. Weight factors were employed to generate a Spread Out Bragg Peak (SOBP).Material and Methods: The study used the ORNL-MIRD phantom to simulate carbon therapy for brain tumors, finding that the optimal energy range for carbon ions was 2420-2560 MeV to effectively cover the tumor. To achieve a homogeneous radiation dose, a Spread Out ragg Peak (SOBP) was generated using multiple Bragg peaks with specific intensity factors. Beam parameters were also evaluated per ICRU guidelines.Results: This study estimated the flux and dose distributions of secondary particles—protons, electrons, neutrons, alpha particles, and photons—in the brain tumor and surrounding tissues. We calculated the cumulative dose from both carbon ions and secondary particles, finding an absorbed dose ratio of 0.003 in healthy brain tissue compared to the tumor, with values of 4.8 × 10-4 for the skull and 2.6 × 10-5 for the thyroid. Notably, neutrons and photons can significantly increase energy transfer to distant organs, raising secondary cancer risk.Conclusion: The findings presented in this article demonstrated that the involvement of secondary particles in the dose received by both the brain and other organs remains minimal, as the highest absorbed dose was predominantly localized within the tumor.

Background: The potential of carbon ion radiation therapy (CIRT) as a curative treatment for localized prostate cancer (PCa) has garnered attention due to its characteristic dose distribution. We prospectively collected and analyzed over five years to investigate the outcomes of localized PCa treated with CIRT at our institution. Patients and methods: The study included patients with histologically confirmed prostate adenocarcinoma. CIRT treatment was administered at a total dose of 57.6 Gy (RBE) in 16 fractions over four weeks. Uroflowmetry (UFM) and residual urine measurements were performed at various time points: before CIRT treatment, one month after starting CIRT, three months after treatment, and annually for five years starting from 1 year after the completion of CIRT. Prostate volume was measured using transrectal ultrasonography (TRUS). Results: A total of 304 prostate cancer patients were analyzed. UFM parameters were significantly worsened immediately after the treatment. However, they recovered to pretreatment levels after three months and remained stable until five years post-treatment. Notably, Average flow rate showed significant improvement after three years of treatment compared to before the treatment. Prostate volume decreased to 80% of baseline in patients treated with CIRT alone and to 60–70% of baseline in those receiving combined CIRT and either short- or long-term ADT. The logistic-binomial analysis identified post-voiding residual urine volume (PVR) as a significant factor for predicting adverse events in the acute phase. Conclusions: Following CIRT treatment, the voiding parameters in PCa patients significantly deteriorated immediately. However, after three months, they returned to their pre-treatment levels and remained stable for five years. [ABSTRACT FROM AUTHOR]

[Objective] With the ongoing advancement of the "Double Ten Thousand Plan", China's domestic virtual simulation experiment teaching system is experiencing high-quality and large-scale development. Currently, research in this field focuses mostly on sharing experiences in constructing and managing specific experimental projects, with limited attention to teaching methods in virtual simulation experiments. Given the evolving landscape, it is necessary to thoroughly review and reflect on the design principles of virtual simulation experiments from a practical perspective to obtain generalizable insights. A key area of interest is integrating appropriate teaching models into virtual simulation courses to foster innovation and challenge. [Methods] This study first analyzed common problems in current virtual simulation experiments in nuclear physics, including monotonous teaching content with insufficient scalability, poor integration of experiments with theory and application, and a lack of personalized student development. To address these issues, an emerging ETA education model was considered. Using the ETA cognitive model as a teaching framework, a virtual simulation experiment case titled "radiation material interaction and shielding principle" was constructed. [Results] According to the requirements of the ETA model, the model divides the experimental content into three logical modules: E, T, and A. The E module features low-difficulty, intuitive, and visual experiments, including track measurements and characteristic physical quantity measurements. The T module emphasizes pattern exploration through experiments, requiring students to compare and validate experimental data with physical theories to establish theoretical understanding. The A module presents three practical nuclear physics scenarios: radiation shielding design, CT detection principles, and heavy ion therapy. These comprehensive experiments help students build their own knowledge systems and apply them to real-world contexts. The modules include over 20 experimental sub-questions with increasing difficulty, fostering a step-by-step increase process, with each experimental topic having a logical and correlated progression. This allows students to discover the alignment between experiments and theory, mastering concepts like radiation-matter interaction and the shielding principle. In addition, the virtual simulation experiment introduces innovative features, such as open-ended questions, scientific research methods, and peer learning, which differ from traditional experiment projects in teaching practice. [Conclusions] Teaching evaluations reveal that this course structure has gained widespread recognition among students who find it challenging and innovative and helps them acquire comprehensive knowledge in nuclear physics experiments. Integrating the ETA model into nuclear physics virtual simulation experiment teaching strengthens the connection among experiments, theory, and application in nuclear virtual simulation courses, promoting a constructivist "student-centered learning" approach. Additionally, this structured design paradigm for virtual simulation projects, centered on specific teaching models, should offer valuable insights for constructing and applying other experimental courses. [ABSTRACT FROM AUTHOR]

Objective. Real-time adaptive particle therapy is being investigated as a means to maximize the treatment delivery accuracy. To react to dosimetric errors, a system for fast and reliable verification of the agreement between planned and delivered doses is essential. This study presents a clinically feasible, real-time 4D-dose reconstruction system, synchronized with the treatment delivery and motion of the patient, which can provide the necessary feedback on the quality of the delivery. Approach. A GPU-based analytical dose engine capable of millisecond dose calculation for carbon ion therapy has been developed and interfaced with the next generation of the dose delivery system (DDS) in use at Centro Nazionale di Adroterapia Oncologica (CNAO). The system receives the spot parameters and the motion information of the patient during the treatment and performs the reconstruction of the planned and delivered 4D-doses. After each iso-energy layer, the results are displayed on a graphical user interface by the end of the spill pause of the synchrotron, permitting verification against the reference dose. The framework has been verified experimentally at CNAO for a lung cancer case based on a virtual phantom 4DCT. The patient's motion was mimicked by a moving Ionization Chamber (IC) 2D-array. Main results. For the investigated static and 4D-optimized treatment delivery cases, real-time dose reconstruction was achieved with an average pencil beam dose calculation speed up to more than one order of magnitude smaller than the spot delivery. The reconstructed doses have been benchmarked against offline log-file based dose reconstruction with the TRiP98 treatment planning system, as well as QA measurements with the IC 2D-array, where an average gamma-index passing rate (3%/3 mm) of 99.8% and 98.3%, respectively, were achieved. Significance. This work provides the first real-time 4D-dose reconstruction engine for carbon ion therapy. The framework integration with the CNAO DDS paves the way for a swift transition to the clinics. [ABSTRACT FROM AUTHOR]

Nanodroplets have demonstrated potential for the range detection of hadron radiotherapies. Our formulation uses superheated perfluorobutane (C4F10) stabilized by a poly(vinyl-alcohol) shell. High-LET (linear energy transfer) particles vaporize the nanodroplets into echogenic microbubbles. Tailored ultrasound imaging translates the generated echo-contrast into a dose distribution map, enabling beam range retrieval. This work evaluates the response of size-sorted nanodroplets to carbon-ion radiation. We studied how thesize of nanodroplets affects their sensitivity at various beam-doses and energies, as a function of concentration and shell cross-linking. First, we show the physicochemical characterization of size-isolated nanodroplets by differential centrifugation. Then, we report on the irradiations of the nanodroplet samples in tissue-mimicking phantoms. We compared the response of large (≈900 nm) and small (≈400 nm) nanodroplets to different carbon-ions energies and evaluated their dose linearity and concentration detection thresholds by ultrasound imaging. Additionally, we verified the beam range detection accuracy for the nanodroplets samples. All nanodroplets exhibited sensitivity to carbon-ions with high range verification precision. However, smaller nanodroplets required a higher concentration sensitivity threshold. The vaporization yield depends on the carbon-ions energy and dose, which are both related to particle count/spot. These findings confirm the potential of nanodroplets for range detection, with performance depending on nanodroplets' properties and beam parameters. [ABSTRACT FROM AUTHOR]

The article discusses the history and development of carbon ion radiotherapy in Europe over the past twenty-five years. It highlights the advantages of using heavier ions in cancer therapy, particularly carbon ions, due to their radiobiological properties that can lead to better tumor control with lower toxicity to normal tissues. The text also describes the establishment of the GSI Helmholtz Center Pilot Project and the Heidelberg Ion Beam Therapy (HIT) Center, which have been instrumental in advancing particle therapy in Europe. The article concludes by emphasizing the potential of heavy ion therapy in treating various types of cancers and the need for continued research to make the therapy more cost-effective and clinically effective. [Extracted from the article]

Background: In carbon ion radiation therapy (CIRT) the predominant method of irradiation is raster scanning, called dose driven continuous scanning (DDCS) by Hitachi, allowing for continuous synchrotron extraction. The reduction in irradiation time is highly beneficial in minimizing the impact of patient and target movement on dose distribution. The RF knock out (RFKO) slow‐extraction method is commonly used for beam on/off control. When the Hitachi synchrotron receives a beam off signal the control system stops the RFKO and after some delay time (t‐delay) during which the beam intensity declines, a high‐speed steering magnet (HSST) is used to sweep the remaining beam from isocenter to a beam dump for safety reasons. Mayo Clinic Florida (MCF) will use a very short delay of the HSST operation from the RFKO beam OFF signal to minimize the delay time and delayed dose. MCF clinical beam intensity, a tenfold increase over HIMAK, is still less than 100 mMU/ms (approximately 4.9 × 109 pps for 430 MeV/u). Purpose: The rapid beam off control (RBOC) proposed for MCF is associated with the occurrence of flap dose (FD), which refers to the asymmetric shoulder of the spot dose profile formed from the beam bent by HSST deviating from its planned spot position on the isocenter plane. In this study, we quantitatively assessed FD, proposed a treatment planning system (TPS) implementation using a flap spot (FS) and evaluated its impact on dose distribution. Method: The experiments were conducted at the Osaka Heavy Ion Therapy Center (HIMAK) varying the t‐delay from 0.01 to 1 ms in a research environment to simulate the MCF RBOC. We studied the dependence of FD position on beam transport and its dependence on energy and beam intensity. FD was generated by delivering 10000 continuous spots on the central axis that are occasionally triggered by an external 10 Hz gate signal. Measurements were conducted using an oscilloscope, and the nozzle's spot position monitor (SPM) and dose monitor (DM). Result: All spot profile data were corrected for the gain of the SPM's beam intensity dependence. FD was determined by fitting the (SPM) Profile data to a double Gaussian. The position of the FS was found to be transport path dependent, with FS occurring on the opposite sides of the scanning x‐direction for vertical and horizontal ports, respectively, as predicted by transport calculations. It was observed that the FD increases with beam intensity and did not exhibit a significant dependence on energy. The effect of FD on treatment planning is shown to have no significant dose impact on the organs at risk (OARs) near the target for clinical beam intensities and a modest increase for very high intensities. Conclusion: Using HIMAK in research mode the implications are that the FD has no clinical impact on the clinical CIRT beam intensities for MCF and maybe planned for higher intensities by incorporating FS into the TPS to predict the modest increased dose to OARs. A method for commissioning and quality assurance of FD has been proposed. [ABSTRACT FROM AUTHOR]

Radiation-induced lymphopenia (RIL) is associated with poor prognosis in patients with locally advanced pancreatic cancers. However, there are no reports comparing the effects of carbon ion radiation therapy (CIRT) and photon beam radiation therapy (RT) on the development of RIL. Differences in RIL after CIRT or photon beam RT and predictive factors for RIL in patients with locally advanced pancreatic cancer were investigated. This retrospective study cohort included 834 patients who received concurrent chemoradiotherapy (CCRT) in 2 separate institutions: 337 and 497 in the CIRT and photon beam RT groups, respectively. Severe RIL was defined as an absolute lymphocyte count (ALC) <0.5 × 109 cells/L. A 1:1 propensity score-matching analysis was performed between the CIRT and photon beam RT groups. Patients were categorized into 3 groups according to the development of recovery from severe RIL: no severe RIL (Group A), recovery from severe RIL (Group B), and no recovery from severe RIL (Group C). Logistic regression analysis was performed to identify the predictive value of severe RIL. The prognostic factors of overall survival (OS) were determined using Cox regression analysis. After propensity score matching, the baseline ALC and planning target volume of the CIRT and photon beam RT groups were comparable. During CCRT, the ALC of the entire cohort decreased and was significantly lower in the photon beam RT group than in the CIRT group (P <.001). Multivariate logistic regression analysis showed that CIRT reduced severe RIL more than photon beam RT. After adjusting for other factors, the RT modality and RIL were significantly associated with OS. Photon beam RT showed a significantly worse OS than CIRT, and Group C showed a significantly worse OS than Group A. CIRT seems to reduce the development of severe RIL. The RT modality and development/recovery from severe RIL were associated with OS in patients who received CCRT for locally advanced pancreatic cancer. The reduction of severe RIL through optimized RT may be essential for improving treatment outcomes. [ABSTRACT FROM AUTHOR]

Neutron capture enhanced particle therapy (NCEPT) is a proposed augmentation of charged particle therapy that exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with 2 different targeted neutron capture agents (NCAs). Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a polymethyl methacrylate phantom either laterally adjacent to or within a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The effect of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in 6 independent experiments. Neutron fluence within the phantom was characterized by quantifying the neutron activation of gold foil. Cells placed inside the treatment volume reached 10% survival by 2 Gy of carbon or 2 to 3 Gy of helium in the presence of NCAs compared with 5 Gy of carbon and 7 Gy of helium with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of carbon or helium (to the treatment volume), compared with no detectable effect on cells without NCA. The mean thermal neutron fluence at the center of the SOBP was approximately 2.2 × 109 n/cm2/Gy (relative biological effectiveness) for the carbon beam and 5.8 × 109 n/cm2/Gy (relative biological effectiveness) for the helium beam and gradually decreased in all directions. The addition of NCAs to cancer cells during carbon and helium beam irradiation has a measurable effect on cell survival and growth in vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumors, by targeting this dose to microinfiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumor tissue within the treatment volume, with a reduction in radiation doses to off-target tissue. [ABSTRACT FROM AUTHOR]

Introduction: This study used the GEANT4 Monte Carlo toolkit for radiation transport simulations in brain carbon therapy, incorporating a human phantom model to accurately assess dose delivery to targeted and non-targeted organs. Weight factors were employed to generate a Spread Out Bragg Peak (SOBP). Material and Methods: The study used the ORNL-MIRD phantom to simulate carbon therapy for brain tumors, finding that the optimal energy range for carbon ions was 2420-2560 MeV to effectively cover the tumor. To achieve a homogeneous radiation dose, a Spread Out ragg Peak (SOBP) was generated using multiple Bragg peaks with specific intensity factors. Beam parameters were also evaluated per ICRU guidelines. Results: This study estimated the flux and dose distributions of secondary particles--protons, electrons, neutrons, alpha particles, and photons--in the brain tumor and surrounding tissues. We calculated the cumulative dose from both carbon ions and secondary particles, finding an absorbed dose ratio of 0.003 in healthy brain tissue compared to the tumor, with values of 4.8 × 10-4 for the skull and 2.6 × 10-5 for the thyroid. Notably, neutrons and photons can significantly increase energy transfer to distant organs, raising secondary cancer risk. Conclusion: The findings presented in this article demonstrated that the involvement of secondary particles in the dose received by both the brain and other organs remains minimal, as the highest absorbed dose was predominantly localized within the tumor. [ABSTRACT FROM AUTHOR]

Few reports have documented how the accuracy of stopping power ratio (SPR) prediction for porous bone tissue affects the dose distribution of scanned carbon-ion beam therapy. The estimated SPR based on single-energy computed tomography (SECT) and dual-energy CT (DECT) were compared for the femur of a Rando phantom which simulates the porosity of human bone, NEOBONE which is the hydroxyapatite synthetic bone substitute, and soft tissue samples. Dose differences between SECT and DECT were evaluated for a scanned carbon-ion therapy treatment plan for the Rando phantom. The difference in the water equivalent length was measured to extract the SPR of the examined samples. The differences for SPR estimated from the DECT-SPR conversion were small with − 1.8% and − 3.3% for the Rando phantom femur and NEOBONE, respectively, whereas the differences for SECT-SPR were between 7.6 and 70.7%, illustrating a 1.5-mm shift of the range and a dose difference of 13.3% at maximum point in the evaluation of the dose distribution. This study demonstrated that the DECT-SPR conversion method better estimated the SPR of the porosity of bone tissues than SECT-SPR followed by the accurate range of the carbon-ion beams on carbon-ion dose calculations. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to quantitatively assess eligible patients and project the demand for particle therapy facilities in India from 2020 to 2040. In addition, an economic analysis evaluates the financial feasibility of implementing this technology. The study also examines the prospective benefits and challenges of adopting this technology in India. Methodology: Cancer incidence and projected trends were analyzed for pediatric patients using the Global Childhood Cancer microsimulation model and adult patients using the Globocan data. Economic cost evaluation is performed for large‐scale combined particle (carbon and proton‐three room fixed‐beam), large‐scale proton (one gantry and two fixed‐beam), and small‐scale proton (one gantry) facility. Results: By 2040, the estimated number of eligible patients for particle therapy is projected to reach 161,000, including approximately 14,000 pediatric cases. The demand for particle therapy facilities is projected to rise from 81 to 97 in 2020 to 121 to 146 by 2040. The capital expenditure is estimated to be only 3.7 times that of a standard photon linear accelerator over a 30‐year period. Notably, the treatment cost can be reduced to USD 400 to 800 per fraction, substantially lower than that in high‐income countries (USD 1000 to 3000 per fraction). Conclusion: This study indicates that, in the Indian scenario, all particle therapy models are cost‐beneficial and feasible, with large‐scale proton therapy being the most suitable. Despite challenges such as limited resources, space, a skilled workforce, referral systems, and patient affordability, it offers substantial benefits. These include the potential to treat many patients and convenient construction and operational costs. An iterative phased implementation strategy can effectively overcome these challenges, paving the way for the successful adoption of particle therapy in India. Plain Language Summary: In India, the number of eligible patients benefiting from high‐precision particle therapy technology is projected to rise till 2040. Despite high upfront costs, our study finds the long‐term feasibility of all particle therapy models, potentially offering a substantial reduction in treatment cost compared to high‐income countries. Despite challenges, India can succeed with an iterative phased approach. [ABSTRACT FROM AUTHOR]

Purpose: As carbon ion radiotherapy increases in use, there are limited phantom materials for heterogeneous or anthropomorphic phantom measurements. This work characterized the radiological clinical equivalence of several phantom materials in a therapeutic carbon ion beam. Methods: Eight materials were tested for radiological material‐equivalence in a carbon ion beam. The materials were computed tomography (CT)‐scanned to obtain Hounsfield unit (HU) values, then irradiated in a monoenergetic carbon ion beam to determine relative linear stopping power (RLSP). The corresponding HU and RLSP for each phantom material were compared to clinical carbon ion calibration curves. For absorbed dose comparison, ion chamber measurements were made in the center of a carbon ion spread‐out Bragg peak (SOBP) in water and in the phantom material, evaluating whether the material perturbed the absorbed dose measurement beyond what was predicted by the HU‐RLSP relationship. Results: Polyethylene, solid water (Gammex and Sun Nuclear), Blue Water (Standard Imaging), and Techtron HPV had measured RLSP values that agreed within ±4.2% of RLSP values predicted by the clinical calibration curve. Measured RLSP for acrylic was 7.2% different from predicted. The agreement for balsa wood and cork varied between samples. Ion chamber measurements in the phantom materials were within 0.1% of ion chamber measurements in water for most materials (solid water, Blue Water, polyethylene, and acrylic), and within 1.9% for the rest of the materials (balsa wood, cork, and Techtron HPV). Conclusions: Several phantom materials (Blue Water, polyethylene, solid water [Gammex and Sun Nuclear], and Techtron HPV) are suitable for heterogeneous phantom measurements for carbon ion therapy. Low density materials should be carefully characterized due to inconsistencies between samples. [ABSTRACT FROM AUTHOR]

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to report initial results of hypofractionated carbon‐ion radiotherapy (C‐ion RT) for inoperable upper tract ureteral cancer. Methods: Retrospective chart review was performed for five consecutive patients with medically inoperable ureter cancer that was treated with radical C‐ion RT between December 2013 and December 2014. The median age of the patients was 80 years (range, 68–84 years). The reasons for inoperability were advanced age, post‐contralateral nephrectomy, alcoholic cirrhosis, both advanced age and contralateral renal function degeneracy, and pneumonia. The median size of tumor was 2.8 cm (range, 2.2–4.0 cm). Diagnostic imaging did not identify lymph node metastases or distant metastases in any case. All patients underwent C‐ion RT (52.8 Gy relative biological effectiveness; 12 fractions in 3 weeks). The clinical target volume encompassed the growth tumor volume with a 5‐mm margin bilaterally; there was a 40‐mm margin craniocaudally but the clinical target volume did not encompass the whole ureter. Results: Within a median follow‐up time of 32.9 months (range, 24–36 months), two patients died and three remained alive. Neither local recurrence nor regional lymph node metastases were observed. Secondary bladder tumor was observed in four patients, and one patient had a liver metastasis. Grade 1 hematuria was observed in two patients, and Grade 3 pyelonephritis was observed in one patient as acute toxicity. Ureteral obstruction was observed in two patients. Conclusion: C‐ion RT might be a useful treatment option for inoperable ureter cancer. [ABSTRACT FROM AUTHOR]

Heavy ion therapy is an important cancer treatment. Accurate evaluation of the biophysical effects of heavy ions is of great significance to improve the refinement level of particle radiotherapy. An aim of this study is to calculate multi-scale relative biological effectiveness (RBE) of heavy ion. Based on multi-scale dosimetry and Monte Carto dose simulation, the RBE of carbon ions were calculated at the macro- and micro-scales, and the results were compared and analyzed to evaluate the biological effects of carbon ions comprehensively. In this study, different dose-effect models of carbon ions were used at the two scales: LQ model was used at macro-scale and microdosimetric kinetics model (MKM) was used at the micro-scale. The Monte Carlo simulation used a water phantom to calculate the macro-scale carbon ion RBE by counting the dose distribution and linear energy transfer (LET), and the information of the particles passing through the voxels was recorded as a secondary source. Micro-dose simulation was carried out with the secondary source to calculate the micro-scale carbon ion RBE. The results show that the RBE calculated at different scales in the plateau region differs by 16%, and the RBE at the Bragg peak differs by 25%. The results of this study presents a method for calculating heavy ion RBE at macro- and micro-scales under the same irradiation situation, and will provide references for the improvement and clinical application of different methods.

Background: Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. Case presentation: We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. Conclusions: This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease. [ABSTRACT FROM AUTHOR]

Australia has taken a collaborative nationally networked approach to achieve particle therapy capability. This supports the under-construction proton therapy facility in Adelaide, other potential proton centres and an underevaluation proposal for a hybrid carbon ion and proton centre in western Sydney. A wide-ranging overview is presented of the rationale for carbon ion radiation therapy, applying observations to the case for an Australian facility and to the clinical and research potential from such a national centre. [ABSTRACT FROM AUTHOR]

Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT–SNT) trial. Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated. [ABSTRACT FROM AUTHOR]

Background: Proton and carbon‐ion therapy may spare normal tissues in regions with many critical structures surrounding the target volume. As toxicity outcome data are emerging, we aimed to synthesize the published data for the toxicity outcomes of proton or carbon‐ion therapy (together known as particle beam therapy [PBT]) for primary nasopharyngeal carcinoma (NPC). Materials and methods: We searched PubMed and Scopus electronic databases to identify original studies reporting toxicity outcomes following PBT of primary NPC. Quality assessment was performed using NIH's Quality Assessment Tool. Reports were extracted for information on demographics, main results, and clinical and dose factors correlates. Meta‐analysis was performed using the random‐effects model. Results: Twelve studies were selected (six using mixed particle‐photon beams, five performed comparisons to photon‐based therapy). The pooled event rates for acute grade ≥2 toxicities mucositis, dermatitis, xerostomia weight loss are 46% (95% confidence interval [95% CI]—29%–64%, I2 = 87%), 47% (95% CI—28%–67%, I2 = 87%), 16% (95% CI—9%–29%, I2 = 76%), and 36% (95% CI—27%–47%, I2 = 45%), respectively. Only one late endpoint (xerostomia grade ≥2) has sufficient data for analysis with pooled event rate of 9% (95% CI—3%–29%, I2 = 77%), lower than intensity‐modulated radiotherapy 27% (95% CI—10%–54%, I2 = 95%). For most endpoints with significant differences between the PBT and photon‐based therapies, PBT resulted in better outcomes. In two studies where dose distribution was studied, doses to the organs at risk were independent risk factors for toxicities. Conclusion: PBT may reduce the risk of acute toxicities for patients treated for primary NPC, likely due to dose reduction to critical structures. The pooled event rate for toxicities derived in this study can be a guide for patient counseling. [ABSTRACT FROM AUTHOR]

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It is difficult to effectively cure patients with unresectable locally recurrent colorectal cancers (LRCRCs) using conventional chemotherapy or chemoradiation therapy. Furthermore, treatment options vary depending on the patient's history of radiation therapy. Carbon-ion radiation therapy (CIRT) is a potentially curative treatment for these patients. Here, we compare the treatment outcomes of radiation therapy–naïve cases (nRT) and re-irradiation cases (reRT). Patients with LRCRC treated with CIRT at QST Hospital between 2003 and 2019 were eligible. CIRT was administered daily 4 d/wk for 16 fractions. The total irradiated dose was set at 73.6 Gy (relative biologic effectiveness–weighted dose [RBE]) for nRT and 70.4 Gy (RBE) for reRT patients. We included 390 nRT cases and 83 reRT cases. The median follow-up period from the initiation of CIRT was 48 (5-208) months. The 3-year overall survival (OS) rates for nRT and reRT were 73% (95% CI, 68%-77%) and 76% (65%-84%), respectively. The 5-year OS rates were 50% (45%-55%) and 50% (38%-61%), respectively. These rates did not differ significantly (P =.55). The 3-year local control (LC) rates for nRT (73.6 Gy) and reRT (70.4 Gy) cases were 80% (75%-84%) and 80% (68%-88%), respectively. The 5-year LC rates were 72% (67%-78%) and 69% (55%-81%), respectively, without a significant difference (P =.56). Our results suggest that CIRT for LRCRC is a very effective and promising treatment for both nRT and reRT cases. [ABSTRACT FROM AUTHOR]

Salvage radical prostatectomy is a postradiation treatment for patients with localized prostate cancer. In 2016, Ozu et al. (Ozu C, Aoki K, Nakamura K, Yagi Y, Muro Y, Nishiyama T, et al. The initial case report: salvage robotic assisted radical prostatectomy after heavy ion radiotherapy. Urol Case Rep 2016; 7 :45-7) first reported salvage robotic-assisted radical prostatectomy (sRARP) after heavy-ion radiotherapy (HIRT). Thereafter, sRARP has been performed in >100 cases. However, it is currently avoided owing to some difficulties. Herein, we report about sRARP in a 67-year-old man who received two sessions of HIRT despite some expected challenges. He was initially treated with HIRT for prostate cancer in 2009 and received the second HIRT as salvage treatment for local recurrence in 2016. In 2019, he had biochemical recurrence and underwent sRARP. There were no significant peri- or postoperative complications. Subsequently, 12 months after sRARP, hormonal therapy was introduced after the diagnosis of biochemical recurrence. The patient's prostate-specific antigen level is currently undetectable. [ABSTRACT FROM AUTHOR]

Particle therapy utilizes high-energy protons and carbon ions to treat patients, leveraging their unique Bragg peak and superior relative biological effectiveness. This treatment modality shows great promise in improving disease cure rates and minimizing treatment side effects. However, its adoption in China is limited by the high cost associated with this advanced radiotherapy technique, highlighting a substantial demand for particle therapy equipment in the country. This report conducts a comparative analysis of cyclotron and synchrotron accelerators, prevalent in clinical particle therapy institutes. We examine their beam parameters and provide detailed insights into the techniques and functionalities associated with each accelerator type. Specifically, we elucidate the processes of beam injection, acceleration, and extraction, highlighting operational intricacies at each phase of the cycle. Furthermore, we present beam intensity and energy modulation for both accelerators in three-dimensional dose delivery. In summary, the synchrotron offers adjustable energy levels and the ability to produce high-energy multi-ions, while maintaining a high beam transmission rate. Conversely, the cyclotron provides continuous beams with rapid intensity modulation and an energy degrader on the beam transport line for energy variation, leading to activation near the degrader. Therefore, when selecting the most suitable accelerator for clinical institutes, factors such as cost, maintenance requirements, treatment efficiency, and clinical needs must be carefully considered. [ABSTRACT FROM AUTHOR]

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study. [ABSTRACT FROM AUTHOR]

Purpose: The in vitro clonogenic assay (IVCA) is the mainstay of quantitative radiobiology. Here, we investigate the benefit of a time-resolved IVCA version (trIVCA) to improve the quantification of clonogenic survival and relative biological effectiveness (RBE) by analyzing cell colony growth behavior. Materials & Methods: In the IVCA, clonogenicity classification of cell colonies is performed based on a fixed colony size threshold after incubation. In contrast, using trIVCA, we acquire time-lapse microscopy images during incubation and track the growth of each colony using neural-net-based image segmentation. Attributes of the resulting growth curves are then used as predictors for a decision tree classifier to determine clonogenicity of each colony. The method was applied to three cell lines, each irradiated with 250 kV X-rays in the range 0–8 Gy and carbon ions of high LET (100 keV/μm, dose-averaged) in the range 0–2 Gy. We compared the cell survival curves determined by trIVCA to those from the classical IVCA across different size thresholds and incubation times. Further, we investigated the impact of the assaying method on RBE determination. Results: Size distributions of abortive and clonogenic colonies overlap consistently, rendering perfect separation via size threshold unfeasible at any readout time. This effect is dose-dependent, systematically inflating the steepness and curvature of cell survival curves. Consequently, resulting cell survival estimates show variability between 3% and 105%. This uncertainty propagates into RBE calculation with variability between 8% and 25% at 2 Gy.Determining clonogenicity based on growth curves has an accuracy of 95% on average. Conclusion: The IVCA suffers from substantial uncertainty caused by the overlap of size distributions of delayed abortive and clonogenic colonies. This impairs precise quantification of cell survival and RBE. By considering colony growth over time, our method improves assaying clonogenicity.

Gold nanoparticle (GNP) radio-enhancement is a promising technique to increase the dose deposition in a tumor while sparing neighboring healthy tissue. Previous experimental studies showed effects on cell survival and tumor control for keV x-rays but surprisingly also for MV-photons, proton and carbon-ion beams. In a systematic study, we use the Monte Carlo simulation tool TOPAS-nBio to model the GNP radio-enhancement within a cell as a function of GNP concentration, size and clustering for a wide range of energies for photons, protons and, for the first time, carbon-ions. Moreover, we include water radiolysis, which has been recognized as a major pathway of GNP mediated radio-enhancement. At a GNP concentration of 0.5% and a GNP diameter of 10 nm, the dose enhancement ratio was highest for 50 keV x-rays (1.36) and decreased in the orthovoltage (1.04 at 250 keV) and megavoltage range (1.01 at 1 MeV). The dose enhancement linearly increased with GNP concentration and decreased with GNP size and degree of clustering for all radiation modalities. While the highest physical dose enhancement at 5% concentrations was only 1.003 for 10 MeV protons and 1.004 for 100 MeV carbon-ions, we find the number of hydroxyl ([Formula: see text]) altered by 23% and 3% after 1 [Formula: see text]s at low, clinically-relevant concentrations. For the same concentration and proton-impact, the G-value is most sensitive to the nanoparticle size with 46 times more radical interactions at GNPs for 2 nm than for 50 nm GNP diameter within 1 [Formula: see text]s. Nanoparticle clustering was found to decrease the number of interactions at GNPs, e.g. for a cluster of 25 GNPs by a factor of 3.4. The changes in G-value correlate to the average distance between the chemical species and the GNPs. While the radiochemistry of GNP-loaded water has yet to be fully understood, this work offers a first relative quantification of radiolysis products for a broad parameter-set.

Inverse treatment planning in intensity modulated particle therapy (IMPT) with scanned carbon-ion beams is currently based on the optimization of RBE-weighted dose to satisfy requirements of target coverage and limited toxicity to organs-at-risk (OARs) and healthy tissues. There are many feasible IMPT plans that meet these requirements, which allows the introduction of further criteria to narrow the selection of a biologically optimal treatment plan. We propose a novel treatment planning strategy based on the simultaneous optimization of RBE-weighted dose and nanometric ionization details (ID) as a new physical characteristic of the delivered plan beyond LET. In particular, we focus on the distribution of large ionization clusters (more than 3 ionizations) to enhance the biological effect across the target volume while minimizing biological effect in normal tissues. Carbon-ion treatment plans for different patient geometries and beam configurations generated with the simultaneous optimization strategy were compared against reference plans obtained with RBE-weighted dose optimization alone. Quality indicators, inhomogeneity index and planning volume histograms of RBE-weighted dose and large ionization clusters were used to evaluate the treatment plans. We show that with simultaneous optimization, ID distributions can be optimized in carbon-ion radiotherapy without compromising the RBE-weighted dose distributions. This strategy can potentially be used to account for optimization of endpoints closely related to radiation quality to achieve better tumor control and reduce risks of complications.

To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.

Background and Purpose: Interferon (IFN) signaling plays an important role in antitumor immune responses. Inhibitors of the DNA damage response, such as ATR inhibitors, can increase IFN signaling upon conventional radiotherapy with X-rays. However, it is not known whether such inhibitors also enhance IFN signaling after irradiation with high linear energy transfer (LET) particles., Materials and Methods: Human glioblastoma U-251 and T98G cells were irradiated with X-rays, protons (LET: 4.8 and 41.9 keV/µm) and carbon ions (LET: 28 and 73 keV/µm), with and without ATR inhibitor (VE-822) or ATM inhibitor (AZD1390). DNA damage signaling and cell cycle distribution were analyzed by immunoblotting and flow cytometry, and radiosensitivity was assessed by clonogenic survival assay. IFN-β secretion was measured by ELISA, and STAT1 activation was examined by immunoblotting., Results: High-LET protons and carbon ions caused stronger activation of the DNA damage response compared to low-LET protons and X-rays at similar radiation doses. G2 checkpoint arrest was abrogated by the ATR inhibitor and prolonged by the ATM inhibitor after all radiation types. The inhibitors increased radiosensitivity, as measured after X- and carbon ion irradiation. ATR inhibition increased IFN signaling following both low-LET and high-LET irradiation. ATM inhibition also increased IFN signaling, but to a lesser extent. Notably, both cell lines secreted significantly more IFN-β when the inhibitors were combined with high-LET compared to low-LET irradiation., Conclusion: These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recently, ultra-high dose rate (> 40 Gy/s, uHDR; FLASH) radiation therapy (RT) has attracted interest, because the FLASH effect that is, while a cell-killing effect on cancer cells remains, the damage to normal tissue could be spared has been reported. This study aimed to compare the immune-related protein expression on cancer cells after γ-ray, conventionally used dose rate (Conv) carbon ion (C-ion), and uHDR C-ion. B16F10 murine melanoma and Pan02 murine pancreas cancer were irradiated with γ-ray at Osaka University and with C-ion at Osaka HIMAK. The dose rates at 1.16 Gy/s for Conv and 380 Gy/s for uHDR irradiation. The expressed calreticulin (CRT), major histocompatibility complex class (MHC)-I, and programmed cell death 1 ligand (PD-L1) were evaluated by flow cytometry. Western blotting and PCR were utilized to evaluate endoplasmic reticulum (ER) stress, DNA damage, and its repair pathway. CRT, MHC-I on B16F10 was also increased by irradiation, while only C-ion increased MHC-I on Pan02. Notably, PD-L1 on B16F10 was increased after irradiation with both γ-ray and C-ion, while uHDR C-ion suppressed the expression of PD-L1 on Pan02. The present study indicated that uHDR C-ion has a different impact on the repair pathway of DNA damage and ER than the Conv C-ion. This is the first study to show the immune-related protein expressions on cancer cells after uHDR C-ion irradiation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background/aim: For patients with unresectable locally advanced pancreatic cancer (LAPC), carbon-ion radiotherapy (C-ion RT) can safely deliver higher doses than conventional photon therapy, increasing the potential for long-term survival. However, achieving meaningful improvements in survival rates requires reliable prognostic biomarkers to identify patients likely to benefit from treatment., Patients and Methods: In this study, we measured plasma levels of soluble interleukin-6 receptor (sIL-6R) before C-ion RT and examined their association with the risk of distant metastasis (DM), local recurrence (LR), and overall survival (OS)., Results: Results showed that patients with higher plasma sIL-6R levels had a lower risk of DM [hazard ratio (HR)=0.53; p=0.033] and improved OS (HR=0.55; p=0.037). No significant association was observed between LR and plasma sIL-6R levels (HR=1.47; p=0.273)., Conclusion: These findings suggest that pretreatment plasma sIL-6R levels may serve as a prognostic marker for C-ion RT in LAPC., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)