The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.

OBJECTIVE: This study aimed to compare the effects of a mobile health intervention based on social cognitive theory with standard care on maximal mouth opening, exercise compliance, and self-efficacy in patients receiving proton and heavy ion therapy for head and neck cancer.
METHODS: This open-label, parallel-group, randomized, superiority trial involved a self-developed \"Health Enjoy System\" intervention. We assessed maximal mouth opening, exercise compliance, and self-efficacy at baseline (T0), post-treatment (T1), and at 1 month (T2) and 3 months (T3) after radiotherapy. Generalized estimating equations were used to analyze differences between the groups over time, with results reported as P values and 95% confidence intervals (CIs).
RESULTS: The study included 44 participants. At T3, the intervention group showed a 6 mm greater increase in maximal interincisal opening than the control group (mean difference = 6.0, 95% CI = 2.4 to 9.5, P = 0.001). There was also a significant difference in exercise compliance between the groups (mean difference = 31.7, 95% CI = 4.6 to 58.8, P = 0.022). However, no significant difference in self-efficacy was found between the groups.
CONCLUSIONS: This study demonstrated that an mHealth intervention incorporating behavior change theory could effectively enhance or maintain maximal mouth opening in patients undergoing proton and heavy ion therapy for head and neck cancer in China. This approach provides valuable support during and after treatment.
BACKGROUND: ChiCTR: ChiCTR2300067550. Registered 11 Jan 2023.

BACKGROUND: MR-integrated proton therapy is under development. It consists of the unique challenge of integrating a proton pencil beam scanning (PBS) beam line nozzle with an magnetic resonance imaging (MRI) scanner. The magnetic interaction between these two components is deemed high risk as the MR images can be degraded if there is cross-talk during beam delivery and image acquisition.
OBJECTIVE: To create and benchmark a self-consistent proton PBS nozzle model for empowering the next stages of MR-integrated proton therapy development, namely exploring and de-risking complete integrated prototype system designs including magnetic shielding of the PBS nozzle.
METHODS: Magnetic field (COMSOL Multiphysics ${\\text{Multiphysics}}$ ) and radiation transport (Geant4) models of a proton PBS nozzle located at OncoRay (Dresden, Germany) were developed according to the manufacturers specifications. Geant4 simulations of the PBS process were performed by using magnetic field data generated by the COMSOL Multiphysics ${\\text{Multiphysics}}$ simulations. In total 315 spots were simulated which consisted of a 40 × 30 cm 2 $40\\times 30\\,{\\text{cm}}^{2}$ scan pattern with 5 cm spot spacings and for proton energies of 70, 100, 150, 200, and 220 MeV. Analysis of the simulated deflection at the beam isocenter plane was performed to determine the self-consistency of the model. The magnetic fringe field from a sub selection of 24 of the 315 spot simulations were directly compared with high precision magnetometer measurements. These focused on the maximum scanning setting of ± $\\pm$  20 cm beam deflection as generated from the second scanning magnet in the PBS for a proton beam energy of 220 MeV. Locations along the beam line central axis (CAX) were measured at beam isocenter and downstream of 22, 47, 72, 97, and 122 cm. Horizontal off-axis positions were measured at 22 cm downstream of isocenter ( ± $\\pm$  50, ± $\\pm$  100, and ± $\\pm$  150 cm from CAX).
RESULTS: The proton PBS simulations had good spatial agreement to the theoretical values in all 315 spots examined at the beam line isocenter plane (0-2.9 mm differences or within 1.5 % of the local spot deflection amount). Careful analysis of the experimental measurements were able to isolate the changes in magnetic fields due solely to the scanning magnet contribution, and showed 1.9  ± $\\pm$  1.2 μ T $\\bf{\\mu} {\\text{T}}$ -9.4 ± $\\pm$  1.2 μ T $\\bf{\\mu} {\\text{T}}$ changes over the range of measurement locations. Direct comparison with the equivalent simulations matched within the measurement apparatus and setup uncertainty in all but one measurement point.
CONCLUSIONS: For the first time a robust, accurate and self-consistent model of a proton PBS nozzle assembly has been created and successfully benchmarked for the purposes of advancing MR-integrated proton therapy research. The model will enable confidence in further simulation based work on fully integrated designs including MRI scanners and PBS nozzle magnetic shielding in order to de-risk and realize the full potential of MR-integrated proton therapy.

OBJECTIVE: To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber.
METHODS: 227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector.
RESULTS: Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose.
CONCLUSIONS: In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose.

OBJECTIVE: Particle therapy treatments are currently limited by uncertainties of the delivered dose. Verification techniques like Prompt-Gamma-Timing-based Stopping Power Estimation (PGT-SPE) may allow for reduction of safety margins in treatment planning. Approach: From Prompt-Gamma-Timing measurements, we reconstruct the spatiotemporal distribution of prompt gamma emissions, which is linked to the average motion of the primary particles. The stopping power is determined by fitting a model of the average particle motion. Here, we compare a previously published implementation of the particle motion model with an alternative formulation and present two formulations to automatically select the hyperparameters of our procedure. The performance was assessed using Monte-Carlo simulations of proton beams (60 MeV to 219 MeV) impinging on a homogeneous PMMA phantom. Main results: The range was successfully determined within a standard deviation of 3 mm for proton beam energies from 70 MeV to 219 MeV. Stopping power estimates showed errors below 5 % for beam energies above 160 MeV. At lower energies, the estimation performance degraded to unsatisfactory levels due to the short range of the protons. The new motion model improved the estimation performance by up to 5 % for beam energies from 100 MeV to 150 MeV with mean errors ranging from 6 % to 18 %. The automated hyperparameter optimization matched the average error of previously reported manual selections, while significantly reducing the outliers. Significance: The data-driven hyperparameter optimization allowed for a reproducible and fast evaluation of our method. The updated motion model and evaluation at new beam energies bring us closer to applying PGT-SPE in more complex scenarios. Direct comparison of stopping power estimates between treatment planning and measurements during irradiation would offer a more direct verification than other secondary-particle-based techniques.

OBJECTIVE: We report on a case of locally advanced hepatocellular carcinoma (HCC) accompanied by an inferior vena cava tumor thrombus (IVCTT), treated successfully with proton-beam therapy (PBT).
METHODS: A 63-year-old male presented with a primary, single HCC with IVCTT, without metastasis to the intrahepatic region, lymph nodes, or distant organs. The clinical staging was identified as T4N0M0 Stage IIIB. The patient\'s liver function was classified as Child-Pugh class A (score: 6), with a modified albumin-bilirubin (mALBI) grade of 2a. The patient had liver cirrhosis due to non-alcoholic steatohepatitis. Magnetic resonance imaging revealed a nodular tumor measuring 13.2×8.9×9.8 cm across segments 1, 6, 7, and 8, along with IVCTT. The patient received PBT, with a total dose of 72.6 Gy (relative biological effectiveness) delivered in 22 fractions. Throughout the PBT treatment, the patient experienced no acute toxicities and completed the therapy as planned. Twelve months following PBT, the patient was alive without evidence of local recurrence, lymph node involvement, or distant organ metastasis. The only late toxicity observed was a mild worsening of the mALBI grade.
CONCLUSIONS: We observed a favorable local response with manageable toxicities in a patient with locally advanced HCC and IVCTT treated with PBT. While this is a single case report, our findings suggest that PBT could be considered a viable treatment option for HCC with IVCTT.

OBJECTIVE: Pre-clinical studies have shown that irradiation with electrons at an ultra-high dose-rate (FLASH) spares normal tissue while maintaining tumor control. However, most in vitro experiments with protons have been conducted using a non-clinical irradiation system in normoxia alone. This study evaluated the biological response of non-tumor and tumor cells at different oxygen concentrations irradiated with ultra-high dose-rate protons using a clinical system and compared it with the conventional dose rate (CONV).
METHODS: Non-tumor cells (V79) and tumor cells (U-251 and A549) were irradiated with 230 MeV protons at a dose rate of >50 Gy/s or 0.1 Gy/s under normoxic or hypoxic (<2%) conditions. The surviving fraction was analyzed using a clonogenic cell survival assay.
RESULTS: No significant difference in the survival of non-tumor or tumor cells irradiated with FLASH was observed under normoxia or hypoxia compared to the CONV.
CONCLUSIONS: Proton irradiation at a dose rate above 40 Gy/s, the FLASH dose rate, did not induce a sparing effect on either non-tumor or tumor cells under the conditions examined. Further studies are required on the influence of various factors on cell survival after FLASH irradiation.

暂无摘要。

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.

OBJECTIVE: To report the outcomes of a large series of intracranial meningiomas (IMs) submitted to proton therapy (PT) with curative intent.
METHODS: We conducted a retrospective analysis on all consecutive IM patients treated between 2014 and 2021. The median PT prescription dose was 55.8 Gy relative biological effectiveness (RBE) and 66 GyRBE for benign/radiologically diagnosed and atypical/anaplastic IMs, respectively. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), overall survival (OS), and radionecrosis-free survival (RNFS) were evaluated with the Kaplan-Meier method. Univariable analysis was performed to identify potential prognostic factors for clinical outcomes. Toxicity was reported according to the latest Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
RESULTS: Overall, 167 patients were included. With a median follow-up of 41 months (range, 6-99), twelve patients (7%) developed tumor local recurrence after a median time of 39 months. The 5-year LRFS was 88% for the entire cohort, with a significant difference between benign/radiologically diagnosed and atypical/anaplastic IMs (98% vs. 47%, p < 0.001); this significant difference was maintained also for the 5-year OS and the 5-year DRFS rates. Patients aged ≤ 56 years reported significantly better outcomes, whereas lower prescription doses and skull base location were associated with better RNFS rates. Two patients experienced G3 acute toxicities (1.2%), and three patients G3 late toxicities (1.8%). There were no G4-G5 adverse events.
CONCLUSIONS: PT proved to be effective with an acceptable toxicity profile. To the best of our knowledge this is one of the largest series including IM patients submitted to PT.