Keloids, characterized by excessive extracellular matrix (ECM) deposition and aberrant fibrous tissue proliferation, present significant therapeutic challenges due to their recalcitrant and recurrent nature. This study explores the efficacy of Carbon Ion Radiotherapy (CIRT) as a novel therapeutic approach for keloids, focusing on its impact on fibroblast proliferation, apoptosis induction, immunogenic cell death (ICD), macrophage polarization, and the TGF-β/SMAD signaling pathway. Utilizing a murine model of keloid formed by subcutaneous injection of zeocin in C57BL/6 mice, we demonstrated that CIRT effectively reduces collagenous fiber synthesis and collagen production in keloid tissues. Further, CIRT was shown to inhibit keloid fibroblast proliferation and to induce apoptosis, as evidenced by increased expression of apoptosis-related proteins and confirmed through flow cytometry and TUNEL assay. Notably, CIRT induced mitochondrial stress, leading to enhanced immunogenicity of cell death, characterized by increased expression of ICD markers and secretion of interferon-γ. Additionally, CIRT promoted a shift from M2 to M1 macrophage polarization, potentially reducing TGF-β release and mitigating ECM deposition. Our findings suggest that CIRT mediates its therapeutic effects through the inhibition of the TGF-β/SMAD signaling pathway, thereby attenuating ECM formation and offering a promising avenue for keloid treatment. This study underscores the potential of CIRT as an innovative strategy for managing keloids, highlighting its multifaceted impact on key cellular processes involved in keloid pathogenesis.

UNASSIGNED: A low linear energy transfer (LET) in the target can reduce the effectiveness of carbon ion radiotherapy (CIRT). This study aimed at exploring benefits and limitations of LET optimization for large sacral chordomas (SC) undergoing CIRT.
UNASSIGNED: Seventeen cases were used to tune LET-based optimization, and seven to independently test interfraction plan robustness. For each patient, a reference plan was optimized on biologically-weighted dose cost functions. For the first group, 7 LET-optimized plans were obtained by increasing the gross tumor volume (GTV) minimum LETd (minLETd) in the range 37-55 keV/μm, in steps of 3 keV/μm. The optimal LET-optimized plan (LETOPT) was the one maximizing LETd, while adhering to clinical acceptability criteria. Reference and LETOPT plans were compared through dose and LETd metrics (D x , L x to x% volume) for the GTV, clinical target volume (CTV), and organs at risk (OARs). The 7 held-out cases were optimized setting minLETd to the average GTV L98% of the investigation cohort. Both reference and LETOPT plans were recalculated on re-evaluation CTs and compared.
UNASSIGNED: GTV L98% increased from (31.8 ± 2.5)keV/μm to (47.6 ± 3.1)keV/μm on the LETOPT plans, while the fraction of GTV receiving over 50 keV/μm increased on average by 36% (p < 0.001), without affecting target coverage goals, or impacting LETd and dose to OARs. The interfraction analysis showed no significant worsening with minLETd set to 48 keV/μm.
UNASSIGNED: LETd optimization for large SC could boost the LETd in the GTV without significantly compromising plan quality, potentially improving the therapeutic effects of CIRT for large radioresistant tumors.

BACKGROUND: Recent reports have described the usefulness of carbon ion radiotherapy (CIRT) for inoperable sacral chordomas. However, its long-term local control rate needs to be improved. The present study identified the risk factors that affect the local relapse of sacral chordomas and the appropriate margins from the tumors.
METHODS: Forty-nine patients with sacral chordoma treated with CIRT between 2011 and 2022 were retrospectively analyzed. Factors predicting the risk of local recurrence were evaluated, including age, sex, tumor size, muscle invaded with tumor, and surgery before CIRT. To determine the appropriate margin, the distance between the clinical target volume (CTV) and the out-field recurrent lesions was analyzed.
RESULTS: The patients included 37 males and 12 females with a mean age of 67.1 years. A multivariate analysis showed that a tumor size >8 cm and invasion into the gluteus maximus muscle were significant risk factors with hazard ratios of 5.56 and 15.20 (p = 0.02 and 0.01), respectively. Out-field recurrence occurred in 13 cases, with 6, 3, and 4 relapses occurring in the muscle, bone, and both, respectively. The tumor occurred within 20 mm from the CTV in 60% of relapses in the muscles.
CONCLUSIONS: The current study presented novel findings on CIRT for sacral chordomas, although there were several limitations, such as a short follow-up period to investigate slow-growth tumors and a small number of tumor specimens owing to inoperative cases. A tumor size >8 cm and invasion into the gluteus maximus muscle were shown to be risk factors for recurrence in the treatment of sacral chordoma with CIRT. Our findings further suggest that an additional 2-cm margin from the CTV in the muscle fiber direction is recommended during CIRT.

The development of new treatment strategies to improve the prognosis of mucosal malignant melanoma of the head and neck (MMHN) after carbon ion radiotherapy (CIRT) is essential because of the risk of distant metastases. Therefore, our objective was to evaluate the outcomes of immune checkpoint inhibitor (ICI) treatment to justify its inclusion in the regimen after CIRT. Thirty-four patients who received CIRT as an initial treatment were included in the analysis and stratified into three groups: those who did not receive ICIs (Group A), those who received ICIs after recurrence or metastasis (Group B), and those who received ICIs as adjuvant therapy after CIRT (Group C). In total, 62% of the patients (n = 21) received ICIs. The 2-year local control and overall survival (OS) rates for all patients were 90.0% and 66.8%, respectively. The 2-year OS rates for patients in Groups A, B, and C were 50.8%, 66.7%, and 100%, respectively. No significant differences were observed between Groups A and B (p = 0.192) and Groups B and C (p = 0.112). However, a significant difference was confirmed between Groups A and C (p = 0.017). Adjuvant therapy following CIRT for MMHN may be a promising treatment modality that can extend patient survival.

The role of external beam radiotherapy (EBRT) in thyroid cancer (TC) remains contentious due to limited data. Retrospective studies suggest adjuvant EBRT benefits high-risk differentiated thyroid cancer (DTC) and limited-stage anaplastic thyroid carcinoma (ATC), enhancing locoregional control and progression-free survival when combined with surgery and chemotherapy. Intensity-modulated radiotherapy (IMRT) and particle therapy (PT), including protons, carbon ions, and Boron Neutron Capture Therapy (BNCT), represent advances in TC treatment. Following PRISMA guidelines, we reviewed 471 studies from January 2002 to January 2024, selecting 14 articles (10 preclinical, 4 clinical). Preclinical research focused on BNCT in ATC mouse models, showing promising local control rates. Clinical studies explored proton, neutron, or photon radiotherapy, reporting favorable outcomes and manageable toxicity. While PT shows promise supported by biological rationale, further research is necessary to clarify its role and potential combination with systemic treatments in TC management.

Renal cell carcinoma (RCC) is considered radio- and chemo-resistant. Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical efficacy in advanced RCC. However, the overall response rate of RCC to monotherapy remains limited. Given its immunomodulatory effects, a combination of radiotherapy (RT) with immunotherapy is increasingly used for cancer treatment. Heavy ion radiotherapy, specifically the carbon ion radiotherapy (CIRT), represents an innovative approach to cancer treatment, offering superior physical and biological effectiveness compared to conventional photon radiotherapy and exhibiting obvious advantages in cancer treatment. The combination of CIRT and immunotherapy showed robust effectiveness in preclinical studies of various tumors, thus holds promise for overcoming radiation resistance of RCC and enhancing therapeutic outcomes. Here, we provide a comprehensive review on the biophysical effects of CIRT, the efficacy of combination treatment and the underlying mechanisms involved in, as well as its therapeutic potential specifically within RCC.

BACKGROUND: Carbon ion radiotherapy (CIRT) is currently used to treat prostate cancer. Rectal bleeding is a major cause of toxicity even with CIRT. However, to date, a correlation between the dose and volume parameters of the 12 fractions of CIRT for prostate cancer and rectal bleeding has not been shown. Similarly, the clinical risk factors for rectal bleeding were absent after 12 fractions of CIRT.
OBJECTIVE: To identify the risk factors for rectal bleeding in 12 fractions of CIRT for prostate cancer.
METHODS: Among 259 patients who received 51.6 Gy [relative biological effectiveness (RBE)], in 12 fractions of CIRT, 15 had grade 1 (5.8%) and nine had grade 2 rectal bleeding (3.5%). The dose-volume parameters included the volume (cc) of the rectum irradiated with at least x Gy (RBE) (Vx) and the minimum dose in the most irradiated x cc normal rectal volume (Dx).
RESULTS: The mean values of D6cc, D2cc, V10 Gy (RBE), V20 Gy (RBE), V30 Gy (RBE), and V40 Gy (RBE) were significantly higher in the patients with rectal bleeding than in those without. The cutoff values were D6cc = 34.34 Gy (RBE), D2cc = 46.46 Gy (RBE), V10 Gy (RBE) = 9.85 cc, V20 Gy (RBE) = 7.00 cc, V30 Gy (RBE) = 6.91 cc, and V40 Gy (RBE) = 4.26 cc. The D2cc, V10 Gy (RBE), and V20 Gy (RBE) cutoff values were significant predictors of grade 2 rectal bleeding.
CONCLUSIONS: The above dose-volume parameters may serve as guidelines for preventing rectal bleeding after 12 fractions of CIRT for prostate cancer.

BACKGROUND: This study aimed to compare the survival outcome and side effects in patients with primary high-grade glioma (HGG) who received carbon ion radiotherapy (CIRT) alone or as a boost strategy after photon radiation (photon + CIRTboost).
METHODS: Thirty-four (34) patients with histologically confirmed HGG and received CIRT alone or Photon + CIRTboost, with concurrent temozolomide between 2020.03-2023.08 in Wuwei Cancer Hospital & Institute, China were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and acute and late toxicities were analyzed and compared.
RESULTS: Eight WHO grade 3 and 26 grade 4 patients were included in the analysis. The median PFS in the CIRT alone and Photon + CIRTboost groups were 15 and 19 months respectively for all HGG cases, and 15 and 17.5 months respectively for grade 4 cases. The median OS in the CIRT alone and Photon + CIRTboost groups were 28 and 31 months respectively for all HGG cases, and 21 and 19 months respectively for grade 4 cases. No significant difference in these survival outcomes was observed between the CIRT alone and Photon + CIRTboost groups. Only grade 1 acute toxicities were observed in CIRT alone and Photon + CIRTboost groups. CIRT alone group had a significantly lower ratio of acute toxicities compared to Photon + CIRTboost (3/18 vs. 9/16, p = 0.03). No significant difference in late toxicities was observed.
CONCLUSIONS: Both CIRT alone and Photon + CIRTboost with concurrent temozolomide are safe, without significant differences in PFS and OS in HGG patients. It is meaningful to explore whether dose escalation of CIRTboost might improve survival outcomes of HGG patients in future randomized trials.

OBJECTIVE: To investigate the role of dosiomics features extracted from physical dose (DPHYS), RBE-weighted dose (DRBE) and dose-averaged Linear Energy Transfer (LETd), to predict the risk of local recurrence (LR) in skull base chordoma (SBC) treated with Carbon Ion Radiotherapy (CIRT). Thus, define and evaluate dosiomics-driven tumor control probability (TCP) models.
METHODS: 54 SBC patients were retrospectively selected for this study. A regularized Cox proportional hazard model (r-Cox) and Survival Support Vector Machine (s-SVM) were tuned within a repeated Cross Validation (CV) and patients were stratified in low/high risk of LR. Models\' performance was evaluated through Harrell\'s concordance statistic (C-index), and survival was represented through Kaplan-Meier (KM) curves. A multivariable logistic regression was fit to the selected feature sets to generate a dosiomics-driven TCP model for each map. These were compared to a reference model built with clinical parameters in terms of f-score and accuracy.
RESULTS: The LETd maps reached a test C-index of 0.750 and 0.786 with r-Cox and s-SVM, and significantly separated KM curves. DPHYS maps and clinical parameters showed promising CV outcomes with C-index above 0.8, despite a poorer performance on the test set and patients stratification. The LETd-based TCP showed a significatively higher f-score (0.67[0.52-0.70], median[IQR]) compared to the clinical model (0.4[0.32-0.63], p < 0.025), while DPHYS achieved a significatively higher accuracy (DPHYS: 0.73[0.65-0.79], Clinical: 0.6 [0.52-0.72]).
CONCLUSIONS: This analysis supports the role of LETd as relevant source of prognostic factors for LR in SBC treated with CIRT. This is reflected in the TCP modeling, where LETd and DPHYS showed an improved performance with respect to clinical models.

OBJECTIVE: This systematic review and meta-analysis aimed to investigate the effectiveness of carbon ion radiotherapy (CIRT) compared to that of conventional radiotherapy in patients with various types of solid tumors.
METHODS: We systematically searched eight electronic databases from inception until August 2022 in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The comparative effectiveness of the different treatment options was assessed by a random-effects meta-analysis.
RESULTS: This review included 34 comparative studies and three treatment groups. Overall, the meta-analysis indicated comparable local control rates between the CIRT and control groups [pooled risk ratio (RR)=1.02, 95% confidence interval (CI) 0.90-1.15]. The local control rate in the CIRT group was higher than that in the photon therapy group, but slightly lower than that in the proton radiation therpy (PRT) group. Additionally, the CIRT group had significantly higher overall survival (OS) (RR=1.19, 95% CI=1.01-1.42) and progression-free survival (PFS) (RR=1.50, 95% CI=1.01-2.21) rates compared to the control group. In the subgroup analysis, survival rates were similar between the CIRT and PRT groups.
CONCLUSIONS: CIRT was associated with improved toxicity, local tumor control, OS, and PFS compared to conventional treatments. Therefore, CIRT was found to be a safe and effective option for achieving local control in patients with solid tumors.