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The therapeutic efficacy of radiotherapy (RT) is primarily driven by two factors: biophysical DNA damage in cancer cells and radiation-induced anti-tumor immunity. However, Anti-tumor immune responses between X-ray RT (XRT) and carbon-ion RT (CIRT) remain unclear. In this study, we, employed mouse models to assess the immunological contribution, especially cytotoxic T-lymphocyte (CTL)-mediated immunity, to the therapeutic effectiveness of XRT and CIRT in shrinking tumors. We irradiated mouse intradermal tumors of B16F10-ovalbumin (OVA) mouse melanoma cells and 3LL-OVA mouse lung cancer cells with carbon-ion beams or X-rays in the presence or absence of CTLs. CTL removal was performed by administration of anti-CD8 monoclonal antibody (mAb) in mice. Based on tumor growth delay, we determined the tumor growth and regression curves. The enhancement ratio (ER) of the slope of regression lines in the presence of CTLs, relative to the absence of CTLs, indicates the dependency of RT on CTLs for shrinking mouse tumors, and the biological effectiveness (RBE) of CIRT relative to XRT were calculated. Tumor growth curves revealed that the elimination of CD8+ CTLs by administrating anti-CD8 mAb accelerated tumor growth compared to the presence of CTLs in both RTs. The ERs were larger in CIRT compared to XRT in the B16F10-OVA tumor models, but not in the 3LL-OVA models, suggesting a greater contribution of CTL-mediated anti-tumor immunity to tumor reduction in CIRT compared to XRT in the B16F10-OVA tumor model. In addition, the RBE values for both models were larger in the presence of CTLs compared to models without CTLs, suggesting that CIRT may utilize CTL-mediated anti-tumor immunity more than X-ray. The findings from this study suggest that although immunological contribution to therapeutic efficacy may vary depending on the type of tumor cell, CIRT utilizes CTL-mediated immunity to a greater extent compared to XRT.
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Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos , Animais , Linfócitos T Citotóxicos/imunologia , Camundongos , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Melanoma Experimental/radioterapia , Melanoma Experimental/terapia , Melanoma Experimental/patologia , Radioterapia com Íons Pesados/métodos , Terapia por Raios X , Feminino , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologiaRESUMO
Carbon ion radiotherapy (CIRT) is a heavy ion charge particle therapy with 29 years of prominent use. Despite advantages like high relative biological effectiveness (RBE), improved quality of life, and reduced treatment time, challenges persist, especially regarding heavy nuclear fragments. Our research addresses these challenges in horizontal irradiation, aiming to comprehend Monoenergetic and Spread-Out Bragg peak (SOBP) carbon ion beam trajectories using cell survival analysis and visualizing biological effects through DNA damage (γ-H2AX). This reveals repair-related protein foci near the Bragg peak. CR-39, a plastic nuclear track detector, was explored to understand high-linear energy transfer (LET) tracks and radiation quality near the Bragg peak. Findings unveil high-LET DNA damage signatures through aligned γ-H2AX foci, correlating with LET values in SOBP. CR-39 visualized high-LET particle exposure, indicating comet-type etch-pits at the Bragg peak and suggesting carbon ion fragmentation. Unexpectedly, dot-type etch-pits in irradiated and post-Bragg peak regions indicated high-LET neutron production. This investigation highlights the intricate interplay of carbon ion beams, stressing the importance of understanding LET variations, DNA damage patterns, and undesired secondary exposure.
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Radioterapia com Íons Pesados , Transferência Linear de Energia , Polietilenoglicóis , Qualidade de Vida , Íons , Carbono , Dano ao DNA , Morte CelularRESUMO
INTRODUCTION: 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. CONCLUSION: 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.
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BACKGROUND: Nasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC. METHODS AND MATERIALS: Twenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method. RESULTS: The median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed. CONCLUSION: Definitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.
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Carcinoma Adenoide Cístico , Neoplasias Nasofaríngeas , Terapia com Prótons , Humanos , Carcinoma Adenoide Cístico/radioterapia , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Adulto , Estudos Retrospectivos , Resultado do Tratamento , Idoso , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Adulto Jovem , Seguimentos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Recidiva Local de Neoplasia/radioterapia , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/métodosRESUMO
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). PATIENTS AND 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. CONCLUSION: 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.
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Glioma , Radioterapia com Íons Pesados , Fótons , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/métodos , Feminino , Masculino , Glioma/radioterapia , Glioma/mortalidade , Glioma/patologia , Fótons/uso terapêutico , Fótons/efeitos adversos , Adulto , Idoso , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/mortalidade , Temozolomida/uso terapêutico , Gradação de Tumores , Adulto Jovem , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
Carbon ion radiotherapy (CIRT) has received attention for the treatment of locally recurrent rectal cancer. When the surrounding primary organs are close to the irradiation site, a spacer is required to ensure safe irradiation. This work describes a novel technique using a bioabsorbable polyglycolic acid spacer placed laparoscopically and presents a technical report with five case studies. The short-term surgical outcomes were as follows: mean operating time 235 min with blood loss of 38 mL. CIRT was planned, and the patients underwent irradiation within 2 months of surgery. No pelvic infections occurred, and all procedures were performed safely. Herein, were present a technical report with reference to a video of the surgical procedure.
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Implantes Absorvíveis , Laparoscopia , Recidiva Local de Neoplasia , Ácido Poliglicólico , Neoplasias Retais , Humanos , Neoplasias Retais/cirurgia , Neoplasias Retais/radioterapia , Laparoscopia/métodos , Recidiva Local de Neoplasia/cirurgia , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Resultado do Tratamento , Duração da CirurgiaRESUMO
BACKGROUND: Local recurrence in locally advanced pancreatic cancer (LAPC) after carbon-ion radiotherapy (CIRT) may partly attribute to low dose-averaged linear energy transfer (LETd), despite high CIRT dose. PURPOSE: This study aimed to investigate the approaches to up-modulate the CIRT LETd and to evaluate the corresponding oxygen enhancement ratio (OER) reduction. METHODS: 10 LAPCs that had been irradiated by CIRT with 67.5 Gy (RBE) in 15 fractions were selected. Their original plans were taken as the control plan for the LETd and OER investigations. Our considerations for up-modulating LETd were: (1) to deliver high doses to gross tumor volume core (GTVcore), while keeping dose constraints of the gastrointestinal (GI) tract in tolerance; (2) to put more Bragg-peak (BP) within the modulated targets; (3) to increase the BP density, high doses were necessary; (4) CIRT LETd could be effectively increased to small volumes; and (5) simultaneous integrated boost technique (SIB) could achieve the aforementioned tasks. The LETd and the corresponding OER distributions of each type of SIB plan were evaluated. RESULTS: We delivered up to 100 Gy (RBE) to GTVcore using SIB. The mean LETd of GTV increased significantly by 21.3% from 47.8 to 58.0 keV/µm (p < 0.05). Meanwhile, the mean OER of GTVcore decreased by 6.6%, from 1.51 to 1.41 (p < 0.05). The GI LETdS in all modulated plans were not more than those in the original plans. CONCLUSIONS: SIB could effectively increase CIRT LETd to LAPC, thus producing reduced OER, which may effectively overcome the radioresistance of LAPCs.
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Radioterapia com Íons Pesados , Transferência Linear de Energia , Neoplasias Pancreáticas , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Neoplasias Pancreáticas/radioterapia , Humanos , Radioterapia com Íons Pesados/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Órgãos em Risco/efeitos da radiação , PrognósticoRESUMO
PURPOSE: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. METHODS: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed. RESULTS: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. CONCLUSIONS: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes.
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Radioterapia com Íons Pesados , Órgãos em Risco , Imagens de Fantasmas , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Eficiência Biológica Relativa , Humanos , Radioterapia com Íons Pesados/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Órgãos em Risco/efeitos da radiação , Radiobiologia , Neoplasias/radioterapia , Transferência Linear de Energia , Cinética , Radioterapia de Intensidade Modulada/métodosRESUMO
Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes. Thus, carbon ion radiation therapy (CIRT) activates anti-cancer immunity. However, cancer is protected by the tumor microenvironment (TME), which consists of pro-cancerous immune cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The TME is too robust to be destroyed by the CIRT-mediated anti-cancer immunity. Various modalities targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages have been developed. Preclinical studies have shown that CIRT-mediated anti-cancer immunity exerts its effects in the presence of these modalities. In this review article, we provide an overview of CIRT-mediated anti-cancer immunity, with a particular focus on recently identified means of targeting the TME.
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Radioterapia com Íons Pesados , Células Supressoras Mieloides , Neoplasias , Humanos , Neoplasias/patologia , Linfócitos T Reguladores , DNA , Microambiente TumoralRESUMO
BACKGROUND: A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size. METHODS: This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4 Gy relative biological effectiveness in 12 fractions, between 2012 and 2022. RESULTS: Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80 years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9-62.4), 74.9% (95% CI, 90.7-59.0), and 66.4% (95% CI, 83.3-49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis. CONCLUSIONS: Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma.
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This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM-I) with a dose escalation plan. The escalated relative biological effectiveness-weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM-I-based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty-three patients with a median tumor size of 4.3 cm (range, 1.7-8.5 cm) were enrolled in the present study. The median follow-up time was 56.1 months (range, 5.7-74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation-induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression-free survival and progression-free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC.
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Carcinoma Hepatocelular , Radioterapia com Íons Pesados , Neoplasias Hepáticas , Lesões por Radiação , Humanos , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Dosagem Radioterapêutica , Radioterapia com Íons Pesados/métodosRESUMO
Reports on the therapeutic efficacy and safety of carbon-ion radiotherapy (C-ion RT) for oligometastatic liver disease are limited, with insufficient evidence. This study aimed to evaluate the clinical outcomes of C-ion RT for oligometastatic liver disease at all Japanese facilities using the nationwide cohort data. We reviewed the medical records to obtain the nationwide cohort registry data on C-ion RT between May 2016 and June 2020. Patients (1) with oligometastatic liver disease as confirmed by histological or diagnostic imaging, (2) with ≤3 synchronous liver metastases at the time of treatment, (3) without active extrahepatic disease, and (4) who received C-ion RT for all metastatic regions with curative intent were included in this study. C-ion RT was performed with 58.0-76.0 Gy (relative biological effectiveness [RBE]) in 1-20 fractions. In total, 102 patients (121 tumors) were enrolled in this study. The median follow-up duration for all patients was 19.0 months. The median tumor size was 27 mm. The 1-year/2-year overall survival, local control, and progression-free survival rates were 85.1%/72.8%, 90.5%/78.0%, and 48.3%/27.1%, respectively. No patient developed grade 3 or higher acute or late toxicity. C-ion RT is a safe and effective treatment for oligometastatic liver disease and may be beneficial as a local treatment option in multidisciplinary treatment.
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Radioterapia com Íons Pesados , Neoplasias Hepáticas , Radioterapia (Especialidade) , Humanos , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/métodos , Japão , Neoplasias Hepáticas/radioterapia , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbon-ion radiotherapy is a radical nonsurgical treatment with high local control rates and no serious adverse events. N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNA (mRNA) and has important effects on the stability, splicing, and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbon-ion radiotherapy of non-small-cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of methyltransferase-like 3 (METTL3) and its mediated m6A modification were elevated in NSCLC cells with carbon-ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3-mediated m6A modification of mRNA inhibited the decay of H2A histone family member X (H2AX) mRNA and enhanced its expression, which led to enhanced DNA damage repair and cell survival.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , CarbonoRESUMO
Following carbon ion beam irradiation in mammalian cells, such as used in carbon ion radiotherapy (CIRT), it has been suggested that the balance between whether nonhomologous end joining (NHEJ) or homologous recombination (HR) is utilized depends on the DNA double-strand break (DSB) complexity. Here, we quantified DSB distribution and identified the importance of each DSB repair pathway at increasing depths within the carbon ion spread-out Bragg peak (SOBP) beam range. Chinese hamster ovary (CHO) cell lines were irradiated in a single biological system capable of incorporating the full carbon ion SOBP beam range. Cytotoxicity and DSB distribution/repair kinetics were examined at increasing beam depths using cell survival as an endpoint and γ-H2AX as a surrogate marker for DSBs. We observed that proximal SOBP had the highest number of total foci/cell and lowest survival, while distal SOBP had the most dense tracks. Both NHEJ- and HR-deficient CHO cells portrayed an increase in radiosensitivity throughout the full carbon beam range, although NHEJ-deficient cells were the most radiosensitive cell line from beam entrance up to proximal SOBP and demonstrated a dose-dependent decrease in ability to repair DSBs. In contrast, HR-deficient cells had the greatest ratio of survival fraction at entrance depth to the lowest survival fraction within the SOBP and demonstrated a linear energy transfer (LET)-dependent decrease in ability to repair DSBs. Collectively, our results provide insight into treatment planning and potential targets to inhibit, as HR was a more beneficial pathway to inhibit than NHEJ to enhance the cell killing effect of CIRT in targeted tumor cells within the SOBP while maintaining limited unwanted damage to surrounding healthy cells.
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Quebras de DNA de Cadeia Dupla , Reparo do DNA , Cricetinae , Animais , Humanos , Cricetulus , Células CHO , DNA , Carbono , Reparo do DNA por Junção de ExtremidadesRESUMO
BACKGROUND/AIMS: Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer. METHODS: We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone. RESULTS: CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining. CONCLUSION: CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities.
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Radioterapia com Íons Pesados , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/metabolismo , Autofagia , Resultado do Tratamento , Neoplasias PancreáticasRESUMO
Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.
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Ferroptose , Radioterapia com Íons Pesados , Humanos , Recidiva Local de Neoplasia/patologia , Terapia Combinada , ImunoterapiaRESUMO
BACKGROUND: There is currently no established imaging method for assessing liver reserve capacity prior to carbon-ion radiotherapy (CIRT) for liver tumors. In order to perform safe CIRT, it is essential to estimate the post-therapeutic residual reserve capacity of the liver. PURPOSE: To evaluate the ability of pre-treatment 99mTc-galactosyl human serum albumin (99mTc-GSA) scintigraphy to accurately estimate the residual liver reserve capacity in patients treated with CIRT for liver tumors. MATERIALS AND METHODS: This retrospective study evaluated patients who were performed CIRT for liver tumors between December 2018 and September 2020 and underwent 99mTc-GSA scintigraphy before and 3 months after CIRT, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month before CIRT were evaluated. The maximal removal rate of 99mTc-GSA (GSA-Rmax) was analyzed for the evaluation of pre-treatment liver reserve capacity. Then, the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using liver SPECT images fused with the Gd-EOB-DTPA-enhanced MRI. GSA-RL before CIRT and GSA-Rmax at 3 months after CIRT were compared using non-parametric Wilcoxon signed-rank test and linear regression analysis. RESULTS: Overall, 50 patients were included (mean age ± standard deviation, 73 years ± 11; range, 29-89 years, 35 men). The median GSA-RL was 0.393 [range, 0.057-0.729] mg/min, and the median GSA-Rmax after CIRT was 0.369 [range, 0.037-0.780] mg/min (P = .40). The linear regression equation representing the relationship between the GSA-RL and GSA-Rmax after CIRT was y = 0.05 + 0.84x (R2 = 0.67, P < .0001). There was a linear relationship between the estimated and actual post-treatment values for all patients, as well as in the group with impaired liver reserve capacity (y = - 0.02 + 1.09x (R2 = 0.62, P = .0005)). CONCLUSIONS: 99mTc-GSA scintigraphy has potential clinical utility for estimating the residual liver reserve capacity in patients undergoing carbon-ion radiotherapy for liver tumors. TRIAL REGISTRATION: UMIN000038328, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043545 .
Assuntos
Hepatectomia , Neoplasias Hepáticas , Humanos , Masculino , Carbono , Hepatectomia/métodos , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/patologia , Cintilografia , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Agregado de Albumina Marcado com Tecnécio Tc 99m , Pentetato de Tecnécio Tc 99m , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
PURPOSE: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. METHODS: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. RESULTS: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. CONCLUSIONS: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.
Assuntos
Íons Pesados , Neoplasias Meníngeas , Meningioma , Terapia com Prótons , Humanos , Pessoa de Meia-Idade , Prótons , Terapia com Prótons/efeitos adversos , China/epidemiologia , Organização Mundial da Saúde , Recidiva Local de Neoplasia/radioterapiaRESUMO
BACKGROUND: Compelling evidence shows the association between the relative biological effectiveness (RBE) of carbon-ion radiotherapy (CIRT) and the dose averaged linear energy transfer (LETd). However, the ability to calculate the LETd in commercially available treatment planning systems (TPS) is lacking. PURPOSE: This study aims to develop a method of calculating the LETd of CIRT plans that could be robustly carried out in RayStation (V10B, Raysearch, Sweden). METHODS: The calculation used the fragment spectra in RayStation for the CIRT treatment planning. The dose-weighted averaging procedure was supported by the microdosimetric kinetic model (MKM). The MKM-based pencil beam dose engine (PBA, v4.2) for calculating RBE-weighted doses was reformulated to become a LET-weighted calculating engine. A separate module was then configured to inversely calculate the LETd from the absorbed dose of a plan and the associated fragment spectra. In this study, the ion and energy-specific LET table in the LETd module was further matched with the values decoded from the baseline data of the Syngo TPS (V13C, Siemens, Germany). The LETd distributions of several monoenergetic and modulated beams were calculated and validated against the values derived from the Syngo TPS and the published data. RESULTS: The differences in LETds of the monoenergetic beams between the new method and the traditional method were within 3% in the entrance and Bragg-peak regions. However, a larger difference was observed in the distal region. The results of the modulated beams were in good agreement with the works from the published literature. CONCLUSIONS: The method presented herein reformulates the MKM dose engine in the RayStation TPS to inversely calculate LETds. The robustness and accuracy were demonstrated.
Assuntos
Radioterapia com Íons Pesados , Terapia com Prótons , Humanos , Terapia com Prótons/métodos , Transferência Linear de Energia , Eficiência Biológica Relativa , Planejamento da Radioterapia Assistida por Computador/métodos , Carbono , Dosagem Radioterapêutica , Método de Monte CarloRESUMO
The errors on the stopping power ratio (SPR) of mouthpiece samples from ERKODENT were evaluated. Erkoflex and Erkoloc-pro from ERKODENT and samples that combined Erkoflex and Erkoloc-pro were computed tomography (CT)-scanned using head and neck (HN) protocol at the East Japan Heavy Ion Center (EJHIC), and the values were averaged to obtain the CT number. The integral depth dose of the Bragg curve with and without these samples was measured for 292.1, 180.9, and 118.8 MeV/u of the carbon-ion pencil beam using an ionization chamber with concentric electrodes at the horizontal port of the EJHIC. The average value of the water equivalent length (WEL) of each sample was obtained from the difference between the range of the Bragg curve and the thickness of the sample. To calculate the difference between the theoretical and measured values, the theoretical CT number and SPR value of the sample were calculated using the stoichiometric calibration method. Compared with the Hounsfield unit (HU)-SPR calibration curve used at the EJHIC, the SPR error on each measured and theoretical value was calculated. The WEL value of the mouthpiece sample had an error of approximately 3.5% in the HU-SPR calibration curve. From this error, it was evaluated that for a mouthpiece with a thickness of 10 mm, a beam range error of approximately 0.4 mm can occur, and for a mouthpiece with a thickness of 30 mm, a beam range error of approximately 1 mm can occur. For a beam passing through the mouthpiece in HN treatment, it would be practical to consider a mouthpiece margin of 1 mm to avoid beam range errors if ions pass through the mouthpiece.