Presenter of 1 Presentation
HIGH-DOSE X-RAY MICROBEAMS DELIVERED AT FLASH DOSE RATES PREVENT RADIATION-INDUCED LIVER FIBROSIS
Abstract
Background and Aims
Normal tissue preservation is the dose-limiting factor in clinical radiation therapy where late pathological changes, such as fibrosis, are the major normal tissue complications that dictate dose prescription. Microbeam radiation therapy (MRT) is a novel radiation modality that shows exceptional normal tissue sparing while delivering high-dose beamlets at ultra-high, FLASH dose rates from synchrotron sources. Explored primarily in the brain and skin, the tissue-sparing effects of MRT have never been investigated in the liver, the second most common site of metastasis and organ at risk for abdominal irradiations. We therefore investigated the effects liver exposure to FLASH MRT following irradiation of the lower right lung.
Methods
C57BL/6J mice were irradiated with two, cross-fired arrays of 50 µm wide microbeams spaced 400 µm apart with peak doses of 400 Gy (dose-rate 991.7 Gy/s). Livers were collected for histological analysis at 12, 24, and 48 hours and 6 months post-irradiation.
Results
Livers did not exhibit any signs of fibrosis 6 months after MRT. Investigation of cell death mechanisms revealed scarce apoptotic cells and the absence of necrosis at earlier time points. Within 48 hours, macrophages were organized into the beam path accompanied by infiltration of hematopoietic and immune cell populations.
Conclusions
We have demonstrated that radiation doses exceeding clinical thresholds can be delivered to the liver via a high dose-rate, spatially-fractionated MRT modality. The absence of pathological changes, such as fibrosis, in normal liver tissues at 6 months post-irradiation suggests that MRT could be used for the safe treatment of liver metastases and primary hepatocellular carcinomas.
Author Of 3 Presentations
SYNCHROTRON MICROBEAM RADIATION - FLASH AND SPATIAL FRACTIONATION, THE BEST OF BOTH WORLDS
Abstract
Background and Aims
Microbeam Radiation Therapy (MRT) is an innovative radiotherapeutic approach by which synchrotron-generated X-rays are spatially fractionated resulting in periodic, alternating dose distribution in the tissue. In parallel to the excellent tumour control, normal tissues show remarkably high resistance. However, the biggest challenge in translating MRT to the clinic are the high peak doses (300-600Gy) delivered at ultra-fast dose-rates, achievable currently only by synchrotron facilities. Therefore, to advance the clinical translation of MRT, new treatment strategies have been explored.
Methods
Microbeam Radiation Therapy, single 400Gy, fractionated (3x133Gy), combination with Au-NP and cisplatin
Results
We have demonstrated that temporally fractionated MRT (3x 133Gy) ablated 50% of murine melanomas, preventing organ metastases and local recurrence for 18 months post-treatment. In the remaining animals, the median survival increased by 2.5-fold compared to single MRT-irradiated mice and by 4.1-fold relative to untreated mice. In a double treatment, 150Gy MRT combined with Au-NP increased the median survival by more than 2-fold compared to a single MRT irradiation, and 6.6-fold compared to untreated mice. Furthermore, 150Gy MRT, when combined with cisplatin, reduced the glioblastoma tumour volume by 6-fold compared to cisplatin alone and 60-fold relative to untreated mice.
Temporally fractionated MRT and low dose MRT combined with Au-NP or cisplatin increased the efficacy of MRT in the case of radioresistant melanoma and glioblastoma, reaching the best reported treatment ratio for complete tumour remission.
Conclusions
Our results demonstrate that MRT administration could be adapted for clinical use by employing multiple fractions with lower peak doses using intersecting arrays or with combined treatment strategies.
DOUBLE-FRACTION SYNCHROTRON MICROBEAM RADIATION OF MURINE MELANOMA IMPROVES LOCAL CONTROL AND TRIGGERS REGRESSION OF LOCOREGIONAL METASTASIS
Abstract
Background and Aims
Experimental synchrotron X-ray-generated microbeam radiation therapy (MRT) represents an innovative mode of cancer radiotherapy with an excellent therapeutic ratio, but optimization of the irradiation protocol is an essential step toward clinical implementation.
Methods
We irradiated B16-F10 melanoma-bearing C57BL/6J female mice with one or two 396-Gy peak-dose fractions of MRT.
Results
The second MRT fraction remarkably attenuated tumour growth. Both single dose MRT and broad beam irradiation quickly accelerated the formation of metastasis in superficial cervical lymph nodes. Remarkably, the second MRT fraction triggered a very pronounced regression of locoregional metastasis that lasted for 5 weeks. This reduction cannot be explained by direct exposure of melanoma cells to low-dose scattered radiation, therefore an abscopal effect is a legitimate explanation. In search for factors that generated this anti-tumor/anti-metastatic response, we measured plasma concentrations of 34 pro-inflammatory and anti-inflammatory cytokines in cohorts of mice that received one or two MRT fractions. Neutrophil and T cell-attracting chemokines CXCL5, CXCL12 and CCL22 were significantly increased two days after the second MRT irradiation, indicating that alleviated melanoma growth and progression in animals treated with two MRT fractions could be a consequence of increased recruitment of anti-tumor neutrophils and T cells.
Conclusions
Our study indicates the approach for an optimal MRT regimen. Alone or in combination with immunotherapy, MRT may be able to not only enhance the local and locoregional control, but also boost abscopal effects. Therefore, MRT may be able to decrease the incidence of metastatic disease, the most common cause of death, even after successful treatment of the primary tumor.
HIGH-DOSE X-RAY MICROBEAMS DELIVERED AT FLASH DOSE RATES PREVENT RADIATION-INDUCED LIVER FIBROSIS
Abstract
Background and Aims
Normal tissue preservation is the dose-limiting factor in clinical radiation therapy where late pathological changes, such as fibrosis, are the major normal tissue complications that dictate dose prescription. Microbeam radiation therapy (MRT) is a novel radiation modality that shows exceptional normal tissue sparing while delivering high-dose beamlets at ultra-high, FLASH dose rates from synchrotron sources. Explored primarily in the brain and skin, the tissue-sparing effects of MRT have never been investigated in the liver, the second most common site of metastasis and organ at risk for abdominal irradiations. We therefore investigated the effects liver exposure to FLASH MRT following irradiation of the lower right lung.
Methods
C57BL/6J mice were irradiated with two, cross-fired arrays of 50 µm wide microbeams spaced 400 µm apart with peak doses of 400 Gy (dose-rate 991.7 Gy/s). Livers were collected for histological analysis at 12, 24, and 48 hours and 6 months post-irradiation.
Results
Livers did not exhibit any signs of fibrosis 6 months after MRT. Investigation of cell death mechanisms revealed scarce apoptotic cells and the absence of necrosis at earlier time points. Within 48 hours, macrophages were organized into the beam path accompanied by infiltration of hematopoietic and immune cell populations.
Conclusions
We have demonstrated that radiation doses exceeding clinical thresholds can be delivered to the liver via a high dose-rate, spatially-fractionated MRT modality. The absence of pathological changes, such as fibrosis, in normal liver tissues at 6 months post-irradiation suggests that MRT could be used for the safe treatment of liver metastases and primary hepatocellular carcinomas.