Search Results (20)

Very-high-energy electrons, coupled with ultra-high dose rates, are being explored for their potential use in radiotherapy to treat deep-seated tumours. The dose per pulse needed to achieve ultra-high dose rates far exceeds the limit of current medical linear accelerator capabilities. A high dose per pulse has been observed as the limiting factor for many existing dosimeters, resulting in saturation at doses far below what is required. The MOSkin, an existing clinical quality assurance dosimeter, has previously been demonstrated as dose rate independent but has not been subjected to a high dose per pulse. Within this study, the MOSkins dose-per-pulse response was tested for linearity, with a dose per pulse as high as 23 Gy within 200 ns at the ANSTO Australian Synchrotron’s Pulsed Energetic Electrons for Research facility. While using EBT-XD film as a reference dosimeter, a dose rate dependence of the EBT-XD was discovered. Once confirmed and a correction factor established, EBT-XD was used as an independent reference measurement. This work presents confirmation of the MOSkin suitability for ultra-high dose-rate environments with an electron energy of 100 MeV, and a theoretical discussion of its dose-rate and dose-per-pulse independence; the MOSkin is the only detector suitable for both clinical quality assurance, and ultra-high dose-rate measurements in its standard, unmodified form. Full article

The results of radiotherapy in patients with primary malignant brain tumors are extremely dissatisfactory: the overall survival after a diagnosis of glioblastoma is typically less than three years. The development of spatially fractionated radiotherapy techniques could help to improve this bleak prognosis. In order to develop technical equipment and organ-specific therapy plans, dosimetry studies as well as radiobiology studies are conducted. Although perfect spheres are considered optimal phantoms by physicists, this does not reflect the wide variety of head sizes and shapes in our patient community. Depth from surface and X-ray dose absorption by tissue between dose entry point and target, two key parameters in medical physics planning, are largely determined by the shape and thickness of the skull bone. We have, therefore, designed and produced a biomimetic tool to correlate measured technical dose and biological response in human cancer cells: a brain phantom, produced from tissue-equivalent materials. In a first pilot study, utilizing our phantom to correlate technical dose measurements and metabolic response to radiation in human cancer cell lines, we demonstrate why an anthropomorphic phantom is preferable over a simple spheroid phantom. Full article

High-Z nanoparticles (NPs) have the potential to revolutionize cancer radiotherapy by radiosensitising tumours. This is particularly important for radioresistant cancers such as glioblastoma. A newer NP candidate in this area is thulium oxide nanoparticles (TmNPs). However, prior to clinical assessment, ideal NP characteristics, including biocompatibility, biosafety, and preferential uptake in cancer, should be assessed. This in vitro study compares the effects of TmNP treatment, without radiation, on 9L gliosarcoma (9LGS), a well-established glioblastoma cell model, with exposure to Madin Darby Canine Kidney (MDCK) cells, a widely used non-cancerous cell model. The findings demonstrated selective uptake of TmNPs in 9LGS over MDCK following treatment. A biological assessment of toxicity confirmed minimal long-term effects on MDCK, whilst TmNPs were observed to induce some notable cell death in 9LGS. Excessive TmNP uptake in 9LGS over time was observed to induce cell vacuolisation, which resulted in cell death via necrosis. It was concluded that this was the explanation for the underlying mechanisms of TmNP toxicity in cancer cells. This study was therefore able to demonstrate not only that TmNPs are a biocompatible, cancer-selective candidate for radiosensitiser usage, but further provided a theory to explain its mechanisms of cancer cell toxicity. Full article

Background/objectives: Brain cancer remains difficult to treat, with survival statistics stagnant for decades. The resistance of glioblastoma brain tumours can greatly challenge the effectiveness of conventional cancer radiotherapy. However, high dose rate radiotherapy has unique effects that allow for normal tissue sparing whilst maintaining tumour control. The addition of targeted radiosensitisers, such as the chemotherapeutic drug methotrexate (MTX) or the high-Z halogenated pyrimidine drug iododeoxyuridine (IUdR), can improve radiotherapy outcomes. Combining these radiosensitiser agents with ultra-high dose rate (UHDR) synchrotron X-rays can bear synergistic effects to enhance the efficacy of these multi-modal UHDR therapies, providing a means to overcome the radioresistance of brain cancer. Methods: Here, we use controlled in vitro assays following treatment, including a clonogenic assay to determine long-term cell survival and γH2AX immunofluorescent confocal microscopy to quantify double-strand DNA breaks (DSBs). Results: We find significant enhancement for highly synergistic combinations of IUdR+MTX with synchrotron X-rays. Cell survival results demonstrate 5.4 times increased 9L gliosarcoma cell killing when these agents are combined with UHDR synchrotron X-rays compared with conventional X-rays alone at the same 5 Gy dose. The underlying mechanisms are unveiled using γH2AX imaging and reveal significant increases in DSBs and dying cells following exposure to UHDR radiation. Conclusions: Our results demonstrate that highly synergistic combination treatments using UHDR synchrotron radiation can yield significantly improved brain cancer killing compared with conventional radiotherapy. We anticipate that these additive, multi-modal combination therapies will provide options for more targeted and effective use of radiotherapies for the future treatment of brain cancer. Full article

Background/Objectives: Brain cancer is notoriously resistant to traditional treatments, including radiotherapy. Microbeam radiation therapy (MRT), arrays of ultra-fast synchrotron X-ray beams tens of micrometres wide (called peaks) and spaced hundreds of micrometres apart (valleys), is an effective alternative to conventional treatments. MRT’s advantage is that normal tissues can be spared from harm whilst maintaining tumour control. Combining MRT with targeted radiosensitisers, such as nanoparticles, chemotherapeutic drugs, and halogenated pyrimidine drugs, can further improve radiotherapy by enhancing radiation damage. However, the underlying mechanisms of MRT are still being understood, which is essential to ensuring the reliable and successful use of MRT. Methods: An in vitro study was performed using γH2AX imaging, and quantification was performed via confocal microscopy and a clonogenic cell survival assay. Results: We show that methotrexate chemotherapeutics and iododeoxyuridine enhance MRT cell-killing and thulium oxide nanoparticles (TmNPs) broaden MRT peaks, and using γH2AX immunofluorescent confocal microscopy to quantify DNA damage, we further our knowledge of MRT mechanisms. γH2AX images verify the biological responses of cells aligning with the physical collimation of MRT, and we can accurately measure MRT microbeam characteristics bio-dosimetrically. The peak-to-valley dose ratio (PVDR), the ratio of the peak dose to the valley dose that characterises an MRT field, was accurately measured biologically using γH2AX imaging, despite studies previously finding this challenging. Conclusions: The measurement of biological PVDR has been performed for the first time with high-Z radiosensitisers, including nanoparticles, and several novel radiosensitiser-enhanced MRT mechanisms were discovered. Our results deepen our understanding of MRT with radiosensitisers, and can contribute to its accurate and future successful use in treating cancer. Full article

Quality assurance (QA) ensures the accurate and safe delivery of radiation treatment. However, there are several challenges for advanced radiotherapy techniques, such as stereotactic radiosurgery (SRS), where substantial doses of radiation with multi-directional beams and variable dose rates are delivered to specific areas. Current dosimeters lack high precision, exhibiting issues with dependency on the angle of measurement and the dose rate. This study investigates the characterization of a two-dimensional edgeless silicon diode array for QA in SRS. This detector underwent evaluation of its dose linearity, percentage depth dose (PDD), output factors (OFs), dose rate variability, and angular dependence with megavoltage linear accelerator beams. The edgeless array demonstrated a linear response in the direct detection of MV therapeutic X-rays with sensitivity of 6.95 × 10⁻³ ± 2.3 × 10⁻⁵ Gy/nC, and the percentage differences for PDD and OF measurements were found to be within 2% compared to the reference detector. A dose per pulse dependence of ±2% was demonstrated across the range of 0.12 to 0.39 mGy/pulse. The angular dependence was within 2% variation for irradiation angles greater than 80° and smaller than 120°; however, a maximum of 4% variation was observed with some diodes for angles between 80° and 120°. The improved performance of the edgeless array is likely to overcome limitations of the current dosimeters for SRS QA by operating without the need of any corrections. Full article

Targeted brain cancer treatments are sorely needed to improve long-term prognosis, particularly for gliosarcoma and glioblastoma patients. Gold nanoparticles (GNPs) have unique properties including high atomic number, biocompatibility, and small size for cancer cell internalization. GNPs are consequently an ideal candidate for improved cancer targeting using image-guided radiotherapy. This work investigated 15 nm AuroVist^TM GNPs for image-guided gliosarcoma radiotherapy and identified optimum GNP concentrations. The GNPs were found to be 15–20 nm using optical surface plasmon resonance absorption, with a (41.3 ± 0.3) nm hydrodynamic diameter. Confocal imaging showed that 50–500 µg/mL of the GNPs was well-internalized into the 9L cells within 24–48 h. γ-H2AX assays showed that 50–500 µg/mL of the GNPs radiosensitized the 9L cells irradiated with 125 and 150 kVp X-rays. However, only 500 µg/mL of the GNPs produced significant long-term dose enhancement with 150 kVp X-rays (with a sensitization enhancement ratio at 10% survival of 1.43, and 1.13 with 50 µg/mL) using clonogenic assay. CT imaging of the GNPs in the 9L tumors in Fischer rats further showed that GNP concentrations above 500 µg/mL were required to distinguish the tumor from the brain, and the GNPs were detected 48 h after injection. These promising results indicate that the GNPs can be used for selective gliosarcoma treatment with image-guided X-ray radiotherapy at concentrations above 500 µg/mL. Full article

Synchrotron Microbeam Radiation Therapy (MRT) is an innovative technique that spatially segments the synchrotron radiation field for cancer treatment. A microbeam peak dose is often hundreds of times the dose in the valley (the sub-millimeter region between the peaks of the microbeams). Peak and valley doses vary with increasing depth in tissue which effects tumor dose coverage. It remains to be seen whether the peak or valley is the primary factor in MRT cancer control. This study investigates how unilateral MRT doses can be modulated using a bolus, and identifies the valley dose as a primary factor in MRT cancer control. Fischer rats bearing 9 L gliosarcoma tumors were irradiated with MRT at the Imaging and Medical Beam Line of the Australian Synchrotron. MRT valley doses of 8–15 Gy (250–1040 Gy peak doses) were used to treat tumors with and without a 5 mm dose-modulating bolus. Long-term survival depended on the valley dose primarily (92% correlation), and the use of the bolus reduced the variance in animal survival and improved to the mean survival of rats treated with MRT by 47% and 18% using 15 Gy and 8 Gy valley doses, respectively. Full article

This work describes the creation and experimental validation of $DoseMRT$, a new software package, and its associated workflow for dose calculations in synchrotron-generated broad beam and microbeam radiation treatment fields. The $DoseMRT$ software package allows users to import CT DICOM datasets into Geant4 for Monte Carlo dose calculations. It also provides basic treatment planning capabilities, simplifying the complexity of performing Geant4 simulations and making our Monte Carlo dose calculation algorithm accessible to a broader range of users. To demonstrate the new package, dose calculations are validated against experimental measurements performed in homogeneous water tank phantoms and the anatomically complex Alderson Radiotherapy Phantom for both broad-beam and microbeam configurations. Additionally, $DoseMRT$ is successfully utilised as the primary method for patient-specific treatment prescription in an in vivo experiment involving tumour-bearing rats at the Imaging and Medical Beamline of the Australian Synchrotron. Full article

The production of anthropomorphic phantoms generated from tissue-equivalent materials is challenging but offers an excellent copy of the typical environment encountered in typical patients. High-quality dosimetry measurements and the correlation of the measured dose with the biological effects elicited by it are a prerequisite in preparation of clinical trials with novel radiotherapy approaches. We designed and produced a partial upper arm phantom from tissue-equivalent materials for use in experimental high-dose-rate radiotherapy. The phantom was compared to original patient data using density values and Hounsfield units obtained from CT scans. Dose simulations were conducted for broad-beam irradiation and microbeam radiotherapy (MRT) and compared to values measured in a synchrotron radiation experiment. Finally, we validated the phantom in a pilot experiment with human primary melanoma cells. Full article

Microbeam radiotherapy (MRT), a high dose rate radiotherapy technique using spatial dose fractionation at the micrometre range, has shown a high therapeutic efficacy in vivo in different tumour entities, including lung cancer. We have conducted a toxicity study for the spinal cord as organ of risk during irradiation of a target in the thoracic cavity. In young adult rats, the lower thoracic spinal cord was irradiated over a length of 2 cm with an array of quasi-parallel microbeams of 50 µm width, spaced at a centre-to-centre distance of 400 µm, with MRT peak doses up to 800 Gy. No acute or subacute adverse effects were observed within the first week after irradiation up to MRT peak doses of 400 Gy. No significant differences were seen between irradiated animals and non-irradiated controls in motor function and sensitivity, open field test and somatosensory evoked potentials (SSEP). After irradiation with MRT peak doses of 450–800 Gy, dose-dependent neurologic signs occurred. Provided that long-term studies do not reveal significant morbidity due to late toxicity, an MRT dose of 400 Gy can be considered safe for the spinal cord in the tested beam geometry and field size. Full article

Microbeam radiation therapy (MRT) utilizes coplanar synchrotron radiation beamlets and is a proposed treatment approach for several tumor diagnoses that currently have poor clinical treatment outcomes, such as gliosarcomas. Monte Carlo (MC) simulations are one of the most used methods at the Imaging and Medical Beamline, Australian Synchrotron to calculate the dose in MRT preclinical studies. The steep dose gradients associated with the 50$\mathsf{\mu }$m-wide coplanar beamlets present a significant challenge for precise MC simulation of the dose deposition of an MRT irradiation treatment field in a short time frame. The long computation times inhibit the ability to perform dose optimization in treatment planning or apply online image-adaptive radiotherapy techniques to MRT. Much research has been conducted on fast dose estimation methods for clinically available treatments. However, such methods, including GPU Monte Carlo implementations and machine learning (ML) models, are unavailable for novel and emerging cancer radiotherapy options such as MRT. In this work, the successful application of a fast and accurate ML dose prediction model for a preclinical MRT rodent study is presented for the first time. The ML model predicts the peak doses in the path of the microbeams and the valley doses between them, delivered to the tumor target in rat patients. A CT imaging dataset is used to generate digital phantoms for each patient. Augmented variations of the digital phantoms are used to simulate with Geant4 the energy depositions of an MRT beam inside the phantoms with 15% (high-noise) and 2% (low-noise) statistical uncertainty. The high-noise MC simulation data are used to train the ML model to predict the energy depositions in the digital phantoms. The low-noise MC simulations data are used to test the predictive power of the ML model. The predictions of the ML model show an agreement within 3% with low-noise MC simulations for at least 77.6% of all predicted voxels (at least 95.9% of voxels containing tumor) in the case of the valley dose prediction and for at least 93.9% of all predicted voxels (100.0% of voxels containing tumor) in the case of the peak dose prediction. The successful use of high-noise MC simulations for the training, which are much faster to produce, accelerates the production of the training data of the ML model and encourages transfer of the ML model to different treatment modalities for other future applications in novel radiation cancer therapies. Full article

Gold nanoparticles are a promising candidate for developing new strategies of therapy against cancer. Due to their high atomic number and relative biocompatibility, they are commonly investigated as radiosensitizers to locally increase the dose of radiotherapy. In order to optimize this radiosensitizing effect, it is necessary to control the positioning of the nanoparticles in the cells. The purpose of this study is to investigate, by means of fluorescent gold nanoparticles in suspension, the dose enhancement on highly radio-resistant cancer cells. These nanoparticles were successfully produced using modern click-chemistry methods, first by attaching a chelating agent Diethylenetriamine pentaacetate benzylamine to L-cysteine, bonding the resulting ligand to a gold core, grafting propargylamine and then utilizing copper-catalyzed azide-alkyne cycloaddition (CuAAC) to fuse AlexaFluor 647 to the ligands. The results of this study prove the success of the reactions to produce a minimally cytotoxic and highly stable nanoparticle suspension that increases the radiosensitivity of gliosarcoma 9L tumor cells, with a 35% increase in cell death using 5 Gy kilovoltage radiation. Their fluorescent functionalization allowed for their simple localization within living cells and detection in vivo post-mortem. Full article

Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor. Full article

High dose rate radiotherapies such as FLASH and microbeam radiotherapy (MRT) both have developed to the stage of first veterinary studies within the last decade. With the development of a new research tool for high dose rate radiotherapy at the end station P61A of the synchrotron beamline P61 on the DESY campus in Hamburg, we increased the research capacity in this field to speed up the translation of the radiotherapy techniques which are still experimental, from bench to bedside. At P61, dose rates of several hundred Gy/s can be delivered. Compared to dedicated biomedical beamlines, the beam width available for MRT experiments is a very restrictive factor. We developed two model systems specifically to suit these specific technical parameters and tested them in a first set of experiments. Full article