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Only two in ten people diagnosed with brain cancer will survive for at least five years, a figure that has barely improved in the last 30 years. Due to the blood-brain barrier and the risk of damaging normal brain tissue, brain cancer treatments are complex and multidisciplinary. Despite advances in surgical techniques, radiotherapy and chemotherapeutics, brain tumours remain challenging to treat. Hence, image-guided microbeam radiation therapy (MRT) with nanoparticle enhancement is being investigated for the treatment of brain cancer in animal models.
Due to the high collimation and brilliance of synchrotron-generated X-Rays, the beam can be filtered and split into different patterns. MRT is a novel method where the X-ray beam is spatially fractionated by a comb-like collimator into 50 µm X-ray beams spaced 400 µm apart. This creates a “valley and peak” dosage regime that appears more efficacious for killing cancer cells than standard broad-beam therapy. A study conducted by PhD candidate – Elette Engels, at the University of Wollongong [1] examined the anti-tumour effects of microbeam irradiation on the brains of rats inoculated with the 9L glioblastoma cancer, finding a significantly increased survival of the MRT-treated rats compared with untreated rats.
The experiments used ANSTO’s Australian Synchrotron facility (The Australian Synchrotron) to generate the X-Ray beam and the Imaging and Medical Beamline (IMBL) to collimate, quantitate and deliver the MRT dose. NIF Facility Fellows at the NCRIS-enabled Monash NIF node, at Monash Biomedical Imaging (MBI), used the Inveon-CT and the Somotom-CT to image the heads of rats with iodine contrast medium. This established the initial size and location of the tumour burden before MRT therapy. The successful development and verification of an image-guided MRT workflow using instrumentation at MBI and the Synchrotron to deliver an anti-tumour MRT dose accurately to a rat model of glioblastoma serve to establish a baseline for the addition of various radiation enhancing nanoparticles. Further details about the methods developed are available for the advanced reader [1,2].
The development of the CT scanning, X-Ray planning and positioning methodology for co-registration of planning images with the microbeam irradiation stage and beam was successful with the confirmation of the registration and image-guided therapy to within 0.3 mm accuracy (Figure 1). Irradiation of rats with intracranial 9L-glioblastoma tumours with MRT produced an average survival of 130 days, compared to the 20-day average survival of the untreated rats (results not shown). The increase in lifespan compared to untreated rats was in excess of 500% and a ‘super rat’ passed away after a long and happy life of more than 300 days. The success of MRT was attributed to successful implementation and development of targeting methodology supplying an adequate tumour coverage with the 15 Gy valley dose.
The successful development of an image-guided MRT workflow linking the radiotherapy infrastructure at IMBL with the imaging infrastructure at MBI has created a unique research environment that has attracted several international studies investigating MRT guided radiation. These include projects with Dr Raphael Serduc from INSERM and the European Synchrotron Radiation Facility, Grenoble, France, Dr Elisabeth Shultke from the University Hospital of Rostock, Germany and Professor Valentin Djonov from the University of Bern, Switzerland. There are also projects closer to home awaiting the lifting of COVID restrictions including a large study with a research group from within ANSTO. While neuronal tumours continue to be very difficult to treat, it is hoped that the promising outcomes from these pre-clinical studies using the unique combination of synchrotron radiation with state-of-the-art imaging will improve future therapeutic outcomes.
This story was contributed by the Monash NIF Node with thanks to NIF Facility Fellows Michael de Veer, Tara Sepehrizadeh and Gang Zheng. We acknowledge the contribution of the IMBL team, in particular Dr Mitzi Klein, veterinarian and IMBL veterinary scientist, and Mr Micah Barnes (IMBL and PeterMac) who developed the image guidance on the IMBL.
For more information on this research, please contact NIF Facility Fellow, Dr Michael de Veer. For more information about brain cancers, please see the Brain Cancer Foundation website or speak with your medical practitioner.
The IMBL beamline uses a variable field superconducting magnet arrayto produce a polychromatic x-ray beam from 3 GeV electrons with a beam current of 200 mA. The resulting x-ray beam has an energy spectrum of 20 to 250 keV. Depending on the treatment requirements, the mean energy of the broad spectrum of radiation produced is is tuned by filtering out the lower energy part of the spectrum to keep and use the high energy part. Changing the array peak field from 1.4 to 4T and filtering allows for instantaneous dose rates of 30 – 7,000 Gy s-1.
The IMBL dosimetry was performed using a PTW PinPointTTM ion chamber (model 31015) and a MOSkinTM detector within 255x25x55mm RMI 457 solid water phantoms. The treatment isocentre of the irradiation stage was calibrated using a small steel ball and adjusted until it was centered in all views. The rat is loaded into the MRT field, and a short radiograph is acquired using a Toshiba x-ray tube and Hamamatsu C10900D flat panel detector. The CT scan data identifying the tumour location and size was co-registered with the radiograph of the rat in the MRT field by co-locating skeletal anatomical landmarks. These were the distal tip of the median line, posterior tip of the occipital bone, left and right zygomatic process of the squamosal bone and the left and right anterolateral corner of the frontal bone.
The National Imaging Facility contributed essential instrumentation and imaging expertise to the project. NIFs investments to co-locate imaging hardware at the Monash Node adjacent to the Imaging and Medical Beamline means international and National researchers have access to high-quality imaging hardware and expertise while undertaking studies at ANSTO’s Australian Synchrotron, a partner NCRIS capability.
Breast cancer, the most common cancer in women worldwide, may one day be treated using the venom of the European honeybee.
Dr Ciara Duffy from Western Australia’s Harry Perkins Institute of Medical Research has found that venom from honeybees can rapidly kill aggressive and hard-to-treat breast cancer cells. NCRIS-enabled facilities at the Centre for Microscopy, Characterization and Analysis (CMCA), UWA, were integral to the research, published recently in the journal Nature Precision Oncology.
Dr Duffy’s research has highlighted the molecular mechanisms for anti-tumour effects of honeybee venom using Microscopy Australia‘s live-cell confocal microscopy to characterise the specific effects on breast cancer cells.
The IVIS Lumina of the NIF UWA Node was used to track in vivo tumour growth in animal models treated with melittin (an active component of the venom), docetaxel (a chemotherapy drug), and a combination of both. The results were efficient in reducing the tumour growth of highly aggressive breast cancer subtypes, particularly when combined.
Research continues to elucidate toxicities, dosages, and delivery mechanisms in animal models before considering human interventions.
Further reading:
Until recently, reptilian evolutionary studies lacked an important resource – a lizard brain atlas. As the subject of numerous ecological and behavioural studies, the Australian tawny dragon (Agamidae: Ctenophorus decresii) was an ideal candidate for creating a high-resolution MRI atlas of a representative scaled reptile (squamata). Such data is not only a resource for studies of the genus but also informs environmental decision making through an improved understanding of animal adaptation and evolution.
In an impressive cross-disciplinary collaboration, then-PhD candidate Dr Daniel Hoops worked with a team of scientists from Spain, Canada, NSW, VIC, ACT, and QLD to explore brain evolution in reptiles.
All brains were scanned at the NCRIS-enabled Western Sydney University (WSU) NIF node on the Bruker 11.7 T MRI scanner. Hundreds of brains of a number of species of Australian tawny dragons of both genders were scanned at the WSU NIF Node at 100 μm resolution. To largely automate the measurement of the volumes of the six subdivisions in each of the models, model-based segmentation was used. First, a global model of the tawny dragon brain was created, and the six subdivisions were traced, drawing on expertise at the NCRIS-enabled QLD NIF node. Tracing was achieved first by using the interpolation function of the program Amira (Fischer 3D), followed by manual correction of every slice in all 3 dimensions, resulting in one 3D label for each subdivision of the tawny dragon MRI model (this process is called manual segmentation).
The 3D printed lizard brain holder designed and printed at the WSU node. The brains are buoyant in Fomblin (a dense fluorinated lubricant with no protons and hence no NMR/MRI signal). The Fomblin eliminates the image artefacts that would otherwise occur due to susceptibility problems from the brain and air interface. The 3D printed brain holder secures the brain in place (the brain stem is just visible in the image). Due to the precise placement enabled by the brain holder, tuning and matching and shimming were only needed for the first brain in a run permitting a throughput of four brains an hour each scanned in 3D at 100 μm isotropic resolution.
There being no neuroanatomical atlas available for an agamid brain required the use of numerous available atlases for the brains of other lizards to delineate the six subdivisions accurately. This presented an opportunity to create our own atlas, and thirteen tawny dragon brains were scanned at a higher 50 μm isotropic resolution. Using the informatics expertise at the QLD NIF node, these images were processed using minimum-deformation modelling to create a 20 μm isotropic atlas.
There is a wealth of ecological data to analyse with brain data. The atlas allows a better comprehension of brain areas (nuclei, fibre tracts) and is a valuable resource for future comparative evolution imaging studies, both on the same and other species. The work also provided a novel application—testing and potentially informing further development—of the minimum-deformation modelling technique used to create the 20 μm isotropic super-resolution dataset from the thirteen 50 μm reptilian brain datasets.
Evidence of concerted brain evolution (brain regions co-evolving) was found for body size and mosaic brain evolution (brain regions evolving independently) for ecological habitat. Furthermore, the MRI atlas was a success and has become a useful resource for Agamid evolutionary studies and evolutionary studies in general. The MRI model and atlas of the tawny dragon brain can be viewed online and downloaded using the Wiley Biolucida Server at wiley.biolucida.net.
Publications
Daniel Hoop’s PhD Thesis
Atlas and data sets
This story was contributed by Dr Tim Stait-Gardner and Dr Daniel Hoops, formerly at ANU, Australia, now at McGill University, Canada.
A post-mortem examination, or autopsy, is a forensic technique for learning about the conditions of a person’s health at the end of life. These are typically carried out as part of a coronial inquiry to establish the cause of death. A post-mortem may also provide information about undiagnosed medical problems of relevance to family members and the research community.
Typically, the post-mortem examination is carried out by pathologists in search of signs about the cause of death. This process must be carried out quickly, both to capture accurate information and to respect the cultural practices of the deceased’s family. However, Forensic Science SA (FSSA) has reported a backlog of post-mortem reports, delaying forensic justice processes and contributing to the distress of family members.
The CT and MRI scanners at the NCRIS-enabled NIF Node at LARIF, at SAHMRI, have supplemented the post-mortem processes of FSSA, including undertaking post-mortem radiology research projects. Due to the success of these procedures, FSSA has now purchased a CT scanner to create a digital record of deceased bodies as a non-invasive, easily stored, digital component of the post-mortem process. By providing additional information, helping direct the post-mortem or support the findings, this change in procedure will increase post-mortem efficiencies, reduce report wait times and ease delays in the justice system.
To learn more about the post-mortem examinations in South Australia, please see this SA Health information. This story was contributed by the LARIF Node.
The NIF Molecular Imaging & Radiochemistry (MIR) Theme is a group of NIF Fellows, Directors, and users of NIF facilities that focus on state-of-the-art radiochemistry and molecular imaging applications using PET, SPECT, and MRI.
Integrating preclinical PET systems into a national resource requires the development of defined QA programs to monitor and integrate the data from individual systems. Hence, the MIR Theme initiated a national quality assurance (QA) program for the NIF preclinical PET instruments.
The first step in this national program is a pilot stage, which has successfully seen ten QA phantoms produced at the University of Queensland’s Centre for Advanced Imaging (CAI). QLD Node Facility Fellow Dr Gary Cowin has led the creation, validation, and distribution of these phantoms to participating NIF sites at Monash, University of Melbourne, SAHMRI, and the University of Sydney/ANSTO. The Theme has developed a standardised method and process for validation, analysis, and central review, and expects the pilot stage to be finalised soon.
The next step in the national program is the expansion stage, in which additional phantoms will be distributed to all participating preclinical sites. The Theme is developing national platforms for the upload, storage, analysis and report generation for PET QA data, maximising the efficiency and integrity of PET data collection across Australia.
This national QA program expects to not only develop a cohesive quantitative validation program but also enhances collaborative partnerships for users of preclinical PET.
For more information, please contact the MIR Theme Chair Prof Andrew Scott or NIF Engagement Manager Dr Noni Creasey.
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