Professor Steve Meikle B. App. Sc (Hons) PhD
Professor of Medical Imaging Physics, Head of the Imaging Physics Laboratory at the Brain and Mind Centre and Research Academic Director (Research Infrastructure) in the Faculty of Medicine and Health.
Summary
Researchers and patients alike are benefiting from a new imaging technology called Long Axial Field of View (FOV) Positron Emission Tomography, also known as Total-Body PET (TB-PET).
This technology advance enables molecular imaging studies to be performed at ultrahigh sensitivity, i.e. an order of magnitude or more higher sensitivity than that of conventional PET systems.
Instead of sequentially taking 20 minutes to image different parts of the body using a conventional PET scanner, TB-PET simultaneously images all the organs and soft tissues in less than a quarter of the time and with less radiation dose to the patient.
There are already two such systems installed in Australia, one at Royal Prince Alfred Hospital in Sydney and one at the new Melbourne Theranostic Innovation Centre (MTIC).
A third system, which will become a flagship of the Australian National Imaging Facility (NIF), will be located at Royal North Shore Hospital in Sydney and used half the time for clinical scans and half the time for research purposes in a partnership between the University of Sydney and Northern Sydney Local Health District.
Importantly, TB-PET enables researchers to capture the dynamics describing tracer kinetics in every tissue of the body (figure 1), which is expected to provide unique insights into the physiological and metabolic processes that affect human health.
TB-PET will benefit cancer patients by producing higher quality PET images in less time and with less radiation dose, enabling more accurate disease staging and optimal monitoring of their response to treatment. It also opens up exciting research opportunities to study a wide variety of other disease conditions, including diabetes, motor neuron disease, infectious diseases and rare childhood disorders.
The Rationale for TB-PET
To obtain a diagnostic full-length PET image requires the patient to be stepped through the scanner, imaging one section of the body at a time (figure 2, top), as is the case for MRI and CT.
For a full description of how the PET scanner is designed and used for nuclear medicine studies, click on this video presentation:
The signal used to create the PET image comes from labelled biomolecules (the radiopharmaceutical), such as the glucose analogue 2-fluoro-2-deoxy-D-glucose (FDG), which are injected into the patient’s arm about 45 minutes before the scanning procedure. The label attached to the glucose molecules is a positron-emitter, such as fluorine-18.
This is a radioisotope produced in a cyclotron (a special type of accelerator) that emits a positively charged particle called a positron when the nucleus decays. Almost immediately, the positron annihilates (converts its mass into energy) to produce two photons travelling in opposite directions away from their origin in the body.
The patient is surrounded by several rings of radiation detectors that detect the photon pairs, which enables the PET computer system to calculate exactly where inside the patient the radioisotope is located and build up an image of glucose consumption throughout the body.
The radioactive labelled FDG circulates throughout the patient’s body via the bloodstream and gradually accumulates in tissues with relatively high glucose consumption, such as the brain, heart and muscles. This is normal. However, cancer cells consume a lot more glucose than normal, healthy cells. Therefore, cancer cells can be identified in the image by their much higher uptake of the radioactive FDG.
Limitations of conventional PET
The conventional PET scanner design has some major disadvantages. For instance:
- Less than 1% of the emitted radiation from the patient’s body is measured by the PET detectors during a stepped scan. This is a very inefficient use of the signal generated by the labelled FDG;
- To compensate for the inefficient detection of available signal, patients are injected with an amount of FDG that causes a radiation dose of approximately 8 mSv which is relatively high compared to other diagnostic imaging modalities (but still less than whole body CT);
- The PET scan takes a relatively long time (approx. 20 min) to acquire sufficient data for a whole-body scan making patient and organ motion and, therefore, image artefacts more likely.
Total-Body PET
Previous studies have shown that the sensitivity of PET could be increased by up to 30-fold (Poon et al., 2012) if the patient’s entire body was surrounded by radiation detectors (figure 1, bottom). It would also make it possible to simultaneously capture dynamic measurements throughout the entire body of:
- blood flow and tracer uptake in all tissues;
- metabolic activity;
- chemical (e.g. neurotransmitter) signalling between cells, tissues and organs; and
- effects of novel administered drugs on all of the above.
What are the advantages and benefits of TB-PET?
Clinical studies
Due to its very high sensitivity, the advantages and clinical benefits offered by TB-PET are:
- Better signal to noise ratio (SNR) which enables more sensitive imaging of sub-clinical disease;
- Faster image acquisition which means greater patient throughput and fewer artefacts caused by patient motion;
- The ability to image at late time points when the radiotracer has decayed to very low levels to enable more accurate dosimetry for radionuclide therapy.
- Lower radiation dose to the patient compared with conventional PET studies enabling imaging of radiation-sensitive subjects, including: children, pregnant patients, and normal subjects and patients requiring regular follow-up PET scans.
Medical Research
Many diseases that carry the greatest societal burden (e.g. diabetes and cancer) are systemic diseases. That is, many different organ systems are involved in the disease. Even brain diseases, such as Parkinson’s disease, schizophrenia, and depression are now thought to be influenced by processes occurring in the rest of the body and may even originate from pathogens outside the brain.
To understand these complex, chronic conditions and identify new potential treatment strategies, new imaging technologies are needed that can measure changes in metabolic pathways and chemical signalling between different organ systems.
Thus, some of the benefits of TB-PET in medical research include:
- The ability to simultaneously record the kinetics of PET tracers in every organ of the body provides a means of investigating:
- novel disease mechanisms;
- new molecular targets for drug therapy;
- novel biomarkers of disease;
- Chemical signalling between organs. For example:
- neurotransmitter signalling between the brain, spine and neuromuscular junction in motor neuron disease;
- hormonal and neurotransmitter signaling between the brain and gut in Parkinson’s Disease & Diabetes
- Labelled imaging probes can be tracked and imaged over long periods of time to monitor:
- the circulation of activated macrophages; or
- labelled nanoparticles or cells; or
- environmental toxins;
- The exquisite sensitivity of TB-PET can be exploited by reducing the radiation dose close to background levels, enabling PET studies on radiation-sensitive subjects, for example:
- pediatric patients;
- normal subjects who have a genetic vulnerability to disease but no clinical symptoms; and
- subjects requiring repeated scans over long periods of time to better understand disease progression and treatment effects.
- TB-PET would be a valuable tool to evaluate novel therapeutic drugs and reduce the cost of their development. Before drugs are used in clinical trials, it is important to understand how the drug behaves in the body. For example:
- Does it bind to the intended target?
- How much is bound to non-target sites throughout the body?
- Where does the drug accumulate in the body? and
- How rapidly does the drug clear from different organs?
- Finally, the increased sensitivity of TB-PET for detecting biomarkers of disease could potentially reduce the number of clinical trial participants required to achieve surrogate endpoints, resulting in accelerated, less costly clinical trials.
The development of TB-PET
Design challenges
To capture the radioactive emissions from all parts of the body mandates a large increase in the number of radiation detectors which substantially increases the manufacturing cost and presents some technical challenges. For example, a TB-PET scanner with a two-metre axial field of view requires approximately 500,000 individual scintillation detector elements and about 50,000 photodetector channels.
Since radiation emitted from all parts of the patient’s body must be recorded, this also poses challenges related to data processing and storage. The data events capturing detected coincidence photon pairs must be recorded at a rate of up to 1.5 GB per second. Furthermore, a typical clinical schedule leads to approximately 10-40 TB of data to store each day.
The EXPLORER Consortium
In 2015, the US National Institutes of Health (NIH) awarded a US$15.5M grant to researchers at the University of California Davis, Lawrence Berkeley National Laboratory, and the University of Pennsylvania to develop TB-PET under the NIH Transformative RO1 High-Risk, High Reward funding scheme. They subsequently partnered with two medical imaging companies, United Imaging Healthcare and Philips Healthcare to form the EXPLORER consortium and developed 4 prototype TB-PET imagers: two primate imaging systems and two clinical systems suitable for human nuclear medicine studies – µEXPLORER (United Imaging Healthcare) and PennPET EXPLORER (Philips Heathcare) (figure 3).
The first commercial long axial FOV systems
The uEXPLORER system was subsequently commercialized by United Imaging Healthcare who in 2019 obtained 510(k) clearance from the FDA for human use in the USA. In late 2020, Siemens Healthineers announced a new product called the Biograph Vision Quadra which uses the same technology as their most advanced PET/CT scanner, the Biograph Vision, but has an axial field of view (FOV) that is four times longer at 106 centimetres (figure 4). Like the PennPET EXPLORER, the Quadra is not strictly speaking a TB-PET system.
However, the axial FOV is sufficient to cover all the major organs of the body, from the top of the head to the thighs of a typical adult, and it has many of the advantages of a TB-PET system, including a greater than 10-fold increase in sensitivity over that of the Biograph Vision (Prenosil et al., 2022).
First human studies
The first uEXPLORER human studies were carried out in collaboration with UC Davis in September 2018 at the Zhongshan Hospital Fudan University, Shanghai. The first TB-PET imaging results were presented at the IEEE Medical Imaging Conference held in Sydney, November 2018 and published in the Journal of Nuclear Medicine in February 2019 (Badawi et al, J Nucl Med 2019; 60:299–303 DOI:10.2967/jnumed.119.226498).
The first TB-PET results from PennPET EXPLORER were also presented at the IEEE Medical Imaging Conference in Sydney; and subsequently published in the Journal of Nuclear Medicine in September 2019 (Pantel et al, J Nucl Med 2019; DOI: 10.2967/jnumed.119.231845).
Figure 5 shows a TB-PET scan of a 61-year-old male volunteer, weighing 65 kg. The volunteer received an injection of 288 MBq of radioactive F-18-FDG and imaged 90 minutes later. The image took 20 minutes to acquire.
Figure 6 shows a F-18-FDG scan of a patient with diffuse large B-cell lymphoma performed on the Siemens Biograph Vision Quadra, demonstrating the potential for fast acquisition by dividing the data into increasingly shorter equivalent scan times. The substantial increase in sensitivity enables scan times of less than 1 minute with relatively little loss of diagnostic image quality.
Low dose TB-PET image
Figure 7 illustrates the potential to inject much less radioactivity without loss of diagnostic image quality. This was a 45-year-old female injected with 25 MBq of F-18-FDG which is approximately one-tenth of the usual amount for a PET scan, resulting in a radiation dose to the patient of <0.1 mSv. Even a 3-minute acquisition at this very low dose produces an image of diagnostic quality (courtesy of UC Davis and United Imaging).
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The Australian National Imaging Facility TB-PET project
The Australian Chief Scientist, Alan Finkel AO, chaired The Commonwealth of Australia’s Roadmap Taskforce which developed the roadmap for Australia’s National Collaborative Research Infrastructure Strategy (NCRIS).
After extensive consultations with the research sector throughout 2015 and 2016, the taskforce released the National Research Infrastructure Roadmap in early 2017. The Roadmap recognized TB-PET as a potentially transformative investment in Australia’s biomedical imaging capability.
In May 2018, the Federal Government announced the allocation of $70 million to the Australian National Imaging Facility (NIF) over 5 years (2018/19-2022/23), which included a substantial contribution towards a national TB-PET facility. The NIF subsequently approved the University of Sydney and the Northern Sydney Local Health District to host the TB-PET facility as a research and clinical partnership.
The TB-PET is located in the Nuclear Medicine Department, Royal North Shore Hospital. As part of the agreement, 50% of its usable capacity is for clinical patient studies and 50% is for research studies. Sydney Imaging is a core research facility of the University of Sydney which will manage research operations on behalf of NIF, with researchers accessing the system via a national merit-based access scheme.
Conclusions
TB-PET represents a major step change in the evolution of PET systems. The order-of-magnitude increase in sensitivity will provide clinicians with a great deal of flexibility when choosing how to trade off image quality against scan time and injected dose. For researchers, the ability to capture dynamic signals from every organ and tissue in the body simultaneously opens up new opportunities to investigate systemic diseases, evaluate novel therapies and study new cohorts who were previously excluded from PET studies due to radiation dose considerations, with the promise of exciting new clinical applications of PET in the near future.
References
Badawi, R. D., Shi, H., Hu, P., Chen, S., Xu, T., Price, P. M., … Cherry, S. R. (2019). First human imaging studies with the EXPLORER total-body PET scanner. Journal of Nuclear Medicine, 60(3), 299–303. https://doi.org/10.2967/jnumed.119.226498
Pantel, A. R., Viswanath, V., Daube-Witherspoon, M. E., Dubroff, J. G., Muehllehner, G., Parma, M. J., … Karp, J. S. (2020). PennPET Explorer: Human imaging on a whole-body imager. Journal of Nuclear Medicine, 61(1), 144–151. https://doi.org/10.2967/jnumed.119.231845
Poon, J. K., Dahlbom, M. L., Moses, W. W., Balakrishnan, K., Wang, W., Cherry, S. R., & Badawi, R. D. (2012). Optimal whole-body PET scanner configurations for different volumes of LSO scintillator: a simulation study. Physics in Medicine and Biology, 57(13), 4077–4094. https://doi.org/10.1088/0031-9155/57/13/4077
Prenosil, G. A., Sari, H., Markus, F., Afshar-oromieh, A., Shi, K., Rominger, A., & Hentschel, M. (2022). Performance Characteristics of the Biograph Vision Quadra PET / CT System with a Long Axial Field of View Using the. 63(3). https://doi.org/10.2967/jnumed.121.261972
Steve Meikle PhD, 17 March 2023
