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- Springer Journals
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- Copyright © The Author(s) 2023
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- 10.1186/s40644-023-00540-3
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Abstract
Recently introduced long‑axial field‑ of‑ view (LAFOV ) PET/CT systems represent one of the most significant advance ‑ ments in nuclear medicine since the advent of multi‑modality PET/CT imaging. The higher sensitivity exhibited by such systems allow for reductions in applied activity and short duration scans. However, we consider this to be just one small part of the story: Instead, the ability to image the body in its entirety in a single FOV affords insights which standard FOV systems cannot provide. For example, we now have the ability to capture a wider dynamic range of a tracer by imaging it over multiple half‑lives without detrimental image noise, to leverage lower radiopharmaceuti‑ cal doses by using dual‑tracer techniques and with improved quantification. The potential for quantitative dynamic whole‑body imaging using abbreviated protocols potentially makes these techniques viable for routine clinical use, transforming PET‑reporting from a subjective analysis of semi‑ quantitative maps of radiopharmaceutical uptake at a single time‑point to an accurate and quantitative, non‑invasive tool to determine human function and physiology and to explore organ interactions and to perform whole‑body systems analysis. This article will share the insights obtained from 2 years’ of clinical operation of the first Biograph Vision Quadra (Siemens Healthineers) LAFOV system. It will also survey the current state‑ of‑the ‑art in PET technology. Several technologies are poised to furnish systems with even greater sensitivity and resolution than current systems, potentially with orders of magnitude higher sensitivity. Current barriers which remain to be surmounted, such as data pipelines, patient throughput and the hindrances to implementing kinetic analysis for routine patient care will also be discussed. Keywords Total‑body, Long axial field of view (LAFOV ) PET, Whole ‑body, PET/CT, Positron emission tomography, Digital PET Introduction The use of positron emitting radiopharmaceuticals for the imaging of human function dates back to pioneer- *Correspondence: ing work in the 1950’s [1, 2] and has, over the course of Axel Rominger this long history, undergone a number of revolutionary axel.rominger@insel.ch developments. Examples include the tremendously suc- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstr. 18, 3010 Bern, Switzerland cessful introduction of 2-[ F]FDG in 1976 [3, 4], the Advanced Clinical Imaging Technology, Siemens Healthcare AG, first single ring PET scanner [5], the first positron emis - Lausanne, Switzerland sion tomograph in 1975 [6] and the development of © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alberts et al. Cancer Imaging (2023) 23:28 Page 2 of 15 three-dimensional PET systems [5]. Although the terms design. For the first time, it is now possible to image the “game-changing” or “paradigm shift” have been overused head and entire trunk simultaneously in adult human to the point of cliché, nuclear medicine has genuinely subjects, furnishing new and unique insights into experienced several disruptive changes that have funda- human function and physiology. It is our position that mentally changed the field in recent decades. One such this represents an entirely new way of performing PET profound change was the successful introduction of mul- and promises to be as revolutionary a change to the field timodal PET/CT imaging at the turn of the twenty-first as the introduction of hybrid imaging. century [7]. This catalysed the field. Presently, PET/CT imaging occupies a central role in the staging and man- Challenges and opportunities agement of a number of cancers [8] as well an increasing Our group received and operated the world’s first clini - role in numerous non-oncological indications. The chal - cal Biograph Vision Quadra (Siemens Healthineers) sys- lenges and complexities of delivering hybrid functional tem at the Department for Nuclear Medicine, Inselspital and anatomical imaging has had profound implications in Bern, Switzerland in October 2020 (https:// www. swiss for the training and organisation of our field [9–14]. inf o. c h/ eng/ wor ld- s - f a st e st- f ull- b o dy - s c ann er- t ur ne d- The detectors used in PET/CT systems have long on- in- bern/ 46184 876). Building upon the pioneering been comprised of scintillation crystals coupled with PennPET and uExplorer, the Biograph Vision Quadra conventional photomultiplier tubes (PMT). Replace- (106 cm aFOV) occupies a middle-ground between ment of this analogue technology with solid state detec- standard FOV and total-body systems, capable of imag- tors based on silicon photomultipliers (SiPM) was an ing the head to the mid-thighs for adult subjects in a sin- important recent development in PET imaging; these gle bed-position [30–32] and where sensitivity does not systems offer a number of technical advantages which substantially improve beyond 100 cm, proving an eco- overcome the limitations of previous analogue sys- nomical use of space and detector material [25, 27, 29]. tems [15]. In particular, the greatly improved time-of- The footprint of this particular system also has the advan - flight (TOF) resolution enables noise reduction and tage that it can be installed into an examination room TOF effective sensitivity gains, resulting in improved with the same dimensions as for a standard axial FOV clinical performance [16–21], including better image (SAFOV) system, meaning that no complex or expensive quality and lesion detection [15, 20, 22, 23]. The first infrastructure adjustments were necessary. A number positron imaging systems comprised of a single ring of terms such as whole-body, total-body, extended and of detectors. Cognisant of the fact that scanner sen- ultra-extended FOV have been used to describe these sitivity and image noise are important limiting fac- systems, which for simplicity we henceforth refer to as tors in PET imaging, scanners have increasingly been long-axial FOV (LAFOV) systems in contradistinction to designed with longer axial field-of-views (aFOV), such SAFOV systems, which we take to mean systems which as the Biograph mCT (Siemens Healthineers, aFOV of can image only a part of the body in a single bed position. 22 cm), Biograph Vision 600 (Siemens Healthineers, The challenges of assembling a multinational team of aFOV of 26.3 cm) [15] and the recently described GE scientists and engineers to install this complex system Discovery MI PET/CT system (General Electric, aFOV during the height of the COVID-19 pandemic notwith- of 30 cm) [24]. The combination of solid state detectors standing, the scanner went live in October 2020; some with increased aFOV coverage represents an important 7000 patients have now been scanned at our centre with improvement upon the previous generation of scanners this system. The aim of this article is to share our expe - and demonstrates an increased photon sensitivity and riences operating the first Biograph Vision Quadra sys - peak noise equivalent count rate (NECR) [25]. How- tem and the insights we have gained. ever, such systems are still limited by the restriction of their FOV to one bed position, requiring continuous Operational considerations and patient throughput bed motion (CBM) for full-body coverage. A substantial in LAFOV scanning leap forward was made with the realisation of extended With a steadily increasing number of clinical indica- FOV PET systems, such as the PennPET Explorer (up tions for PET/CT imaging, demand for PET services to 140 cm aFOV) and the uExplorer (United Imaging, are increasing, adding to pressure on waiting lists [33]. 194 cm aFOV) as well as the Biograph Vision Quadra as There is therefore a clear rationale for increasing patient described earlier [26–28]. The design of these systems is throughput in many PET/CT centres, and the ability based on pioneering work which surmounted a number to scan more patients with less activity is an attractive of technical challenges [25, 27, 29]. Rather than repre- prospect. A standard acquisition at 2 min per bed posi- senting an incremental improvement, these systems can tion can take between 15 and 20 min on a SAFOV sys- be understood to represent a new, truly revolutionary tem depending on body length, although it is well worth A lberts et al. Cancer Imaging (2023) 23:28 Page 3 of 15 noting that this is already very fast compared to other interactions [38] or to enable whole-body, multi-organ imaging modalities, such as MRI, and is substantially kinetic imaging [39] which potentially reveals insights faster than the acquisition times used on first generation which previous generation SAFOV could not provide. PET/CT systems. Nevertheless the time taken per scan Figure 1 shows an example of a patient acquired using a does potentially represent a bottle-neck in the number dynamic imaging protocol with our LAFOV system and of scans which can be performed. With a LAFOV sys- demonstrates the high-temporal resolution and low- tem, a comparable acquisition can be obtained in just noise whole-body dynamic data which can be achieved 2 min when using standard activities, with the possibil- using LAFOV systems. ity for maintaining adequate image quality in as short Although some high volume centres may be able to as 30s [31]. Theoretically, allowing an additional 8 min make full use of a LAFOV scanner’s additional capacity for getting the patient on and off the examination table, and while there are a number of compelling arguments 60 patients could be imaged on a single LAFOV scan- for activity reduction, it is our view that this is only one ner in the course of a 10 h working day, although addi- small part of the LAFOV story. Indeed, although reduc- tional acquisitions such as contrast enhanced CT could ing the applied activity by 50% is laudable [40], high- take additional time. Given that the optimal number of sensitivity digital PET/CT systems were already able to uptake rooms is the ratio of uptake time to scan time provide similar reductions [18, 20, 21, 23]. Moreover, we [34], theoretically only six uptake rooms or hot waiting find that this focus on activity and time does not fully areas would be needed, ideally with additional chang- leverage the benefits that high-quality and total-body ing rooms to optimise patient flow. However, this would data might deliver. Fundamentally, a lower-activity scan be a significant increase in patient throughput for most presented in the same static standardised uptake value centres, and many more personnel would be needed to (SUV) map with marginally lower image noise, while an realise this demanding timetable. Beyond operational improvement, does not necessarily represent a quantum consideration, there are also compelling arguments for leap into previously unknown technology or afford any shorter scan durations [35] such as reduction in motion new insight when compared to imaging with a SAFOV artefact and patient comfort, although the impact of this system using SiPM [41]. Instead, high-count statistic on image quality is yet to be assessed. The premise of total body imaging affords the ability to probe whole- short duration protocols is also the use of standard activi- body pharmacokinetic data [39, 42–44] and organ-organ ties; instead, the higher sensitivity can also be exploited interactions [38] in a way that the physics of a SAFOV to reduce dose, as will be discussed later in this article. system could not allow [45, 46]. In our view, it is these At our centre, we have opted to balance quality and previously hidden insights that are the most exciting and speed by providing patients with 6 min total scan time, promising aspect of LAFOV systems, and one which has which is both shorter than a standard acquisition on a the potential to revolutionise the way in which PET/CT SAFOV system and with substantially superior count imaging is performed. In this article, we will share some rates [31]. For paediatric patients, we routinely inject a of our insights and experiences in using this new technol- lower activity of 0.5-1.0 MBq/kg (substantially lower than ogy and explore some novel directions for research which EANM/SNMMI guidelines [36]). This is combined with might be performed with this scanner, as well as some of a 10 min acquisition, already shorter than an equivalent the challenges we have encountered. SAFOV scan in many cases and resulting in a “win-win” scenario when imaging children. At other centres, ultra- Managing LAFOV data low activity and short scans which obviate the need for The substantially higher count densities result in sedation or anaesthesia have also been reported, improv- increased data volumes, which can be as high as 4-5GB ing patient flow and patient safety [37]. for a standard SAFOV scan and as high as 40-50 GB for a LAFOV scan when the PET list-mode raw data is Improving the view: whole‑body imaging stored and depending on activity, scan length and addi- In common with most centres, our SAFOV imaging tional PET data such as deep inspiratory or triggered protocol captures the skull base to the mid-thigh, where acquisitions. One hour long dynamic acquisitions are restriction of the examination volume allows the scan to larger yet, and can consume between 500GB and a tera- be completed faster. One advantage of the uExplorer is byte of storage. For day-to-day clinical purposes, these the ability to capture the entirety of the human organ- data sizes have no impact on the archiving and viewing ism from head to toe; other LAFOV systems can cap- of clinical images if only secondary static reconstruc- ture the head and torso in a single FOV. This ability to tions are stored in clinical archiving systems (PACS). image the entire torso represents a significant advan - However, it is often the case that when performing tage, for example when exploring whole-body organ research, storage and subsequent retrieval of the full Alberts et al. Cancer Imaging (2023) 23:28 Page 4 of 15 Fig. 1 Selected time frames for a patient examined at the University Hospital, Bern with breast cancer (top row between 0‑60s p.i.; bottom row circa 5 min, 30 min and final static scan at 55–65 min) demonstrate the excellent temporal and spatial resolution offered by LAFOV systems. The radiopharmaceutical (2‑[ F]FDG) can be traced through the pulmonary vasculature, arteries and venous system with small to medium sized vessels visible raw data set is needed for research specific reconstruc - years of clinical operation generated approximately tions or analysis of the raw data. Since LAFOV systems 16 TB of data, the equivalent of list most data for lend themselves well to whole-body dynamic imaging, dynamic acquisitions for roughly 25-30 patients using the problem of storage of raw data-sets is likely to be the Biograph Vision Quadra. It is therefore an under- encountered by many users of this system. By way of statement to state that the unprecedented volumes of example, in our first two years of operation, storage of data generated by a LAFOV system places undue bur- the list-mode for our single LAFOV PET alone con- den on the IT networks available in most nuclear medi- sumed almost 4.5 petabytes of data-storage; by com- cine centres. It also underscores the vital importance of parison the ATLAS project at CERN, one of the most interdisciplinary team-working when realising nuclear complex and data intensive experiments yet devised medicine research projects with LAFOV, where IT by mankind requires 10 petabytes of data storage per technicians, data scientists and nuclear medicine physi- annum and is supported by a team of 5700 scientists, cists have a vital role to play in helping to manage and engineers and administrators with access to one of manipulate these large datasets. Potential operators the world’s most advanced IT infrastructures (https:// of these systems who foresee the need to store large atlas. cern/ Resou rces/ Fact- sheets). Storage of such data amounts of raw data for research purposes will need to volumes is a fundamental change by many orders of factor in the challenges in doing so when drawing up magnitude compared to previous generation systems, their plans. The concept of “big-data” has become cli - e.g. the storage of raw data for our two predecessor ché; if exciting ideas such as exploring the metabolic analogue Siemens Biograph mCT systems over several connectome using large numbers of PET datasets to A lberts et al. Cancer Imaging (2023) 23:28 Page 5 of 15 explore organ-organ interactions are to be truly real- the publication of more studies which might help answer ised [38, 47], then the challenges inherent to storing, these questions. retrieving and sharing such large datasets using current In this regard, perhaps a salutary lesson can be learnt technology and infrastructure need to be met. from the introduction of combined PET/MRI scanners. There are a number of reports of low-activity proto - Although introduced with much fanfare as a “game- cols in conjunction with LAFOV scanners, often justified changing” development, after almost a decade, PET/MRI on grounds of dose reduction. Although there is a clear remains far from being adopted universally as a standard rationale to reducing radiation dose, the clinical benefit examination. Although the advantages of combining the of doing so is not clear, as will be discussed later in this high sensitivity of PET imaging with the high anatomical article. In our view, a more compelling justification, and resolution of MRI are readily apparent [55], as is the pos- one which is rarely mentioned in the low-dose litera- sibility to reduce radiation exposure through omission of ture, is the idea of data-economy: low-activity, low-count the CT component, there are no routine clinical indica- scans, potentially augmented by AI de-noising [48–50] tions where PET/MRI has become the standard of care, are two potential lean-data solutions. and a number of clinical and financial hurdles remain High volume, systems level analysis or artificial intelli - before PET/MRI can be adopted as a routine clinical gence driven analysis of total-body PET data may reveal examination [56, 57]. Consequently, PET/MRI has not insights into multi-organ metabolic networks. However, replaced PET/CT in the majority of centres and remains the storage, retrieval and reconstruction of large vol- as a complementary tool at a limited number of sites. umes of raw data for research is clearly impracticable The assessment of disruptive technologies can be chal - without dedicated approaches to storing, reconstructing lenging [58]. Traditional methods of evidence generation and transferring data. It is correctly stated that a SAFOV can take many years to obtain and the demand for evi- system collects less than 1% of annihilation photons pro- dence to justify expenditure can act as a hindrance to the duced [26]. However, if these additional events detected adoption of cutting edge technologies. It is therefore an by LAFOV cannot be marshalled and stored in a manage- individual and centre-specific decision as to whether the able fashion where list mode data can be retrieved, e.g. to potential benefits to installing and operating a LAFOV subject them to further analysis such as radiomics, where system justify the expenditure involved. study specific retrospective reconstruction of list mode data is required for harmonisation purposes [51, 52], or From low dose to ultra‑low dose for the training of AI models directly on sinogramme Instead of focussing on throughput, LAFOV systems can data [53], the full panoply of benefits which the large furnish substantial reductions in applied activity, and datasets produced by LAFOV are at risk of being lost if consequently the radiation dose to the patient and car- mere static reconstructions of SUV maps are stored in egivers as well as allowing more patients to be examined clinical PACS systems for convenience. for a given activity of radiopharmaceutical [26, 31]. In some applications, LAFOV systems can be used to scan where trace amounts of a radiotracer are available, for Assessing and implementing a disruptive technology example when imaging long-half life radiopharmaceuti- In an editorial in this journal, Hicks and van den Abbeele 89 cals such as [ Zr] or in low-count applications such as ask whether LAFOV will be an expensive folly or will 90 the imaging of [ Y] [59, 60]. In certain circumstances, become the next clinical standard for PET/CT [54]. We very low activity acquisitions can be performed, such as remain agnostic on this topic: while it is clear that total the patient in Fig. 2 where 20.8 MBq was applied to an body imaging has a number of research applications 86 kg adult male, and provided an image of good quality which might inform future clinical practice, it remains when compared to a previous scan on the same patient to be seen whether the higher sensitivity offered by such using an analogue scanner five years previously (Bio - scanners translates either to improved scan performance graph mCT, Siemens Healthineers) with 340 MBq. A or are more cost effective compared to SAFOV systems. low dose approach lends itself very well to imaging chil- If LAFOV scanning is to become the next clinical stand- dren. In Fig. 3 we show an example of the type of image ard, and not just restricted to blue-sky research at aca- 18 quality available with just 14 MBq of 2-[ F]FDG in an demic centres, high quality and prospective evidence is 8 year old child with Hodgkin Lymphoma. This results necessary. A search of clinicaltrials.gov for “total-body in an impressively low equivalent dose of 0.3 mSv for the PET/CT” reveals nine prospective studies in various PET component. Appropriateness criteria which jus- stages of completion, including one comparative imag- tify alternative examinations based on equivalent dose ing study at our own centre. As the number of centres alone in paediatric patients will need to be revisited [61]. operating LAFOV systems increases, we look forward to Moreover, standard doses can be used but with shorter Alberts et al. Cancer Imaging (2023) 23:28 Page 6 of 15 a high equivalent dose modality, that ionising radiation in children is inherently bad and MRI with anaesthesia is post hoc ergo propter hoc safer [62]. The combination of fast anaesthesia free imaging [37, 63] with ionising radiation dose comparable to routine conventional radio- graphs might upend this received wisdom. Djekide et al. argue that with the advent of LAFOV systems, paediat- ric PET – historically underutilised [64, 65] is “ready for prime time” [61]. We agree with this sentiment entirely, and eagerly anticipate more studies assessing the poten- tial benefits of paediatric LAFOV PET. However, when reducing activity care must be taken to ensure that the scan quality is not compromised, where higher noise images can obscure small lesions [23, 66]. Dose optimisation is not synonymous with dose reduction, and activities should be defined accord - ing to their diagnostic yield rather than arbitrary or subjective image quality [67, 68]. The magnitude of any theoretical benefit to an individual patient through only modest reductions in radiation dose, for example a 50% reduction in activity [40] is questionable. Moreover, as nuclear medicine physicians, we must be careful that we do not inadvertently contribute to radiation induced Fig. 2 Indicative imaging quality for a low dose PET/CT acquisition on a LAFOV with 20 MBq of 2‑[ F]FDG (left) and a full dose with phobia through overstating the risks of radiation doses 340 MBq on an analogue SAFOV system (right). The scan times for routinely used in diagnostic procedures, which in many both are equivalent at 20 min. Maximal intensity projections (MIP) cases are smaller in magnitude than the risks inherent and co‑registered PET/CT axial slices (bottom) for the same patient to the car journey to the hospital [69–72]. Furthermore, are shown care must be taken that the potential advantages of a high-quality, low-noise examination are not unneces- examination protocols, which might make the require- sarily forfeited in the pursuit of radiation doses lower ment for anaesthesia or sedation less likely, and PET/CT than those already accepted as safe in routine clini- has potentially very important advantages in this regard cal imaging. For example, the present generation of compared to the lengthy scan procedures encountered in SiPM-based PET-scanners are known to demonstrate whole-body MRI [37]. Convention holds that PET/CT is higher detection rates [15, 18–20], diagnostic certainty Fig. 3 Indicative imaging quality for a low dose PET/CT acquisition in an 8 year old child (weight 27 kg) with Hodgkin Lymphoma. The images on the left were obtained in a 12 min scan using 27 MBq of 2‑[ F]FDG, the images on the right were obtained in a 12 min acquisition using just 14 MBq of 2‑[ F]FDG, resulting in an equivalent dose for the PET component of just 0.27 mSV A lberts et al. Cancer Imaging (2023) 23:28 Page 7 of 15 and inter-rater reliability [22] and these benefits could also envisage a role for CT-less reconstruction of data in extend to LAFOV systems. research settings and for multiple-time point imaging. Concentrating efforts on applied activity also excludes one of the two hybrid modalities in PET/CT. Even when Rethinking imaging protocols taking existing dose reduction techniques for the CT Free of the constraints imposed by lower sensitivity scan- component [73] and protocol optimisation into account ners, we have also had occasion to re-imagine a number of [74, 75], a low dose non-contrast enhanced CT for atten- imaging protocols. For example, the recommended uptake uation correction (AC) is still in the order of 1-3 mil- time for [ Ga]Ga-PSMA-11 of 60–90 min post-injection lisieverts (mSv). Instead, novel approaches for AC are (p.i.) is a compromise between applied activity and the to exploit domain-integrated AI [76] or naturally occur- short half-life of the radiotracer, where later imaging can ring Lu in the scanner’s Lutetium Oxyorthosilicate result in intolerable image noise. However, this is not the scintillators. High sensitivity LAFOV systems are able optimal time-point for imaging from a pharmacokinetic to detect sufficient signal from these background radia - perspective [88]. Increasing uptake over time increases tion events and use them as a transmission source (LSO- lesion contrast. Later imaging might also be of diagnostic TX) [77, 78]. The scanner can be configured to provide utility [89–91] and might provide improved prognostic “CT-less” attenuation maps for the attenuation correc- information, for example in a preliminary work Abdel- tion of PET scans, and can be performed either before hafaz et al. demonstrated the superiority of Deauville scor- or after the PET acquisition in a manner akin to the ing at 2 h compared to the standard 1 h using 2-[ F]FDG, transmission source scans performed prior to the advent and is another example of how imaging protocols which of PET/CT [79]. AI can also be used to estimate attenu- have been ingrained over many years might be revisited in ation maps using non AC-PET images [78, 80]. When the light of high sensitivity LAFOV systems [92]. Imaging combined with low-activity scans, it is now possible to can be possible over many half-lives without impairment obtain quantitatively reliable PET images with radiation in imaging quality [93] and impressive results have been doses under 0.5 mSv. In contrast to a marginal improve- obtained for very long half-life tracers such as [ Zr] [94]. ment through 50% reduction in the PET activity only, this Novel methods of imaging, such as using [ Y] post selec- combined approach could take the modality from one of tive internal radiation therapy (SIRT) for liver malignancy the most dose intensive modalities to being in the same is possible with impressive image quality using a tracer bracket as plain radiographs [78, 81]. Discussions about which was not traditionally considered amenable to PET radiation dose can be very emotive [67]; efforts to reduce (Fig. 4) [60]. From our own work, we have been able to them will very likely make PET a more viable modality in demonstrate the advantage of imaging at later time-points paediatrics and obstetric imaging [64, 82, 83], as a sensi- when lesion uptake is higher and background clearance tive screening tool [84] and as a more acceptable tool for greater [89, 93, 95–97]. Previously, using lower sensitiv- research with healthy individuals or for multiple-tracer ity scanners, such systems were limited by the high image studies. After nearly two decades of successful hybrid noise or the need to use substantially higher doses of the imaging [7] it might seem counterintuitive to use novel radiopharmaceutical. Now, using LAFOV systems, it is approaches to use CT-less attenuation techniques. After possible to obtain high count density acquisitions within all, CT provides important anatomical detail and train- reasonable time-frames: to achieve similar count statistics ing programmes have been substantially reconfigured to for a 10 min LAFOV acquisition with the Siemens Bio- ensure that nuclear medicine physicians are able to make graph Vision Quadra would take an impracticable 88 min maximum use of this information [9, 11–14, 85–87]. using flow-motion with a table velocity of 0.2 mm/s. For However, we envisage a number of situations where this example, in Fig. 5 we show the image quality achievable approach might be useful. For example, when using a in a standard 2 min/bed position (for 106 cm FOV 16 min LAFOV scanner there are a number cases where whole- scan time) compared to a 16 min single bed position acqui- body PET data is incidentally acquired (for example sition using a LAFOV system for a late acquisition at 4 h whole body data for a dedicated brain acquisition). These p.i, with [ Ga]Ga-PSMA-11. This higher sensitivity can be data could then be attenuation corrected for review and used to capture high quality images after nearly four half- analysis even though they do not lie in the clinical volume lives, with improved lesion uptake and lower background. of interest. For example dedicated parathyroid and brain Moreover, this greater dynamic range captures a wider imaging, performing an additional diagnostic or AC-CT temporal range of kinetic data. The ability to perform of the body is not clinically required or justified. In some multi-time point imaging is of great interest for theragnos- circumstances, such as imaging of brain tumours, an tic dosimetry [98]; it is currently a major shortcoming of anatomic modality such as MRI is already available, and radioligand therapy that individualised dose planning is, in the AC-CT has no additional diagnostic benefit. We can many cases, not currently possible. Alberts et al. Cancer Imaging (2023) 23:28 Page 8 of 15 90 90 Fig. 4 Example image quality following 1GBq of [ Y ] Therasphere for treatment of hepatocellular carcinoma. [ Y ] is traditionally challenging to image, either using Bremsstrahlung or as a result of the low (32 per million) rate of positron emission Fig. 5 Example of a simulated “low‑ dose” or late acquisition at 4 h p.i. For comparison the 16 min/b.p. acquisition (right hand side) is shown alongside a sample re‑binning of the same data for a guideline recommended 2 min/b.p. acquisition, with resultant reduction in image quality 68 68 following a clinically standard application of 192 MBq of [ Ga]Ga‑PSMA‑11. Owing to the short half‑life of [ Ga] (68 min) later acquisitions were limited by poor count statistics and noise. It should be noted that 2 min/bp in continuous bed motion (cbm) can take up to 16 min on previous generation SAFOV scanner designs It is also clear that a number of tumour entities are sessions, or the need for two full-dose scans, the flexibil - best imaged by multiple tracers. For example, even with ity of the LAFOV to obtain qualitatively acceptable scans a state-of-the-art digital PET/CT and at high PSA val- at low dose affords the possibility to seamlessly perform ues at recurrence, up to 5% of prostate cancers do not additional imaging with a second tracer at low-dose, or express sufficient the prostate specific membrane anti - vice-versa [100]. One barrier to the implementation of gen (PSMA) to be usefully imaged by this technique [15]. dual-tracer protocols in PET/CT imaging is the inabil- Additional 2-[ F]FDG PET/CT is a useful adjunct for ity to discriminate between the signal from each tracer, theragnostic assessment for PSMA-radioligand therapy, although the abbreviated dynamic protocols can be used and combined FDG/PSMA PET might be useful in renal to distinguish each tracer’s kinetic behaviour or the imag- cell carcinoma [99]. As an alternative to multiple imaging ing of prompt gammas and triplets have been proposed A lberts et al. Cancer Imaging (2023) 23:28 Page 9 of 15 to differentiate between a pure positron and non-pure scans can be obtained within minutes (although it should positron emitters [101]; the high sensitivity of LAFOV be noted that similar scan times are routinely encoun- lends itself to these methods well and is a feature which tered in whole body MRI, and the increased scan capac- future users of these systems might explore [102]. ity generated by reduced acquisition times could be used flexibly to accommodate this in selected patients). How - The future of PET is quantitative ever, LAFOV scanners with higher sensitivity open up While reduction in activity and assessment of subjec- the possibility for quantitative imaging techniques to be tive image quality is important, these represent only translated into the clinic with comparable time frames incremental improvements upon already established to static acquisition such as an abbreviated 20 min pro- techniques. PET data are commonly presented by way tocol, aided by dual-phase, combined population-based of weight, activity and decay normalised uptake (SUV) input function protocols or AI approaches [42, 106–111]. maps which are semi-quantitative in nature and which Noise in dynamic acquisitions directly contributes to physicians are trained to interpret in a qualitative and noise in kinetic parameter estimates; for the first time subjective fashion. The shortcomings of SUV [103] or the LAFOV systems allow a radiopharmaceutical to be closely related metabolic tumour volume (MTV) are well traced throughout the entire body with excellent tempo- known [104]. The few established or routinely reported ral and spatial resolution, as shown in Fig. 1. Previously, scoring systems employ semi-quantitative, single-time the requirement for an input function restricted SAFOV point measurements of SUV relative to a reference analysis to a single organ or region. Many studies must organ or blood pool, such as the Deauville, Hopkins and first be performed before abbreviated dynamic imaging Krenning scores. In contrast, there are established and can become a validated and routine clinical tool rather quantitative methods for the analysis of dynamic PET than as a research tool. Nevertheless, LAFOV makes it data which can reveal deeper insights into physiological feasible to perform whole-body quantitative kinetic anal- parameters that are not possible from single-time point ysis within currently routine scanning times. An exam- analysis, such as the Patlak-Gjeddes plot [105]. Despite ple patient with whole-body kinetic analysis performed clear benefits to this approach [39], such as improved on a LAFOV is shown in Fig. 6. As shown in this figure, lesion detection though higher tumour to background high quality Patlak tracer flux (Ki) images have improved ratios [44], they have enjoyed very limited adoption in target-to-background compared to the SUV images. routine clinical imaging. Four decades on from Patlak’s Furthermore, the distribution volume (DV) images can pioneering work, nuclear medicine images are still pre- provide additional biological information regarding the sented in semi-quantitative SUV maps and there are no Lymphoma. Previously, the complexity of parametric clinically validated uses for kinetic modelling in diag- imaging analysis made this technique available only to nostic imaging. There are a number of reasons why this centres with advanced tools and kinetic imaging experts. is the case. In our view the requirement for a patient to Now, automated software which can perform direct para- be scanned for up to an hour (e.g. in a dynamic 2-[ F] metric imaging analysis is available on some commercial FDG PET scan) is a clear barrier in an era where PET PET scanners and extension of this software to LAFOV Fig. 6 Example static SUV map for a patient with Lymphoma at 2‑[ F]FDG PET/CT (A), Patlak K map demonstrating metabolically trapped FDG (B) and Patlak distribution volume (DV ) showing non‑trapped FDG (C) Alberts et al. Cancer Imaging (2023) 23:28 Page 10 of 15 will allow the design of more effective clinical protocols in obtaining repeatable and reliable radiomics data [51, for practical clinical parametric imaging without the 119–122], a particular problem is their sensitivity to need for additional complex or time-consuming image noise [123], for which low-noise high-quality LAFOV analysis. acquisitions might be well positioned to address. Training the molecular imager of the future Future directions in LAFOV scanning Cognisant of a preponderance of data that fully quanti- The pioneering PennPET and the first commercially tative kinetic analysis will yield superior results to tradi- available systems (uExplorer and Siemens Biograph tional single-time point imaging, if successfully translated Vision Quadra) are certainly not going to be the last into clinical routine, it promises to fundamentally alter word on LAFOV PET and further developments in PET the way in which PET data are interpreted and reported. technology are eagerly anticipated. For example, where In recent decades, training programmes in nuclear medi- the cost of the scanner is tightly linked to the cost of the cine have been reconfigured with heavy emphasis on scintillation crystals, sparse detector designs are a poten- training in anatomic imaging modalities or the training tial solution to improvement in axial coverage without of dual-certified radionuclide radiologists. Consequently, increase in scanner cost [124], although this will come in many countries there has been a decline in the num- at the price of lower sensitivity. The use of cheaper BGO ber of nuclear medicine physicians being trained [85–87]. crystals is a possibility, but more clarity is currently We predict that LAFOV PET could act as a catalyst for required about the performance of such systems, such as truly quantitative functional and kinetic imaging. With TOF capability and count rate performance. exciting possibilities on the horizon, such as personal- Any efforts to reduce the capital cost associated with ised cocktails of multiple tracers or the ability to probe PET/CT is welcome; this resource intensive imaging whole-body metabolic connectome data, interesting modality is not just the luxury of rich economies, but rep- questions will arise about how we might best train and resents a standard of care for a wide variety of indications educate nuclear medicine residents to best exploit these and is increasingly performed in low and middle income technologies. Whereas physician training has previously countries, where inequality in access is an important emphasised mastery of anatomical imaging modalities, issue [125]. An exciting design for an entirely novel PET/ nuclear-medicine specific skills and knowledge, such as CT system is the Jagiellonian PET (J-PET). The use of the ability to code and manage data, perform and inter- plastic scintillation detectors has multiple advantages in pret kinetic modelling and knowledge of advanced radi- terms of engineering practicability, cost, weight and sen- omics techniques might need to be given greater weight sitivity. They are compatible for MRI inserts and exhibit to educate the molecular imager and therapist of the substantially faster scintillation time (0.5 ns versus 40 ns future. for LSO and 300 ns for BGO). This ultrafast time-of-flight (TOF) resolution could also provide direct knowledge Low dose or low noise? of the annihilation location and might even obviate the LAFOV PET images are characterised by their high tem- need for reconstruction algorithms [126, 127]. Although poral and spatial resolution. Cinematic rendering pro- much work is required before such systems can be intro- vides life-like 3D visualisation of anatomical structures duced into clinical operation, these exciting develop- which can be useful in educational scenarios and in ments demonstrate that hardware development for PET/ demonstrating complex 3D anatomy in multidisciplinary CT is far from over. Needless to say, these systems might meetings, and can now be applied to PET-data also [112]. also compound the aforementioned data storage issues; Moreover, we posit that these low-noise and high signal in our view this gives further cause for urgency in resolv- images can afford improvements in PET quantification ing these issues. and textural analysis: indeed radiomics is based upon the Whereas traditional scintillation crystals have regis- premise that additional biological information is con- tered the incident photon via the photoelectric effect, the tained in these features [113–115]. Despite claims made plastic scintillators can determine the polarisation of the for its superiority over traditional methods of PET image annihilation photon through the detection of primary interpretation and decades of research effort, there is still and secondary Compton scattering. Intriguingly, this no routine clinical application for radiomics analysis and raises the notion of extracting quantum information from only limited consensus about how such images are best metabolic processes in the body [128, 129], e.g. provid- reconstructed, analysed and interpreted. There has been ing a non-invasive and quantitative means to interrogat- a surfeit of studies which cannot be replicated [116, 117] ing tissue hypoxia in vivo [130–134]. Moreover, beyond and numerous features are redundant and non-reproduc- sensitivity and TOF-resolution, PET-data is limited by its ible [118]. Amongst the numerous issues to be addressed relatively poor spatial resolution compared to CT or MRI A lberts et al. Cancer Imaging (2023) 23:28 Page 11 of 15 Acknowledgements [5]. Future scanner designs may address this limitation, We thank our technologist staff for their critical contribution to the daily e.g. it is possible that ultra-fast TOF resolution might also acquisition of such PET data. aid spatial resolution [135, 136]. Authors’ contributions Conception of the paper: IA, AR. Design of the work: IA, HS, AR. Acquisition and analysis: IA, HS, CM, AA, KS. Interpretation of data: not applicable. Creation Conclusion of new software: not applicable. Drafted or substantively revision of the work: There have been many important developments in All authors. The authors read and approved the final manuscript. PET technology over its long history. However, at sev- Funding eral points technological developments have resulted No funding. in sea changes for the field, most notably the intro- duction of hybrid imaging which led to the rapid Availability of data and materials Not applicable. incorporation of PET/CT for the standard investi- gation of a plethora of diseases and had significant Declarations implications for the training and organisation of our field. Although LAFOV systems allow room for some Ethics approval and consent to participate reduction in applied activity or faster acquisitions, we Not applicable. argue that these represent only the low-hanging fruits Consent for publication amongst the myriad of benefits that this new technol- Not applicable. ogy can offer. Instead, we are convinced that the sum Competing interests of a LAFOV system is greater than the total of its HS is a full‑time employee of Siemens Healthcare AG, Switzerland. AR has parts: we are particularly encouraged by the ability to received research support and speaker honoraria from Siemens. All other obtain whole-body tracer kinetics, ultra-low noise and authors declare no conflict of interest. high count rate data which, for the first time, makes the adoption of quantitative kinetic analysis feasible Received: 14 January 2023 Accepted: 25 February 2023 and promises to reveal deeper insights into human pathophysiology and function which traditional, sin- gle time-point and semi-quantitative analysis of PET data cannot provide. The increased sensitivity allows References 1. Sweet WH. The uses of nuclear disintegration in the diagnosis and treat‑ a greater dynamic range, meaning that tracers can be ment of brain tumor. N Engl J Med. 1951;245:875–8. https:// doi. org/ 10. imaged over many more half-lives capturing a wider 1056/ NEJM1 95112 06245 2301. range of biokinetics, or multiple time point imaging 2. Wrenn FR Jr, Good ML, Handler P. 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Toussaint M, Lecomte R, Dussault JP. Annihilation photon acolinearity with ultra‑fast ToF‑PET. In: 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC); 2020. p. 1–4. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions
Journal
Cancer Imaging – Springer Journals
Published: Mar 18, 2023
Keywords: Total-body; Long axial field of view (LAFOV) PET; Whole-body; PET/CT; Positron emission tomography; Digital PET